About this Author
Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases.
To contact Derek email him directly: derekb.lowe@gmail.com
Twitter: Dereklowe
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Category Archives
October 2, 2009
Posted by Derek
There's been a lot of valuable research into the placebo effect in recent years. That has interest in and of itself, and it also has a practical side. Understanding how people feel better on their own could tell us more about how to make our actual drugs work better, and it could also help us design clinical trials more efficiently. It would be a great help to know accurately how much of a positive effect is due to an investigational drug, without having to run thousands of people to separate that out statistically from a robust (but highly variable) placebo effect.
A new paper in the journal Pain (which has always gotten my vote for "Most To-the-Point Journal Title Possible") sheds some light on this issue, and on the mirror image "nocebo effect". The authors have looked over trials of several migraine drugs. In each case, there was a study arm and a placebo arm, and (since no one knew which group they were in), every patient got the lecture about possible side effects if you were in the treatment group.
The key point is that the migraine trials were investigating three different classes of drugs (anti-inflammatories, triptans, and anticonvulsants), and these three, not surprisingly, have different sets of possible side effects. The patients taking the drugs certainly manifested some of these, but what about the placebo groups?
Well, the placebo groups in the anti-inflammatory trials reported more dry mouth, nausea and vomiting than the placebo arms of the triptan studies. The placebo patients in the anticonvulsant trials, though, had a higher incidence of fatigue, sleepiness, and dizziness than the anti-inflammatory placebo groups reported. In short:
We found specific side effects in the placebo arms of anti-migraine trials when analyzing the three groups of drugs. We observed that the side effects that are expected for the active drug against which the placebo is compared, are also more frequent in the placebo group. In particular, anticonvulsant-placebos appear to have a higher rate of AEs (adverse events) than the other two classes of anti-migraine drugs. . .
. . .Moreover, it is also important to note that a larger number of patients in the anticonvulsant-placebo group discontinued the study (withdrawals due to AEs) than those in the triptan-placebo and NSAID-placebo groups. Both patients’ and experimenters’ expectations may have affected the AEs occurrence in the placebo groups. . .
This sort of thing has been observed before, but this is a particularly neat example. As a researcher (or a patient), it's important to remember that we tend to get what we think we're going to get. And we need to be aware of that, and be ready to correct for it if we have to.
Comments (27)
+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | The Central Nervous System
August 24, 2009
Posted by Derek
Eli Lilly announced some bad news last week when they dropped arzoxifene, a once-promising osteoporosis treatment (and successor to Evista (raloxifene), which has been one of the company's big successes).
If this drug had been found ten or fifteen years ago, it might have made it though. But the trial data showed that while it made its primary endpoints (reducing vertebral fractures, for example), it missed several secondary ones (such as, well, non-vertebral fractures). And the side effect profile wasn't good, either. That combination meant that the drug was going to face at hard time at the FDA for starters, and even if it somehow got through, it would face a hard time competing with generic Fosamax (and Lilly's own Evista).
So down it went, and it sound like the right decision to make. Unfortunately, given the complexities of estrogen receptor signaling, the clinic is the only place that you can find out about such things. And there are no short, inexpensive clinical trials in osteoporosis, so the company had to run one of the big, expensive ones only to find out that arzoxifene didn't quite measure up. That's why this is a territory for the deep-pocketed, or (at the very least) for those who hope to do a deal with them at the first opportunity.
One more point is worth emphasizing. Take a look at the structures of the two compounds (from those Wikipedia links in the first paragraph). Pretty darn similar, aren't they? Arzoxifene is clearly a follow-up drug in every way - modified a bit here and there, but absolutely in the same family. A "me-too" drug, in other words, an attempt to come up with something that works similarly but sands off some of the rough edges of the previous compound. But anyone who thinks that development of a follow-up compound is easy - and a lot of people outside the industry do - should consider what happened to this one.
Comments (14)
+ TrackBacks (0) | Category: "Me Too" Drugs | Clinical Trials | Drug Development | Toxicology
August 4, 2009
Posted by Derek
Now, while we've been talking about how much basic research is done in industry, or how much clinical research gets done in academia, here's something that might bear on the discussion. Too much of what looks like useful clinical research on the academic side is actually wasted effort. The New York Times has been running a series called "The Forty Year War", looking at the history of the "War on Cancer", and the latest installment is on clinical trials.
It's been a problem for some time now that there aren't enough patients to go around for many cancer trials. Breast cancer is an especially problematic area, last I heard. It's high-profile, fairly high-incidence, and a lot of investigational anticancer agents are lined up to take a whack at it. So many, in fact, that there aren't enough breast cancer patients available in the US, nowhere near, and the same situation obtains in a number of other areas.
Much of this problem comes from low recruitment rates. As the Times article makes clear, only three per cent of adult cancer patients are enrolled in any kind of trial at all. Many cancer patients want to stick with the best therapy that's currently known, and don't want to add any uncertainty to what they're already dealing with. It's hard to blame them, but that does make the state of the art advance more slowly.
Another factor that may come as a surprise is that many oncology practices find that they lose money by participating in trials. The reimbursement-to-paperwork ratio doesn't always come out very well, especially for centers that don't do a lot of clinical research and haven't been able to streamline the process as much as possible. When they look at the number of patients that they can serve, given the time that's taken up, the trials start to make less sense.
Finally, and this is the least excusable factor on the list, there are many trials that really shouldn't be run at all. The Times does work in a line about how some studies by drug companies are just "designed to persuade doctors to use their drugs." My take on that is that these studies usually are designed to do that by showing that their drug actually works better, which is not such a bad thing. But note this other problem:
There are more than 6,500 cancer clinical trials seeking adult patients, according to clinicaltrials.gov, a trials registry. But many will be abandoned along the way. More than one trial in five sponsored by the National Cancer Institute failed to enroll a single subject, and only half reached the minimum needed for a meaningful result, Dr. Ramsey and his colleague John Scoggins reported in a recent review in The Oncologist.
Even worse, many that do get under way are pretty much useless, even as they suck up the few patients willing to participate. These trials tend to be small ones, at single medical centers. They may be aimed at polishing a doctor’s résumé or making a center seem at the vanguard of cancer care. But they are designed only to be “exploratory,” meaning that there are too few patients to draw conclusions or that their design is less than rigorous.
“Unfortunately, many patients who are well intentioned are in trials that really don’t advance the field very much,” said Dr. Richard Schilsky, an oncologist at the University of Chicago and immediate past president of the American Society of Clinical Oncology.
I don't want to dump a bucket of tar on all academic and publicly funded clinical research, because there's a lot of good stuff that goes on as well. (And remember, the publicly basic research is very valuable indeed). But the next time someone tells you about the number of clinical trials run outside of the drug industry, you might want to keep those above figures in mind.
Not all trials are created equal, not by a long shot. But the ones that we run in industry, from what I can see, tend to have a better chance of relevance. That's partly because we're spending our own money on them, and with a goal of finding drugs that people will spend money on in turn. It focuses one's efforts. It's not like we never waste money in this business, but I'm very much willing to bet that we waste it less often than happens with public funds. Companies trying to get an agent through the clinic tend not to set up meaningless trials just to make everyone's resume look better. That I can tell you.
Comments (24)
+ TrackBacks (0) | Category: Academia (vs. Industry) | Cancer | Clinical Trials
July 20, 2009
Posted by Derek
Here's an interesting look at the current state of the Alzheimer's field from Bloomberg. The current big hope is Wyeth (and Elan)'s bapineuzumab, which I last wrote about here. That was after the companies reported what had to be considered less-than-hoped-for efficacy in the clinic. The current trial is the one sorted out by APOE4 status of the patients. After the earlier trial data, it seems unlikely that there's going to be a robust effect across the board - the people with the APOE4 mutation are probably the best hope for seeing real efficacy.
And if bapineuzumab doesn't turn out to work even for them? Well:
“Everyone is waiting with bated breath on bapineuzumab,” said Michael Gold, London-based Glaxo’s vice president of neurosciences, in an interview. “If that one fails, then everyone will say we have to rethink the amyloid hypothesis.”
Now that will be a painful process, but it's one that may well already have begun. beta-Amyloid has been the front-runner for. . .well, for decades now, to be honest. And it's been a target for drug companies since around the late 1980s/early 1990s, as it became clear that it was produced by proteolytic cleavage from a larger precursor protein. A vast amount of time, effort, and money have gone into trying to find something that will interrupt that process, and it's going to be rather hard to take if we find out that we've been chasing a symptom of Alzheimer's rather than a cause.
But there's really no other way to find such things out. Human beings are the only animals that really seem to get Alzheimer's, and that's made it a ferocious therapeutic area to work in. The amyloid hypothesis will die hard if die it does.
Comments (21)
+ TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials | Drug Industry History | The Central Nervous System
June 23, 2009
Posted by Derek
What's really going on with Medarex and ipilimumab? The company made news over the weekend with a press release from the Mayo Clinic, detailed what appears to be a substantial response in two prostate cancer patients. But the more you look at the story, the harder it is to figure out anything useful.
As this WebMD piece makes clear, this study is not a trial of ipilimumab as a single agent. The patients are undergoing prolonged androgen ablation, the testosterone-suppressing therapy that's been around for many years and is one of the standard options for prostate cancer. The trial is to see if ipilimumab has any benefit when it's added to this protocol - basically, to see if it can advance the standard of care a bit.
WebMD quotes Derek Raghavan at the Cleveland Clinic as saying that androgen ablation can sometimes have dramatic results in patients with locally advanced prostate cancer, so it's impossible to say if ipilimumab is helping or not. That's why we run clinical trials, you know, to see if there's a real effect across a meaningful number of patients. But (as this AP story notes) we don't know how many patients are in this particular study, what its endpoints are, or really anything about its design. All we know is that two patients opted out of it for surgery instead. (Credit goes to the AP's Linda Johnson for laying all this out).
Ipilimumab is an antibody against CTLA-4, which is an inhibitory regulator of lymphocytes. Blocking it should, in theory, turn these cells loose to engage tumor cells more robustly. (It also turns them loose to engage normal tissue more robustly, too - most of the side effects seem to be autoimmune responses like colitis, which can be very severe. The antibody has been studied most thoroughly in melanoma, where it does seem to be of value, although the side effect profile is certainly complicating things.
So overall, I think it's way too early to conclude that Medarex has hit on some miracle prostate cure. This press release, in fact, hasn't been too helpful at all, and the Mayo people really should know better.
Comments (27)
+ TrackBacks (0) | Category: Clinical Trials | Drug Development | Press Coverage | Toxicology
June 9, 2009
Posted by Derek
Here's a fascinating (and alarming) look at the clinical data from the recent trial of Avastin (bevacizumab) in adjuvant colorectal cancer (that is, post-surgical therapy). This was an issue in the recent Roche/Genentech takeover, since it could significantly enlarge the market for the drug. According to the In Vivo Blog, the one-year interim look at the data (adding Avastin to the standard chemotherapy regimen) was nearly good enough to stop the trial early. There were 2,710 patients enrolled, and an additional six events would have pushed things over the top, statistically.
The trial went on, though, with two more years of standard therapy as follow-up. But by the (pre-set) three-year endpoint it turned out that there was no eventual real benefit to adding Avastin back in that first year. So what's the story? Is it that you need to keep giving the combination regime? Would those-one year results have held up? Or is this just a case of real long-term survival numbers wiping out what seems to be a promising short-term result?
It looks like Genentech may be gearing up to put that first theory to a test, and I wish them luck. Long-term tolerability will be an issue, and long-term cost will be a big one, too. They're going to have to show some pretty impressive numbers to overcome those two concerns. . .as impressive as, well, as those first-year interim ones they had. Will that effect dissipate or not?
Time and money will answer that little question. But for now, consider what would have happened if a few more patients had shown disease-free survival in time for that interim analysis. The trial would have been stopped early, all kinds of people would have gone on Avastin for their first year of adjuvant therapy. . .and this year we would have seen that it was apparently doing no good at all, at least in the take-it-for-a-year-and-stop mode. Clinical trial design: a real high-wire act.
Comments (9)
+ TrackBacks (0) | Category: Cancer | Clinical Trials
June 8, 2009
Posted by Derek
There is no good way to spin a Phase III failure. By then you've made it past the main reasons for a drug to wipe out (PK and total mechanistic failure). A breakdown at this stage is a more subtle affair (well, except for the money involved, which is not subtle at all). For example, a drug might show efficacy in a carefully constructed Phase II trial, but can't perform under the wider (and more realistic) conditions of Phase III.
That's what appears to have happened to Merck's MK-7418 (rolofylline, formerly KW-3902). This adenosine A1 antagonist, which Merck picked up by buying NovaCardia a couple of years ago, was being developed for acute heart failure. That's a tough indication, and this isn't going to improve that reputation. (This Forbes piece has a tour of the pile of discards that this area has become over the years. Rolofylline looked as if it might work in Phase II, but (from what I can tell from the press releases) missed every endpoint in Phase III.
On a chemical note, rolofylline is a rather odd-looking molecule. You don't see many noradamantanes hanging off of drug structures. I'm sure this wasn't the reason for the compound's failure (after all, it made it through Phase I and Phase II), but it's sure not something I have on my list of structural fragments to try.
Comments (13)
+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials
June 4, 2009
Posted by Derek
Here's an interesting situation for you: according to IguanaBio, a shareholder lawsuit over the failed Vytorin ENHANCE clinical trial (that's caused Schering-Plough and Merck so much grief) is going to use posts on CafePharma as evidence.
That will be worth watching. CafePharma's message boards have been described (accurately, I'd say) as often being the electronic equivalent of a bathroom wall. There's good information in there, but the signal/noise ratio is abysmal due to the number of ticked-off people who go there to vent. There do appear to have been some posts suggesting strongly that the ENHANCE data were grim, and who knows? They could have been speaking from real knowledge. But there's no way to be sure - and for every post that turns out to be prophetic, there are ten that are totally wrong.
So I'm surprised that these are going to be considered admissable. Anyone investing on the basis of CafePharma board chatter deserves to lose their money - which will go out in brokerage commission fees, if nothing else. Let's see how this plays in court. . .
Comments (8)
+ TrackBacks (0) | Category: Business and Markets | Cardiovascular Disease | Clinical Trials | Drug Industry History
June 1, 2009
Posted by Derek
Well, the ASCO meeting has been roaring along, with dozens of press releases coming out. (Go to Google News and type that acronym in if you want to get the full experience). They range from the pretty-interesting to the despair-inducing, but one bit of news struck me as particularly worth noting. That's the early-stage deal between Merck and AstraZeneca to combine two of their development candidates in a Phase I trial.
That's Merck's AKT inhibitor MK-2206 and AZ's Mek inhibitor AZD6244, and there's room to think that combining those two mechanisms could be beneficial. But as that In Vivo Blog link details, this deal wasn't initiated through any official contact between the two companies. Rather, someone from Merck and someone from AZ got to talking while they were going through airport security in Dublin, and recognized each other's names. A mere year and a half later, the deal was born.
There's a lot to learn from that story. For one, big drug companies are not, for the most part, looking to do early-stage deals with other big drug companies. Perhaps we'll see more of these in the future, but in general, it's about the least likely form of partnership. Another thing to note is how long it took for this idea to bear fruit. Eighteen months is about right for companies of this size to make up their minds about something like this - and you can decide that (since the oncology field is so complicated) that this is a reasonable period of evaluation, or you can decide, equally objectively, that delays of that magnitude remind you of a sauropod turning around in puzzlement three hours after something bit its tail.
I'm impressed that the deal was made at all. The usual path for new ideas of this sort is to the graveyard, especially in very large organizations, so I have to assume that some people within each company must have really pushed things along to make it happen. It's part of the general bias toward inaction: it's harder to get beaten up for decisions that you didn't make, compared to decisions that you did. Missed opportunities are often invisible.
So, no matter how long it took, or even whether it works out, I still have to congratulate the people involved on getting this agreement to happen. It's worthwhile, I think, just because it's the sort of thing that doesn't happen very often. And I have the feeling that (in the coming years) we're going to have to explore a lot of things in this industry that haven't happened very often. We'll need the practice!
Comments (4)
+ TrackBacks (0) | Category: Business and Markets | Cancer | Clinical Trials | Drug Development | Drug Industry History
May 22, 2009
Posted by Derek
I’ve been getting a lot of objections to my opinion on Arena’s obesity candidate lorcaserin. Specifically, the first level of the dispute seems to be whether or not the recent clinical trial results met the FDA’s criteria for efficacy or not. So, let’s look at the details. Here’s how Arena press-released the results of the trial:
The hierarchically ordered endpoints were the proportion of patients achieving 5% or greater weight loss after 12 months, the difference in mean weight loss compared to placebo after 12 months, and the proportion of patients achieving 10% or greater weight loss after 12 months. Compared to placebo, using an intent-to-treat last observation carried forward (ITT-LOCF) analysis, treatment with lorcaserin was associated with highly statistically significant (p<0.0001) categorical and average weight loss from baseline after 12 months:
-- 47.5% of lorcaserin patients lost greater than or equal to 5% of their
body weight from baseline compared to 20.3% in the placebo group. This
result satisfies the efficacy benchmark in the most recent FDA draft
guidance.
-- Average weight loss of 5.8% of body weight, or 12.7 pounds, was achieved
in the lorcaserin group, compared to 2.2% of body weight, or 4.7 pounds,
in the placebo group. Statistical separation from placebo was observed
by Week 2, the first post-baseline measurement.
-- 22.6% of lorcaserin patients lost greater than or equal to 10% of their
body weight from baseline, compared to 7.7% in the placebo group.
Lorcaserin patients who completed 52 weeks of treatment according to the protocol lost an average of 8.2% of body weight, or 17.9 pounds, compared to 3.4%, or 7.3 pounds, in the placebo group (p<0.0001).
Now let’s go to the FDA’s 2007 draft guidance for weight management therapies. Regarding the primary efficacy endpoint in a Phase III trial of such a new agent, the agency says:
The efficacy of a weight-management product should be assessed by analyses of both mean and categorical changes in body weight.
• Mean: The difference in mean percent loss of baseline body weight in the active-product versus placebo-treated group.
• Categorical: The proportion of subjects who lose at least 5 percent of baseline body weight in the active-product versus placebo-treated group.
And here’s the part that people keep wanting me to highlight:
In general, a product can be considered effective for weight management if after 1 year of treatment either of the following occurs:
• The difference in mean weight loss between the active-product and placebo-treated groups is at least 5 percent and the difference is statistically significant
• The proportion of subjects who lose greater than or equal to 5 percent of baseline body weight in the active-product group is at least 35 percent, is approximately double the proportion in the placebo-treated group, and the difference between groups is statistically significant
So lorcaserin showed 47.5% of patients losing at least 5% of their body weight, versus 20.3 for placebo. And yes, that does appear to meet what the FDA's looking for in terms of categorical efficacy, which is why the company highlighted that result in their press release. And yes (here it comes, Arena fans), the FDA does say ("in general") that an agent can be considered efficacious if a compound meets either the mean or the categorical standards.
But (and you knew that this paragraph was going to start with that word). . .but the FDA does not say "efficacious enough for approval". In general, to use their phrase, the agency does approve things that are efficacious and show safety. But they do that on their own terms, and they are (for better or worse) completely within their rights to turn around and ask for more details - for example, how well a compound like this performs as a combination therapy (which is how many physicians would likely wish to prescribe it).
Then we have the issue of "efficacious to interest a partner". Arena is surely looking to do that, since (as noted the other day) it does not appear that they have the resources to push the product through on their own. Given the potential size of the market for an effective obesity drug, we can be sure that a number of potential partners have been approached, and have taken a meaningful look at the data. So far, no one has taken them up on it. And whatever one thinks about the press coverage that lorcaserin has received (or the reaction from analysts who follow the stock, which has also not been good), it's for sure that these opinions don't count for much when it comes time for two companies to do a deal. Put more directly, if Arena sits down with Merck or Pfizer, what I say on this blog means nothing at all once the door closes. Heck, what they say at JP Morgan means nothing at all, either, because we're all outsiders. Potential partners are getting a chance to look over Arena's prospects, and if the numbers look convincing, someone will bite. If no one bites, we can assume that no one was convinced.
Or perhaps they're waiting for Arena to get even more cash-strapped and desperate. That isn't a very nice way to do business, but isn't unheard of, either, and I can tell you that these aren't very nice times in the drug business. At any rate, for those Arena fans who have been waiting for me to say something about all this, well, here you are. This is as good as you'll get from me - but really, you're wasting your time. You need to be hoping to persuade the people who can initiate nine-figure wire transfers.
Comments (8)
+ TrackBacks (0) | Category: Business and Markets | Clinical Trials | Diabetes and Obesity | Regulatory Affairs
May 14, 2009
Posted by Derek
And while we're on the subject of clinical trials, and the headaches associated with them, this is a neat little article over at Slate on the subject. Darshak Sanghavi from UMass does a good job of explaining the surrogate-endpoints problem in clinical results, relating it to reality TV:
. . .In the federal Multimodal Treatment Study, hundreds of kids with ADHD, whose families were desperate enough to enroll them in a randomized study, entered a well-funded and highly supervised National Institute for Mental Health program complete with specialized therapy, regular evaluation by developmental experts, and careful drug prescription—a setup that's about as realistic as a date on The Bachelor. Within that very unusual, closely monitored environment, as reported in 1999, stimulant medications caused modest improvement after about a year. In response, use of these products surged nationwide, and Ritalin and its peers became household brands. But in March, the researchers described what happened after the lights went out. In their subsequent years in the real world, the drug-treated kids ultimately ended up no better off than the others.
Epidemiologists call this the problem of "surrogate endpoints," and it's no surprise to fans of reality television. Garnering the greatest number of text-messaging votes after a brief performance doesn't always mean you'll be a successful pop star; winning the final rose after an on-air courtship doesn't mean you'll have a happy marriage; and getting higher scores on a simple rating scale of attention-deficit symptoms doesn't mean you'll later succeed in school. In medicine, this problem happens all the time.
He doesn't shy away from some of the big surrogates in the clinical world, the biggest of which are cholesterol levels. That one, as he says, is at least considered a validated marker (with some relation to real-world mortality and morbidity), but there's plenty of room to argue about that, too. Ask Gary Taubes , who has a lot of provocative things to say about the whole low-fat idea. And if that one is still worth arguing over, what about the less validated endpoints?
In the end, I agree with Sanghavi that we really don't have any good alternatives yet. The real endpoints, in most cases, just take too long to measure. No one can finance a twenty-year clinical trial, and no one would put up with one even if it were feasible. We're stuck with what we have, and we just have to make it work the best we can.
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+ TrackBacks (0) | Category: Clinical Trials
Posted by Derek
Late last year, I wrote about a possible new way to fund drug discovery, a private-equity model that seemed to be in the works at Goldman Sachs. The driving force behind the idea seemed to be Jon Symonds, former CFO at AstraZeneca.
Well, as the InVivoBlog noted yesterday, Symonds has suddenly decamped to Novartis. He’s press-released as their new CFO (after the current one retires), which makes you wonder what’s happened to that drug funding plan. Given the current environment for new financing schemes, and for banking in general (not to mention the current environment at Goldman Sachs), has the whole idea just been shelved?
As the In Vivo folks go on to say, financing clinical candidates in this way isn’t necessarily a bad idea – it just might be a bad time to try it out. There are a lot of issues to be worked out, but it’s looking more and more like no one’s going to be working them out any time soon. . .
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+ TrackBacks (0) | Category: Business and Markets | Clinical Trials | Drug Development
May 6, 2009
Posted by Derek
Here's a good example of why all of us in the industry tiptoe into Phase I trials, the first-in-man studies. A company called SGX, recently acquired by Eli Lilly, has been developing a kinase inhibitor (SGX523) targeting the enzyme cMET. That's a well-known anticancer drug target, with a lot of activity going on in the space.
SGX's specialty is fragment-based design, and they've spoken several times at meetings about the SGX523 story. The starting point for the drug seems to have come out of X-ray crystallographic screening (the company has significant amounts of X-ray synchrotron beamline time, which you're going to need if you choose this approach). They refined the lead, in what (if you believe their presentations) was a pretty short amount of time, to the clinical candidate. It seems to have had reasonable potency and pharmacokinetics, very good oral bioavailability, no obvious liabilities with metabolizing enzymes or the dreaded hERG channel. And it was active in the animal models, however much you can trust that in oncology.
So off to the clinic they went. Phase I trials started enrolling patients in January of last year - but by March, the company had to announce that all dosing had been halted. That was fast, but there was a mighty good reason. The higher doses were associated with acute renal failure, something that most certainly hadn't been noticed in the mouse models, or the rats, or the dogs. It turns out that the compound (or possibly a metabolite, it's not clear to me) was crystallizing out in the kidneys. Good-looking crystals, too, I have to say. I can't usually grow anything like that in the lab; maybe I should try crystallizing things out from urine.
Needless to say, obstructive nephropathy is not what you look for in a clinical candidate. There's no market for instant kidney stones, especially when they appear all over the place at the same time. The patients in the Phase I trial did recover; kidney function was restored after dosing was stopped and the compound had a chance to wash out. But SGX523, which was (other than its unlovely structure) a perfectly reasonable-looking drug candidate, is dead. It didn't take long.
Comments (38)
+ TrackBacks (0) | Category: Cancer | Clinical Trials | Toxicology
May 5, 2009
Posted by Derek
Back when I joined the first drug company I ever worked for, the group in the lab next door was working on an enzyme called ACAT, acyl CoA:cholesterol acyltranferase. It’s the main producer of cholesterol esters in cells, and is especially known to be active in the production of foam cells in atherosclerosis. It had already been a drug target for some years before I first heard about it, and has remained one.
It hasn’t been an easy ride. Since 1990, several compounds have failed in the clinic or in preclinical tox testing. The most recent disappointment was in 2006, when pactimibe (Daiichi Sankyo) not only failed to perform against placebo, but actually made things slightly worse.
Lipid handling is a tough field, because every animal does is slightly differently. There are all sorts of rabbit strains and hamster models and transgenic mice, but you're never really sure until you get to humans. Complicating the story has been the discovery that there are two ACATs. ACAT-1 is found in macrophages (and the foam cells that they turn into) and many other tissues, and ACAT-2 is found in the intestine and in the liver. Which one to inhibit is a good question - the first might have a direct effect on altherosclerotic plaque formation, while the second could affect general circulating lipid levels. Pactimibe hits both about equally, as it turns out.
Now a second study of that drug has been published this spring. This one was going on at the same time as the earlier reported one, and was stopped when those results hit, but the data were in good enough shape to be worked up, and the company paid for the continued analysis. The new results look at patients with familial hypercholesterolemia, who got pactimibe along with the standard therapies. Unfortunately, the numbers are of a piece with the earlier ones: the drug did not help, and actually seemed to increase arterial wall thickness. I think it's safe to say, barring some big pharmacological revelation, that ACAT inhibitors are a dead end for atherosclerosis.
I bring this up for two reasons. One is that the group that was working next door to me on ACAT was the same group that discovered (quite by accident) the cholesterol absorption inhibitor ezetimibe, known as Zetia (and as half of Vytorin). Although its future is very much in doubt, it's for sure that that compound has been a lot more successful than any ACAT inhibitor. The arguing goes on about how helpful it's been (and will go on until we see the next trial results for another couple of years), but it's already made it further than ACAT.
And that's actually my second point. I suspect that almost no one in the general public has ever heard of ACAT at all. But it's been the subject of a huge amount of research, of time and work and money. And while we've learned more about lipid handling in humans, which is always valuable, the whole effort has been an utter loss as far as any financial return. I have no good way of estimating the direct costs (and even worse, the opportunity costs) involved with this target, but they surely add up to One Hell Of A Lot Of Money. Which is gone, and gone with hardly a sound outside the world of drug development. And this happens all the time.
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+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Drug Development | Drug Industry History | Toxicology
March 31, 2009
Posted by Derek
One of the drug targets for obesity that’s been kicking around for years now is a serotonin-receptor based idea, a 5-HT2c agonist. There are several lines of evidence that make this a plausible way to affect appetite – well, as plausible as any of the appetite-based obesity targets are. I’ve long been wary of these, since we’ve found (over and over) that human feeding behavior is protected by multiple, overlapping redundant pathways. We are the descendants of a long line of creatures that have made eating and reproducing their absolute priorities in life, and neither of those behaviors are going to be altered lightly. The animals that can be convinced to voluntarily eat so little that they actually lose weight, just through modifying a single biochemical pathway, are all dead. Our ancestors were the other guys.
Arena Pharmaceuticals is the latest company to give us more evidence for this point of view. Many drug discovery organizations have taken a crack at 5-HT2c compounds, as a look at the patent literature will make clear. But Arena got theirs, Locaserin, well into the clinic, and yesterday they announced the results. And. . .well, it depends on how you spin it. If you’re a glass-half-full sort of person, you could say that twice as many people in the drug treatment group lost at least the FDA’s target of their body mass, as compared to placebo.
Unfortunately, the glass-half-empty people are probably going to win this one. The FDA wants to see 5% weight loss (versus placebo) with a drug therapy, arguing (correctly, I think) that showing less than that really doesn’t give you much risk/benefit over just plain old diet and exercise. Arena’s compound averages out at 3.6%, and I don’t see how that’s going to cut it, especially with a new central nervous system mechanism. By “new”, I don’t mean “new to science” – as mentioned above, this idea has been around for years. But it would be a new thing to try out in millions of patients if you let a drug through, that’s for sure. I think it’s safe to say that a certain fraction of those are going to react in ways that you didn’t expect. 5-HT2 receptors are involved in a lot of different things, and there's bound to be a lot about any agent in this class that we don't know. Locaserin seems to have been well tolerated in trials, but I personally would be jumpy if I were taking something like this out into the broad population.
That’s not why I think this compound won’t make it, though. The FDA doesn’t even have to talk safety; they can reject it just on the grounds of efficacy. And it’s hard to imagine a lot of insurance plans picking up the tab for something with only those levels of clinical support, too. Arena's CEO says that he's pleased with the results of the trial. No, he isn't. Of course, he also says that he's convinced that the company will get Locaserin approved and find a partner to market it with, too. But then, that's his job.
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+ TrackBacks (0) | Category: Clinical Trials | Diabetes and Obesity
March 30, 2009
Posted by Derek
Over the years of this blog, I’ve occasionally made comments about how no one really knows much about how drugs for the major central nervous system diseases work. Well, actually, I’ve stated things more forcefully than that, but you get the idea. And although many people who work in the area have written in to say that they agree, I’ve had questions from people completely outside it (journalists and others) about whether I’m serious when I say these things.
Oh, I am. For the latest piece of evidence, see what’s just happened to LY2140023, Eli Lilly’s new drug candidate for schizophrenia. The company was running a three-armed Phase II trial: placebo vs. their existing drug Zyprexa vs. the new one, which is a metabotropic glutamate ligand. And what happens? The placebo group performs about twice as well as the usual average in such trials, for some reason. And that not only swamped the investigational drug, but Zyprexa as well, which has been on the market for years.
Now, there's been a lot of argument about whether the current generation of antipsychotic drugs is really better than the older ones. But I believe that they're all supposed to come in better than a placebo. As Lilly points out, though, "inconclusive trials are common in neuroscience", and they're going to run another one and hope that the patients don't all start improving again on powdered sucrose or whatever the placebo was. But this is especially surprising (and disappointing) because an earlier Phase II trial, run in a very similar design to the latest one, showed the compound working very well indeed. How do you go from such impressive results to no better than placebo in the same sort of trial design? Easy - just make sure that you're developing a drug for schizophrenia. Or depression. Or chronic pain, or Alzheimer's. Stick with the central nervous system, and your drug discovery career will never be boring.
Oh, and one last note: after all the recent stories about buried clinical results, I'm glad to see a company fall completely flat with one of its most promising drugs - and then get up at a large scientific meeting and tell everyone about it in detail. It's not that it's so unusual, but it's good to show people that it happens, and how it's handled when it does.
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+ TrackBacks (0) | Category: Clinical Trials | The Central Nervous System
March 23, 2009
Posted by Derek
Last week's discussions around here about the merits (and demerits) of pharma-industry research seem to be coming at what's either a really good or a really bad time. Take a look at this Washington Post article on the handling of clinical data at AstraZeneca.
These details have come up during a large array of lawsuits over Seroquel (quetiapine). And if they're as represented in this article, it doesn't make AZ's marketing folks look very good, and (by extension) the rest of the industry's. We shouldn't be doing this sort of thing, on general principle. But if that's not enough, and it probably isn't, here's a more practical concern: does it take much imagination or vision to think that, with all kinds of health care reform ideas in the air, this sort of behavior might just make Congress want to reform our industry really good and hard?
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+ TrackBacks (0) | Category: Clinical Trials | Press Coverage | Regulatory Affairs | The Central Nervous System | Why Everyone Loves Us
March 20, 2009
Posted by Derek
Of course, no sooner do I come out defending drug company research than we have this to think about:
"An influential Harvard child psychiatrist told the drug giant Johnson & Johnson that planned studies of its medicines in children would yield results benefiting the company, according to court documents dating over several years that the psychiatrist wants sealed. . .much of (Dr. Joseph Biederman's) work has been underwritten by drug makers for whom he privately consults. An inquiry by Senator Charles E. Grassley, Republican of Iowa, revealed last year that Dr. Biederman earned at least $1.6 million in consulting fees from drug makers from 2000 to 2007 but failed to report all but about $200,000 of this income to university officials.
. . .One set of slides in the documents referred to “Key Projects for 2004” and listed a planned trial to compare Risperdal, also known as risperidone, with competitors in managing pediatric bipolar disorder. The trial “will clarify the competitive advantages of risperidone vs. other neuroleptics,” the slide stated. All of the slides were prepared by Dr. Biederman, according to his sworn statement."
There are other examples. Some of this is marketing-speak, to be sure. But mixing up the marketing stuff with the inner workings of the clinical trials is a very bad idea. For sales and marketing people, it's always onward and upward, positive attitude, create-your-own-successful-reality. You most definitely do not want that worldview in a clinician: "Just the facts, ma'am" is more like it. And that doesn't sound like what we're seeing here.
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+ TrackBacks (0) | Category: Clinical Trials | The Dark Side
Posted by Derek
So, in light of the Reuben scandal of forged data about pain management in surgery patients, the question naturally comes to mind: how much role did industry play? I’ve seen articles (and had comments here) to the effect that industry-sponsored research is worthless: discount it, can't trust it, bought and paid for, and so on.
The problem is, you can't completely shake that accusation. Industries (and not just the drug industry, by any means) are willing to pay for results that tell them what they want to hear. And while at times that's crossed over into outright fraud, many times it's just that you can set up all kinds of studies, in all kinds of ways, and get all kinds of answers. Run enough of them, and you can choose the ones you like and pretend the others aren't there.
The whole idea of scientific research is that you don't operate like this, of course, and eventually these things do get settled out. If the drug industry really did make sure that only happy results came out, we'd never have catastrophic clinical trial failures, and never have any drugs recalled from the market. And things like the (Nobel-worthy) H. pylori story behind stomach ulcer formation never would have seen the light of day if the industry were capable (on the other hand) of burying everything it didn't want to hear about.
But there are biases, real and potential, and they always have to be looked out for. One error, though, is to assume that these biases can be eliminated by turning to academic research instead. That's the point of a recent Op-Ed in the Washington Post by David Shaywitz, who's worked both sides of the business:
Part of the problem is that we've been conditioned to trust university research. It is based, after all, on the presumably lofty motives of its practitioners. What's not to like about science carried out by academics who have nobly dedicated their lives to understanding the unknown, furthering knowledge and serving humanity?
. . .University researchers are in a constant battle for recognition and the rewards associated with success: research space, speaking engagements, funding and autonomy. Consequently, while academic research is often described as "curiosity-driven," the reality is messier, as (curiously) many researchers tend to pursue the trendiest technologies and explore topics that happen to be associated with the most generous levels of research support.
Moreover, since academic success is determined almost exclusively by the number and prestige of research publications, the incentives to generate results are exceedingly powerful and can encourage investigators to see patterns that may not exist, to disregard contradictory observations that might be important, to overvalue data that might be preliminary or unreliable, and to embrace conclusions that deserve to be viewed with far greater skepticism.
Shaywitz goes on to make the same point I did above - that the system is ultimately self-correcting - but is calling for people to recognize that academic research is also done by human beings, with all that entails. John Tierney at the New York Times had taken up this topic last fall, and wondered about what would happen if enough researchers decided to stop taking industry funding because they were tired of having their integrity questioned.
Tierney's responded to the Shaywitz piece now as well. The comments from his readers are all over the place each time. Some of them are (correctly, to my mind) going along with the idea that research always comes in with various potential biases and agendas, and should be judged case-by-case no matter the source. There are, naturally, some who aren't buying anything that might get industrial research off the hook.
"In industry sponsored comparative studies of medical treatments, the sponsor’s product always comes out on top," says one commenter there. But that's not true. I can give you plenty of examples right off the top of my head. For sure, we try to run studies that will show a benefit for our therapies - but we also have to pin these down to the real world for people (and the FDA) to have a better chance of trusting the results. We're not going to set up a trial that we have good reason to think will fail: life is too short, and the supply of funds is not infinite. You target the diseases (and the patients) that you think will benefit the most (and show the most impressive results, naturally).
And that's a bias to consider right there: we don't set up our trials randomly, so keep that in mind. But no one sets up drug trials randomly, anywhere. There's always a reason to do something so expensive and time-consuming - you should always keep that in mind, weigh it in your calculations, and decide from there.
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+ TrackBacks (0) | Category: Clinical Trials | Press Coverage | The Dark Side | Why Everyone Loves Us
February 12, 2009
Posted by Derek
Just ask La Jolla Pharmaceuticals, whose small stock is down about 90 per cent on the bad news. They follow a distinguished list of wipeouts in this area. Immunology is hard.
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+ TrackBacks (0) | Category: Clinical Trials
February 9, 2009
Posted by Derek
Viropharma has announced that their Phase III trial of maribavir, a compound targeting cytomegalovirus, failed big-time. Well, they didn't used the term "big-time", but they might as well have. The treatment group (patients with recent bone marrow transplants) showed no difference in CMV infection rates compared to placebo. This is especially disappointing, considering that the compound looked pretty good in Phase II. That's a useful lesson in the difference between Phase II and the real world.
The company has been through this before. Back in the late 1990s, they were working on another antiviral, Pleconaril, that in those heady days caused their stock to shoot up well over $50/share. Some people had gotten it into their heads that the stuff was going to cure the common cold and who knows what else besides. In the spring of 2000, the bad news came in that the drug would do nothing of the kind. I was short the stock at that point, and I've long wished that I had a videotape of me trying to call my broker after I saw the stock quote that morning. I kept missing the buttons on the phone; it was pretty entertaining.
Maribavir isn't one of VPHM's own creations, actually - they licensed it from GSK, and it's a good ol' nucleoside analog in the tradition of many antivirals. But that's a tough area to work in, and today's bad news is just more proof.
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+ TrackBacks (0) | Category: Clinical Trials | Infectious Diseases
January 5, 2009
Posted by Derek
In past years, around this time I’ve often done a look back at the previous year in the drug industry. I hope that no one will be disappointed if I scuttle that tradition, because honestly, I have no desire whatsoever to relive what drug research went through in 2008. It may have been the toughest year for industry scientists in the modern era – everyone I know struggles to find a comparison.
I’d rather spend my energies on 2009. Let’s just stipulate that 2008 was, on balance, horrendous: what does that tell us? How did we end up in this position, and how can we avoid more of the same? There’s a lot of arguing room in those questions, but I think that we can agree that the proximate cause is that we’re not coming up with enough good drugs. 2008, for all its ugliness, was a handful of good products away from being a decent year. Why were we short that handful?
You have to go back some years to answer a question like that, given the industry’s lead time. The projects that were begun in the mid-to-late 1990s are clearly not coming through in the way that everyone had hoped. Is it that our attrition rate has gone up, or have we just not taken enough things to the clinic, or some of each?
Let’s think about that first problem, which certainly seems to be real enough. Is it that the easy targets have all been worked over, leaving us with only the tough ones? I don’t think that’s the whole explanation, although that’s certainly part of it. Still, even some of the big drugs from years past wouldn’t have made it through our current structures. So are the hurdles set too high during development – that is, do we know too much about potential problems, without having learned a corresponding amount about how to fix them? That’s got to be a big factor, which leads to a New Year’s resolution: try to spend as much time fixing problems as finding them. That’s a hard one to live up to, but it’s a goal to work toward.
And if we’re going to talk about that latter number, we’re going to have to cut through the often artificial “projects advanced” figures that circulate inside companies. Anyone who’s been around this business has seen some long shots (and some outright losers) officially pushed forward just to make some year-end target. Now, long shots are fine. To a good approximation, everything we do is a long shot. And everything has to go to the clinic eventually (or die) – but we have to make sure that we’re not just checking boxes. So that’s another resolution: spend less time kidding ourselves.
Of course, there’s a flip side to the number of compounds going to the clinic. Could it be that we’re being too cautious, because we have too many potential worries (those high hurdles mentioned above)? Should we be taking more things forward? Well, that’s an expensive proposition, the way things are set up now. So here’s another hard-to-live-up-to resolution: find ways to go to the clinic without betting our shirts every time. That’s been a big focus the last few years (biomarkers, etc.), but we need every idea and technique we can think of (microdosing? Simulations, even?). The cost of getting answers in humans is getting too high for us to try out as many ideas as we need to.
And here's a less macro-scale resolution, which I plan to start putting into practice immediately: don't let fear run your research. Try some things that you aren't sure about. Take some chances. Put down some bets. I've got several that I've let sit in the should-I-do-this limbo for too long, and I'm going to do something about that. Join me?
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+ TrackBacks (0) | Category: Clinical Trials | Drug Development | Drug Industry History | Who Discovers and Why
December 9, 2008
Posted by Derek
Now, here’s an odd item from the Financial Times (registration required):
Goldman Sachs is in talks to provide hundreds of millions of dollars of funding to a large pharmaceutical company, in the first evidence of a new business model for the sector that will see financing shifted away from funding companies and towards targeted co-development of specific medicines. . .
. . .(The model involves) a different approach, creating a "research pool" into which pharma companies would place a range of experimental drugs in a single therapeutic area in early-stage phase 1 and 2 trials, where their specialists would work alongside external experts including scientists, chemists and clinical research organizations.
This was announced at a conference run by the newspaper, so they’re really the only source for information on this. I haven’t been able to find anything from Goldman about it, for example, and the minimal press coverage so far has all pointed back to this article. (Ed Silverman picked it up at Pharmalot, for example).
So one wonders what’s up, because the information that’s given raises more questions than it answers. I presume that the assumption is that since only a few early-stage clinical compounds ever make it, that this gives everyone a chance to share the risk. But which therapeutic area are we talking about here? How are things apportioned when one compound makes it through? And what if more than one does? And where are these external experts coming from, and who pays them?
This could be very interesting, because I think that we need to be open to some new research models in the industry. The current one isn’t exactly spewing results these days. But I wish that I knew more about what this proposal involves – anyone out there have any more details that they can share?
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+ TrackBacks (0) | Category: Business and Markets | Clinical Trials | Drug Development
December 2, 2008
Posted by Derek
Ever since the catastrophic failure of Pfizer's HDL-raising CETP inhibitor torcetrapib in late 2006, everyone involved has wondered just what the problem was. There was a definitely higher cardiovascular-linked death rate in the drug-treatment group as opposed to placebo - which led to the screeching halt in Phase III, as well it might - but why? Is there something unexpectedly bad about raising HDL? Or just in raising it by inhibiting the CETP enzyme, which might well provide a different lipoprotein profile than other high-HDL ideas? Was it perhaps an off-target effect of the drug that had nothing to do with its mechanism? And for any of these possibilities, is there the possibility of a biomarker that could warn of approaching trouble?
There are now two analyses of clinical data that may shed some light on these questions (thanks to Heartwire for details and follow-up). The first, a new analysis from Holland of the RADIANCE trial data, shows an electrolyte imbalance (low potassium and higher sodium) in the treatment group. Measuring carotid wall thickness, they found no correlation between the degree of HDL elevation and progress of disease, which is disturbing. The only correlation was with lower LDL levels, and the authors point out that torcetrapib has unappreciated LDL-lowering activity. (Of course, there are easier and more proven ways to do that!)
The second, the ultrasound-monitored trial called ILLUSTRATE led by the Cleveland Clinic, actually did show a correlation between HDL levels and disease progression, as measured by PAV (per cent atheroma volume). This paper concludes that the drug did perform mechanistically, but that needs some qualification. Overall, there was no real significant change in PAV, but looking more closely, the individual changes did seem to correlate with the amount of HDL elevation each group of patients achieved. Only the very highest-responding group showed any regression, though.
Interestingly, this study also showed the same sort of electrolyte imbalance, and both teams seem to agree that torcetrapib is showing off-target mineralcorticoid effects. Steve Nissen of the Cleveland group is more optimistic (a phrase one doesn't get to write every day). He thinks that a CETP inhibitor that doesn't hit the adrenals might still find a place - but I have to say, looking over the data, that it sure won't be the place that the companies involved were hoping for. Instead of being world-conquering cardiovascular wonder drugs, perhaps the best this class of compounds can hope for is a niche, perhaps alongside statin therapy. I just don't see how this level of efficacy translates into something all that useful.
But we'll see. Merck's anacetrapib is still going along. The data we have so far suggest that the compound raises HDL without effects on blood pressure, as opposed to torcetrapib. So maybe (for whatever reason - blind luck, I'd say) this compound doesn't do anything to the aldosterone pathway. But does it do anything to atherosclerosis? That's the question, and that's what the big money will have to be spent on in Phase III to find out. A comment at the Wall Street Journal's Helath Blog has it right:
Welcome to the challenges of pharmaceutical research. Pharmacogenomic evidence originally led Pfizer to hope that elevating HDL through inhibiting CETP would be beneficial. A biomarker assessment in patients suggests that plaque reduction is associated with the highest HDL elevations. Yet, with torcetrapib, there appears to be a safety biomarker popping up. Are either the efficacy or safety signals really biomarkers of long term clinical outcome? You only need to ante up $800M to run mortality and morbidity trials for 5 or more years. Any investors?
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+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Toxicology
November 25, 2008
Posted by Derek
Avandia (rosiglitazone) has been under suspicion for the last couple of years, after data appeared suggesting a higher rate of cardiovascular problems with its use. GlaxoSmithKline has been disputing this association all the way, as well they might, but today there’s yet more information to dispute.
A retrospective study in the Archives of Internal Medicine looked at about 14,000 patients on Medicare (older than 65) who were prescribed Avandia between 2000 and 2005. Now, looking backwards at the data is always a tricky business. For example, comparing these patients to another group that didn’t get the drug could be quite misleading – the obvious mistake there is that if someone has been prescribed Avandia, then they’re likely getting it because they’ve got Type II diabetes (or metabolic syndrome at least). Comparing that cohort to a group that isn’t showing such symptoms would be wildly misleading.
But this study compared the Avandia patients to 14,000 who were getting its direct competitor, Actos (pioglitazone). Now that’s more like it. The two drugs are indicated for the same patient population, for the same reasons. Their mechanism of action is supposed to be the same, too, as much as anyone can tell with the PPAR-gamma compounds. I wrote about that here – the problem with these drugs is that they affect the transcription of hundreds of genes, making their effects very hard to work out. Rosi and pio overlap quite a bit, but there are definitely (PDF) genes that each of them affect alone, and many others that they affect to different levels. Clinically, though, they are in theory doing the exact same thing.
But are they? This study found that the patients who started on Avandia had a fifteen per cent higher deaths-from-all-causes rate than the Actos group. To me, that’s a startlingly high number, and it really calls for an explanation. The Avandia group had a 13 per cent higher rate of heart failure, but no difference in strokes and heart attack, oddly. The authors believe that these latter two causes of death are likely to be undercounted in this population, though – there’s a significant no-cause-reported group in the data.
The authors also claim that the two populations were “surprisingly similar”, strengthening their conclusions. I think that that’s likely to be the case, given the similarities between the two drugs. GlaxoSmithKline, for their part, is saying that these numbers don’t match the safety data they’ve collected, and that a randomized clinical trial is the best way to settle such issues.
Well, yeah: a randomized clinical trial is the best way to settle a lot of medical questions. But neither GSK (nor Takeda and Lilly, makers of Actos) have seen fit to go head-to-head in one, have they? My guess is that both companies felt that the chances of showing a major clinical difference between the two was small, and that the size, length, and expense of such a trial would likely not justify its results. And if we’re talking about the beneficial mechanisms of action here, that’s probably true. You’d have quite a time showing daylight between the two drugs on things like insulin sensitivity, glycosylated hemoglobin, and other measures of diabetes. Individual patients may well show differences, and that's useful in practice - but that's a hard thing to show in a large averaged set of data. But how about nasty side effects? Maybe there's some room there - but in a murky field like PPAR-gamma, you'd have to have a lot of nerve to run a trial hoping to see something bad in your competitor's compound, while still being sure enough of your own. No, it's disingenuous to talk about how these questions need to be answered by a clinical trial, when you haven't done one, haven't planned one, and have (what seemed to be) good reasons not to.
This kind of study is the best rosi-to-pio comparison we're likely to get. And it does not look good for Avandia. GSK is going to have to live with that - and in fact, they already are.
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November 24, 2008
Posted by Derek
Since I was talking about Nitromed on Friday, let me mention another attempt to combine two known drugs into a new therapy. Another Cambridge company whose front doors I walk by once in a while is CombinatoRx. If they'd had that name back in the early 1990s, you'd have assumed that they did combinatorial chemistry, but their plan is to take approved drugs and find greater-than-the-sum-of-their-parts combinations to approve as a single pill.
That's not easy. It's hard enough figuring out just how single drugs behave in the real world, and any physician will tell you all about what fun it is to deal with drug interactions. Finding beneficial drug interactions, especially unknown ones, is a real uphill climb. But CombinatoRx thought they had one in the mixture of low-dose prednisolone and dipyridamole.
Prednisolone is a well-known corticosteroid which is used to suppress inflammation and the immunen response. Dipyridamole is a multi-mechanism drug that increases the free concentration of adenosine, and it's been used to inhibit clotting and lower pulmonary hypertension. Blood pressure problems are common with prednisolone, and the company believed that the prednisolone dose could be taken down to non-side-effect levels in the presence of the other drug. So they formulated a combination pill (Synavive, CRx-102) to test this out in osteoarthritis patients. The stakes were high - here's a writeup from before the results came out last month.
Things did not work out. The Phase IIb study definitively missed its endpoints. Not only did Synavive not compare to prednisolone alone, it didn't reach statistical significance versus the placebo group, either. The stock dropped 72% the next day, and the company has now announced layoffs that total 65% of its workforce.
What I have to wonder, though, is how things would have worked out in the long run even if the trial had succeeded. As Nitromed's experience shows, it's a hard business convincing insurers to pay a premium for two generic drugs just because they're now available in one pill. I know that CombinatoRx was making much out of their proprietary formulation, no doubt anticipating such objections. But I wonder if a company in this space would have to actually run a head-to-head against the two-generic-pill dosing regimen to really convince people that it had something to offer. And that would take nerves of steel, for sure. . .
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November 12, 2008
Posted by Derek
Should millions more people be taking Crestor? That’s a real balancing act. You have a decrease in heart attacks, but from a fairly small incidence rate. So at a minimum, you’ll need to balance the costs of those coronary events versus the cost of paying for all that Crestor. And statins are not without side effects themselves, so you’ll need to adjust your figures for the incidence of rhabdomyolosis, among other things. (For example, is the increased evidence of high blood sugar in the Crestor treatment group a real effect, or not? If so, you’ll need to add a bit of diabetes cost to the spreadsheet). In any case, the cost of getting all these people screened for C-reactive protein levels in the first place needs to be added in as well.
Naturally, as in any of these calculations, you’re going to have to figure how much should be spent to prevent each excess death, once you’ve decided that these deaths can indeed be considered excess. (Unfortunately, the answer cannot always be “as much as it takes”, since there is not enough money in the world to treat everyone for everything, forever). And that brings up another key question: would putting high-CRP patients on Crestor save lives at all?
Well, you’d think so, what with lowering the incidence of those coronary events. But mortality figures are tricky. In all the graphs presented in the NEJM paper, the “deaths from all causes” one is the least compelling. That shouldn’t be a real surprise, since cutting something down in the 1% range isn’t going to bend the curve very much on its own. But if you look closer at the data, things are even fuzzier.
As pointed out to me by a correspondent, the Crestor-treated group for some reason showed a lower death rate from cancer (35 deaths versus 58). It doesn’t seem particularly likely that this is a real effect – I’ve never heard of statins showing a protective effect like this, although if someone knows differently, I’d be glad to hear about it. The paper makes nothing of this comparison, at any rate. Minus this effect, though, the death rate between the two groups might well be within the error bars. The argument for Crestor would then have to be made purely on treatment costs, as in the first paragraph, because you’d be saving few, if any, lives at all.
And maybe there’s a case to be made. I’m not a public health expert, so I don’t know what numbers to put into those calculations. But it’s important to realize, contrary to some of the headlines out there, that it’s actually a hard call to make. I note that AstraZeneca is being cautious about what all this means for sales of Crestor. They’re wise to be.
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November 10, 2008
Posted by Derek
AstraZeneca took a pretty big risk in running a trial as big as the JUPITER one, but it seems to have paid off for them. As everyone has been reading, it appears that their Crestor (rosuvastatin), lowers the risk of cardiovascular events in patients with elevated C-reactive protein, even those with reasonable cholesterol numbers. (NEJM paper here).
These patients don’t have an awful lot of heart attacks, but they did have less while on the drug. That’s going to be enough, all by itself, to expand the market for Crestor (and probably the other statins as well). The question is whether the others will have the same effect. You’d think so, especially a similar strong one like Lipitor, but AstraZeneca is the only company with numbers for its own product.
The question will be whether it’s worth treating such a wider patient population at these intent-to-treat numbers, a point made in an accompanying editorial in the New England Journal of Medicine:
The relative risk reductions achieved with the use of statin therapy in JUPITER were clearly significant. However, absolute differences in risk are more clinically important than relative reductions in risk in deciding whether to recommend drug therapy, since the absolute benefits of treatment must be large enough to justify the associated risks and costs. The proportion of participants with hard cardiac events in JUPITER was reduced from 1.8% (157 of 8901 subjects) in the placebo group to 0.9% (83 of the 8901 subjects) in the rosuvastatin group; thus, 120 participants were treated for 1.9 years to prevent one event.
It’s interesting to imagine these numbers flipped over, though – if a drug caused heart attacks at these same statistical levels in these same patients, it would be taken off the market immediately. Look, for example, at the risks of cardiovascular problems with Vioxx. The VIGOR trial showed 17 heart attacks in a group of over 4,000 patients, a rate (at the highest dose) of about four times the naproxen-treated control group. In relative risk terms, that’s a serious alarm bell – but in absolute risk, not so much.
This isn’t a completely fair comparison, of course – in the case of statins, cardiovascular events are what you’re trying to treat for in the first place, as opposed to having them as a totally unrelated side effect in a pain medication. And there were other options than a Cox-2 inhibitor for many (although not for all) of the people taking Vioxx. And there’s the general primum non nocere principle: when we find that a drug is causing actual harm (as opposed to doing nothing), it’s likely to be withdrawn, even if the harm is at very low statistical levels.
But at the same time, not giving people something that could prevent these heart attacks is still rather equivalent to causing said heart attacks – isn’t it? We have to make the call of whether the cost, and the statin side effects, are worth it. That’s not an easy one (for one thing, there was a statistically significant difference in the number of Crestor-treated patients showing diabetic symptoms in this trial). And when a drug shows harmful side effects, we should make the call in the same way. I just don’t see the two situation treated in a similar manner much of the time, though.
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+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials
October 17, 2008
Posted by Derek
Here's a good article over at the In Vivo Blog on this year's crop of expensive Phase III failures. They've mostly been biotech drugs (vaccines and the like), but it's a problem everywhere. As In Vivo's Chris Morrison puts it:
Look, drugs fail. That happens because drug development is very difficult. Even Phase III drugs fail, probably more than they used to, thanks to stiffer endpoints and attempts to tackle trickier diseases. Lilly Research Laboratory president Steve Paul lamented at our recent PSA meeting that Phase III is "still pretty lousy," in terms of attrition rates -- around 50%. And not always for the reasons you'd expect. "You shouldn't be losing Phase III molecules for lack of efficacy," he said, but it's happening throughout the industry.
Ah, but efficacy has come up in the world as a reason for failure. Failures due to pharmacokinetics have been going down over the years as we do a better job in the preclinical phase (and as we come up with more formulation options). Tox failures are probably running at their usual horrifying levels; I don't think that those have changed, because we don't understand toxicology much better (or worse) than we ever did.
But as we push into new mechanisms, we're pushing into territory that we don't understand very well. And many of these things don't work the way that we think that they do. And since we don't have good animal models - see yesterday's post - we're only going to find out about these things later on in the clinic. Phase II is where you'd expect a lot of these things to happen, but it's possible to cherry-pick things in that stage to get good enough numbers to continue. So on you go to Phase III, where you spend the serious money to find out that you've been wrong the whole time.
So we get efficacy failures (and we've been getting them for some time - see this piece from 2004). And we're getting them in Phase III because we're now smart and resourceful enough to worm our way through Phase II too often. The cure? To understand more biology. That's not a short-term fix - but it's the only one that's sure to work. . .
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+ TrackBacks (0) | Category: Clinical Trials | Drug Development | Drug Industry History | Pharmacokinetics | Toxicology
July 31, 2008
Posted by Derek
Today we take up the extremely interesting story of Rember, hailed in this week’s press as a potential wonder drug for Alzheimer’s. There are a lot of unusual features to this one.
To take the most obvious first, the Phase II data seem to have been impressive. It’s hard to show decent efficacy in an Alzheimer’s trial – you can ask Wyeth and Elan about that, although it’s a sore subject with them. But Rember, according to reports (this is the best I've seen), was significantly more effective than the current standard of care (Aricept/donezepil, a cholinesterase inhibitor). In light of some of the more breathless news stories, though, it’s worth keeping in mind that this was efficacy in slowing the rate of decline – not stopping it, and certainly not reversing it. Especially in the later stages of the disease, it’s extremely hard to imagine reversing the sort of damage that Alzheimer’s does to the brain (and yes, I know about the TNF-alpha reports – that subject is coming in a post next week). If Rember is twice as effective as Aricept, that's great - except Aricept's efficacy has never been all that impressive.
But that's still something, considering how the drug is supposed to work. Its target is different than the usual Alzheimer’s therapy. Accumulation of amyloid protein has long been suspected as the cause of the disease, but there have always been partisans for another pathology, the neurofibrillary tangles associated with tau protein. Arguments have been going on for years – decades – about which of these has more to do with the underlying cause(s) of Alzheimer’s. Rember is the first clinical shot (that I’m aware of) at targeting tau. If the first attempt manages to show such interesting results, it’s a strong argument that tau must be important. (Other people are working in this area, too, of course, but my impression is that it's nowhere near as many as work on amyloid).
That’s food for thought, considering the amount of time and effort that’s been expending on amyloid. It may be that both pathologies are worth targeting, or it may even be that these results with Rember are a fluke. But it’s also possible that tau is really the place to be, in which case the amyloid hypothesis will take its place in the medical histories as a gigantic dead end. I’m not quite ready to bet that way myself, but it’s definitely not something that can be ruled out. I wouldn’t put all my money on amyloid either, at this point. (Boy, am I glad I'm not still working in Alzheimer's: this sort of stuff is wonderful to watch from the outside, but from the inside it's hard to deal with).
Now, what about the drug itself? It’s coming from a small company called TauRx, whose unimpressive web site just went up recently. The underlying science (and the clinical data) all come from Dr. Claude Wischik of the University of Aberdeen, who has so far not published anything on the drug. The presentation this week has, by far, been the most that anyone’s seen of it (papers are said to be in the works).
And Rember itself is. . .well, it’s methylene blue. Now there’s an interesting development. Methylene blue has been around forever, used for urinary tract infections, malaria, and all sorts of things, up to treating protozoal infections in fish tanks. (For that matter, it’s turned up over the years as a surreptitious additive to blueberry pies and the like, turning the unsuspecting consumer’s urine greenish/blue, generally to their great alarm: a storied med school prank from the old days). What on earth is it doing for tau protein?
According to TauRx, the problem is that the aggregation of tau protein is autocatalytic: once it gets going, it's a cascade. They believe that methylene blue disrupts the aggregation, and even helps to dissociate existing aggregates. Once they're out in their monomeric forms, the helical tau fragments are degraded normally again, and the whole tau backup starts to clear out.
Now for another issue: there's been some commentary to the effect that Rember can't possibly make anyone any money, because it's a known compound. Au contraire. While we evil pharmaceutical folks would much rather have proprietary chemical matter, there are plenty of other inventive steps worth a patent. For one thing, I suspect that formulation will be a challenge here (and that Medpage story seems to bear this out). I doubt if methylene blue crosses the blood-brain barrier so wonderfully, and I also believe that it's cleared pretty well (thus that green urine). So TauRx had to dose three times a day, and their highest dose didn't seem to work, probably because of absorption issues. (That's also going to lead to gastrointestinal trouble). So formulating this ancient stuff so it'll actually work well could be a real challenge: t.i.d with diarrhea is not the ideal dosing profile for an Alzheimer's therapy, to put it mildly.
And for another, there's always mechanism of action. I deeply dislike patent claims that try to grab hold of an entire area, but there's so much prior art in tau that no one could try it. But use of a specific compound (or group of compounds) for a specific therapy: oh, yes indeed. It's a complicated area, and the law varies between Europe and the US, but it definitely can be done. The people who say that this can't be patented should check out the issued patents US7335505 or US6953794. Or patent applications US20070191352, WO2007110627, WO2007110629, and WO2007110630. There you go; that wasn't hard. Mind you, there might be some prior art for using such compounds as cognition-improving agents: I'd start here if I were in the business of looking into that sort of thing.
Finally, is methylene blue (or some derivative thereof) actually going to be a reasonable drug? There's that dosing problem, for one thing, but the long history in humans is encouraging (and is a key part of TauRx's hopes not to spend so much money on toxicity testing in the clinic - talks with the FDA should be starting soon). There have been contradictory reports (plus, minus) on the effects of the compound on the brain in general, though, so they may have to do more work than they're planning on. All in all, a fascinating story.
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+ TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials | Patents and IP | Regulatory Affairs
July 29, 2008
Posted by Derek
I've talked about a lot of difficult therapeutic areas, but here's another boulevard of broken dreams: schizophrenia drugs. I was working on follow-ups to a promising clincial candidate, which has since been promising a number of times without ever delivering. It certainly missed its endpoints in schizophrenia by a mile in Phase II. That was actually my introduction to the drug industry back in 1989 - I followed that up with several years working on Alzheimer's, another notorious graveyard of good ideas, which makes me wonder why I didn't just quit at some point and open that chain of all-you-can-eat catfish restaurants that the Northeast so desperately needs.
Of course, once in a while a drug for dementia actually works a bit, and since there's a huge underserved market out there, it's a prize worth seeking (ask Lilly or J&J). But clinical success rates are absolutely horrific in the whole CNS area, and the latest company to demonstrate this is Vanda Pharmaceuticals in Maryland (I've always wondered if they're named after a spectacular, and spectacularly finicky, genus of orchid).
Vanda's drug iloperidone has been kicking around for years now. Hoechst Marion Roussel (now Aventis) seems to have discovered it in the early 1990s, and they, Novartis, and Titan have all handed it off to someone else over the years. Vanda was the last in line, but they got the dreaded "Not Approvable" letter from the FDA yesterday, and the company's stock was blitzed, down 73 per cent at the close. And the thing is, this drug got a lot closer than anything I used to work on. Vanda did hit their endpoints against placebo and against haloperidol, but the problem is, these are not necessarily the standard of care in schizophrenia:
" The FDA stated that Vanda had demonstrated the effectiveness of iloperidone at 24 mg/day in the 3101 study for which the company reported results in December, 2006, and that the efficacy was similar to the active comparator, ziprasidone (Geodon(R), Pfizer Inc.). In addition, the FDA also stated that iloperidone was superior to placebo in patients with schizophrenia at doses of 12-16 mg/day and 20-24 mg/day in a prior study. However, the FDA expressed concern about the efficacy of iloperidone in patients with schizophrenia relative to the active comparator, risperidone (Risperdal(R), Johnson & Johnson), used in prior studies. The FDA indicated that it would require an additional trial comparing iloperidone to placebo and including an active comparator such as olanzapine (Zyprexa(R), Eli Lilly & Company) or risperidone in patients with schizophrenia to demonstrate the compound's efficacy further. The FDA also stated that it would require Vanda to obtain additional safety data for patients at a dose range of 20 to 24 mg/day."
So iloperidone works, but quite possibly not well enough compared to what's already on the market. That alone won't quite sink your drug - you can always hunt for a patient cohort that benefits from a new compound, and you'll quite likely be able to find one if you have the resources. But as that last line mentions, there are additional safety concerns.
Reading between the lines, it would appear that iloperidone had the best chance of distinguishing itself in efficacy at the higher doses, but that the FDA wanted to make sure that side effects didn't start kicking in up there. This paper makes you wonder if one problem is the (dreaded) QT interval prolongation. Many other factors have looked relatively clean in some of the reported trials.
I greatly doubt if we'll see iloperidone surface again. Vanda wouldn't seem to have the resources, and too many other organizations have passed on it. At this point, it's hard to see why more money would be put into the compound. . .
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+ TrackBacks (0) | Category: Business and Markets | Clinical Trials | The Central Nervous System
July 22, 2008
Posted by Derek
Merck took the unusual step of delaying its earnings release yesterday until after the close of the market. A report on another clinical study of Vytorin (ezetimibe), their drug with Schering-Plough, was coming out, so they put the numbers on hold until after the press release yesterday afternoon. Naturally, this led to a lot of speculation about what was going on. A conspiracy-minded website vastly unfriendly to Schering-Plough suspected some sort of elaborate ruse to drum up publicity.
But that sort of thinking doesn't take you very far, unless you count the distance you rack up going around in circles. As it turned out, the SEAS trial (Simvastatin and Ezetimibe in Aortic Stenosis) was, in fact, very bad publicity indeed for the drug and for both companies. In fact, a real conspiracy would have made sure that these numbers never saw the light of day, or were at least released at 6 PM on a Friday. But no, the spotlight was on them good and proper.
This trial studied patients with chronic aortic stenosis, which is a different condition than classic atherosclerosis. The two have enough similarities, though, that there has been much interest in whether statin treatment could be effective. The primary endpoint, a composite of aortic valve and general cardiovascular events, was missed. Vytorin was no better than placebo. It reached significance against one secondary endpoint, reducing the risk of various ischemic events, but not in any dramatic fashion.
That's not necessarily a surprise, since there's not a well-established therapy for aortic stenosis (thus the trial design versus placebo). As several commenters to the conference call after the press conference pointed out, this shouldn't change clinical practice much at all. But it's not what Merck and Schering-Plough needed to hear, that's for sure, because the sound bite will be "Vytorin Fails Again".
Actually, the sound bite will be even worse than that. There are a lot of headlines this morning about another observation from the SEAS trial: that significantly more patients in the treatment arm of the study were diagnosed with cancer. That's a red warning light, for sure, but in this case we have at least some data to decide how much of one.
For one thing, as far as I know there have been no reports of increased cancer among the patients taking Vytorin out in the marketplace - of course, one could argue that this might have been missed, but if the effect were as large as seen in the SEAS study, I don't think it would have been. Analyses of the earlier Vytorin trials and the ongoing IMPROVE-IT trial versus Zocor have also shown no cancer risk, and the latter trial is continuing. So for now, it would appear that either this was a nasty result by chance, or (a longer shot) that there's something different about the aortic stenosis patients that leads to major trouble with Vytorin.
None of these scientific and statistical arguments, and I mean none of them, will avail Schering-Plough and Merck. Among people who've heard of Vytorin at all, the first thing that will come to mind is "doesn't work", and after today's headlines, the second thing that will come to mind is "cancer". Just what you want, to put out press releases that your compound, even though it failed to work again, isn't actually a cancer risk. You really couldn't do worse; a gang of saboteurs couldn't have done worse. Of course, there's no such gang: the companies themselves authorized these trials, thinking that there were home runs to be hit. But all these sidelines - familial hypercholesteremia, aortic stenosis - have only sown fear, confusion, and doubt. The only thing that I can see rescuing Vytorin as a useful drug is for the IMPROVE-IT results to show really robust efficacy in its real-world patients. And I wonder if even that could be enough.
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+ TrackBacks (0) | Category: Business and Markets | Cancer | Cardiovascular Disease | Clinical Trials | Toxicology
July 8, 2008
Posted by Derek
There was a story yesterday about GlaxoSmithKline taking what’s being called an unusual step to prioritize their clinical candidates. According to the Wall Street Journal, they invited officials from the national health care plans of several European countries to a presentation on the company’s pipeline and asked them which ones they’d be more likely to pay for (and what they’d need to see in the clinic to convince them to do that).
Actually, I think the unusual thing here is that they made a formal meeting out of the whole process. I believe that this sort of thing goes on already – after all, drug companies spend a lot of time trying to figure out the size of potential markets and what the eventual purchasers will be willing to pay. In Europe, those are the national health care systems, and if they’re not willing to pay, your drug will go nowhere. In the US, you’re going to want to sound out the big health insurance companies for the same kind of reality check.
And I don’t see how GSK showed these officials anything that you wouldn’t see (or haven’t seen) at an investor’s conference – otherwise, we’d have seen some Regulation FD disclosures, since the company’s stock is listed on the NYSE. This seems to have been a one-stop rundown of what’s already been disclosed about the whole pipeline, but with opinions specifically solicited along the way– and the company’s not obliged to say what those opinions were or what they’re doing in response to them. GSK got a lot more previously unavailable information out of this process than the health care officials did.
How much, though, will this help? For one thing, I suspect that the officials didn’t say much that GSK didn’t know about what everyone wants for a new drug. They want it to work better than anything that’s currently on the market, with fewer side effects, and for less money. (There, that was easy). And predicting the future doesn’t always work too well. The medical landscape could always change by the time the drugs make it up to the regulatory stage. There will also be a lot more information (good and bad) about the compounds themselves by that time, much of which could make these earlier discussions moot. “Remember that oncology drug we were developing? Well, turns out that it doesn’t work against quite as many different tumors as we were hoping, but. . .” or “Remember that CNS drug we were telling you about back in ’08? Well, turns out that it also has this little cardiovascular thing going, too, and. . .” In the end, the drugs will do what they will in the clinic, and the company will have to bring what it has, not what the regulators asked for.
And even though companies are already supposed to be doing this kind of legwork, there are still some spectacular disconnects. Sanofi-Aventis, for example, did manage to get Acomplia (rimonabant) on the market in Europe (which is more than they ever managed in the US), but they didn’t get the national health care to pay for it. More recently, as in "yesterday", the UK's health care system just told Glaxo itself that they're not going to pay for Tykerb/Tyverb (lapatinib), because they don't see the benefit for the price. And when we’re talking about totally mistaken ideas about market size and acceptance, how can we not mention Pfizer’s Exubera?
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+ TrackBacks (0) | Category: Clinical Trials | Drug Development | Regulatory Affairs
June 30, 2008
Posted by Derek
I was mentioning the gamma secretase enzyme around here just the other day as a longstanding target for Alzheimer's therapy. I remember the periodduring the 1990s when the enzyme hadn't been identified yet, and frankly, it was a lot easier to get excited about it then. That's because when it was finally worked out, the protease turned out to be a big multifunctional multiprotein complex, and among its many functions was affecting Notch signaling.
That's worrisome, because a lot of important cellular development pathways go through the Notch receptor, and these are things that you'd really rather not mess with. (Just run the word "notch" through PubMed to see what I mean). Indeed, some of the toxic effects of the earlier gamma secretase inhibitors seem to have been mediated through just those side effects. So for some years now in the gamma secretase field, the hunt has been on for compounds that will shut down beta-amyloid production without messing with the other functions of the enzyme complex.
Myriad Genetics took such a compound of theirs, Flurizan, into the clinic, after licensing it out to the Danish CNS drug company Lundbeck. They claim that these aren't straight inhibitors, but rather change the activity of the protease in some way that relatively less amyloid is produced. The drug showed some effects in Phase II studies - nothing to jump up and down about, but enough for Lundbeck to pony up for Phase III.
They wish now that they hadn't. As of this morning, the drug appears to have missed all its clinical endpoints in the Phase III trial: no improvement in cognition, no improvement in quality of life. There's no way to spin this kind of result, and the company announced at the same time that they're discontinuing any further work on the compound. (Interestingly, this news seems to have actually made some of its investors happier). It's Lundbeck, though, that seems to be left holding the bag, and their stock is getting hammered to multiyear lows. They have a monstrous patent expiration coming up in 2012 (Lexapro, by far their biggest drug ever), which might explain why they took a flier on the Myriad compound in the first place. The whole effort looks like something of a Hail Mary throw on their part - and most of those go down as incomplete. . .
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+ TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials
April 16, 2008
Posted by Derek
A recent interview in Nature Reviews Drug Discovery with John Powers, formerly of the FDA, points out some problems in designing antibacterial drug trials. Some of these are unique to this area, although others we're stuck with wherever we go.
For one thing, it’s surprisingly hard to make sure, when you’re selecting patients, that the people you’re letting into the trial have the disease that you’re trying to treat. The example used is that some 5% of the patients who present with cough actually have pneumonia. Pneumonia is a very good disease to treat with antibacterial drugs, but you’d better make sure that your patients actually have it. There are some tests available to make sure that a given pathogen is present, although they aren’t available in every case you’d want them to be. If you don’t have such a screen, you risk having a very heterogeneous patient population, which will likely as not obscure the effectiveness of the drug you’re testing.
Then there’s the related difficulty in treating some conditions that you’d think would be clear cases for antibacterials: ear infections, for example. The problem is, it’s surprisingly hard to show benefit for some of these things with existing drugs. The underlying infection may be hard to get to (poor circulation in the infected area), or it may be an intrinsically heterogeneous condition like sinusitis. (That can be the result of umpteen different sorts of bacteria, or it could well be something viral, or several varieties of fungal infection, or allergies, what have you). There’s no point in running a head-to-head with an existing medication in these cases; you should run against placebo. That'll be enough of a challenge.
Another problem is that some of the bacterial diseases progress rather quickly – ahead, in some cases, of our ability to usefully diagnose them. That presents a real challenge for a clinical design, one that is dealt with, in many cases, by not attempting to gather rigorous clinical data under these conditions at all. In this field, diagnostic tools have to be fast if they’re going to be of much use.
There are two sides to all these problems: not only do you want to get the drug to the people who need it (and who will respond to it) the most, you want avoid giving it to people who won’t respond at all. That’s not just for the reasons given above (it’ll mess up your data), although that’s enough all by itself. No, the other problem is that spreading your drug around to inappropriate patient populations will just bring on resistance even faster. That’s going to happen no matter what, of course – the key is to have it happen as slowly as possible.
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+ TrackBacks (0) | Category: Clinical Trials | Infectious Diseases
April 9, 2008
Posted by Derek
I don't usually do more than one post a day, but this really caught my eye. In an ongoing review of Pfizer's (now discontinued) inhaled insulin (Exubera), an increased chance of lung cancer has turned up among participants in the clinical trials. Six of the over four thousand patients in the trials on Exubera have since developed the disease, versus one of the similarly-sized control group. Six isn't many, but with that large a sample size, it's something that statistically can't be ignored, either.
The concerns would have to be, naturally, that this number could increase, since damage to lung tissue might take a while to show up. This, needless to say, completely ends Nektar's attempts to find another partner for Exubera. Their stock is getting severely treated today (down 25% as I write), but things are even worse for another small company, Mannkind, that's been working on their own inhaled insulin for years now (down 58% at the moment).
There's no guarantee that another inhaled form would cause the same problems, but there's certainly no guarantee that it wouldn't, either. Whether this is an Exubera-specific problem, an insulin-specific one, or something that all attempts at inhaled proteins will have to look out for is just unknown. And unknown, in this case, is bad. It's going to be hard to make the case to find out, if this is the sort of potential problem waiting for your new product. Inhaled therapeutics of all sorts have taken a huge setback today.
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+ TrackBacks (0) | Category: Cancer | Clinical Trials | Diabetes and Obesity | Toxicology
April 4, 2008
Posted by Derek
This is turning into Cardiovascular Week around the blog, I have to say, and not in a good way. The latest news is the failure of a drug candidate from Takeda, TAK-475 (lapaquistat). They were in the lead in the field of squalene synthase inhibitors for cholesterol lowering (many other companies have taken a crack at this target, and dropped out along the way)., and their compound once had hopes of being a pretty big deal.
Not any more. In retrospect, the bell sounded late last year, when the company had to stop dosing at their highest level. Elevated transaminase levels were being seen in the treatment groups as the dose went up, which is a sure sign of trouble, as in liver damage trouble. Some investors seem to have held out hope for the compound to show enough efficacy at the lower doses, but Takeda has announced that the safety/efficacy ratio doesn’t justify taking the drug forward.
Liver enzymes are definitely one of those things you worry about when you go into man. There are all sorts of assays that are supposed to give you a read on that problem beforehand, and it’s safe to assume that Takeda ran them. But you’re never sure until you hit humans. Animals can react very differently to some compounds, although that can go either way. But if you set off liver enzyme trouble in rats or dogs your compound is probably dead, no matter how it might act in humans. You won’t get the chance to find out, most of the time.
The alternative is to use human liver tissue, but cultured human liver cells rapidly lose their native abilities and become untrustworthy as a model for the real world. Human liver slices are another alternative, but those are rather hard to come by, as you can well imagine, and the data from them have a reputation for being hard to interpret and hard to reproduce. No, for now, there’s no way to really know what will happen in humans without, well, using humans.
The big question that always gets asked in these failures is whether this is a compound-specific effect, a compound class effect, or a mechanistic effect. Most of the time it’s one of the first two. There are particular compounds, and particular structural series, that are known to be Bad News for liver enzymes. There will be some lingering doubt, though, because there’s plenty of squalene synthase activity in the liver, and it’s not impossible that any compound that hits it could cause the same trouble.
There are a number of other inhibitors out there – interestingly enough, they may have other uses besides lowering cholesterol. For some time, it’s been thought that such compounds might be useful antibiotics, since many bacteria need cholesterol synthesis pathways to survive. And there’s a recent report in Science putting this to the test in a particularly relevant system, particularly virulent strains of Staphylococcus aureus.
The “aureus” part of the name refers to the yellow hue that many strains of the bug exhibit, which seems to be correlated with how nasty they are as an infectious agent. The color comes from staphyloxanthin, a pigment that seems to be used as a defense agent by the bacteria by neutralizing reactive oxygen attacks from a host’s immune system. As the current work shows, the first enzyme in the biosynthetic pathway for staphyloxanthin (known as CrtM) has a lot of structural similarities to human squalene synthase. The authors prepared a number of known squalene synthase inhibitors from the literature, and found that one class of them (the phosphonosulfonates) also inhibit CrtM.
They went further, showing that one of these compounds (a BMS clinical candidate from about ten years ago) actually works quite well as an antibiotic in vitro and in an in vivo mouse model. I'm not sure why this compound didn't go further, but perhaps it (and the others in its class) will have a second life in the antiinfectives world. . .
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+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Drug Development | Infectious Diseases
April 1, 2008
Posted by Derek
Ezetimibe, known as Zetia and as the key component of Vytorin, was invented by friends and colleagues of mine. It was the first drug I ever saw discovered after I joined the drug industry. The initial discovery of the whole compound class happened around the corner from my lab, and the compound that became ezetimibe itself was synthesized down the hall. So, no, I’m not taking the current news about it very well. The situation is still quite confused, but there looks to have been enough stupidity, greed, and plain bad luck involved to make anyone despair. Read on – but I should warn you, I’m probably just going to get madder and madder as the post continues.
As anyone unfortunate enough to be holding Merck or Schering-Plough stock already knows, both companies took a pounding yesterday after the American College of Cardiology issued its recommendation on the use of Vytorin (ezetimibe / simvastatin). This call was based on the now-infamous ENHANCE trial, which was just published in the New England Journal of Medicine. The main points of the study had already come out in January, of course, but a closer look at the data has done nothing to help explain its results: no improvement over existing therapy. Addition of the cholesterol absorption inhibitor to the statin appears to have done nothing to help clear arteries (based on measurement of intima-media thickness) over what could be done with the statin alone. Ezetimibe seems to have had no bad effects, fortunately, but no good ones, either.
The ACC’s verdict is that Vytorin should only be used as a last resort, and that patients currently taking it should strongly consider going back to plain statin therapy. Based on these study results, that seems like a reasonable recommendation. There’s a large outcome trial (IMPROVE-IT) underway comparing the two treatments, but we’re not going to see results from that one for another three years at the earliest. Until then, there doesn’t seem to be any reason to recommend Vytorin. (There may not be any reason to recommend it afterwards, either, but we’ll have to wait to see about that). Fortunately for everyone involved, no one seems to have been harmed, outside of the insurance companies who have paid out for Vytorin for the last few years – they not doubt have their own views on the subject.
It’s important to remember that this result is indeed a surprise, since the combination definitely does do a better job at lowering LDL. (As an editorial in the NEJM puts it, this "dramatically contradicts our expectations"). You’d think that extra LDL reduction would be associated with a better outcome, but one of the panelists at the ACC, Dr. Harlan Krumholz, points out (PDF) that hormone therapy lowers LDL as a side effect, but isn’t associated in that case with better atherosclerosis outcomes, either. Does that mean that there’s more to the effect of statins than just lowering LDL, too? That possibility has to be taken seriously. The non-lipid effects of inhibiting HMGCoA reductase, the statin target, may be part of the answer, although the authors of the NEJM paper are reluctant to make that their whole explanation.
What they suggest instead is disturbing. The study may have been doomed from the start. The ENHANCE subjects were not taken from the general population, but rather were patients with a genetic abnormality in LDL handling, familial hypercholesterolemia. The idea was that these patients would be even more likely to show a benefit from Vytorin. But as the NEJM authors make clear, this may at one time have been a good patient population to show benefits in, but now the great majority of people with this condition are treated with statins starting at an early age. This, naturally, has an effect on their arterial walls. So the subjects of this trial may have already had a head start on reducing their arterial thickness, which means there may well have been a limit on what any particular therapy could have accomplished. Instead of being a better group to demonstrate your LDL-lowering powers in, they could well be worse.
If that’s true, there is, in fact, a chance that the IMPROVE-IT trial could show a clear benefit for Vytorin, since it’s being run in a broader population. (Just watch the confusion if that happens). But what will that mean? The results will be far too late to help Merck and Schering-Plough, and will be a clear disservice to the patients that could have benefited from the drug before then. ENHANCE would then turn out to have been a huge mistake.
But not content with that, the companies have managed to make it into a complete disaster. The controversy has been whether Merck and Schering-Plough sat on the results of the trial or spent extra time trying to find a way to make them look more appealing. This has drawn the attention of Sen. Charles Grassley and an investigative committee, which is the sort of thing that no company can wish for. Yesterday Grassley released some of the text of his letters to the management of both companies, and these include quotes from e-mails sent by John Kastelein, the lead investigator on ENHANCE. They do not look good, not by any stretch of the imagination:
” Is it correct that SP has decided not to present at AHA, but to await the two other, completely unvalidated, endpoints, which analysis is going to take us straight into 2008??!!??
If this is true, SP must have taken this decision without even the semblance of decency to consult me as PI of the study. I can tell you that if this is the case, our collaboration is over…This starts smelling like extending the publication for no other [than] political reasons and I cannot live with that.”
In another e-mail, Kastelein expresses more frustration that the results would not be presented at that AHA meeting (as indeed they weren’t, in the end), and says that ”. . . you will be seen as a company that tries to hide something and I will be perceived as being in bed with you!”
Schering-Plough, for its part, says that these statements are taken out of context, but good grief, what other context could that possibly be? Kastelein has also backed off, saying that he wasn’t accusing the company of “deliberately withholding data for political reasons”, but again, it’s hard to read those excerpts in any other way. These days, no one should make statements in e-mail that they’re not comfortable seeing printed in the Wall Street Journal, which is where I got these.
And does it need to be said that this is exactly, I mean exactly the kind of thing that the drug industry does not need? Vytorin as a drug is easy to forgive – the combination makes perfect sense, and the fact that it didn’t show a good result in ENHANCE took everyone by surprise. (And, as mentioned above, it may in the end turn out to be a good therapy in the end). But the marketing of Vytorin is perhaps another thing – the companies really made a huge aggressive push to get as much of the cholesterol-lowering market as they could. That’s no sin by itself, unless business is a sin, but if you’re going to push that hard, you’d better make sure that you’re standing on something firm.
This trial definitely wasn't that sort of foundation, and the fallout from it has been made much, much worse by its handling. It's distressing to me that the management at Merck and Schering-Plough would even take the chance, in this climate, of being seen as data-massaging study-burying slime. What words do I find if that's what they turn out to be?
Ezetimibe was (and is) a wonderful scientific story in the drug discovery labs, and its development is a testament to some very dedicated and persistent people. What a pity that it's all come to this.
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+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Press Coverage | The Dark Side | Why Everyone Loves Us
March 17, 2008
Posted by Derek
I'm a bit under the weather today, so this one will be short. Since we were talking about CNS drugs and clinical trials the other day, I thought I'd mention this article from Neuropsychopharmacology.
The authors compare reported trials of first- and second-generation antipsychotics, looking to see if potentially biasing factors have skewed the results. One (perhaps surprising) result is that the authors couldn't confirm that the newer drugs necessarily work better through showing fewer extrapyramidal side effects (those are the muscle and coordination problems seen with many drugs in this class). While they may well show fewer EPS problems, that doesn't seem to be related to their efficacy.
Something of a relief is that the efficacy of the various drugs didn't seem to be related to whether or not the drug industry sponsored the trials involved. Given the publication bias of submitting favorable results (and given the obvious commercial interests involved), that's perhaps surprising. But it's welcome data to bring up the next time someone e-mails me about the eeevil Pharma companies and their bought-and-paid-for studies. I don't get a steady stream of that stuff, fortunately, but it still shows up often enough.
I still keep an occasional eye on the antipsychotic drugs, since that was the first therapeutic area I ever worked in when I joined the industry. The project came to a bad end, which was probably a good thing for my professional development. We took the drug into Phase I, gave substantial doses to normal volunteers, and rejoiced when it did nothing to them whatsoever. Then the compound went into Phase II and into real schizophrenics, and it did nothing whatsoever to them either, sad to say. And so it goes in CNS drug development. I don't think that study was ever published; if it had been it would have presumably made the correlation between industry sponsorship and efficacy even less likely. . .
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March 12, 2008
Posted by Derek
Well, I wish I hadn’t been right about this one. Last month I spent some time expressing doubts about Merck’s new obesity drug candidate taranabant, a cannabinoid-1 ligand similar to Sanofi-Aventis’s failed Acomplia (rimonabant). S-A ran into a number of central nervous system side effects in the clinic, and although they’ve gotten the drug approved in a few markets, it’s not selling well. US approval, now long delayed, looks extremely unlikely.
I couldn’t see why Merck wouldn’t run into the same sort of trouble. If a report from a Wall St. analyst (Aileen Salares of Leerink Swann) is correct, they have. Merck’s presenting on the compound at the next American College of Cardiology meeting (at the end of this month in Chicago), and information from the talk has apparently leaked out in violation of the ACC's embargo. There appears to be some difficulty both on the efficacy and side effect fronts – bad news all around.
The company was aiming for a 5% weight loss, but only reached that at the highest dose (4 mg). The report is that CNS side effects were prominent at this level, twice the rate of the placebo group. The next lower dose, 2 mg, missed the efficacy endpoint and still seems to have shown CNS effects. According to Salares, nearly twice the number of patients in the drug treatment group dropped out of the trial as compared to placebo, citing neurological effects which included thoughts of suicide.
While there’s no confirmation from Merck on these figures, they’re disturbingly plausible, because that’s just the profile that got rimonabant into trouble. If this holds up, I think we can say that CB-1 ligands as a CNS therapeutic class are dead, at least until we understand a lot more about their role in the brain. Two drugs with different structures and different pharmacological profiles have now run into the same suite of unacceptable side effects, and the main thing they have in common is CB-1 receptor occupancy. There’s always the possibility that a CB-1 antagonist (or inverse agonist) might have a use out in the periphery – they could have immunomodulatory effects – but anyone who tries this out would be well advised to do it with a compound that doesn’t cross the blood-brain barrier.
And as for taranabant, if the data are as reported I don’t see how Merck can get this compound through the FDA. Even if they did, by some weird accident, I don’t see why they’d pull the pin on such a potential liability grenade. Can you imagine what the labeling would have to look like in order to try (in vain, most likely) to insulate the company from lawsuits? That makes a person wonder how on earth the company could have been talking about submitting it for approval later this year, which is what they were doing just recently. They must have had these numbers when they made that statement – wouldn’t you think? And they must have immediately realized that this would be trouble – you’d think. If that Leerink Swan report is correct, the company’s recent statements are just bizarre.
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March 10, 2008
Posted by Derek
There’s an article in the latest Nature Reviews Drug Discovery on recent drug attrition rates that caught my eye. The authors are looking over 2006-2007 trials and approvals, comparing the biotech industry with traditional pharma. ("Biotech" is defined as a company that's included in either the American Stock Exchange's biotech index and/or the NASDAQ's). In that period, the biotechs scored 47 FDA approvals (45% of the total approvals), but had 68 Phase III failures, which is 74% of that total. Pharma companies had only 5 Phase III failures during that stretch – the other 18 were biotech/pharma joint ventures, and those had a corresponding 16 approvals.
That’s food for thought, all right. The authors make much of the comparatively higher success rate for the biotech/pharma alliance compounds versus the biotechs that went it alone. I have to say, though, that the first explanation that came to my mind was one that they mention, but refer to as “cynical”: that the products which got partnered were disproportionately drawn from the list of those more likely to succeed in the first place.
But is “higher success rate for alliances” really the way to look at the data? Coming at the figures from another direction, I’d argue that “lower success rate for anything labeled biotech” would be a better fit. After all, the FDA approval/Phase III failure numbers are 47/68 for biotech, and 16/18 for biotech/pharma codevelopment, and I’d argue that those ratios are a lot closer to each other than either one is to the ratio for pure pharmaceutical companies, which was 36/5. Look at it this way: if the biotech-alone success rate was as good as the alliance one, you’d expect maybe 53 failures for those 47 successes instead of the 68 that really took place. But if biotech had the same success rate as pharma alone, those 47 winners would have been accompanied by only about 7 failures.
Cynics with a different orientation might wonder if the higher failure rate comes from a higher number of attempts on innovative drugs in biotech, as opposed to follow-ups and me-toos. But looking at another table in the same paper, where the authors split such compounds out, the me-too data in the pharma industry shows 15 FDA approvals versus 1 Phase III failure. The corresponding biotech figures show 20 approvals and 17 failures, so even the follow-on drugs have a harder time of it. (In case you're wondering, the figures from the opposite end of the spectrum, the new compound/new indication class, are 17 approvals versus 4 failures for pharma, as opposed to a toe-curling 9 approvals and 42 failures for biotech). Breaking down the numbers in another way, biotech companies had 37 out of 115 compounds in the me-too class (32%), while pharma had 16 out of 41 (39%), which isn't that big a difference.
This sort of thing is particularly interesting for someone of my age or older, because it brings back memories of the 1980s and the first big biotech boom, back when Genentech and Biogen went public and Cetus was still a going concern. The pitch back then was that biotech products were actually going to have a higher success rate, because they were, after all, mostly proteins that were already in use by the body, right? The definition of "biotech" has changed a lot since then, though - if you look at those companies in the two indices linked above, you'll notice that many of them don't work on biological products at all, but would be better classified as "small pharma". But I'm not sure if the general public appreciates that distinction. . .
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February 27, 2008
Posted by Derek
There’s an interesting analysis in the latest PLoS Medicine on the clinical effectiveness of four modern antidepressant drugs: Prozac (fluoxetine), Effexor (venlafaxine), the partially discontinued Serzone (nefazodone), and Paxil (paroxetine). The authors compared all the published placebo-controlled studies on these drugs, and further included all the regulatory filing data. (Update: not so! See below). The result made headlines all over the place yesterday, because one of the things they found was that these drugs hardly seem, compared to placebo, to do anything at all.
Here’s the odd part: that shouldn’t have been such a big surprise. It wasn’t surprising to the authors of the paper – in fact, they started with the belief that this would be the case, because that analysis has been done before. Their interest was in seeing if there was some difference between different populations of depressed patients – is there some group for which the drugs really show efficacy or not?
As it turns out, there is, but perhaps not for the reasons you’d think. The most severely depressed cohort do seem to show a statistically meaningful response, but that seems largely because the placebo group’s response goes down. That’s been the difficulty with antidepressant clinical trials forever: there is a huge placebo response. This isn’t news; people have been studying this effect and trying to figure out what it means (or figure out a way around it) for years.
So, what does this do to the whole popular culture around the SSRI drugs – you know, “Listening to Prozac”, “Prozac Nation”, all that sort of thing? In this case, popular culture probably has it wrong. These drugs are not magical happy pills, but “Placebo Nation” just doesn’t have the same ring to it. The whole subject is too tangled to make for a catchy title.
It makes sense, though, that this is the area of drug discovery where the biggest placebo effect would turn up – you’d have to think that for depressed patients, a big step would have to be the thought that something can actually affect their condition. It’s bound to help for them to believe (correctly) that their moods aren’t necessarily part of the drab fabric of the universe, but depend instead on the (changeable) chemical weather inside their brains. Knowing those things, and the act of taking a medication that is supposed to work, is enough to help between a quarter and a half of depressed patients right there.
The actual mechanism of the placebo effect is a field of great interest and potentially great importance. (See here, here, here, and here). News like this makes a person wonder, though: if large parts of the public become convinced that antidepressant drugs don’t work, will they? And the question remains: do the SSRI drugs do anything at all through their supposed chemical mechanisms? (It's not like we know). One way to find out would be to run a placebo versus placebo trial. You could blind things at the start, even though everyone was getting the same sugar pills, and you’d presumably see the same response in each group. Then you unblind and cross everyone over, telling people that they’d been in one group and were now headed to the other. Careful work would give you four study arms: (1) people who responded to placebo, and who were then told they’d been taking sugar but were now getting the real drug, (2) people who responded and were told that they were taking a real drug but were now being switched off of it, (3) people who didn’t respond, but were told that this was because they’d been taking sugar, but help was now on the way, and (4) people who didn’t respond, and were told that they’d been getting (apparently ineffective) drug, but were now coming off even that. Fascinating stuff, but we’re going to have to wait for the North Koreans to set it up for us, because no other regulatory agency would let it through.
But from this latest analysis, we can conclude something interesting. The fact that the placebo effect diminishes in the most severely depressed patients, but that the drugs continue to show the same level of efficacy, suggests that they do have some effects of their own. To me, that’s the real news from this study. It reminds me of G. K. Chesterton’s line about journalism being the business of saying “Lord Jones Is Dead” to people who never knew he was alive. In this case, the headlines have been “Antidepressants Don’t Work”, but that should have been the headline years ago. This one should have come in as “Antidepressants Might Actually Do Something”.
Update: A closer look, as suggested in the comments section, shows that the trials included in the meta-analysis were mostly quite short (six weeks or less), when a good deal of evidence would suggest that these drugs take longer to become truly worthwhile. And there is only one study on moderate depressed patients, making it hard to draw conclusions about that group. See the comments page on the article here for more criticisms. So, do antidepressants work or not? You can find an answer that fits, no matter what you need it to be. . .
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February 8, 2008
Posted by Derek
There’s an excellent article in Nature Reviews Drug Discovery that summarizes the state of the HDL-raising drug world. It will also serve as an illustration, which can be repeated across therapeutic areas, of What We Don’t Know, and How Much We Don’t Know It.
The last big event in this drug space was the catastrophic failure of Pfizer’s torcetrapib, which wiped out deep into Phase III, taking a number of test patients and an ungodly amount of money with it. Ever since then, people have been frantically trying to figure out how this could have happened, and whether it means that the other drug candidates in this area are similarly doomed. There’s always the chance that this was a compound-specific effect, but we won’t know until we see the clinical results from those others. Until that day, if you want to know about HDL therapies, read this review.
I’d guess that if you asked a thousand random people about that Pfizer drug, most wouldn’t have heard about it, the same as with most other scientific news. But many that had might well have thought it was a cholesterol-lowering drug. Cholesterol = bad; if there’s one thing that the medical establishment has managed to get into everyone’s head, that’s it. The next layer of complexity (two kinds of cholesterol, one good, one bad) has penetrated pretty well, but not as thoroughly. A small handful of our random sample might have known, though, that torcetrapib was designed to raise HDL (“good cholesterol”).
And that’s about where knowledge of this field stops among the general population, and I can understand why, because it gets pretty ferocious after that point. As with everything else in living systems, the closer you look, the more you see. There are, for starters, several subforms of HDL, the main alpha fraction and at least three others. And there are at least four types of alpha. At least sixteen lipoproteins, enzymes, and other proteins are distributed in various ratios among all of them. We know enough to say that these different HDL particles vary in size, shape, cholesterol content, origin, distribution, and function, but we don’t know anywhere near as much as we need to about the details. There’s some evidence that instead of raising HDL across the board, what you want to do is raise alpha-1 while lowering alpha-2 and alpha-3, but we don’t really know how to do that.
How does HDL, or its beneficial fraction(s) help against atherosclerosis? We’re not completely sure about that, either. One of the main mechanisms is probably reverse cholesterol transport (RCT), the process of actually removing cholesterol from the arterial plaques and sending it to the liver for disposal. It’s a compelling story, currently thought to consist of eight separate steps involving four organ systems and at least six different enzymes. The benefits (or risks) of picking one of those versus the others for intervention are unknown. For most of those steps, we don’t have anything that can selectively affect them yet anyway, so it’s going to take a while to unravel things. Torcetrapib and the other CETP inhibitors represent a very large (and very risky) bet on what is approximately step four.
And HDL does more than reverse cholesterol transport. It also prevents platelets from aggregating and monocytes from adhering to artery walls, and it has anti-inflammatory, anti-thrombotic, and anti-oxidant effects. The stepwise mechanisms for these are not well understood, their details versus all those HDL subtypes are only beginning to be worked out, and their relative importance in HDL’s beneficial effects are unknown.
At this point, the review article begins a section titled “Further Complications”. I’ll spare you the details, but just point out that these involve the different HDL profiles (and potentially different effects) of people with diabetes, high blood pressure, and existing cardiovascular disease. If you’re thinking “But that’s exactly the patient population most in medical need”, you are correct. And if it’s occurred to you that this could mean that an HDL drug candidate’s safety profile might be even more uncertain than usual, since you won’t see these mechanisms kick in until you get deep into the clinical trials, right again. (And if you thought of that and you don’t already work in the industry, please consider coming on down and helping us out).
Much of the rest of the article is a discussion of what might have gone wrong with torcetrapib, and suffice it to say that there are many possibilities. The phrases “conflicting findings”, “remain to be elucidated”, “would be important to understand” and “will require careful analysis” feature prominently, as they damn well should. As I said at the time, we’re going to learn a lot about human lipidology from its failure, but it sure is a very painful way to learn it.
And that is the state of the art. This is exactly what the cutting edge of medical knowledge and drug discovery looks like, except for the fact that cardiovascular disease is relative well worked out compared to some of the other therapeutic areas. (Try central nervous system diseases if you want to see some real black boxes). This is what we’re up against. And if anyone wants to know how come we don’t have a good therapy yet for Disease A or Syndrome B. . .well, this is why.
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+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Drug Development | Toxicology
January 14, 2008
Posted by Derek
Merck and Schering-Plough have released the data on a study of genetically high-LDL patients taking a statin alone (Zocor, simvastatin) or the combination of the statin and Schering-Plough's cholesterol absorption inhibitor (Vytorin, simvastatin and ezetimibe). Vytorin has a good share of the market, and has already been shown to lower cholesterol.
And so it did this time: the Vytorin patients showed a 58% decrease in LDL, while the Zocor group showed a 41% reduction. But this trial went further, looking at the growth of atherosclerotic plaques. You'd figure that a greater decrease in LDL would mean a greater decrease in the size and growth of plaques.
You'd be wrong. The Vytorin group's carotid arteries, measured in a standard way (intima-medial thickness, IMT) came out as 0.0111 mm, while the Zocor group's came out as 0.0058 mm. This is making the headlines as "twice as bad as Zocor", but the difference actually isn't statistically significant (p = 0.29). Steve Nissen of the Cleveland Clinic is quoted as saying that this is "as bad a result for the drug as anybody could have feared", but that's not quite right. If that p value had been, say, 0.01, that would be worse. Strictly speaking, you can't call the two groups different. They don't seem to have been different in cardiovascular outcomes.
But here's the real point: that's bad enough. The whole point of Vytorin is that it's supposed to be more effective than a statin alone, and what you can say about this trial is that it sure didn't prove that. But that carotid artery thickness is definitely a concern - the numbers appear to have big error bars on them, but they're certainly not pointing in a good direction. And it's going to be difficult, perhaps impossible, to ever know if that effect is real, because it'll be mighty hard to get another trial of this sort off the ground after results like this. How can you enroll a treatment group for a drug that has been shown to have no benefit?
Well, OK, there's that LDL reduction. But the downstream clinical data (the artery measurements and outcomes) overrule that. The point of taking a cholesterol medication is not to make your lab test numbers go up and down, the point is to have fewer heart attacks and strokes. We use those blood lipid numbers as a convenient surrogate, but it's been obvious for a long time now that we have, to put it delicately, an imperfect understanding of their relevance. Data closer to real mortality and morbidity outcomes will win.
Now what? This is clearly terrible news for Merck and (especially) for Schering Plough. The companies already were under pressure for having taken so long to work up the data for this trial, which delay ended up just drawing even more attention to these bad results. Now, how do you go out and sell Vytorin (or Zetia, the cholesterol absorption inhibitor alone)? Why do insurance companies have motivation to pay for it? And when are we ever going to understand the complexities human lipid behavior and cardiology?
More on ezetimibe, written in happier days, here , here, here, and here. .
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October 24, 2007
Posted by Derek
GSK opened up their books today, and the magnitude of their Avandia problem has become clear. This was a big part of the company’s sales, and the recent cardiovascular worries have really knocked down the numbers. The response, as has been the trend this year, is for the company to announce layoffs.
And man, have there ever been layoffs in the industry this year. There’s a list of the larger ones over at FierceBiotech, and it does not make for cheerful reading. In January, Pfizer announces 10,000 job cuts and closes their Ann Arbor site. That same month, Bayer-Schering closes the doors on research buildings in Connecticut and California (layoffs which were announced in 2006 and are thus not on the Fierce list). Bayer-Schering, who really should have run that B-S initial thing past a couple of native English speakers, announces 6,100 more job cuts in March. In July, AstraZeneca doubles down on its earlier layoff announcement and says that 7,600 jobs will disappear, and J&J announces a 4% reduction in its workforce (5,000 jobs). Then in August, Amgen cut over 2,000 jobs of its own.
In September, most everyone held on to the jobs for the moment But Novartis said this month that they’re going to trim over 1200 positions in the US, mostly through attrition. And now we have GSK with disappointing earnings and an announcement of unspecified layoffs, and bear in mind, this is just the news from the big outfits. The usual turmoil has been going on among the smaller companies (Idenix, Palatin, Sonus, and others), whose fortunes depend more on single drugs.
What a year – and hey, there’s still time to announce more layoffs before the holidays, so we may not be through yet. It’s tempting for some people to look at a list like this and say “Outsourcing! China! India!”. And I can’t deny that some of these jobs have headed there, just as some possible hiring expansions have been muted for the same reasons at other companies.
But outsourcing isn’t the whole story. Many of these job cuts have been in the sales forces, and they’re definitely not outsourcing the sales reps to Shanghai. Ditto for the people in Regulatory Affairs and Legal. Outsourcing is changing the size and shape of layoffs, but it’s not providing the motive force for them. That force, simply enough, is just that we’re not selling enough drugs, mostly because we don’t have enough good drugs to sell. Some areas have had too few projects even to start with (anti-infectives?), and everyone has had too few make it all the way through the clinic and the FDA.
And some of those failures have been extraordinarily large and expensive. Unfortunately, this has been the case for a while now. Over the last few years, we’ve had drugs that have failed terribly late in the clinic (torcetrapib, among others), drugs that have made it through trials but failed at the FDA (rimonabant, among others), and (most expensively of all) drugs that have made it to market and been pulled back early in their product lifetimes, after the big promotion money’s been spent and before any of it gets made back (Bayer’s Baycol and Pfizer’s Exubera – among others).
Add in the ones that never lived up to their planned potential (Iressa, Macugen, yes, yes, among others) and you have a gigantic revenue shortfall. Now, it’s true that not all of these would have made it under any conditions. Drugs fail. But do they fail like this, so relentlessly and so expensively? And it’s not that we aren’t killing all sorts of stuff off earlier in the development pipeline – no, these things are what’s left after the dogs are gone.
What to do? If I knew how to answer questions like that, I'd be dictating this from the deck of my yacht. The glass-half-full perspective is that there sure are a lot of opportunities for anything that can open up some new therapeutic areas or help with drug failure rates in the existing ones. It won't take much, considering where we're starting from. Yesterday I was encouraging people to try out some high-risk ideas, and here, in case anyone was wondering, is an excellent place for them.
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July 23, 2007
Posted by Derek
Four years ago I wrote about an unusual Roche diabetes compound targeting glucokinase. The odd thing about it was that it made the enzyme more active, which is something you can only rarely hope to do. Enzymes generally run near the top of their specs, unless there's some built-in switch that keeps them damped down until they're needed. That's often phosphorylation, but another trick inside the cell is to keep the concentrations of substrate low (or the concentrations of some inhibitor high). But once they go, they usually go about as fast as they can. This glucokinase example is still about the only one I can think of in drug development, and it's had a fair amount of attention over the years.
Maybe I should switch the tense, though, because reader Daniel H. has informed me that Roche seems to have stopped work on the compound in Phase II. The company had taken their lead compound (R1440) through several different trials, so something seems to have been working, but they don't seem to have given any reasons as to why they abandoned it.
After that much Phase II work, the most likely answer is some sort of toxicity, the kind that comes up too close to the efficacious dose. A company may try several different dosing regimens, combinations with other drugs, or patient populations trying to get around a problem like that, and perhaps what we're seeing is the end of the line. Nothing looked safe enough to spend the really large money on Phase III.
By now, there are several other companies in the same area, and I'm sure they're rather curious about all this, too. Is glucokinase activation dead as a target? As with many questions in this industry, you'll have to have either a lot of money or a lot of patience to find out. And if you want to come down and try drug development yourself, you'll need a lot of both.
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June 15, 2007
Posted by Derek
Everyone will have heard the news about Wednesday's FDA Advisory Commitee vote on Accomplia / Zimulti (rimonabant). If you'd tried to convince folks a few years ago that this drug wouldn't make it to a vote until summer of 2007, and would be unanimously rejected when it did, you'd have been looked at with pity and concern. No, this drug was going to conquer the world, and now people are talking merger-of-desperation.
Hey, you don't even have to go back a few years. Here's an article from 2006:
"A new anti-obesity pill that market observers say could become the world's biggest-selling drug is close to getting approval from the European Commission. . .
Gbola Amusa, an analyst with research firm Sanford C Bernstein, said that Acomplia could achieve $4.1bn in annual sales by 2010, in part because it has been shown in clinical trials not only to trim fat but to increase levels of good cholesterol and control diabetes.
"In the blue sky scenario, this could become the world's best- selling drug as the indication is so broad," he said. "It has a path to revenues that we rarely ever see from a pharma product."
Oh, the blue sky scenario. I'm no stranger to it myself - I love the blue sky scenario. But how often does it ever descend to earth? It's not going to do it this time. Sanofi-Aventis was reduced to making the suggestion that every potential patient be first screened for depression, which doesn't sound like the sort of iron wrecking ball that usually gets welded to the world's best-selling drugs.
In the wake of this development disaster, here are a few points that may not get the attention they deserve: first, consider the money that S-A has spent on this drug. We're never going to be shown an accurate accounting; no one outside the upper reaches of the company will ever see that. But I seriously doubt if they've ever spent more on any program. There's an excellent chance that most of it will never be recovered, not by rimonabant - it'll have to be recovered by whatever drugs the company can come up with in the future. They'll be priced accordingly.
Second, think about the position of their competitors. All sorts of companies have pursued this wonder blockbuster opportunity. If you run CB-1 antagonists through the databases, all kinds of stuff comes hosing out. Merck and Pfizer are the companies that were most advanced - you don't get much more advanced than Phase III clinical trials - but plenty of others spent time and money on the chase. All of those prospects have taken grievous damage. Odds are that rimonbant's problems are mechanism-related, and proving otherwise will be an expensive job. This is something to consider when you next hear about all those easy, cheap me-too drugs.
And finally, it's worth thinking about what this says about our abilities to prosecute drug development in general. Just as in the case of Pfizer's torcetrapib, we have here a huge, expensive, widely anticipated drug that comes down out of the sky because of something we didn't know about. It's going to happen again, too. Never think it won't. This is a risky, white-knuckle business, and it's going to be that way for a long time to come.
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+ TrackBacks (0) | Category: Clinical Trials | Diabetes and Obesity | The Central Nervous System | Toxicology
June 11, 2007
Posted by Derek
The FDA briefing documents for Wednesday's discussion of Accomplia / Zimulti (rimonabant) have been posted, and they're an interesting read indeed. As everyone in the industry knows, this drug was once looked on as the next potential record-breaker, and writing the first part of this sentence in that verb form tells you a lot about what's happened since. It's the first antagonist targeting the cannabinoid CB-1 receptor, and at one point it looked like it was going to make people lose their excess weight, shed their addictions, and for all I know refinance their mortgages.
But then the delays hit in the US - long, long ones, delays which made fools of everyone who tried to predict when they would be over. And the drug meanwhile made it to market in Europe, where it has very quietly done not very much.
Now we may be seeing some of the reasons for the FDA'a "approvable" letter over a year ago. It's not efficacy - the FDA's briefing summary states that:
"Rimonabant 20 mg daily vs. placebo was associated with statistically and clinically
significant weight loss. Rimonabant 5 mg daily vs. placebo was associated with
statistically significant but clinically insignificant weight loss. . .rimonabant 20 mg daily vs. placebo was associated with a statistically significant 8% increase in HDL-C and a statistically significant 12% decrease in TG levels. There were no significant improvements in levels of total or LDL-C in the rimonabant 20 mg daily vs. placebo group. . .rimonabant 20 mg compared with placebo was associated with a statistically significant 0.7% reduction in HbA1c in overweight and obese subjects with type 2 diabetes taking either metformin or a sulfonylurea."
Not bad - just the sort of thing you'd want to go after the whole obesity/diabetes/cardiovascular area, you'd think. But the problem is in the side effects, and one in particular:
"The incidence of suicidality – specifically suicidal ideation – was higher for 20 mg
rimonabant compared to placebo. Similarly, the incidence of psychiatric adverse events,
neurological adverse events and seizures were consistently higher for 20 mg rimonabant compared to placebo. . ."
They're also concerned about other neurological side effects, and seizures as well. The seizure data don't look nearly as worrisome, except in the obese diabetic patients, for whom everything seems to be amplified. And all of this happens at the 20-mg dose, not at the 5 (which doesn't do much for weight, either, as noted above). And for those who are wondering, yes, on my first pass through the data, I find these statistics much more convincing than I did the ones on the Avandia (rosiglitazone) association with cardiac events.
I had my worries about rimonabant a long time ago, but not for any specific reason. It's just that I used to work on central nervous system drugs, and you have to be ready for anything. Any new CNS mechanism, I figured, might well set off some things that no one was expecting, given how little we understand about that area.
But isn't it good to finally hear what the arguing is about? Sanofi-Aventis has been relentlessly tight-lipped about everything to do with the drug. I can see why, after looking at the FDA documents, but this isn't a problem that's going to go away by not talking about it. The advisory committee meeting is Wednesday. Expect fireworks.
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+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Diabetes and Obesity | The Central Nervous System | Toxicology
June 4, 2007
Posted by Derek
We have a new phrase to toss around in in the industry: "Phase Zero". That's what they're calling a recent trial of an anticancer drug from Abbott (ABT-888), which was tested in humans before any safety dosing (Phase I) had been done.
So, how exactly can you do that? By giving extremely small amounts of the drug, that's how, and looking to see if you can detect a change in some marker for eventual efficacy. In this case, the marker was inhibition of the activity of PARP, poly(ADP-ribose) polymerase, which is involved in the cellular response to DNA damage. Inhibiting it should make cells much more likely to die once such damage had been detected, which one of many such signals that cancer cells tend to ignore under normal conditions. Abbott's drug seemed to do the trick, so work on it will continue.
The good part of this is that the drug got into humans more quickly than usual, and that its mechanism of action has now been verified (to a first degree of approximation, anyway - it hits the target). This should make a company a bit more confident about moving on to larger trials, and could potentially weed out losers early in the game.
But there are bad parts, too. For one thing, the patients in a phase zero trial have no hope of benefit from the drug: the dose is just too small. The small doses could give results that (for better or worse) aren't relevant to the later real-world ones, too. Another problem is that reliable biomarkers are thin on the ground despite great sums of money being spent to find and validate them. If you're going to let the future of your drug ride on one of these trials, you'd better be confident that you know what it's telling you. (And if you're not going to let the future of the drug ride on a phase zero trial, why are you running one, eh?)
What would be worth knowing is how many drugs fail because of lack of effect on their intended target, as opposed to those which hit the target but still have no effect. You'd also want to know: of that first group, what portion are going to be amenable to robust biomarker studies. Those two fractions would tell you how much of an impact this whole idea will have. Right now, I think the error bars are way too large to make a prediction. . .
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June 3, 2007
Posted by Derek
Today's New York Times had a long front-page story from Janet Roberts and the paper's Scourge of the Drug Industry, Gardiner Harris. Titled "After Sanctions, Doctors Get Drug Company Pay", it details (through the example of one particular Minnesota psychiatrist) a practice of physicians who have had medical board problems continuing to get money for participating in clinical studies.
Dr. Faruk Abuzzahab has definitely had his run-ins with the medical authorities. And over the years he's also definitely had payments from various companies. It's not a story to make you feel warm and fuzzy, that's for sure. There are some things about it that puzzle me, though. For one thing, it appears that Abuzzahab is no bargain as a clinical investigator:
"Separately, the F.D.A. in 1979 and 1984 concluded that Dr. Abuzzahab had violated the protocols of every study he led that they audited, and reported inaccurate data to drug makers. He routinely oversaw four to eight drug trials simultaneously, often moved patients from one study to another, sometimes gave experimental medicines to patients at their first consultation, and once hospitalized a patient for the sole purpose of enrolling him in a study, the F.D.A. found. . .
A simple Google search reveals Dr. Abuzzahab’s 1998 medical board disciplinary file, which was reported at the time by a local newspaper and a TV station. In 1998, The Boston Globe featured Dr. Abuzzahab in a front-page article questioning the safety of psychiatric drug experiments. And in 1999, the NBC program “Dateline” did a segment about a woman who committed suicide while in a drug experiment he supervised.
In June 2006, the medical board criticized Dr. Abuzzahab, this time for writing narcotics prescriptions for patients he knew were using false names, a violation of federal narcotics laws.
Despite all this, drug makers continued to hire him. Dr. Abuzzahab’s résumé lists 11 publications or research presentations since 2000, when the medical board lifted its restrictions on his license."
Well, I haven't seen the guy's résumé, but a PubMed search shows only one paper since that year, and only one other since 1983. His publication record thins out drastically after the early 1980s; this is not someone who cares about blazing across the sky of the scientific literature.
What exactly does he care about, though? Money? According to the graphic that accompanies the story, Abuzzahab received $55,000 from several drug companies over an eleven-year period. That's better than a kick in the ankle, but it doesn't seem like enough cash to turn a busy psychiatrist's head, either. I've not had the opportunity to find out if I can be bought or not, fortunately, but I can tell you this: it would take more than five grand a year to do it.
And just what is it that GSK, Wyeth, J&J and the other companies who've paid him are hoping to get? The first thought is that they're hoping to influence his prescribing habits, because it doesn't sound as if the clinical data he's generating are worth all that much. Is that amount of money enough to do it? Presentations by a well-known and well-respected figure could also be expected to influence the scrip-writing of others, but Dr. Abuzzahab doesn't seem, in recent years, to have been that kind of person.
No, this sort of thing doesn't look good at all. The Times story gives a reader the impression that companies are disproportionately funding physicians with disciplinary problems, although there's no evidence to back that up. But the funding should be disproportionate in the other direction, which doesn't seem to be the case. Not good, not good at all.
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May 31, 2007
Posted by Derek
GlaxoSmithKline is breaking out the data to respond to the Nissen and Wolski NEJM paper on the possible cardiovascular risks of Avandia (rosiglitazone). In a letter published by The Lancet (PDF), the company's chief medical officer, Ronald Krall, defends the drug (and the company):
"GlaxoSmithKline did similar meta-analyses in 2005 and 2006 and found hazard ratios in the same direction as Nissen and Wolski. However, all these results are highly dependent on the methods used and the studies included, given the small number of events reported. For example, the actual number of myocardial infarctions in the Nissen and Wolski meta-analysis yields a very low frequency of events (0·6%), and the absolute difference in rates of myocardial infarctions between rosiglitazone and controls is less than 0·1%.
These observations support a view expressed by Nissen and Wolski them-selves: “a meta-analysis is always considered less convincing than a large prospective trial designed to assess the outcome of interest.”
He then goes back over the data in the three large trials that bear on the question. Reanalyzed data from the ADOPT study still do not show a statistically meaningful cardiovascular risk for rosiglitazone versus the other two diabetes drugs in the trial (metformin and glibenclamide). (There's no placebo group - this is one of those head-to-head comparisons of a drug versus its strongest competitors, a type of study that some people believe never takes place). The second completed study, DREAM, looked at co-administration of rosiglitazone and the ACE inhibitor ramapril. There were four groups - placebo only, rosi and placebo, ramapril and placebo, and rosi plus ramapril. The first three showed no difference in cardiovascular events, but the last one did, for unknown reasons.
These two studies are in the Nissen/Wolski meta-analysis, of course, but as I noted originally, it was the sum of the smaller studies that gave them their cardiovascular warning. But when the statistically less powerful trials show one thing that isn't borne out by the larger ones, the issue is (at the very least) still in doubt. The letter also points out that the company's database mining of managed-care patients taking rosi has shown no increase in cardiovascular risks.
Other controlled studies are ongoing, the (now highly awaited) RECORD and another one called ACCORD. Both are designed from the start to address cardiovascular outcomes (which are a major complication in diabetic patients). Krall's letter lifts the veil a tiny bit on RECORD, saying that the independent review board has now completed an interim analysis of its cardiovascular data and concluded that the trial should continue. This would not be the case, you'd have to presume, were the numbers to clearly show increased CV deaths in the treatment group.
My take on this is that the company has a pretty strong case so far, certainly strong enough to wait for the ongoing trials to settle the issue. What never fails to disappoint me, though, is the way that stories like this are jammed into ready-made templates. Depending on the editorial writer, the appearance of the NEJM paper became "FDA Corrupt, Broken: Snores While Dangerous Drugs Kill Thousands", or "Giant Drug Company Sells Heart Attack Poison, Doesn't Give Hoot". Or maybe just "Drug Approval System Completely Broken - Again".
Now, Steve Nissen does sound the alarm a lot, but I have no doubt that his intentions are honorable. His paper, to me, was the equivalent of saying "Hey, you people may have a problem here. Did you know that?" GSK's response, then is "Yeah, we've looked at that, too, but we don't see it. Are you sure your numbers are good?" Meanwhile, the studies which should answer the question for good are already years into their runs. If this is our standard for a broken drug approval system, we've certainly become mighty fastidious over the years. For what it's worth, The Lancet agrees.
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+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Diabetes and Obesity | Press Coverage
May 29, 2007
Posted by Derek
Here's a question for people working in the industry: when you see your own company's press releases, just how close to reality do you feel they come? Could someone wanting to invest in your company's stock form an accurate picture of your drug pipeline's potential by reading them, or not?
I ask because (in my experience) the answer to that second question is very much in doubt. There are several reasons: First, from what I've seen, many companies have their official pipelines cluttered with compounds that aren't being developed - at least, not in the same way that the really important ones are. (Projects can get sent "into the clinic" for many reasons, not all of them productive). And canceled projects often linger on the list before they're removed, too. A dedicated reader of the company's SEC filings and press releases can work some of these things out, but no one makes it easy.
Then there are the press releases about specific projects, which. . .well, they're press releases, if you know what I mean. The bad news is skulking in a subordinate clause somewhere in the fifth paragraph, while the good news is up on stage, expensive spotlights reflecting off its refined makeup and tasteful clothes. This isn't a particular failing of the drug industry; it's a failing of press releases (or, more likely, of human nature).
This has a bearing on the issue of disclosure of clinical trial information, naturally. I think that we're moving toward some sort of standardized disclosure, and that there's little that can be done (in the long run) to stop it. I think the positives outweigh the negatives, although it's not as easy a match to score as you'd guess. (Lack of knowledge of statistics, to pick one big issue, could make the whole thing a pile of dry wood for fools to make bonfires of). More on this in a future post. . .
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May 24, 2007
Posted by Derek
Steve Nissen has (once again) made waves with an analysis of cardiovascular risk. This time the subject is Avandia (rosiglitazone), a therapy for diabetes that's the oldest PPAR-gamma drug on the market. A meta-analysis of 42 reported clinical trials of the drug led to the conclusion that rosiglitazone is associated with a statistically significant risk of cardiac events.
The similarities to the Vioxx situation are what have made headlines (and what sent GlaxoSmithKline's stock down about 8% on the day the paper was released). But there are some important differences. Merck's ran into the Vioxx numbers in their own clinical data - the arguing has been whether they recognized the effects earlier (or should have), but it was a specific trial of theirs that led to the statistics that sank the drug. A meta-analysis is a much different beast, since you're trying to fit a large number of different trials, run in different ways for different reasons, into the same framework. Not everyone trusts them, even when the analysis is performed by someone as competent as Nissen, who does mention the limitations of the approach in the paper:
"Our study has important limitations. We pooled the results of a group of trials that were not originally intended to explore cardiovascular outcomes. Most trials did not centrally adjudicate cardiovascular outcomes, and the definitions of myocardial infarction were not available. Many of these trials were small and short-term, resulting in few adverse cardiovascular events or deaths. Accordingly, the confidence intervals for the odds ratios for myocardial infarction and death from cardiovascular causes are wide, resulting in considerable uncertainty about the magnitude of the observed hazard. Furthermore, we did not have access to original source data for any of these trials. Thus, we based the analysis on available data from publicly disclosed summaries of events. The lack of availability of source data did not allow the use of more statistically powerful time-to-event analysis. A meta-analysis is always considered less convincing than a large prospective trial designed to assess the outcome of interest."
And that's what's happening here. A number of people at large diabetes treatment centers aren't ready to buy into a cardiovascular risk for Avandia yet, because they're wary of the statistics. There's a large cardiovascular outcome trial of the drug going on now, which won't wrap up until 2009, but several people seem to want to wait for that as a more definitive answer.
If Nissen's data hold up - and statistically, I'm definitely not up to the task of evaluating his approach - then we might be looking at a Vioxx-like risk level. Out of some 14,000 patients on the drug in the various studies, there were 86 heart attacks in the treatment groups, and 72 in the controls. That comes out to be statistically significant, but (as you can see) the problem is that Type II diabetics have a high background rate of CV problems. Looking at Nissen's Table IV, it also seems clear that most of the significance he's found comes from the pooling of the smaller studies. The larger trials are nowhere near as clear-cut, which makes you wonder if this effect is real or an artifact.
I'm certainly not prepared to say one way or another, and I just hope that the ongoing trial settles the question. It's certainly not unreasonable to imagine a PPAR gamma drug having this side effect, but if this were a strong mechanism-based phenomenon the numbers would surely be stronger. If a risk is confirmed, though, we'll then be faced with a risk-benefit question. Does the glycemic control that Avandia provides lead to enough good outcomes to offset any cardiovascular risk over a large population? If you think getting the current numbers is a tough job, wait until you try to work that one out.
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+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Diabetes and Obesity | Toxicology
April 13, 2007
Posted by Derek
I've been out of the research labs for over two months now, and you know what I miss the most? No, not the safety meetings (hah!) or the smell of the solvents - what I miss is getting fresh data on experiments. Waiting for results on something crucial is hard to take, but it's also exciting, and there's nothing I've found outside of science that compares.
I've sat at my desk holding a warm printout from an LC/MS, or with a newly arrived e-mail from the biologists, and I swear, I've closed my eyes for a moment before I've looked at them. That's the last moment of not knowing; after that you're living in the new world that the experiment made. I don't know what I'd do with a job that didn't have that feeling in it, and honestly, that's one reason I'm still looking.
It occurs at all sorts of levels - checking the NMR to see if your reaction worked or not, waiting for the PK results to see if your idea raised the blood levels, holding your breath when the compound goes into two-week tox testing. And beyond that things get really terrifying, when human data start coming in from the clinic.
Ask Vertex. I wrote here about their antiviral compound (telaprevir, VX-950) for hepatitis. It's a huge market that really needs a better drug, and a lot of people have taken swings at it. Well, on Saturday night in Barcelona, the company is presenting their latest clinical data, and investors are checking their heart rates. The drug's success would be the biggest event in the history of the company (and a huge advance in hepatitis therapy), and failure (the antiviral norm, unfortunately) would be very, very hard to take.
The company's top clinicians already know the answer, of course, because a person's got to have time to make slides. They've had the experience I was talking about, on a scale that few people have ever felt. You click a button, turn a page, and the future writes itself out there in front of you. . .
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+ TrackBacks (0) | Category: Clinical Trials | Infectious Diseases | Who Discovers and Why
March 26, 2007
Posted by Derek
Amgen served up a nasty surprise on Friday with the results of a trial they're running on their Vectibix (panitumumab) cancer therapy. It's an EGFR inhibitor (same space as Imclone's Erbitux) and this trial was the first to test a "dual biologics" approach to colon cancer. One group got the standard of care (oxaliplatin and irinotecan chemotherapy, plus Genentech's Avastin VEGF inhibitor), and other other got that plus Vectibix.
Unfortunately, in one of those unexpected results that cancer trials are always delivering, the two-protein-therapeutics group actually showed slightly worse survival data than did the standard-of-care group, and that takes care of that. By itself, this result isn't enough to call Vectibix a failure by any means. But its expected rise to overshadow Erbitux has clearly been delayed.
Imclone's stock price reflects this. Does it ever - my modest short position in their stock is now underwater good and proper. Their stock's up 45% so far this year, with a lot of that in just the last two weeks. But these are early days (he said to himself abstractedly, looking out the window with his brokerage statement in his lap). Both drugs are in similar Phase III trials against colorectal cancer (as that first link, to Bioworld Today, details) and eventually we're going to have about as good a head-to-head comparison as you can expect in this area. Whether that'll be enough to decide anything, well. . .
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March 22, 2007
Posted by Derek
Jim Hu has a good post on some proposed new FDA rules for its advisory panel members. Some sort of changes have been coming for a while now - here's an op-ed that I wrote on the subject back in 2005. I argued that many of the best scientists and clinicians in a given field already work with the industry (which isn't such a bad thing when you think about it), and that restrictive requirements for serving on advisory panels could do more harm than good.
Well, here's the new proposal: the cutoff is $50,000 in the previous 12 months. At that or above, you won't be allowed on the panel. Between $1 (presumably) and $50,000, you can sit on the panel, but won't be allowed to vote. My guess is that that's going to have a pretty big impact if it goes through, and that we're going to see some very different committee rosters.
Or, of course, maybe we're going to see some new forms of relationships between drug companies and their consultants. That's what happens whenever efforts are made to regulate money in the political world, and it wouldn't surprise me a bit here. There are two ways to look at this: if you're suspicious of the FDA's motives (like, say, Rep. Maurice Hinchley of New York, who has a bill mandating these changes and more coming along), then you'll probably see the whole process as a form of organized bribery, wheel-greasing to get defective drugs past the regulatory authorities. Another way to look at it, though, is that outside experts have something that the drug companies need (expertise, and more importantly, expertise from another point of view than the one from inside the company), and that they're willing to pay for it. This may seem odd, but these consultants don't always tell us what we want to hear.
The tough part is when a drug is on the edge of getting approved or not - it has some good points, some bad ones, and the decision could go either way. That's when suspicions are raised that an extra $50,000 here and there is what tipped things over to approval. I don't see that happening, myself (although readers are invited to submit counterexamples). Many approvals can be honestly argued either way, because these medical questions are inherently one big grey area.
The media reaction to this story is rather more toward the former point of view, though. The Washington Post's take on the story is that ". . .the new guidelines implicitly acknowledge what critics have long said -- that it is possible to find enough qualified experts who do not have ties to drug and device manufacturers." And Gardiner Harris in the New York Times gives one sentence to someone at the American Enterprise Institute, while leaving plenty of space for words from Rep. Hinchley and my own representative, Rosa DeLauro, both of whom are good places to go for "corporate poisoners" quotes.
Well, this is the first act of a rather long session of political theatre. There are 60 days of public comment on this proposal, then more wrangling comes along after that. Then there are the bills in the House, which if things go on long enough will get thrown into the next election cycle, and on it goes. It's worth watching, but be ready for a protracted show.
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+ TrackBacks (0) | Category: Clinical Trials | Drug Development | Press Coverage | The Dark Side | Why Everyone Loves Us
March 20, 2007
Posted by Derek
Pfizer's enormous torcetrapib failure last fall wasn't the only time a company has come to grief in the cardiovascular area, and it's not going to be the last one, either. That's been proven this week by a much smaller company, Atherogenics, and their lead drug, AGI-1067 (partnered with AstraZeneca).
The company is targeting expression of the VCAM-1 protein in blood vessels. That's an immunoglobin that seems to be involved in the adhesion of various blood cell types to the vessel walls, and as such is considered a very interesting target for atherosclerosis. AtheroGenics has been working on a series of drug candidates that interfere with the expression of VCAM-1 (through blocking an oxidative pathway in the endothelial cells) and could thus slow the development of arterial plaques (or reduce the size of plaques that had already formed).
Such is the hope, anyway. AGI-1067 behaved well in animal models, and went through numerous Phase I trials in combination with other cardiovascular agents. That link will also take you through the Phase IIa and IIb trials, which showed some real effects in reduction of plaque volume. Those results led to this Phase III trial (with the acronymn ARISE), which expanded the number and variety of patients while looking at real-world endpoints.
That's just how things should work. You see if the drug is tolerated, alone and with the therapies it's going to be given with. Then you check some primary endpoints, to see if the mechanism you're targeting is really being affected. Finally, you see if that's actually going to do a real number of patients any good: I, II, and III. And, unfortunately, III is where the Atherogenics drug ran into trouble.
They missed their primary endpoint, which was a composite score of cardiovascular adverse events - death, heart attack, stroke, angina, etc. Overall, AGI-1067 was no better than placebo when given along with the standard drugs for this patient population. There's no way to call that good news, and no one's even trying. At the same time, though, the company claims to have seen positive effects in some disease states. What subgroups those are, and how positive those effects were, won't be known until next week's meeting of the American College of Cardiology in New Orleans. It's impossible to say if this is just wishful thinking, or a drug worth salvaging.
That's just what the people at AstraZeneca have to decide. The company's pipeline could use some help (not that this distinguishes them very much these days), so they don't want to walk away from something promising. At the same time, they can't afford to throw good development money after bad, either. But the stakes are much, much higher for AtheroGenics, since this physiological pathway is basically the platform for the entire company. There are doubtless some very difficult and unpleasant meetings in progress, not the tiniest bit of fun for anyone involved. My. . .well, heart, goes out to everyone involved. . .
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+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Drug Development
February 7, 2007
Posted by Derek
Antiviral drugs are one of those big unmet medical needs that we talk about in the drug industry. The reason we talk about them is, of course, that from a business standpoint - and this is a business, for sure - "unmet need" is equivalent to "unmade profit".
The problem is, the reason that some of these big opportunities are unclaimed is that they're not easy to address. As I've said here before, one big problem with antivirals is that there are a very limited number of good targets for drugs. After all, viruses are pretty stripped-down to start with: they do a limited number of things, but they do them very well indeed. Compared to a relatively target-rich therapeutic area like cancer, infectious disease is a desert.
One well-known oasis, though, contains the viral proteases. Many viruses carry these as a key part of their machinery, to help "unpack" necessary proteins from larger precursors. Famously, that's how many of the anti-HIV drugs work, and the same general strategy should be applicable to several other viral types.
Hepatitis C has been one of the big targets for many years now. Various development programs have come and gone, but no one has been able to really nail this one. Vertex is now in the middle of trying to, and as Adam Feuerstein points out, they're really betting a large part of the company on the attempt. Over the next few months, results should start coming out for their PROVE trials of telaprevir (VX-950), and for Vertex's sake, the drug had better work. A herd of competitors, probably led by Schering-Plough, is ready to take over should anything slip.
"Work" is defined as "work well enough so that people don't have to take injections of interferon". That'll depend, as always, on the balance of efficacy and toxicity, and it's the side effect profile that everyone will be watching, since it's widely assumed that the drug will in fact do some good against the disease. The nerve-wracking thing about working for a small-to-medium sized company has always been that your future ends up depending on single events like this, and I wish everyone at Vertex good luck. (Of course, as people at Pfizer will tell you, your future even at a gigantic company can end up depending on the results of one clinical trial - this industry is getting altogether too exciting for a lot of people to take).
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January 10, 2007
Posted by Derek
After yesterday's post, several people brought up the issue of inverted screening cascades. What happens when your compound works better in the mice than it did in the cells? Worse, what if it would have worked in the mice, but you never put it in there because it was so weak in the cell assays?
These kinds of questions are worth worrying about, because we almost never get a chance to answer them. For obvious reasons, the vast majority of compounds that make it into animal models are ones that looked good in the earlier steps. You'd have to think that the hit rate in vivo would be much lower for the dud compounds, but you'd have to be pretty arrogant to think that it would be zero, too.
As I recall (and I was just down the hall when it happened), the discovery of Schering-Plough's cholesterol absorption inhibitor came out of a compound that made it into an animal model and worked well, even though it turned out later to be a loser at the project's original target. (I believe that the in vitro assay was down that week for some reason, but one of my former colleagues will probably set me straight if I'm wrong about that). This sort of thing is food for thought, all right, extreme example though it might be. Even if your compounds don't suddenly hit a new target, there's still room for plenty of surprises in pharmacokinetics and the like.
But it would be unethical just to shove everything into animals, tempting though it is sometimes. And it would cost an insane amount, too - let's not forget that. But I do advocate getting as close to the real disease as quickly as possible. You can really waste time and effort by over-optimizing in vitro, all the time convincing yourself that you're doing the right thing.
Then there's the ultimate question in this line: how many compounds are there that don't work well in the animal models, but would be good in humans? I've wondered about this for many years, and I'm going to go on wondering, because data points are mighty scarce. Human biomarkers might eventually lead to some companies crossing their fingers and going into man with a compound that they expect to outdo the animal models. But it's going to take a lot of nerve. (And here's another complication - those upside surprises that might show up in the animals? How many of those are going to translate to humans, do you think? Not all of them, clearly. . .)
I have no doubt that there are many potentially useful drugs that are abandoned early. False negatives are probably on the shelves all around us. I don't see that as a strong argument against animal use (what, after all, is the alternative?), but it sure isn't a big argument for it, either. It's just, for now, the way things are.
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+ TrackBacks (0) | Category: Clinical Trials | Drug Assays | Drug Development
December 11, 2006
Posted by Derek
Since I've been getting some more less-than-friendly email from Kevin Trudeau fans recently, I thought I'd take a minute to point out something that may not have been generally appreciated. What does the complete failure of a drug like Pfizer's torcetrapib say about the evil-pharma conspiracy theories that Trudeau and his type like to spin?
I mean, think it through: Pfizer spends hundreds of millions of dollars, only to find that their drug has unexpected toxicity. Not the horrible, chemical-weapon toxicity that the conspiracy mongers talk about, mind you: 11 deaths per thousand versus 6 deaths per thousand. But development stops immediately, as it should, the very day that Pfizer's executives get the news. Two days after trumpeting the compound as the biggest thing in their pipeline, they pull it and walk away from the billions of dollars that could have been.
How, exactly, does this fit the Evil Conspiracy worldview? Isn't this, according to Trudeau, exactly the same as all the other drugs already on the market? Why would a company walk away from all that cash just because of a measly little figure like 5 excess patient deaths per thousand? If you believe Kevin Trudeau, everyone who takes anything is being poisoned already.
I know I'm going to regret making this offer, but here goes: I'd be interested in hearing a Trudeau-ite explain this one to me. If you buy into his story, why any drug ever fails in the clinic must be a real head-scratcher, since you'd think that the Evil Pharma Overlords would be able to hocus the data enough to make any sort of toxic junk look good. And this one must seem especially weird.
So tell me, you folks who are convinced that I and all my colleagues in the drug industry are poisoning the world: why did torcetrapib fail? Ground rules: you have to know what torcetrapib is, and you have to have some basic understanding of what it was (in theory) supposed to do. ("Improve cholesterol to try to prevent heart attacks" is enough of an answer for that one - there's a free one for you). And you have to be able to spell Pfizer, and to have read at least one news story about the drug's demise. Have at it in the comments section.
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+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Snake Oil
December 4, 2006
Posted by Derek
One thing that the Pfizer debacle makes you wonder about is: were they trying too hard? Torcetrapib seems to have done a fine job raising HDL on its own - so it was only natural to think of combining it with an LDL-lowering statin. If it turns out, though, that the fatal problems that have turned up were the result of the combination therapy, what then? Will the story be that Pfizer brought the roof down on itself by trying to extend the profitable lifetime of Lipitor?
It turns out that we can answer that question. What if the compound had been developed by a company that didn't have a statin of its own to promote? We don't have to wonder: that's the situation with the Roche/JTT compound. Roche has no statin in its stable. But when you look at the trials they they've been running, well. . .
. . .patients will be randomized to receive either CETP inhibitor (900mg po) or placebo po daily for 24 weeks, with concomitant atorvastatin 10 to 80 mg daily. . .
. . .This study will evaluate the efficacy and safety of three doses of CETP Inhibitor when co-administered with pravastatin. . .
. . .Patients eligible to participate in the extension study will continue on the treatment they were originally assigned to ie CETP inhibitor (900mg po) or placebo daily, with concomitant daily atorvastatin (10 to 80mg po). . .
So why the constant statin drumbeat? There's actually a good reason. As it happens, monotherapy trials of torcetrapib seemed to show that it could lower LDL a bit on its own - but only in patients without high triglycerides. Unfortunately, most of the patient population for the drug has high triglycerides, so there you are. You could always try to make the argument that HDL elevation alone might be beneficial, but no one's quite sure if that would be enough, especially given that lowered LDL has been shown to be beneficial in cardiac outcomes.
Roche, of course, is at the moment just packed with people who'd like to know what (if anything) there is about the statin/CETP combination that could turn awful. I wonder how long it'll be before we find out?
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+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Toxicology
December 3, 2006
Posted by Derek
This is a complete clinical disaster: the world's largest drug company just ditched their potential biggest drug. And this comes two days after a press conference where they talked about how they were planning to submit it for approval within months. Development of torcetrapib, the cholesteryl-ester transfer protein inhibitor designed to raise HDL levels, has been halted. Last week, that sentence would have been the subject of nightmares at Pfizer, but now it's the top of the news. No alarm clock buzz will make it go away. If you're looking for an example of just how difficult drug development is, look no more.
The story broke on Saturday: the 15,000-patient trial that was underway (half on Lipitor, half on Lipitor plus torcetrapib) showed excess deaths in the combination group (82 versus 51). That figure's impossible to ignore or explain away, and now the problem will be to explain what caused it. There are other CETP inhibitors in development, such as JTT-705 (from Japan Tobacco and Roche) and one from Merck as well. Both these companies have just had a tremendous shock, since we don't know (yet) if the patient deaths were due to CETP inhibition itself, the combination of it with the HMG CoA reductase inhibition of the statin, an off-target effect of torcetrapib with the statin, or just an off-target effect of the drug on its own. I'm sure that intense reviews of all the clinical data are going on. Things just got much more complicated.
As for Pfizer, they now have a monstrous hole in their near-term pipeline. Looking back, they've had a terrible run the last couple of years, with a number of promising drugs dropping on them, but nothing compared to this. I don't think anyone's had one to compare with this, at least in terms of the expectations for a drug. I was just talking with some people from the company last week (along with many of my colleagues), looking into employment possibilities. After this, I think we may have to keep moving. I don't think that Pfizer's going to be in the mood for hiring.
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+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials
October 26, 2006
Posted by Derek
The late-stage clinical failure of a small company/big company drug partnership story gets told over and over, and today it was the turn of Renovis and AstraZeneca. Renovis had come up with a candidate (NXY-059) for post-stroke therapy that targeted free-radical oxidative damage. Initial clinical trials were fairly positive, but this latest one, a larger and more rigorous effort, totally failed to demonstrate any benefits for the drug.
They've got plenty of company. I've lost count of the number of neuroprotective drug candidate failures I've heard about during my time in industry. It's humbling, like much of drug discovery is when you look at it closely. I mean, if you get your information from the newspapers or (God help you) television news segments, you'd think that we know just how tissues are damaged after an event like a stroke, which means we know just how to block the process, so all it takes it just sending in some drug to keep it from happening. The folks in the lab coats should be whipping one right out any day now.
Nope. Hasn't worked out. Excitatory glutamate toxicity for example, was all the rage about ten years ago, but a number of Phase II and III wipeouts showed that even if these drugs could work (a big if), they would have to be given very, very quickly, which isn't clinically realistic. Since that run of failures, a new set of standards were developed to try to improve the quality of clinical candidates and trials in the field. The Renovis drug is one of the first to come in under those criteria, but little good did they do in this case. Neuroprotection is hard.
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+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | The Central Nervous System
September 25, 2006
Posted by Derek
Looking through my files, I found a chart which I clipped out of Genetic Engineering News back in late 2004 or so. It's a table of expected drug launches and sales potentials, based on data from Mehta Partners (a well-known and often-quoted pharmaceutical-sector investment and consulting firm).
Now that we're in the last quarter of 2006, this little document has gone from looking hopeful to looking downright creepy. The Y axis is sales potential, divided into eight tiers, and the X axis is a timeline, quarter-by-quarter. Let's take it from the upper left corner and look at the expected big winners from 2005 and 2006:
Macugen: Expected launch 1Q 05, sales potential 1.25 to 1.5 billion. The reality: the launch went off pretty much as expected, but the sales, well. . .they're running at about 10% of that peak estimate. OSI bought the drug's developer, Eyetech, and people wondered at the time what they were thinking. Maybe they're wondering now, too. . .
Indiplon: Expected launch 4Q 05, sales potential 1.25 to 1.5 billion. The reality: oh, dear. Neurocrine is trying to go it alone until they find a new partner, and they're still in there pitching, but this has been a real development disaster.
Let's pause a moment to note that both of these were printed in green type, which the chart helpfully informs us were considered "low risk" at the time. After meditating on the implications of that statement, we move on to:
Edifoligide: Expected launch 4Q 05, sales potential 1.25 to 1.5 billion. The reality: Aaargh. The drug, an oligonucleotide "decoy" designed to tie up a particular set of transcription factors involved in vein graft failure, completely missed its clinical endpoints in a major trial. Bristol-Meyers Squibb dropped it; its developer (Corgentech) went through a near-death experience and emerged with a changed name and an (appropriate) focus on pain management.
Accomplia: Expected launch 1st half 06, sales potential 1.5 to 2.75 billion. The reality: the drug is slowly, slowly creeping into the market in Europe. But no one has any idea of when it might be approved in the US (where most of that money is going to be made, if it ever is), and Sanofi-Aventis has been extraordinarily uncommunicative on the issue. It won't be 2006, that's for sure. Next year? That's what they thought last year. . .
Plavix (for Japanese market): Expected launch 1st half 06, sales potential 1.25 to 1.5 billion. The reality: they made it in May of this year, but the cost has been heavy. And, of course, Plavix and its profits have been making the news for other reasons entirely.
Asoprisnil: Expected launch 2nd half 06, sales potential 1.25 to 1.5 billion. The reality: who knows? Takeda/Abbott and Schering, after some clinical difficulties, have written off 2006 and refuse to say when the uterine bleeding drug might be submitted for approval. Judging from the lack of recent statements, the outlook isn't good.
Not a pretty picture. Just think of how many investment decisions were made based on forecasts like this - it's enough to give you the shivers. But I'm not really blaming Mehta Partners for this - after all, they did what they could with the information they had from the companies involved. And the companies aren't completely to blame, either - many of them really believed that these things were going to work, or at least do better than they have, and they put a lot of their own money on those opinions. No, it's hard to find someone to take the entire fall. Research and development ishard.
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September 17, 2006
Posted by Derek
Novartis has been looking pretty impressive lately. They've announced promising data for their odd immunosuppresive drug Fingolimod (FTY720) in multiple sclerosis therapy. The study isn't very large (255 patients), but the statistics versus placebo look pretty strong. The compound is also showing promise in transplantation, and no doubt the company is looking into other autoimmune disorders as well.
I should note that the drug's target (which appears to be a sphingosine phosphate receptor) wasn't known for many years. It started out as a structural variation on another compound with known effects, it but turned out to have a different (and more useful) profile. This one, if it works, will be more a triumph of persistance and deep pockets rather than drug design, but we'll take 'em where we can get 'em.
The company also has reported data on a new bisphosphonate (Aclasta, aka Reclast) for osteoporosis, notable because it's only dosed once a year. This one had over seven thousand patients, followed for three years, so it's a substantial piece of work, with what appear to be very strong statistics indeed. Novartis appears ready to hammer Fosamax (aledendronate), which has been coining money for Merck for many years now, since they specifically studied a subgroup of patients who were switched from that drug.
One of the notable things about these two drugs is that they're addressing chronic, slow-moving diseases with difficult clinical endpoints. These therapeutic areas are tough to work with in the clinic, and very costly to explore. There are many companies in the industry that would immediately try to outlicense a new osteoporosis clinical candidate rather than try to develop it themselves. You won't see many small biotechs trying to go it alone in areas like this, that's for sure.
So even though I make fun of Pfizer (especially) for being too huge, Novartis is one of the counterexamples. They (along with Merck and GlaxoSmithKline) show that size can have advantages, if you use some of that muscle in the research buildings. FIguring out why some large research organizations are more productive than others, and what part of that isn't due just to chance, has stumped better pundits than me, though. . .
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+ TrackBacks (0) | Category: Business and Markets | Clinical Trials
August 14, 2006
Posted by Derek
The New England Journal of Medicine has published an authoritative wrap-up of the Tegenero/TGN1412 case. This, you'll remember, was the T-cell stimulating antibody trial that went disastrously wrong, sending six first-in-man voluteers into intensive care. (They remained there for one to three weeks, but all of them survived). As minor side effects, this event also sent the company into bankruptcy and the drug candidate straight down the waste chute.
The article makes for grim reading, and I'd be interested to hear what some of the med-bloggers have to say about it. I'm no MD, but the patient charts on admission to the ICU look pretty terrifying to me - pulmonary and renal failure, coagulation throughout the vasculature, severe (and surprising) near-total loss of lymphocytes and monocytes, and much, much more. The phrase "empirical treatment" shows up a lot in the account of their cases, which I take to mean "what seemed reasonable, since we'd never seen anything quite like this before".
As it turned out, the empirical treatment - intubation, dialysis, transfusions, whacking doses of steroids and anti-IL-2 receptor antibodies - seems to have done the trick. This was a "cytokine storm", a known immune phenomenon never observed in such isolation before. (It's usually set off by infection or some endotoxin).
An accompanying perspective article talks about some the issues that were tossed around on this site at the time (a href="http://pipeline.corante.com/archives/clinical_trials/">here - scroll back to March), such as the similarities (and differences) between the CD28-targeting Tegenaro antibody and the comparatively successful ones targeting CLT-4. No one is still quite sure why TGN1412 did what it did, but the authors have a couple of suggestions: for one thing, the affinity of the antibody was probably quite different in humans than in the other species used preclinically. In primate studies, the animal were dosed with the exact same antibody (anti-human-CD28) used in the clinical trial, but it surely has weaker binding to the primate T-cell receptor.
Another factor, which as they point out is not often appreciated, is that laboratory animals (particularly rodents) have much more naïve immune systems than wild-type animals (like us). The clinical trial subjects surely had far more memory T cells, activated by previous exposures to all sorts of antigens, than the mice used in the early models. Perhaps this added to the trouble.
At any rate, we don't seem to be hearing much about how TGN1412 might still go back into the clinic, like we were at the time. The NEJM authors correctly point out that before anyone goes after any of the costimulatory T-cell receptors again, we're going to need to know a lot more than we do now. And even then, you have to think, it's going to require an awful lot of nerve.
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June 26, 2006
Posted by Derek
The latest round in the fit-to-never-end saga of the Vioxx APPROVe trial and the New England Journal of Medicine is here. The journal today released a correction of the orginal paper, perspective article on the statistics of the original study, and some inconclusive correspondence about the (recalculated) risks.
The correction is notable for removing the earlier statements that it appears to take 18 months for risk to develop in the study's Vioxx patient group. And since Merck's made a big deal out of that timing, this has already become the headline story. (I can recommend this overview by Matthew Herper at Forbes).
The perspective article, by Stephen Lagakos of Harvard, may be fairly heavy going for someone who doesn't who isn't statistically inclined. I include in that group - please correct me if I'm wrong here - the great majority of newspaper reporters who might be covering the issue (Herper and a few others excepted). I'm no statistician myself, but I spend more time with the subject than most people do, so I'll extract some highlights from Lagakos's piece.
He has a useful figure where he looks at the two incidence curves for the Vioxx and placebo groups. These are the curves that have been the source of so much controversy: whether or not there was an increased risk after 18 months of Vioxx therapy or not, or if the risk was clear from the outset, and so on. As Lagakos points out, in a slap at Merck's public treatment of the graphs:
"It may then be of interest to assess how the cumulative incidence curves might plausibly differ over time. Doing so by means of post hoc analyses based on visual inspection of the shapes of the Kaplan-Meier curves for the treatment groups can be misleading and should be avoided. A better approach is to create a confidence band for the difference between the cumulative incidence curves in the treatment and placebo groups - that is, for the excess risk in the treatment group."
He does just that, at the 95% confidence level. What it shows is that well past the disputed 18-month point, the 95% confidence band still contains the 0% difference line, and there's room around it on both sides. As he summarizes it:
"The graph shows that there are many plausible differences, including a separation of the curves at times both before and after 18 months, and a consistently higher or lower cumulative incidence in the rofecoxib group, relative to the placebo group, before 18 months."
In other words, the data don't really add much support to anyone's definitive statements about Vioxx risks before 18 months. The 95% band only widens out to a plus or minus 1% difference in cumulative incidence rates at a time between 18 and 24 months. At that point, the upper and lower bounds are both creeping up, though, but the band only rises to an all-positive difference between the two groups at the 30-month mark. By the 36-month point, the last in the study, the 95% confidence band is between a 1% and a 4.5% risk difference for Vioxx therapy compared to placebo.
This doesn't help Merck - in fact, since they've made such a lot of noise about this 18-month threshold, it does them quite a bit of damage. But it doesn't directly help the plaintiffs who are suing them, either - the good news for them is that Merck is looking bad again.
Lagakos goes on to talk about what these demonstrated long-term risks can tell us about short-term ones. Assuming that the risk for, say, 12 months of Vioxx is somewhere between the placebo group and the 36-month figure (a reasonable assumption), these figures will set the upper and lower bounds. The most optimistic outcome, then, is that 12 months of Vioxx does nothing to you at all, compared to placebo, even after another two years of observation. And the most pessimistic outcome is that the Vioxx you took continues to increase your risk the same as if you'd been taking it the whole three years (a damage-is-already-done scenario). Although Lagakos doesn't name these as such, you could call these two boundries the Merck line and the Trial Lawyer line, because they correspond to what each side would fervently like to believe is true.
Combining this with his 95% confidence band plot, you end up with a figure that shows that, within 95% confidence, the excess risk for a 12-month treatment could still range anywhere from zero up to the worst that was seen in the full-term-treatment group. So, because this range still includes the no-effect outcome, you can't conclude that a shorter course of Vioxx was harmful. But because it includes the data of the out-to-three-year group, you can't conclude it's safe, either. And that's really the best you can do. If you're not willing to make those starting assumptions, you can't really say anything about the shorter courses of treatment at all.
This is, I think, a valid way of looking at the controversy, but in the end, it's not going to satisfy anyone. It makes me think that both Merck and the lawyers going after them will either: (a) pick their favorite sections from this article and beat each other with them like pig bladders, or (b) ignore it completely. (I think that the first one is already happening, with the advantage, for now, to the lawyers). If Merck can make a successful counterattack that the data don't show that Vioxx was harmful for shorter doses, either, perhaps they can get something out of this. That depends, of course, on people believing a single word that they say. Which they're making more difficult all the time.
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+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Toxicology
June 20, 2006
Posted by Derek
A comment to the last post asked a good question, one that occurs to everyone in the drug industry early in their career: how many useful drugs do we lose due to falsely alarming toxicity results in animals?
The answer is, naturally, that we don't know, and we can't. Not in the world as we know it, anyway. The only way to really find out would be to give compounds to humans that have shown major problems in rats and dogs, and that's just not going to happen. It's unethical, it's dangerous, and even if you didn't care about such things, the lawyers would find some thing you did care about and go after it.
But how often does this possibility come up? Well, all the time, actually. I don't think that the industry's failure rates are well appreciated by the general public. The 1990s showed that about one in ten compounds that entered Phase I made it through to the market, which is certainly awful enough. But rats and dogs kill compounds before they even get to Phase I, and the failure rate of initiated projects making it to the clinic at all is much higher.
So it's not like we take all these rat-killers on to humans, despite what the lunatic fringe of the pharma-bashers might think. Nope, these are the safe ones that go on to cause all the trouble. "Oh, but are they?" comes the question. "How do you know that your animal results aren't full of false green lights, too?" That's a worrisome question, but there are a lot of good reasons to think that the things we get rid of are mostly trouble. For all the metabolic and physiological differences between rodents, dogs, and humans, there are even more important similarities. The odds are that most things that will sicken one of those animals are going to land on a homologous pathway in humans. And the more basic and important the pathway is, the greater the chance (for the most part) that the similarities will be still be strong enough to cause an overlap.
But there are exceptions in both directions. We know for a fact that there are compound that are more toxic to various animal species than they are to humans, and vice versa. But we play the odds, because we have no choice. Whenever a compound passes animal tox, we hope that it won't be one of the rare ones that's worse in humans. But when a compound fails in the animals, there's simply no point in wondering if it might be OK if it were taken on. Because it won't be.
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+ TrackBacks (0) | Category: Animal Testing | Clinical Trials | Toxicology
May 18, 2006
Posted by Derek
A quick request: I'd be interesting in hearing anyone's experiences with any of the various adaptive clinical trial designs. I'm starting to work on an article on the subject, and thought it would be worth hearing some real-world experiences. Feel free to e-mail me or use the comments - thanks!
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May 3, 2006
Posted by Derek
So, as mentioned, the DC Circuit Court of Appeals came down with an interesting ruling (PDF available here). Here's the background of the case, as summarized in the majority opinion:
The Abigail Alliance for Better Access to Developmental Drugs ("the Alliance") seeks to enjoin the Food and Drug Administration ("FDA") from continuing to enforce a policy barring the sale of new drugs that the FDA has determined, after Phase I trials on human beings, are sufficiently safe for expanded human testing (hereafter "post-Phase I investigational new drugs"). More specifically, the Alliance seeks access to potentially life-saving post-Phase I investigational new drugs on behalf of mentally competent, terminally ill adult patients who have no alternative to government approved treatment options . . .
The Alliance contends that the FDA's policy violates the substantive due process rights to privacy, liberty, and life of its terminally ill members. The complaint presents the question of whether the Due Process Clause protects the right of terminally ill patients to decide, without FDA interference, whether to assume the risks of using potentially life-saving investigational new drugs that the FDA has yet to approve for commercial marketing but that the FDA has determined, after Phase I clinical human trials, are safe enough for further testing on a substantial number of human beings. . .
As you may be able to tell from the direction that's taking, the majority opinion says that yes, the FDA does violate due process in these cases. They're reasoning from the Glucksberg case, in which the Supreme Court laid down some guidelines for such claims, but not being a con-law scholar, I'm not qualified to address this line of thinking. They also work from precedents which hold that patients have a due process right to refuse life-saving treatments, and hold that there's a similar right to access potentially life-saving ones. "In both cases", the majority opinion says, "the key is the patient's right to make her decision about her life free from government interference. . .the Alliance seeks for its members the same right of access enjoyed by those terminally ill patients lucky enough to secure a spot in Phase II trials. Accordingly, we hold that the district court erred in dismissing the Alliance's complaint . . ."
I'm torn by this line of reasoning. My libertarian streak likes the talk about being free from government interference, but my drug-industry experience keeps suggesting some practical difficulties. (For one thing, if we're telling the government to get lost, why mandate Phase I trials in the first place?) There's a pretty strong dissenting opinion from the recently-appointed Justice Griffith that goes into these problems. First off, he has a problem with the line of reasoning that the majority used:
. . .It does not help the majority's cause that the Supreme Court has rejected several similar challenges. . .To be sure, the Supreme Court has not addressed the constitutional argument raised by the Alliance. But contrary to the tradition asserted by the majority, there is a tradition of courts rejecting arguments that the Constitution provides an affirmative right of access to particular medical treatments reasonably prohibited by the Government.
It's the last paragraph of his dissent that I find rather persuasive, though:
The majority's new right to procure and use experimental drugs raises a number of vexing questions that are now constitutional issues, potentially insulated from the tug and pull of the political process. If a terminally ill patient has such a right, are patients with serious medical conditions entitled to the benefit of the same logic and corresponding access? If an indigent cannot afford potentially life-saving treatment, would the Constitution mandate access to such care under the right recognized by the majority? Can a patient access any drug . . .if she believes, in consultation with a physician, it is potentially life-saving? Would the majority's right guarantee access to federally-funded stem cell research and treatment? Perhaps most significantly, what potential must a treatment have in order for the Constitution to mandate access? Because the majority does not answer this last question, the District Court faces an impossible task on remand.
These are just the sort of problems that I think are glossed over by Justices Ginsberg and Roberts. Where do we draw the line? There are all sorts of things that make it through Phase I that wipe out in Phase II and beyond for lack of efficacy. It's all very well to talk about potentially life-saving therapies, but that potential is, in many cases, pretty damn well hidden. What sort of Phase I study is enough to trigger this right to treatment? (And who pays for it, for that matter, and how is that figure arrived at?) And it's important to realize that Phase I only studies acute safety, for the most part. Keep in mind that compounds drop out in Phases II and III for safety problems that only showed up in larger samples and longer trials. The threat of lawsuits is bad enough already, with drugs that have made it through a lot more than Phase I. How are we going to fare with even earlier compounds?
Justice Griffith is correct in seeing this as a practice that can only expand. The demand is certainly there. I'm more willing than I was a few years ago to see what a safety-trial-only system for pharmaceuticals would look like, but this isn't, to my mind, the way to get there. We're not running Phase I trials in a such a way that they can stand on their own for drugs to go right into patients - perhaps not even patients that are dying. If we want to change that, let's change it - but from the ground up, not by going through a hybrid regime that might give us the worst of both approaches.
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March 26, 2006
Posted by Derek
Here is the voice of someone who is under a great deal of stress and is not thinking clearly:
Thomas Hunig, the German professor who founded the TeGenero company, said he still hoped the drug, TGN1412, could be brought to the market.
He said he was devastated that the six men were taken ill but said that he was "not going to give up".
Professor Hunig said: "I do hope TGN1412 can come to the market. This tragic incident does not exclude the theoretical application of TGN1412 some time in the future.
Let me be one of the voices informing Prof. Hunig: there is an almost overwhelming likelihood that his drug will never again come near a human being, much less near the market. Pharmaceutical companies drop compounds all the time that show far less severe side effects than this in rats - a disaster like this in man is the end of the line. That's not to say that the whole idea of a CD28-derived drug is dead (although it's going to be slow going after this), but TGN1412 is not going to be it. Go look for a clinical supervisory board - outside of North Korea, that is - that would allow another dosing in humans. Good luck.
Says Prof. Hunig:
""I don't want to hurt anybody in any way. I don't want to come across as a crazy scientist who wants to save his baby despite the victims he has taken. Definitely not."
Someone needs to point out that he's doing a pretty poor job of not coming across like that. Talking about the wonderful science involved and all the work that's gone into the project doesn't help, either. Arguments about how much time and effort have been spent are irrelevent - that's a sunk cost if ever there was one. And the science is no doubt nifty in the extreme, but our scientific understanding of the drug and its effects is clearly a bit. . .incomplete, which places an upper bound on just how nifty it can be.
I feel like the guy in the Monty Python sketch: Dr. Hunig, your drug has ceased to be.
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+ TrackBacks (1) | Category: Clinical Trials
March 20, 2006
Posted by Derek
When everyone first heard about the TeGenaro/TGN1412 Phase I disaster, the immediate question was whether it could have been prevented. As mentioned before, the main problem I had was that the volunteers seem to have been dosed fairly quickly, rather than waiting longer to see how the first patient did. That alone would have contained the tragedy to one person. But even then, we'd all be asking how that one case could have been avoided. I'm not well-versed enough in immunology to say for certain, but according to the Times of London, there's some earlier work that might have given everyone pause if it had been sufficiently appreciated.
They quote Angus Dalgleish, a British professor of immunology, as saying that he was amazed that the TGN1412 trial had been allowed, considering that at the ASCO meeting last year, a team from the National Cancer Institute presented the results of a study of an anti-CLTA4 antibody in cancer patients. They didn't see the catastrophic results of TGN1412, but the trial was rough enough. Nearly half of the patients in the high-dose group saw a harmful immune response - most of them recovered, but one needed surgery. That target is another receptor on the surface of T-cells, and it's involved in the same general activation/deactivation pathway that CD28 (TGN1412's target) is. CLTA4 activation blocks the activating effect of the CD28 pathway - in fact, it's only induced after the CD-28 receptor has been stimulated, and it seems to come on in order to damp it down. Immunology's full of these reverse-reverse things.
So one net result of either approach is to enhance CD28 signaling - TeGenaro's antibody strongly activates CD28 directly, and Medarex's inhibits its inhibitory pathway. Still, the two therapies were aiming at opposite endpoints: TeGenaro was mainly hoping to enhance the activity of regulatory T-cells (which would then decrease autoimmune activity) while the NCI group was hoping to generate a stronger overall immune response against renal tumors. Of course, it looks like the "stronger overall immune response" part of this pathway wins out.
Here's the abstract from the meeting, which tells us that the anti-CLTA4 antibody they're talking about is MDX-010, from Medarex. They've been working on it for years, and have (for example) reported similar results in 2004 in a study against metastatic melanoma. Their first attempts in this area were reported in 2003 in PNAS.
And it's still being studied - in fact, it's one of the more advanced things in Medarex's pipeline. Here's a trial that's in recruitment right now for late-stage melanoma, in combination with a potential melanoma vaccine, MDX-1379, and here's one for prostate cancer, in combination with androgen therapy. They wouldn't have made it to Phase III with this if they'd constantly seen the kinds of effects reported by the NCI group.
So the Times article is semi-right, although it gives the impression that there's this one study from last year that should have definitely raised the warning. But anti-CLTA4 therapy has been around for several years now, and it's well-represented in the literature. And it's still in advanced clinical trials, to boot. This is the sort of thing that both TeGenaro and the review board that approved its study would have been well aware of, and would have taken into account. It now appears that blocking CLTA4 is something that has to be approached with caution, while activating CD28 directly is disastrous, but I'm not sure that was obvious before this trial.
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+ TrackBacks (0) | Category: Clinical Trials
March 17, 2006
Posted by Derek
I don't often do updates on the weekends around here, but I wanted to point out this update from the BlackTriangle blog in the UK on the TGN1412 antibody trial. Anthony Cox has all the latest information from the medical and the British press, including many details which haven't been mentioned in most reports.
For one thing, it's now being said that not only were the primate tests clean, but these first-in-man doses were set at 1/500th of the primate dose. As the latest articles in Nature and New Scientist show, there are plenty of immunologists around who are expressing doubts about TeGenaro's therapeutic approach. But it's hard to say how much of that is ex post facto - after all, a review board signed off on this, and they presumably included some competent people.
My guess is that it's going to be a long time before anyone tries another immunomodulatory antibody in humans. . .and it wouldn't surprise me to learn that it's going to be more difficult to recruit for many Phase I trials in general. That isn't good.
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+ TrackBacks (0) | Category: Clinical Trials
March 15, 2006
Posted by Derek
(Update, March 17: See also later entry here.
There's been a severe problem with the first-in-man dosing of a new antibody in England. TeGenero, a small company in Germany, was testing their most advanced candidate, TGN1412, which is a monoclonal antibody against CD28. That's a glycoprotein on the surface of many types of T cells, and it seems to be extremely important in several mechanisms that activate them. Accordingly, finding something to modulate its activity would seem to be a promising way to attack autoimmune and other inflammatory diseases.
But when TGN1412 went into six volunteers in Phase I this week, all of them ended up in the hospital, and two of them are gravely ill. The press reports make it seem like some sort of anaphylactic reaction, but it sounds like they're not treating it like simple anaphylaxsis, so there must be something more going on. That's a very surprising outcome, since if anything you'd expect the immune response to be downregulated in response to the drug. (Update: this is only partly true - see end of post.) But there's an awful lot about human immunology that we don't understand, to put it mildly. TeGenero says that:
"These events were completely unexpected and do not reflect the results we obtained from initial laboratory studies which enabled us to progress investigations into human volunteers. . .The drug was developed in accordance with all regulatory and clinical guidelines and standards. In pre-clinical studies, TGN1412 has been shown to be safe and the reactions which occurred in these volunteers were completely unexpected”
I have to believe that this is correct. Neither TeGenero, the company conducting the trial for them (Parexel), or the British regulatory authorities have anything to gain from taking a drug into humans that had shown severe effects in animals, despite rumors to the contrary that seem to be going around in England. There's a breathless report in The Independent (I know, that's redundant) to this effect:
"The men, who were offered £2,000 to take part, were recruited by the US company Parexel, for the trial in its 36-bed unit on the Northwick Park hospital campus. They reportedly signed a contract warning that side-effects in rats and mice included "increased urine volume, decreased faeces, redness of the skin". Dogs experienced "increased heart rate and decreased blood pressure"."
I have news for the Independent, though - if we killed off every drug that showed effects like this, we'd never take anything into humans at all. The dog cardiovascular effects would be worth checking out in detail before going forward, naturally, but that's what dogs are for, to show you cardiovascular side effects. And I note that none of these effects have anything to do with devastating immune reactions. If that's all that TeGenero saw in the animal studies, I can see why they were shocked at the human results.
But antibodies are powerful - no one should forget that. Every antibody therapy has a small but real risk of setting off something terrible, and if you're targeting the immune response itself, well, the risk just goes up. The immune system is a bit like demonlogy: don't call anything up that you don't know how to send back down. Unfortunately, we don't know many effective spells yet.
My sympathies go out to those affected and their relatives and friends, of course. They shouldn't, as far as I can see, torture themselves thinking that this could have been foreseen. I hope that everyone makes it through.
Update: I've inadvertently glossed over some of the mechanism of TGN1412. Its binding to CD28 actually sets off the receptor's signaling - it's an antibody agonist. This makes it a T-cell activator, but it seems to particularly activate the class known as regulatory T-cells. These are modulators of the activity of other classes of T-cells involved in autoimmune responses.
So there's a way that things could have gone wrong - if TGN1412 isn't quite as selective in the real-world human immune system as it is in the animal models. Alternatively, even if it is selective but the spectrum of human T-cell response to CD28 ligands is intrinsically somewhat different, things could have gone off the rails very quickly. There appears to have been little reason to suspect either of these possibilities going into the clinic. We're going to learn something important about human immunology from this incident, but this is certainly a hell of a way to do it.
More: BlackTriangle has a roundup of some reactions in Britain.
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+ TrackBacks (2) | Category: Clinical Trials
January 19, 2006
Posted by Derek
I currently have a piece up on the Medical Progress Today site, about what an 18th-century minister has to offer modern clinical trial design. (Statistics groupies will have already guessed the subject matter from that clue)!
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+ TrackBacks (0) | Category: Clinical Trials
January 15, 2006
Posted by Derek
The FDA has released some new guidelines intended to make it easier to get drugs into the earliest stages of human trials. Considering how often we fail at those stages of development, anything that increases our number of shots on goal is good news.
The first part of the new approach is a set of official standards for what are known as "Exploratory INDs". (An IND (Investigational New Drug) application is the mound of paperwork that you have bring to the FDA in order to dose human subjects). What they're doing here is making it easier to test limited numbers of people at smaller doses, just to see if you can narrow down your drug candidates with some realistic data. This "microdosing" approach has been tried in Europe for the last few years, and it's definitely time the the agency laid out the rules for its application over here.
I think that for the most part the key data obtained in these trials will be pharmacokinetics - you could take three or four roughly equivalent drug candidates in and see which one had the best blood levels and distribution before committing yourself. (Fancy mass spectrometry techniques can allow you to see very small amounts of compound or metabolites in samples these days). This approach will also work out well if you have some sort of clinical marker that you trust. Sub-effective doses of the drug candidates could still point you to which ones are having the effect you want, if the signal-to-noise ratio of your surrogate marker is good enough. Imaging studies would be another good use for these trials.
If I'm reading their guidelines right, the FDA can let you go into human microdosing with only rat data. That sounds either exciting or alarming, depending on your point of view, but given the low doses involved, I think it's a good thing. For dosing up to pharmacologically active levels, though, they want the traditional rat/dog safety package, which is certainly reasonable.
The second part of the new standards are for manufacturing drug substances for these early trials. What they're doing, it seems, is loosening up the "Current Good Manufacturing Practice" rules a bit for small exploratory studies. This is mostly going to help out the smaller companies and (especially) academia. CGMP is no fun to follow if you're not set up for it, and it is rather odd to make the five-gram-batch folks jump through almost the same hoops as the five-thousand-kilo people. For the larger companies with lots of CGMP capacity, though, I don't see this change making much of a difference.
It'll be interesting to see what sort of coverage this gets in the press - assuming it gets much at all, that is. There's room for a sufficiently motivated complainer to go on about the FDA loosening up on its regulation of unknown toxic drug substances, poisoning America, slippery slope, etc. If any readers spot someone taking this tack, forward the reference to me, and I'll reward you with a laudatory mention here. It'll look great on your CV. Trust me.
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+ TrackBacks (0) | Category: Clinical Trials
December 14, 2005
Posted by Derek
Pfizer's going to pull out the stops and spend up to $100 million to try to show that their COX-2 drug Celebrex is worth it. And they're going right to the source: the Cleveland Clinic. The study will be run by Steve Nissen, and he's forbidding the investigators under him from accepting money from all sides: drug companies, securities firms, trial lawyers, the lot. Celebrex will be compared head-to-head in high-cardiac-risk arthritis patients versus naproxen and ibuprofen (no aspirin, because of the near-certainly of bleeding problems at the doses involved).
A disproportionate number of arthritis sufferers are in the higher-risk groups, so this would seem to be an appropriate patient population. They're going to need to round up 20,000 of them, though, which is going to take some time, and the whole study won't finish up until 2009, at the current best guess. (Celebrex doesn't come off patent until 2013, in case you're wondering). I hammer on Pfizer a lot around here, because I think they're too big to be effective as a company. But I have to say that this is one case where being humungous (and, for now, full of cash) is an asset. This is going to be a long a costly trial, and you can count the drug companies capable of funding it on one hand.
Merck's taking a few shots in the press today, since they'd said that a study like this basically couldn't be run. No one would do it unless they felt they had to, that's for sure. But the loss of Vioxx as a competitor may have made this study possible for Pfizer, in that it could allow them to earn back the expense more easily. Celebrex first has to show that it doesn't have the cardiac risks associated with Vioxx (which are tiny, but real). If it doesn't do that, it's dead. But if it makes it past that, and actually works better than the cheaper alternatives, Pfizer will own the market. They'd at worst dominate it over some other COX-2 stragglers like Novartis's Prexige, which I don't think has even been filed for US approval yet. Novartis is on that short list of companies that can afford this kind of clinical expense for a single trial, and they may have to consider doing a big head-to-head with Celebrex if they want to stay in the market. Smaller studies aren't going to cut it in the COX-2 area any more.
Comments (17)
+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials
December 1, 2005
Posted by Derek
Many people might not have noticed Rigel Pharmaceuticals until their stock fell down the stairs today. We'll pause a moment to consider the fate of this upbeat analyst, whose clients were long-and-wrong if they followed his recommendation to buy the stock a couple of weeks back. (There's a case to be made for buying the stock now that it's been hammered, but that's a topic for another day).
Rigel had taken an inhibitor (R112) of a kinase enzyme called Syk into the clinic for nasal allergies, and they missed their endpoints by a mile. They ran about 400 patients through a seven-day course of either their inhaled drug, a placebo, or Beconase, an inhaled steroid from GSK. Beconase was significant against placebo, but R112 wasn't.
But what must have been especially hard to take was that they'd already run an earlier trial with over 300 patients, where R112 seemed to work pretty well versus placebo. These results were a big part of why Rigel's stock was as high as it was. What went wrong?
We can start with the clinical trials themselves. I'm going to stipulate that today's result was correct, and that the compound did indeed fail. I think the two trials were measuring similar endpoints, so one possibility is that the earlier one was just run incompetently. I'm not in a position to say, and you'd like to rule that explanation out, but it's a possibility. What looks like a good P value can cover a multitude of sins.
A second level of explanation is the drug's mechanism. It's hard to believe that the underlying biology is completely mistaken, though. Syk is a reasonable target for allergy. It's involved in the signaling inside mast cells (and some other members of the immune system) after they're stimulated by an antigen, and blocking it would seem to be just the ticket.
I'm going to go with a hybrid theory. The first efficacy trial was only a two-day evaluation. Perhaps there's a compensatory mechanism that kicks in and cancels out the effect of the drug on repeated dosing? That would make this failure a team effort between the biology and the design of the first trial, and that's what seems most likely to me in the absence of other data. Fortunately for Rigel, this wasn't a particularly long or expensive trial - they announced only back in August that they'd enrolled their first patients. It's a nasty failure, but they got out of it relatively cheaply.
And they have deals with a range of other companies for other kinase inhibitor projects. One of them, though, is of particular interest after today's news. Pfizer is a partner of theirs for their next-generation Syk kinase inhibitors, this time aimed at the asthma market. Is my compensatory mechanism guess correct, and does it apply to that therapeutic area, too? Pfizer will be paying to find out. . .
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+ TrackBacks (0) | Category: Clinical Trials
October 20, 2005
Posted by Derek
I wrote a brief wrap-up on the FDA's concerns about the new Bristol-Meyers Squibb / Merck diabetes drug Pargluva (muraglitazar). It's officially "approvable", but the FDA wants more cardiovascular safety data before it can be sold. But just this morning the JAMA web site has rushed out an article from a team at the Cleveland Clinic on the drug's clinical trial data. (Accompanying editorial here). It's very disturbing, in more ways than one.
At the time, I said that "By my reading, the cardiovascular event profile of the drug subjects looks slightly but noticeably worse than that of the placebo group. There are plenty of possible extenuating factors, and the number of patients involved is small, but I think that this is going to be a problem for the companies during the FDA hearing. Here's the list of questions the FDA has proposed for discussion (PDF again), and you can see that edema and cardiovascular safety loom large. . ." That's fine, as far as it goes, but I didn't dig far enough into the data, and I wonder if the advisory panel did, either.
What the authors of this new paper have noticed is the number of patients taking a low dose of muraglitazar - lower than the companies ended up seeking approval for. They didn't show enough beneficial effects for that dose to be worthwhile, but since muraglitazar's cardiovascular problems appear to be strongly correlated with dose, these patients also had no cardiovascular events at all. The problem is that these patients were included in the risk calculations, and that makes the drug look safer than it would be under real-world conditions.
The Cleveland group's recalculations now put the risk of cardiovascular events with clinically relevant doses of muraglitazar at 20% higher than the placebo group, and at 67% higher than the combined placebo-standard of care group. (That includes patients treated with pioglitazone, a PPAR-gamma compound that's been approved for some years now). Put that way, this sounds like a huge increase, but it's important to remember that both of these figures, though real, are pretty small. The placebo group had about 34 events per 1000 patient years, and the drug treatment group, in the new analysis, had around 40 events. So, back-of-the-envelope, for every thousand patients on muraglitazar, you might expect an extra 6 cardiovascular incidents per year. The similarities to the Vioxx data are not hard to spot, and in fact the authors of this paper have been very much involved in that controversy as well.
But I'm not going to push that comparison. This is a different case than Vioxx, a drug that (for many patients) really does seem to do more than existing compounds can. The problem here is that muraglitazar (and all the PPAR alpha-gamma compounds that have gone into development) was supposed to be better for cardiovascular outcomes than the plain PPAR-gamma compounds that are already out there. Needless to say, it was also supposed to be better than a damned placebo, which it isn't. The entire dual-PPAR-agonist idea is in trouble. The whole point of adding PPAR-alpha activity was to improve blood lipid profiles, and pretty much the whole point of doing that is to improve cardiovascular health. The first part is working, but the second part, the important part, just doesn't seem to be happening. Looking at the data, I find it hard to imagine why anyone would take muraglitazar over the exisiting therapies, when there's no evidence for what is supposed to be its main advantage.
As if that weren't bad enough, there's also a background worry about cancer rates with PPAR compounds. The muraglitazar data aren't totally reassuring on this front, either. Other compounds in this class died because of carcinogenicity in long-term rodent studies, and muraglitazar is the first compound to actually make it past such studies. But the data submitted to the FDA show that rats given the compound at high doses do indeed show bladder cancer - it just seems to be less of a problem than it was for the earlier compounds from Merck, Kyorin, Novo, Dr. Reddy's, et al. For a marginal compound, though, this is a real issue.
I don't necessarily think that the people at BMS (and Merck, a latecomer to this compound) were sitting around wondering about just how to snow the FDA. But it would certainly cheer me up if I could rule that out, wouldn't it, now? At the very least, the companies weren't being as critical of themselves as scientists have to be, and they've committed a mistake that would flunk a PhD candidate or get a paper tossed back from a well-refereed journal. Something has gone seriously wrong here. We're supposed to be better than this.
What on Earth were they thinking, submitting data in a way that makes it look like they were trying to pull a fast one with the cardiovascular risk factors? Now, of all times? Who knows, maybe people at BMS had just convinced themselves that things were fine, somehow - the capacity for human self-deception is limitless. But didn't anyone at Merck turn pale and have to sit down when they saw these numbers? I didn't realize how bad the situation was back in September, but even then I wondered about this, saying: "I can't predict which way this one is going to go, and neither can anyone else. But post-COX-2 is a bad time to be coming to the FDA with possible low-level cardiac risks in your clinical data. . ." Now that the risks look even worse, I'm baffled. You people want the sky to come down on your heads?
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+ TrackBacks (0) | Category: Clinical Trials | Diabetes and Obesity | The Dark Side
September 22, 2005
Posted by Derek
One of the other incorrect lessons that people might take away from the press accounts of the antipsychotic trial is that drug companies have been comparing their medications to placebo too often. And why would you do that unless you were scared that you wouldn't be better than the competition? What's with these people, anyway?
Well, there are fields where placebo-controlled trials take place, and fields where they don't. It depends on the disease and options available to treat it. Cancer trials, for example, are very rarely run against placebo, unless there's just nothing left to do. (You'll see this with drugs that are meant for late-stage patients or those who have failed existing therapies.)
Antipsychotics are generally compared to an existing standard of care, because it's unethical to leave someone untreated when they've already been diagnosed as schizophrenic. The problem that the CATIE trial uncovered, though, is that many trials are run against haloperidol (known as Haldol). That's a typical older drug, and companies have been showing that they have better efficacy and fewer side effects than it does. (It's known to have significant problems with tardive dyskinesia, among other things).
But now we know that perphenazine is a better standard among the older drugs, mostly because of fewer side effects. I don't think that anyone is going to be able to run a haloperidol-controlled trial for a new antipsychotic. Now you're going to have to beat perphenazine, which will be a higher standard. The newer drugs have been able to get rid of the so-called extrapyramidal side effects, like tardive dyskinesia, but they haven't been able to increase their efficacy that much. That's not going to be enough any more - the ante has gone up in the field of schizophrenia therapy.
Now, if you think that your new drug is really going to cream the competition, running a trial against them is a smart move. There's no better way to persuade people to prescribe your drug than to show that it's clearly better than what's out there now. Another time you see head-to-head trials is when a company is making a run at the leader in a given category. The various attempts to out-do Lipitor are good examples, not that any of them have succeeded. But there really wasn't a clear leader in the antipsychotic area, and thus no real target to try to knock down. I'd bet that the companies involved strongly suspected that their own drugs weren't head and shoulders above everything else, either. This is the perfect situation for an outside agency like the NIH to do a comparison study, because if you're waiting for the companies involved to do it, you're going to have a pretty long wait.
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+ TrackBacks (0) | Category: "Me Too" Drugs | Clinical Trials | The Central Nervous System
September 21, 2005
Posted by Derek
You've probably seen the headlines about the recent NIH-sponsored "CATIE" study comparing five anti-psychotic medications. The result, which is what made the whole thing newsworthy to the popular press, was that it was hard to distinguish among them, with the oldest generic working as well as (or better than) the newer drugs.
But I think that people outside of the medical world are going to learn the wrong lessons from all this. Does this study mean that everyone taking anti-schizophrenia medication should switch to the old generic? Not at all, although if they need to try a different medication, they should definitely consider it. Does it mean that all these newer drugs are unnecessary? No, again. There's an awful lot of patient-to-patient variation in central nervous system drugs. Says the study's principal investigator, Dr. Jeffrey Lieberman of Columbia:
"There is considerable variation in the therapeutic and side effects of antipsychotic medications. Doctors and patients must carefully evaluate the tradeoffs between efficacy and side effects in choosing an appropriate medication. What works for one person may not work for another."
But I think that this study does make clear that the newer antipsychotics aren't as good as they should be. The field is a tough one, as I know from personal experience, having played a small role in helping a company spend I've-no-idea-how-many millions of dollars to find out that a potential schizophrenia medication didn't do squat. There's a lot of room for improvement, and we haven't been able to improve things very much.
It's important to emphasize that this was a surprising result. No one expected the side effect profiles of the four "second-generation" drugs to be so similar to the older one (perphenazine), and so similar to each other. That's one reason that a study like this is so valuable - huge clinical trials that tell you something that you already knew aren't too wonderful. I think that this is an excellent thing for the NIH to be doing. Tomorrow: what this says about head-to-head trials in general.
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+ TrackBacks (0) | Category: "Me Too" Drugs | Clinical Trials | The Central Nervous System
September 8, 2005
Posted by Derek
There's a lot of metabolic disease news this week from the FDA. We'll get to the inhaled insulin decision next week, but I thought I'd try to catch the next one before it happens. On Friday they're reviewing the first PPAR alpha-gamma ligand to make it to the regulatory approval stage, Bristol-Meyers Squibb's unmelodious "Pargluva" (muraglitazar), which sounds more like a disease than a drug. This is a therapeutic class that everyone had great hopes for a few years ago, with most of the big players competing at full speed. In theory, this combination should help with insulin sensitivity, cholesterol, and triglycerides all at the same time, which you'd think would be just what an overweight type II diabetic patient (and there are many) might need.
But development of these compounds has been a nightmare, with bad and unexpected toxicity cropping up deep in the late-phase work. BMS (and their late-arriving partner Merck) managed to get past those rapids and through clinical trials. But their drug shows a side effect that all PPAR-gamma drug programs have had to worry about, namely edema.
They also seem to have some (perhaps related) worries about cardiovascular events, which are broken out into completely separate categories in the FDA briefing document (big PDF). That document, whopper thought it is, is worth a look if you want to see what it's like to decide whether to approve a new drug or not. I wouldn't like to have to explain it all to a lay jury, that's for sure. No doubt a few whoops and hollers, along with the occasional choked tearful expression, would help.
By my reading, the cardiovascular event profile of the drug subjects looks slightly but noticeably worse than that of the placebo group. There are plenty of possible extenuating factors, and the number of patients involved is small, but I think that this is going to be a problem for the companies during the FDA hearing. Here's the list of questions the FDA has proposed for discussion (PDF again), and you can see that edema and cardiovascular safety loom large. I can't predict which way this one is going to go, and neither can anyone else. But post-COX-2 is a bad time to be coming to the FDA with possible low-level cardiac risks in your clinical data. . .
By the way, with thousands of people involved in the clinical studies, there are bound to be some. . .unplanned adverse events. I quote without comment from the briefing document linked to above, just in case you thought (for some odd reason) that running clinical trials was easy. . .
"Subject CV168021-29-21 was a 44-year old white maile with a 3-year history of diabetes and history of overweight, hypercholesterolemia and impotence. On study day 29 the subject died as the result of a gun shot wound.
Subject CV-168006-5-3 was a 62-year old white female with a history of hypertension, smoking, and alcohol use. On study day 112 she died in a motor vehicle accident. Her car was stopped at a light when struck by a truck. The investigator considered the event not likely related to study drug."
Yes, one would, on the whole, conclude that it wasn't . . .
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+ TrackBacks (0) | Category: Clinical Trials | Diabetes and Obesity
August 23, 2005
Posted by Derek
I'll tell you a company that's been watching what's happened to Merck and thinking hard about it: Sanofi. Well, OK, everyone in the industry has been looking at Merck's situation and shuddering, but I suspect the people at Sanofi(-Aventis) are especially jumpy. Why? Rimonabant.
Rimonabant, which will come to the market next year (most likely) under the name Acomplia, is one everyone's short list of potential multibillion dollar drugs. It'll be the first new drug treatment for obesity in years, and it's the first one ever with its mechanism of action (antagonism of the CB(1) receptor). It has potential for many sorts of addiction therapy as well. Although there's room to argue about just how effective it is compared to existing therapies, and there's some concern about how many HMOs will pay for it, there's little doubt that it's going to sell like crazy.
And there's the worry. There is absolutely no way that large enough clinical trials could be run on a drug like this to predict everything that might happen when millions of people start taking it. Can't be done. You can get down to a margin of safety that will get you past the FDA, but that isn't enough, now is it? No, if one person out of a hundred thousand has a nasty side effect, that's enough to bring the sky down on your head. And we can't test down to the level of one-per-hundred-thousand effects.
A fine situation, isn't it? This same argument applies to every new drug, naturally, but especially to a groundbreaking compound like rimonabant. That's just what we needed, an incentive not to be first in class with a new drug. What, exactly, are we doing to ourselves?
Comments (3)
+ TrackBacks (0) | Category: "Me Too" Drugs | Clinical Trials | Diabetes and Obesity
June 30, 2005
Posted by Derek
Gruntdoc wonders about why a particular combination therapy isn't available yet. Skin infections with methacillin-resistant staphylococcus aureus (MRSA), which I hope I never come any closer to experiencing, are treated with one of several antibiotic combinations, but they're all administered as separate drugs.
The answer is what you might suspect: the FDA would want clinical trials of the single-dose combination, just to make sure that things work the way that they're supposed to. Any company developing the combo would have to recoup those costs, not to mention the costs of then beating the drum for the idea that the new combination is a better idea. But the antibiotics in question are generics, which means that there could be some real cost-containment issues over the use of a more expensive combination.
But we have a rather close example at hand: the recently approve BiDil. (Here's the package insert, in PDF format.) That's a combination of two generics, too, which (famously) shows far better effects in the black population than it did in general clinical trials. Nitromed, the developer of the therapy, had to run some pretty reasonable-sized ones, and they spent a lot of money in the process.
They started by establishing that the blood levels of the two drugs were reasonable when given in combination, and went on to a group of 186 male patients. That trial (with 273 in the placebo group) didn't show a benefit, but hinted at one in the black subjects. The company also ran an 804-patient trial against enalapril, and saw the same trend, which led to the definitive 18-month trial in 518 black patients (with a roughly equal number in the placebo arm.) Keep in mind, this is all for two drugs whose individual efficacy was well-studied.
Note added after original post: Nitromed was after something more than the individual efficacy of each drug. Their hypothesis was that the combination would make the blood-pressure-lowering effect much more pronounced, and that this would translate into clinical benefit as seen in eventual mortality. Why this only seems to be the case in the black population is a head-scratcher. The situation for combination antibiotics would be simpler. So. . .
A combination antibiotic trial wouldn't be as long, or as expensive. But it wouldn't be negligible, either, and it's likely that some companies have run the numbers and decided that the investment would be unlikely to pay off.
Comments (3)
+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Infectious Diseases
March 22, 2005
Posted by Derek
Speaking of cancer trials, I mentioned the other day how they tend to be smaller than those for many other diseases. But that doesn't mean that they're always easy to run, as a search for "clinical trial design oncology" will show. Note the number of people offering to help you out, via seminars, consulting visits, books, and entire journals devoted to the topic.
The problems start early. Patient recruitment is a big problem for many of the less common types of cancer, and it's getting to be a problem for the better-known ones, too. If you look at all the therapies that are being aimed at breast cancer, for example, and run the numbers, it looks like there aren't enough breast cancer patients in the US to fill out all the trials that would be needed. Cost is, of course, a big reason why a lot of clinical trial work is being done overseas these days, but access to a new pool of patients is a factor, too.
Which brings up another complication - do you want patients who've tried other drugs? That depends on where you're targeting your therapy. If you hope for it to be a first-line drug, you probably want patients that are newly diagnosed. There's a steady supply of those, but not everyone who's newly diagnosed is going to be willing to participate in a clinical trial, not when there might be more proven treatments available. The worst case is when you're looking for drug-naÔve patients with advanced types of cancer. That's feasible (in theory) for some of the ones that creep up on you (like colorectal cancer), but next to impossible for some others.
But if your drug is going to be a second-line therapy, then you should go ahead and see how it performs in patients who've already been through the first-line stuff. There is, unfortunately, a steady supply of those people, too, and they're often more willing to take a chance.
Your clinical trial design will also be influenced by the kind of cancer you're hoping to treat. If you're looking at a very specific type or two, as is the case with Novartis's Gleevec, you may have to cast the net pretty widely to round up enough people. (We'll ignore the fact, for now, that Gleevec sells a billion dollars a year, which means that a lot of people are getting it when it has very little chance of doing anything for them.) If you have a new mechanism that hits all kinds of cancer cells, then you may want to dip into all sorts of different patient populations to see if one of them looks like a good place to take your stand in later Phase II and III trials. The danger in doing that is that your patients may be such a mixed bag that you can't get good statistics on anything.
Ah, statistics. You'll have noticed that I'm referring to cancer patients as if they were so many terms in an equation, which from the standpoint of drug development is exactly what they are. That comes across, to those outside the medical and scientific areas, as a pretty cold way to talk. Guilty as charged - but keep this in mind: people who work for drug companies get cancer, too, as do our friends and relatives. And we're just as upset as anyone else when that happens. But without the icy numbers, and lots of them, we're not going to be able to do anything to help.
Comments (6)
+ TrackBacks (0) | Category: Cancer | Clinical Trials
September 16, 2004
Posted by Derek
OK, I couldn't resist. Let me reiterate that I completely admire the NIH's commitment to basic research; it's one of the real drivers of science in this country. But they're not a huge factor in clinical trials. Academia does more basic research than pharma; pharma does more clinical work than academia. Here are some statistics from a reader e-mail:
"As a person who was an NIH staffer (funding clinical trials, no less) and is now on the pharma side (mostly spending on manufacturing development; we will spend more on clinical trials as we get bigger), I have seen both sides.
Most of NIH spending is very far from clinical utility. Last time I checked (and it has been a while), more than 90% of NIH funds went to what most people would consider non-clinical research, e.g., studies of animals and cells, etc. (If the NIH was named by its major function, it would probably be called the National Institutes of Molecular Biology ;-) The reason NIH is able to claim that half of its money goes to clinical research' is that any study that involves a human or *human tissues* counts. So a bench study looking at receptors on human renal cells counts as 'clinical research.' The number of studies examining 'whole' humans is in the 5% range.
On the other hand, pharma, as you know, spends a lot of money on research with legal (protecting patent claims), manufacturing (cGMP issues, etc.) and marketing goals that don't necessarily help anyone's health.
Regarding the clinicaltrials.gov numbers, by my reckoning the 8000 NIH studies and the 2400 'industry' studies probably represent about the same investment in *therapeutic* clinical trials. If you break down the NIH trials, about 1800 (22%) are Phase I, 3000 (37%) are Phase II, 1100 (14%) are Phase III, and the rest (2150, 27%) are observational and other. (If you want to check, I did a search within the results for the appropriate phrases and subtracted from the total for the remainder). Figures for industry are 460 (19%) Phase I, 1060 (44%) Phase II, 770 (32%) Phase III, and 133 (5%) other.
In my experience each phase of clinical trials multiplies costs by about 10 times (e.g., Phase I = X; Phase II = 10X, Phase III = 100X), so the clinicaltrials.gov figures imply that the costs of Phase I, II, and III trials funded by industry are over 80% of those funded by NIH (costs are overwhelmingly driven by Phase III trials). And this is despite the close to 100% capture of NIH trials versus the unknown percentage capture of industry trials that you noted in your post."
Comments (1)
+ TrackBacks (0) | Category: Academia (vs. Industry) | Clinical Trials | Drug Development
September 14, 2004
Posted by Derek
OK, one more on this topic before moving on to other things for a while. The Bedside Matters medblog has a better roundup of the reactions to my post than I could have done myself. And "Encephalon" there also has one of the longer replies I've seen to my initial post, worth reading in full.
I wanted to address a few of the issues that it raises. Encephalon says:
"Dr. Lowe makes his point with the sort of persuasive skill one suspects is borne of practice - I shouldn't be surprised if he has had to make his case to the unbelieving on a very regular basis. And that case is this: that pharmaceutical companies do in fact spend enormous sums of money in developing the basic science breakthroughs first made in academic labs to the point where meaningful therapeutic products (ie, '$800 mil' pills) can be held in the palms of our doctors' hands, ready to be dispensed to the next ailing patient.
So far as that claim goes, I don't think any reasonably informed individual would dispute it. . ."
It tickles me to be called "Doctor" by someone with a medical degree. On the flip side, though, it's a nearly infallible sign of personality problems when a PhD insists on the honorific. And I appreciate the compliment, but it's only fairly recently that I've had to defend this point at all; I didn't even know it was a matter of debate. The thing is, you'd expect that a former editor of the New England Journal of Medicine would be a "reasonably informed individual", wouldn't you? I don't think we can take anything for granted here. . .
He then spends a lot of time on the next point:
"It is a myth, and I would argue a more prevalent one than the myth that Big Pharma simply leaches off government-funded research, that the NIH does little to bring scientific breakthroughs to the bedside (once they have made them at the bench). . .Using arguably one of the best (databases) we've got (the NIH's ClinicalTrials.gov**) we get the following figures: of the 15,466 trials currently in the database, 8008 are registered as sponsored by NIH, 380 by 'other federal agency', 4656 by 'University/Organization', and 2422 by Industry. While I am suspicious that the designation 'university/organization' is not wholly accurate, and may represent funding from diverse sources, and while the clinical trials in the registry are by no stretch of the imagination only pharmaceutical studies, the 8388 recent trials sponsored by Federal agencies are no negligeable matter. I think Dr. Lowe will agree.""
I agree that NIH has a real role in clinical trials, but I don't think it's a large as these figures would make you think. Clinicaltrials.gov, since it's an NIH initiative, is sure to include everything with NIH funding, but there are many industry studies that have never shown up there. (And I share the scepticism about the "University" designation.) When the Grand Clinical Trial Registry finally gets going, in whatever form it takes, we can get a better idea of what's going on. I also think that if we could somehow compare the size and expense of these various trials, the Pharma share would loom larger than the absolute number of trials would indicate.
Encephalon goes on to worry that I'm denigrating basic research: "The impression a lay person would get reading Dr. Lowe's 'How it really works' is that basic science work done by the NIH is really quite trivial. I don't think he meant this. . ."
Believe me, I certainly didn't. Without basic biological studies, there would be nothing for us to get our teeth into in the drug industry. If we had to do them all ourselves, the cost of the drugs we make would be vastly greater than it is now. It's like the joking arguments that chemist and pharmacologists have in industry: "Hey, you guys wouldn't have anything to work on if it weren't for us chemists!" "Well, you'd never know if anything worked if it weren't for us, y'know!" Academia and industry are like that: we need each other.
Comments (0)
+ TrackBacks (0) | Category: Academia (vs. Industry) | Clinical Trials | Drug Development
September 9, 2004
Posted by Derek
So is this the attitude we're up against? Here's a thread on Slashdot on the clinical trial disclosure issue - titled, I note in light of yesterday's post, "Medical Journals Fight Burying of Inconvenient Research". My favorite verb again! The comments range from the insightful to the insipid (for another good reaction to the clinical trial controversy, go here.)
A comment to the original Slashdot item disparages the idea that NIH is the immediate source of all drugs, and recommends reading my site, both of which actions I appreciate. But the first response to that was:
"No, (NIH-funded labs) just do the basic research that results in the drug leads. The companies then do the expensive but scientifically easy trials and rake in all the money (and now it seems, the credit as well)."
Wrong as can be, and in several directions at once. In a comment below, blogger Sebastian Holsclaw urges that we take this kind of talk seriously because it's more widespread than we think. I'm afraid that he might be right. The problem is that many people don't seem to understand what it is that people like me do for a living. I think that there must be plenty who don't even grasp how science works in general. Allow me to go on for a while to explain the process - I'd appreciate any help readers can provide in herding the sceptics over to read it.
Try this: If Lab C discovers that the DooDah kinase (a name I whose actual use I expect any day now) is important in the cell cycle, and Lab D then profiles its over-expression in various cancer cell lines, you can expect that drug companies will take a look at it as a target. Now, the first thing we'll do is try to replicate some of the data to see if we believe it. I hope that I'm not going to shock anyone by noting that not all of these literature reports pan out.
But let's assume that they do this time, making DooDah a possible cancer target. What then? If we decide that the heavy lifting has been done by the NIH-funded labs C and D, then what do we have so far? We have a couple of papers in the Journal of Biological Chemistry (or, if the authors are really lucky, Cell) that, put together, say that DooDah kinase is a possible cancer target. How many terminally ill patients will be helped by this, would you say? Perhaps they can read about these interesting in vitro results on their deathbeds?
What will happen from this point? Labs C or D may go on to try to see what else the kinase interacts with and how it might be regulated. What they will not do is try to provide a drug lead, by which I mean a lead compound, a chemical starting point for something that might one day be a drug. That's not the business these labs are in. They're not equipped to do it and they don't know how.
(Note added after original post): This is where the drug industry comes in. We will try to find such a lead and see if we can turn it into a drug. If you believe that all of what follows still belongs to the NIH because they funded the original work on the kinase, then ask yourself this: who funded the work that led to the tools that Labs C and D used? What about Lab B, who refined the way to look at the tumor cell lines for kinase activity and expression? Or Lab A, the folks that discovered DooDah kinase in the first place twenty-five years ago, but didn't know what it could possibly be doing? These things end up scattered across countries and companies. And all of these built on still earlier work, as all the work that comes after what I describe will build on it in turn. That's science, and it's all connected.
Here in a drug company, we will express the kinase protein - and likely as not we'll have to figure out on our own how to produce active enzyme in a reasonably pure form - and we'll screen it against millions of our own compounds in our files. We'll develop the assay for doing that, and as you can imagine, it's usually quite different than what you'd do by hand on the benchtop. Then we'll evaluate the chemical structures that seemed to inhibit the kinase and see what we can make of them.
Sometimes nothing hits. Sometimes a host of unrelated garbage hits. For kinases, these days, these usually aren't the case - owing to medicinal chemistry breakthroughs achieved by various drug companies, let me add. So if we get some usable chemical matter, then I and my fellow med-chemists take over, modifying the initial lead to make it more potent, to increase its blood levels and plasma half-life when dosed in animal models, to optimize its clearance (metabolism by the liver, etc.), and make it selective for only the target (or targets) we want it to hit. Often there are toxic effects for reasons we don't understand, so we have to feel our way out of those with new structures, while preserving all the other good qualities. It would help a great deal if the compounds exist in a form that's suitable for making into a tablet, and if they're stable to heat, air, and light. They need to be something that can be produced by the ton, if need be. And at the same time, these all have to be structures that no one else has ever described in the history of organic chemistry. To put it very delicately, not all of these goals are necessarily compatible.
I would love to be told how any of this comes from the NIH.
Now the real work begins. If we manage to produce a compound that does everything we want, which is something we only can be sure of after trying it in every model of the disease that you trust, then we put it into two-week toxicity testing in animals. Then we test in more (and larger) animals. Then we dose them for about three months. Large whopping batchs of the compound have to be prepared for all this, and every one of them has to be exactly the same, which is no small feat. If we still haven't found toxicity problems, which is a decision based on gross observations, blood chemistry, and careful microscopic examination of every tissue we can think of, then the compound gets considered for human trials. We're a year or two past the time we've picked the compound by now, depending on how difficult the synthesis was and how tricky the animal work turned out to be. No sign of the NIH.
The regulatory filing for an Investigational New Drug needs to be seen to be appreciated. It's nothing compared to the final filing (NDA) for approval to market (we're still years and years away from that at this point), but it's substantial. The clinical trials start, cautiously, in normal volunteers at low doses, just to see if the blood levels of the compound are what we think, and to make sure that there's no crazy effect that only shows up in humans. Then we move up in dose, bit by bit, hoping that nothing really bad happens. If we make it through that, then it's time to spend some real time and money in Phase II.
Sick patients now take the drug, in small groups at first, then larger ones. Designing a study like this is not easy, because you want to be damn sure that you're going to be able to answer the question you set out to. (And you'd better be asking the right question, too!) Rounding up the patients isn't trivial, either - at the moment, for example, there are not enough breast cancer patients in the entire country to fill out all the clinical trials for the cancer drugs in development to treat it. Phase II goes on for years.
If we make it through that, then we go on to Phase III: much, much larger trials under much more real-world conditions (different kinds of patients who may be undergoing other therapy, etc.) The amount of money spent here outclasses everything that came before. You can lose a few years here and never feel them go by - the money that you're spending, though, you can feel. And then, finally, there's regulatory approval and its truckload of paperwork and months/years of further wrangling and waiting. The NIH does not assist us here, either.
None of this is the province of academic labs. None of it is easy, none of it is obvious, none of it is trivial, and not one bit of it comes cheap. We're spending our own money on the whole thing, betting that we can make it through. And if the idea doesn't work? If the drug dies in Phase II, or, God help us all, in Phase III? What do we do? We eat the expense, is what we do. That's our cost of doing business. We do not bill the NIH for our time.
And then we go do it again.
Comments (28)
+ TrackBacks (0) | Category: Academia (vs. Industry) | Clinical Trials | Drug Development
September 8, 2004
Posted by Derek
I haven't been covering all the twists of the clinical-trial-disclosure story, because there have been so many of them. The drug industry is proposing its own plan, various companies are jumping out with theirs, the big medical journals have another one, and it won't be long before Congress sticks its oar in, too. Clearly there's still some wrangling to come - but equally clearly, we're going to get some sort of meaningful clinical trial data repository.
And as I've blogged here, I don't necessarily have a problem with that, although some of the ">details concern me. My problem, speaking as someone who pays his mortgage with ill-gotten loot from the rapacious drug industry, is with how we've handled the whole thing: poorly.
The verb that almost every story has used is "bury." The drug makers will no longer be able to bury their failed trials, the buried data will now have to be made public, and so on and so on. That's right, we take the data and stick it in a hollow tree stump. You would never know that every clinical trial in the US has to be registered with the FDA (or the equivalent authority in the case of offshore studies.) And you'd never guess that if we want the FDA to act, we have to submit all our clinical data, bad and good.
(Now, a situation where we could indeed use more transparency is when a trial is run, but the company decides that the results weren't good enough to support some new FDA action (a labeling extension, most of the time.) Then the results don't see the light of day, although I think that they should. But even then, the FDA knows that a trial was run.)
Where has my industry been while we've been pummeled in the press? Issuing press releases that nobody believes or even reads? Our industry organization's home page is a sinkhole of grinning publicity head shots and soft-focus stock pictures of cute babies. Find someone who can stand to look at it for two minutes, and I'll show you someone with a stronger stomach than I have. Why isn't our side of the story getting out?
Comments (1)
+ TrackBacks (0) | Category: Clinical Trials
August 31, 2004
Posted by Derek
As came up in the comments to the previous post, there's not as much price competition inside a given drug category as you'd think. That's not because we're Evil Price Gougers, at least not necessarily. As I was pointed out yesterday, "me-too" type drugs aren't as equivalent as some people think. The main reason we go ahead with a drug in a category where there's already competition is because we think we have some advantage that we can use to gain market share.
This is a constant worry in every drug development effort where there's already a compound out there. I've personally, many times, been in drug project meetings where we've looked at the best competing compound (one that's either already marketed or well into clinical trials) and said "We haven't beaten them yet. We're not going to make it without some kind of unique selling point." The best of those, naturally, would be superior efficacy or a superior safety profile. Then you have easier dosing, fewer interactions with other drugs, and so on. I need to emphasize this: I have seen drug projects killed because no case for an advantage could be made.
Now, there's room to argue about how much better efficacy a drug needs to be a real advance in the field, or at least a bigger seller. You can argue about any of those possible advantages I listed, and it's true that drug companies push some compounds that aren't exactly huge leaps over the previous state of the art. (You see more of that when there's a case of shriveled pipeline in progress.) But there has to be something, and the bigger the difference, the better it is for us. We're motivated, by market forces, to come up with the biggest advances we can. The sales force would much, much rather be out there with data to show that the new drug beats the competition in a clean fight, as opposed to saying that it beats the old one on points, in a subset of patients, if you massage the data enough and squint hard, and besides it tastes better, too. . .
And as I've pointed out before, we often find out things about compounds long after they've reached the market. Lipitor, as discussed yesterday, is a case in point. I have not been a Lipitor fan in the past. The statin field seemed already pretty well served to me (as it did to a number of people inside Warner-Lambert during the drug's development, frankly.) The drug made its way forward based on efficacy in the clinic: it seemed to do a better job lowering cholesterol and improving the LDL/HDL ratio. How much advantage that is in the long term is another question, but those are the best markers we have.
The whole antiinflammatory c-reactive-protein story about the drug only came up after it was already on the market. The marked differences between it and the other statins, which I have to assume at this point are real, are a pleasant surprise to everyone involved. Warner-Lambert (and then Pfizer) thought it was a better compound, but not to this degree or for these reasons, I'l bet. I'd say that this is another argument for having multiple drugs in the same category. We don't, and can't, know everything that they'll do.
Comments (2)
+ TrackBacks (0) | Category: "Me Too" Drugs | Cardiovascular Disease | Clinical Trials | Drug Development | Drug Prices
Posted by Derek
Allow me to get a little defensive. If I understand some of the critics of my industry, we spend most of our time making "me-too" ripoff drugs rather than doing something that provides any clinical benefit to patients. And, if I have this right, here's how we determine efficacy: we run clinical studies until we get the answer we want, and then we bury all the other ones. (Mind you, we bury the data by giving it to the FDA, but stay with me here.)
OK, now let's try to explain this. Merck has just released a study on its statin drug, Zocor. Following in the footsteps of two other studies with Pfizer's statin, the market-leading Lipitor, Merck dosed patients who had just suffered heart attacks. Lipitor treatment seemed to show a real benefit in these situations, lowering the rate of later cardiovascular trouble, and Merck was hoping for (and no doubt expecting) the same thing.
But they were rudely surprised. At the lower doses of Zocor, they failed to show any benefit at all. And at the highest dose, while they managed to show a lower rate of second heart attacks, they still didn't reach significance versus the placebo group. Worst of all, several of the high-doses patients showed the muscle-weakening condition rhabdomyolosis. That's the bane of statin drugs, and the reason why Bayer pulled their compound (Baycol) from the market. (Just to complicate things, one of Merck's placebo patients showed rhabdomyolosis, too, which is food for thought and should give you an idea of how much fun it is to interpret clinical trial data.)
So what's going on here? Zocor and Lipitor both work by inhibiting HMG-CoA reductase. They hit the same mechanism. Were the patients different? The study's authors say it's possible. The patients in the Lipitor studies seem to have been receiving more aggressive therapy in addition to the drug. Are the drugs different? That's possible, too. Lipitor, as it turns out, seems to lower the inflammation marker C-reactive protein much more than Zocor, and that could potentially make a difference.
But if the drugs are really different, what happens to the idea that Lipitor is just a me-too, yet another statin piling on the profits? If we in the industry hadn't kept banging away at these drugs, we wouldn't have ever known that better ones could be found. Would we? As I've pointed out in the past, if you're going to market a drug in a category where the competition is ahead of you, you'd better have some improvement to point at or set about finding one. Lipitor came into the market under the banner of "lower dose / higher efficacy", and it may be picking up more advantages as time goes on.
Now, if we believe that the drugs aren't different, which will be an interesting thing to try to prove at this point, then we have to figure out how much weight to put on this study. How does it go into the Great Clinical Trial Repository? With an asterisk? Then shouldn't the earlier two studies with Lipitor have one, too? This is the same situation I spoke of before.
And what about this clinical trial data in general? Isn't this the sort of bad news that we're supposed to be sweeping under the rug over here? A full article in JAMA complete with vigorous editorial commentary. . .some rug. Oh, and one other thing: those two earlier Lipitor studies that showed a benefit. One of them was from Pfizer(/Pharmacia), as you'd expect. But the other one was from their competition. Bristol-Meyers Squibb has been trying to prove that their statin, Pravachor, is better than Lipitor, and failing. Where's that damn rug when you need it?
Comments (5)
+ TrackBacks (0) | Category: "Me Too" Drugs | Cardiovascular Disease | Clinical Trials
August 9, 2004
Posted by Derek
The New York Times has a good article this week on a trend in clinical trials that's been developing for several years - small intensive trials in humans, run before giving the go-ahead for the real thing.
It makes a lot of sense, but only when you can use it to ask (and answer) the right questions. That's where technologies like functional NMR imaging or PET scans come in, because they allow you access to in vivo data that's otherwise unobtainable. Take, for example, the studies mentioned in the Times article, where they look at glucose uptake in a solid tumor. That's a reasonable proxy for its metabolic activity, as you'd guess, and it'll give you a quick read on whether your targeted cytotoxic compound is having the effect you want.
What you'd do, normally, is dose the compound for days or weeks, then use NMR or another imaging technique to see if the tumor has changed size. That's clearly a more convincing answer, but it takes a more convincing amount of time and money to get it. And if your compound isn't having an effect on a fast marker like the tumor's metabolic rate, it's probably not going to have any effect after you dose it for two months, either. You're better off trying something else.
But if your new cancer therapy is, say, a compound that interferes with cell division, then you're not going to have that clear an answer through that glucose uptake technique. Same problem if the cancer you're treating is a more diffuse one like leukemia, because there's not such a clear tissue to image. (There are other approaches to each of those problems, naturally, but I just wanted to emphasize that each clinical trial is its own set of new problems, even inside the same general therapeutic area.)
And even when you get to the traditional large-scale trials, there's a huge need for surrogate markers that can show progress against slow-moving diseases. Glycosylated hemoglobin as a measure of efficacy in diabetes is a good validated example. It still takes quite a while to establish (weeks or months of dosing), but that's like lightning compared to the progress of diabetes complications themselves. You can do a quick assay in this field - the oral glucose tolerance test - but the improvement in that assay isn't so quick to come on.
The CNS diseases are a real clinical challenge, which is why their trials are so brutally expensive. There are hardly any markers at all for most of them. Everyone would love to have a short-term noninvasive readout for Alzheimer's, but despite years of effort, no one has quite made it. (And that's despite the definition of "short-term" in Alzheimer's is rather permissive.) Similarly, it would be good to be able to get a faster readout on depression, whose therapies are notorious slow starters.
There's a bigger problem, though, looming over some of the generally accepted markers - what effect do they really have on long-term mortality and morbidity? Glycosylated hemoglobin has been pretty well correlated in diabetes over the long term, so that one's pretty safe. But the question is worth asking, for example, about HDL and LDL levels. Yes, things do line up well, up to a point. But does long-term administration of statin drugs, say, help as much as we'd like to hope it does over, say, twenty years? The jury's still out on that one.
Comments (5)
+ TrackBacks (0) | Category: Clinical Trials
June 21, 2004
Posted by Derek
The placebo effect is a real problem in some clinical trials. It varies, but in things like antidepressants it's a major factor (while with, say, pancreatic cancer it doesn't change the results too much.) In a given sample of depressed patients, there are a fair number of people (20 or thirty percent) who will respond if you give them 50 milligrams of confectioner's sugar which they truly believe to be an efficacious drug.
Of course, the majority will respond as if you'd given them, well, confectioner's sugar, but that group of placebo responders will blow your statistical workup to pieces. This is one of the reasons that you see multiple trials for antidepressants, because the trials themselves often just produce noisy data. Of course, one way to interpret this is that the antidepressants themselves are fairly worthless. That's a tempting conclusion, and for some people, they clearly don't do much good. But you can find others that truly appear to have been helped. Depressed patients, even ones who may look and act similarly, are clearly a heterogeneous population.
What if those strong placebo-responders could be weeded out of the patient population before you even started the clinical trial? This question is a good test of a person's attitude toward the drug industry. Many folks will hear that idea and cry "Fraud! Stacking the deck!" But think about it. If you could find the people who will improve when given a sugar pill, then you could pull them aside and just go ahead and give 'em the sugar pill. Hey, it's effective therapy, and that's what counts, right? And they'll miss out on the side effects of the antidepressant drugs themselves, and every drug has side effects at some level - every single one.
Meanwhile, once those folks have been sorted out, you're left with a cohort of patients who need all the help they can get, and now you're in a statistical position to see if you can really provide any. As far as I can see, everyone comes out ahead.
It turns out that there may be ways to see who's a strong placebo effect candidate and who isn't. There have been several studies in the last few years that show some real correlations in brain activity during placebo situations, and this has lead to the idea of a test for it.
If this goes on, though, there could be some interesting developments. What if everyone becomes aware of the test to see if you're going to get a placebo? Will the responders still respond if they thing there's a reasonable chance that they didn't get a "real" drug? I think that what we'll need to do is present the test as a standard procedure, to help figure out which therapy would work the best - not a method to see if you get a drug or not, but a method to see which drug you should get. That should keep things working.
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June 15, 2004
Posted by Derek
So it turns out that the major medical journals have their own plan for bringing on a clinical trial database: they're going to require companies to register trials before they'll allow publication of their results. I was taken aback at not having heard anything about this idea, until I saw that no one else in the drug industry seems to have, either.
I don't really have a problem with this at all. For one thing, it's better than having the state sue you into doing something - this is a good old free-market fight. Most of the major medical journals need revenue from pharmaceutical advertising, and the companies need the prestige of publishing in them. Come, then, let us reason together.
And the first step here, merely registering the fact of a trial, will sidestep some of the issues I brought up the other day with how to report the final data. I know that there will be pressure to include that data as well, and if we can find a way to deal with those reporting issues, we should. But even a registry of trials would show that something had been tried, naturally leading to questions about how things came out. (That's important for the medical editors' side of this dispute, because the studies that companies don't want to talk about aren't going to be submitted for publication, anyway - the journals have no other leverage at that point.)
Now, one way around this would be for companies to forsake publication in the journals involved (a tough thing to do, mind you) and just present the data with a big splash at a prestigious meeting or two. If you see more professional societies joining this trial-registry movement, especially ones that don't publish their own journals but still sponsor large meetings, then I think the outcome will have become clear.
I think, though, that people have some odd ideas about how clinical trials work and how many of them there are. Consider columnist Michelle Malkin, who wrote about this story today:
From Statistics 101 we know that if a product is as effective as a placebo, 1 in 20 trials will produce a statistically significant finding due to random chance. Since companies run dozens of trials on each major compound, it is not too hard to produce at least one positive, statistically significant finding suitable for publication. The rest are buried in the "circular file." This is great marketing but it is not science.
Um, we don't actually run "dozens" of trials on every major compound. We don't have enough money to do that, as hard as that may be to believe, and in many cases there just aren't enough patients to go around. So we just don't get to play with the statistics in this way. It would be irresponsible, she's right about that, but we don't do it.
And that argument would only hold if all 20 trials were run the exact same way (Statistics 101, you know.) Twenty different trials, each run a different way on different patient groups, can produce results all over the map. Trying to do metastatistics over the whole group is not a job you want; it's often not even possible. And besides, even if they were all the same, the level of statistical significance that Malkin's talking about (1 in 20 by random chance) isn't very high at all. A clinical trial has to be a lot more significant than that to convince anyone at either the FDA or the company itself.
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June 9, 2004
Posted by Derek
There have been plans, over the years, for some sort of data repository for clinical trials. Nothing's ever worked out. The only place that all of this is collected is at the FDA, and they only have the ones that companies have submitted because they were requesting a new approval or a new indication. If companies run studies but they give up on regulatory filing, the data can never see the outside world at all.
That's the heart of the New York - GSK suit, as I was discussing yesterday (although, as I pointed out, in this case the data were made public, although nowhere near to the extent that the more positive study was). Presumably, the ideal that Eliot Spitzer seeks would be a central database of all clinical studies conducted on marketed drugs - along with, it seems, a requirement to go into the results of all of them in marketing presentations. (Actually, I think the ideal that Eliot Spitzer seeks is a world in which he is a senator from or the governor of New York, but that's another story. . .)
This sounds like a reasonably clear mandate, but in practice it's quite tricky. It's worth thinking about what a clinical data repository would look like. You'd have to include the statistical workup from the end of the trial, that's for sure. The raw data makes for quite a heap, and extracting the useful conclusions from it is not the work of a moment. You have to be well informed about how and why the trial was designed to even know where to start, and you have to be well informed about statistics to know when to stop.
Even with all the conclusions attached, an open raw-data repository would be a real invitation to cranks of all kinds to go in and massage the data. I've spoken about this issue before, because companies themselves can be guilty of trying to extract more conclusions than the data will support. Imagine the ax-grinding subgroup analysis and selective data mining that would go on - for one thing, the trial lawyers would be adding statisticians to their staffs to do nothing but comb through the numbers all day, looking for tort-worthy tangles.
Even if you just have the worked-up data in the repository, you still face the problem of data overload. Heavily studied drugs can have a long list of differently designed trials attached to them, all of which are either asking different questions or asking the same one in different ways. Digging through them is not something you can do on your lunch break.
An even tougher problem is what to do about poorly designed or poorly executed studies. That seems to be the case with the Paxil 377 data I spoke about yesterday, which is why one of the study's co-authors wanted to publicize it in the first place. Who gets to decide if a particular study is valid? Whose comments and conclusions will be attached to the results? Who gets to weight them against the other results collected on the same drug?
These are the sorts of issues that are wrangled about in the regulatory approval process, and the disagreements can be heated, even in a roomful of people who all know what they're doing. How many physicians would be willing to consult a Central Clinical Trial Database and do the wrestling themselves? How many would even have the time? For the most part, practioners have as their default setting to trust the FDA, since they've analyzed the data already.
As for what companies can say to doctors, limits in this area have banged right into free-speech considerations in the courts. Attorney General Spitzer's on-message response to this is that you can't use a First Amendment argument to justify fraud, and I'll let that one go by without swinging at it. But what would he have disclosure look like? Should it be verbal (and in that case, how would it be enforced?) Should it be a written handout on the total clinical data generated for a new drug? That makes more sense, but then we get back to the question of how summarized the results should be, and who gets to write the summaries.
The thing is, I think that a clinical data repository would be useful. I know that I'd like to go data-mining through previous studies, looking for things that are relevant to my current projects. And I'd like to see what happened in failed trials so we can be sure not to run ours in the same fashion (which was Dr. Miner's point about the 377 Paxil study). It could be worth trying, but I worry that it might require the world to be a little better than it really is to work. We'll see.
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June 8, 2004
Posted by Derek
New York Attorney General Eliot Spitzer has found what must look like another target-rich environment: the pharmaceutical industry. As many readers will have seen, he's initiated a lawsuit against GlaxoSmithKline for their handling of clinical trial data for the antidepressant Paxil (paroxetine). As far as anyone can tell, this suit is the first of its kind.
There's a specific side to this story, and a there's general one about the handling of all clinical trial data. I think I'm going to end up splitting the difference, but first things first: in this case, SmithKline (as it was at the time) ran different studies on the effectiveness of Paxil in adolescent patients. One study (#329) had positive results, and another (#377, slightly later) showed no benefit versus placebo. Spitzer points out that the successful first study was widely publicized, presented at several scientific meetings, and eventually published. SmithKline (and later GSK) made it part of their sales pitch to physicians.
Meanwhile, the 377 study was presented once, at the annual meeting of that same academy, and never showed up as a full paper in the literature. The presentation wasn't SmithKline's idea; they weren't going to publish or present at all. It was suggested by two of their academic collaborators (Robert Milin and Jovan Simeon). And as you can imagine, it has not been a feature of GSK's promotional literature.
All this, in the eyes of Attorney General Spitzer, adds up to an indictment for fraud - and yes, that's exactly the word he uses. Here we have all the elements of a great case: buried information that would have been harmful to a large corporation, and a whistleblower who brought it to light. It sounds more like a screenplay - as you read about it, you can start mentally casting the movie.
But there are complications. For one thing, SmithKline made no objection when Dr. Milin told them of his plans to present the 377 study. I don't know what the terms of the research agreement were in this case, but often enough the company can exercise a veto in such cases, since they paid for the study. And second, Milin himself is, according to Barry Meier's story in the New York Times last week, a strong believer in the use of Paxil in adolescents. He considers the 377 study to have failed because of a flawed design, not because the drug isn't useful. And as for publishing the results in a journal, that would have actually been quite difficult. Inconclusive or negative results are very hard to publish in general, and in this case even the positive study wasn't the easiest thing to get into the literature. According the Times article, the paper probably bounced around a couple of times before finding a home. It ended up in the Journal of the American Academy of Child and Adolescent Psychiatry, and appropriate venue but hardly the highest-impact journal in the world. And finally, GSK provided details of both studies to the FDA, as it is required to do.
So hiding information, which is the basis of the fraud allegation, lies in the way that GSK detailed physicians. I wouldn't expect them to go out of their way to present data showing that the drug didn't work, but if one of the study's own authors felt that it was flawed, then I really wouldn't expect them to talk about it much. I can see what Spitzer's trying to do, all right, and I can see what he thinks he has. But I don't think that's what's really there.
All this, presumably, is supposed to further the cause of releasing clinical trial data. Under the current system, the company can show it only to the FDA (or other regulatory agencies) if it chooses, and if they give up on the compound, no one has to see it at all. There have been calls over the years to establish a clinical trial database, but nothing's ever come together.
And you know, I actually think that a general trial database could be a good idea. (It could also be a disaster, and the industry has chosen to avoid the latter rather than seek the former - we'll go into some of the complications tomorrow.) But I think that Eliot Spitzer may have picked the wrong grandstand to make a speech from, and should have thought twice before striking up the band. Then again, that's not the sort of behavior that got him to where he is now. . .
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March 15, 2004
Posted by Derek
In my March 11 piece below, I mentioned the possibility of Pravachol competing on price with Lipitor. But over at Forbes, Matthew Herper has pointed out that it's currently more expensive. What BMS is going to do with this drug, I can't imagine.
There's also a good story in the Newark Star-Ledger about the whole comparative-trial situation. (That paper does a pretty good job with the drug industry, since so many of the big players are right in its back yard.)
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| Category: Business and Markets | Cardiovascular Disease | Clinical Trials
March 11, 2004
Posted by Derek
Just a brief note today about the "PROVE-IT" study that Bristol-Meyers Squibb ran and has now reported on. This was their big shot at Pfizer's Lipitor, their chance to show that their own statin, Pravachor, was just as good or better. The study was big, it was long, and man, was it expensive. It's just the sort of thing that I was talking about when I wrote recently about comparative drug trials.
And it shows why more of them aren't done. Because, as is well known, when you strike at a king, you have to kill him. BMS found, no doubt to their dismay, that Lipitor is actually a better drug. It's not a gigantic difference, and you can still argue about the dosages, but BMS's drug definitely failed to realize the hopes they had for it. Here are two competing views on the issue, one from DB's Medical Rants (keep scrolling up) and one from Medpundit.
Now what? How do they promote it? The question that BMS is going to get is "Why should anyone take your drug instead of Lipitor?" The only thing I can think of is for them to compete on price. "Take Pravachor - it's proven to be sort of, you know, inferior, but it's sure cheaper!" Doesn't quite have that compelling zing, does it?
If comparative drug trials are going to be done, they're either going to have to be required by law - in which case, as I pointed out, we in the industry will pass along those costs to the consumer, thanks - or they'll have to be done by a third party. (In which case it'll be paid for by everyone who pays taxes, not just the eventual users of the drugs involved.) If you're waiting for more companies to do them on their own, you're going to have a long wait. Especially after something like this happens.
I'll leave everyone with a homework question: Can anyone think of another case - I can't - where a company sponsored a study of their product against a competitor, found that theirs fell short, and publicized it? UPDATE: I mean, outside the drug industry. It's happened several times to us (Zyprexa!) I'm talking Ford / Honda, Dell / Gateway examples, and I can' think of one. Admittedly, as I've said before, health care is different, but still. . .
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| Category: Business and Markets | Cardiovascular Disease | Clinical Trials
February 29, 2004
Posted by Derek
Some interesting mail has come in after last week's post on comparative clinical trials. Reader C.B. that I spoke about here some time ago, but should have raised again:
"It seems to me that something else is being left out: not all patients respond the same way to any particular drug. . . Suppose that drugs X and Y are equally efficacious when given to the appropriate patient, but the population more responsive to X is smaller than that benefiting from Y. A simple comparative trial would suggest that Y was more effective because it assumes a single type of patient. On the basis of the results, people who should get X would only be allowed Y. . ."
It's true, there are a number of cases like this, and this is one of the traditional arguments for multiple drugs in a given class. I've made it myself. Given the state of the art, it's nearly impossible to untangle these things. In almost all cases, we have no idea why some people respond better to a particular therapy; it's trial and error. Clinically, these things are bottomless pits, so I think that comparative trials are going to be most useful in areas where a large number of patients respond to both drugs under study.
But we're in the process of inventing ourselves out of this situation. That's why all that money is being poured into pharmacogenomics - and quite rightly, although the end result is that many drugs are going to have their potential market size whacked into a rather more compact shape. The great thing about pharmacogenomics is that we're finally going to know who should take our latest drug, and we'll be able to find them and sell it to them. The terrifying thing, from the marketing standpoint, is that we're simultaneously going to find another group of patients, a potentially larger group with the same disease, who will never take that drug at all. It's going to be a better world, but one in which some business models (cancer therapy!) are going to have to change.
And in a similar vein, reader R. D. writes:
"I have yet to see someone make a rational case for why me-toos are bad. At most, the argument seems to be that if pharma would just stop spending all its time coming up with me-toos, we could get around to curing cancer and parkinsons and stuff. I think that's bunk. You and I both know that any pharma that could come up with cures for things like cancer or parkinsons could start their own mint. The reason they haven't is because it's HARD, not because they prefer to make less money by painting their old pills purple and trying to convince everyone that they're new and improved."
Purple? What on earth can you be talking about? No, the argument he's talking about is one that (in this form) I don't have too much time for, either. The me-too drugs are there to keep the coffers full to pay for the research that doesn't work out, and to tide companies over the dry spells. I can see the objections to the areas where there are six and eight therapies all piled up on top of each other (for example, does the world really need Crestor?) But if Crestor makes money, some of that's going to pay for something new.
And the reason for that touches on another favorite whipping boy: marketing and promotion costs. Keep in mind the inverse relationships between advertising costs, novelty, and the chances of success. A new drug that does something no one's ever seen for a major disease previously thought untreatable - isn't that what makes everyone happy? How much, comparatively, would have to be spent to market such a therapy? There's no competition - it would sell itself! But what are the chances that any of us are going to find and develop such a wonder?
(OK, some of you are saying "Viagra! First on the market, first in the category, promotion out the wazoo!" But keep in mind: no one was sure that men would actually go to their doctor and admit their symptoms - thus the advertising blitz. And Prizer knew, with all the other companies working on PDE subtypes, that competition would be coming soon. They needed all the brand recognition that they could buy.)
Meanwhile, contrast a first-ever wonder drug with, say, the umpteenth statin. It's a crowded field, and you have to spend like crazy to make headway. The thing was a bit lower-risk to develop, since you knew that the rationale was there. But your cost-of-sales figures are going to be uglier, and nothing's ever going to help them.
My point is that a company needs both of these kinds of drugs. You can't hope to live only on the first kind, because they happen so seldom and so unpredictably. And no one's trying to live only on the second kind, either, because you've traded higher costs their for relative security. Everybody developing one of the first class wishes they had some of the second to tide them over. And everyone with drugs in the second class is looking for one from the first.
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+ TrackBacks (0) | Category: Clinical Trials | Drug Prices | Why Everyone Loves Us
February 26, 2004
Posted by Derek
I've already had some reader mail (see here) about this article in today's New York Times. It starts out looking like a real pharma-bashing exercise. Up to a point, it is - and up to a point, it's deserved, too. But in the end it's a more subtle piece, not that you'd guess that from the opening paragraphs. (I have my own solution to the problem the article raises, and it will bring joy to no one. Read on.)
The issue is comparability of drugs, especially drugs with the same broad mechanism of action. Look at all the statins or antiinflammatories on the market: is there one that's better than the others? Of course, if you listen to the companies that make them and promote them, the answer is clear. Their product is best! But, as in any other industry, that's not the most reliable guide.
The article uses the example of two marketed forms of the protein erythropoetin, one from Amgen, and one from Johnson and Johnson. J&J's product is about one-third the cost of Amgen's. Is there any reason to pay for the more expensive option? Medicare has asked the National Cancer Institute to run a study to answer that question, but (as the Times points out early and often) there is a provision in the latest Medicare legislation that keeps the program from even using such evidence of functional equivalance in its payment decisions. As you'd imagine, Amgen is arguing that this provision makes the planned Medicare/NCI comparison study a moot point. Why compare?
This would seem like an easy call: the drug companies are slamming the door on something that might cut into profits. Hey, I work here, and I'm sure that that was the motivation, too. But I should add the standard comparisons to other industries at this point, though, and note that car makers are not required to prove that their latest models actually work better than the older ones, or better than the competition's. Nikon doesn't have to run head-to-head trials with Canon, nor Gateway with Dell.
I like those examples, but I realize that there are some other considerations. For one thing, we're talking about public funds here, right? Partly, yes, although the managed-care corporations have a big interest in this, too. I'd add that the government spends a lot of money on goods and services that are not required to be comparison tested (but are selected on the basis of lowest bid.) We'll get back to that topic in a couple of paragraphs. The other big factor is that my car and computer comparisons are discretionary purchases. Health care is treated differently. It's an emotional issue, a life-and-death issue, and it's always going to be held to a different standard than other businesses.
So, let's test! But as the article makes clear, it's not as easy to test these things as you'd think:
. . .Rarely are such studies able to answer all the most important questions. The National Cancer Institute has been mulling the appropriate design for the Aranesp-Procrit trial for nearly two years and will probably need another year before starting the test. . . In the end, more than one trial may be needed, Dr. Feigal (of NCI) said.
Dr. Feigal declined to estimate the cost or size of the eventual trial or trials, but similar tests have cost millions of dollars. Indeed, for comparative trials to be the size needed to measure true differences between drugs, they generally need to be large, lengthy and expensive.
Indeed they do. The article goes on to talk about the hypertension drug comparison study that got such play in the media a few months ago - not least from the New York Times itself. It hasn't settled the question, though. There are still real doubts about which therapy is most effective (for one thing, because patients in the study didn't take more than one type of drug, although in the real world this is a common mode of treatment.) This was a huge study already, and adding arms to assess combination therapies would have bulked it up considerably.
Still, I'm in favor of doing some head-to-head tests, because I think that there are several therapies out there that don't offer much for their price. (I'm looking at you, Nexium!) Here's my proposal - and yes, I'm going to go ahead and treat the drug industry unlike any other. If a company wants to bring out a me-too therapy, it will be required to show evidence of whatever factor differentiates it from the existing agents. The company gets to choose the battlefield: more efficacy? Quicker onset? Fewer follow-up visits to the doctor? Whatever. Pick a reason you're going to promote the drug, and come up with data to back it up. I think we'd end up with fewer me-toos on the market, but we'd lose fewer of them than many critics might think. Many times, drugs that look the same can indeed act differently. Admittedly, it would take some careful clinical work to bring some of the differences out, though.
This change would require a major shift at the FDA. For existing therapeutic modes, you'd need to switch at some point from placebo-controlled trials to competition-controlled trials. Perhaps you could run an initial test-the-water placebo control (after all, these are drugs that have a high chance of working), and from then on you run versus the competition. There are complications - which competitor, for example. But it's possible to do, and it's an idea that has been talked about for a long time.
And who's going to pay for all this? Well, you are (if you're a patient, that is.) Believe me, we're going to pass those costs on, and pronto. Raise the regulatory barrier, pay more money: it's a law of nature. And the lost revenue from the me-too drugs, which have higher chances of success (but still aren't sure things!) will be passed on, too. I think that there are still savings to be realized here - but they're not going to be as big as they seem.
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January 13, 2004
Posted by Derek
I wanted to take a moment to mention some interesting posts around Blogdom that readers may not have seen. In a response to the news on secretin for autism (see my post below), Dwight Meredith writes on what it was like at its peak of interest:
Human secretin, swine secretin, herbal secretin (which as far as I can tell is an oxymoron) and synthetic secretin were all hawked relentlessly to the parents of autistic children. The price of secretin skyrocketed. People were paying $2,000 for an amount of secretin that before the buzz had cost about $30. It is not an exaggeration to say that parents were mortgaging their homes to purchase secretin for their kids. We now know that a sugar pill would have been equally effective.
Please note that all of that buzz was generated by the fact that a few autistic children had improved after being given secretin for digestive problems. The autism community could not wait for double blind and placebo tested trials. We wanted our miracle and we wanted it now.
This is a man who writes from personal experience, I should note. And I can understand the desperation (well, as much as anyone in my position can - I have two small children, neither of whom have - thus far - shown any neurological abnormalities.) What I have trouble imagining, though, is what goes through the mind of someone who peddles "herbal secretin" to parents who are begging for something to help their autistic child.
Herbal secretin? They didn't even bother making it sound like anything but a heartless scam. Figured the customer base would be too desperate to care, I suppose. I'm ashamed to be in the same phylum with creatures who would do something like this.
There's a larger point about the wait for double-blinded trials, too, of course, which I should save for a longer post. The short form is that I can see the point that some people make, that it would be better to require safety (Phase I) trials, then stand back and let efficacy be sorted out in the marketplace. (SMU's Steve Postrel and I had a long e-mail exchange on that subject a year or so ago.) But then I hear about this sort of thing, and start to think that this is one of those sensible ideas that would only work on some other species than humans.
The other post I wanted to mention is over at Colby Cosh's site. Talking about medical progress, he hits on the idea of looking at the causes of death in the records of ballplayers from the old days, who were in their physical prime. It's an alarming list, and most of the things on it are, fortunately, in the process of disappearing from the world. And good riddance. As Cosh says: "I don't know how anybody kept from just going insane before antibiotics existed, with death lurking around every corner."
One final note - I've forgotten to mention that Charles Murtaugh is back blogging again. There's lots of good new stuff; just start at the top and work your way down.
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+ TrackBacks (0) | Category: Autism | Blog Housekeeping | Clinical Trials | Drug Industry History
December 20, 2002
Posted by Derek
As I mentioned yesterday, I think the kind of study that compared diuretics with other hypertension medicines was a very good thing. So why don't we see more of these?
There are several reasons. It's worth thinking about the different levels of testing, and what questions they're designed to answer. At the first level, you have questions about specific drugs - is Drug A safe to take, compared with taking nothing? Does Drug A work, compared with taking a placebo? These are the usual subjects of Phase I and II clinical trials.
There's a third question, namely, how good is drug A versus other drugs that work the same way? That one doesn't get answered as often as it should, because the FDA generally only requires testing against placebo. A debate has been going on about when it's appropriate to run head-to-head trials rather than placebo-controlled, and it happens more often than it used to. Drug companies aren't always eager to try this, because they sometimes fear that the advantages of their new compound may turn out to be more subtle than they'd like. But if they think they've got a clear edge, then a trial like this is just the thing. I think we're going to be seeing more and more FDA requests for these sorts of trials, which will definitely make life harder for drug development, but in a good cause.
Beyond specific drug questions, you get to mechanism issues: Does therapy A work better than therapy B? That's what the diuretic study was designed to answer, and it's the rarest kind of all. It's a situation, though, like the old proverb that says when you strike at a king, you have to kill him. If you run one of these trials and your advantage isn't there, you're probably sunk - and if a safety liability shows up versus the existing therapy, you're completely sunk. This is what happened to Bristol-Meyers Squibb when they run Vanlev (omepatrilat) against Vasotec (enalapril) for hypertension. Vanlev's never going to see the light of day, and neither is any other ACE/neutral endopeptidase inhibitor combination.
As one of the interviewees in Wall Street Journal noted:
Duke's Dr. Catliff says it isn't reasonable to expect the pharmaceutical industry to onduct head to head studies needed to answer questions of both science and money. "It's sort of an all or nothing game," he says. There is a potential gain for the winner, but a huge risk for a loswer. Some results could essentialy kill the market for a drug. "The industry can't afford to take that kind of risk."
Well, whether it's reasonable or not, he's right that companies aren't going to line up to do this sort of study. The business is risky enough already, thanks. No one company is going to try it unless they're forced to (like BMS.) That goes double when you're comparing existing therapies, things that are already on the market. But that doesn't mean that I don't think this kind of study should be done - on the contrary. I think that the NIH's model for the ALLHAT hypertension study could be the way to go - let people run the study who won't be cutting their own throats by running it. It'll be interesting to see if they get a general mandate (and funding) to do just that.
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+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials
November 14, 2002
Posted by Derek
I recently mentioned the non-cholesterol effects of HMG-CoA reductase inhibitors (statins,) so I thought I'd follow up on that with a discussion of the recent news (Nature, Nov. 7) that they could be beneficial for multiple sclerosis.
The mechanism of MS is clear, up to a point. (I know, everything is clear, up to a point, but bear with me.) It's an autoimmune disease, a T-cell response to the body's own myelin sheaths around the nerves. This inflammation damages the myelin (a full immune assault damages just about anything,) and thus affects nerve impulse transmission. Over time, the neurons themselves are irreversibly damaged (or so it seems; reversal of neurological damage is a hot topic these days, and no one's sure what might be possible eventually.) The course of the disease varies a great deal from person to person, since immune systems vary, too. Current therapy can slow the progression down a bit, but nothing stops it.
The idea that statins might help in something like MS isn't actually new. The drugs have long been known to have some immunological effects: as far back as 1995 — yep, way back then — a study showed that heart transplant patients had a better outcome when pretreated with pravastatin.) Since then, a number of miscellaneous signaling pathways involved in inflammation have been shown to be affected by one statin or another. (So many, in fact, that it was getting hard to sort out what was going on.)
The latest work is a very nice study using a mouse model of MS called EAE (experimental autoimmune encephalomyelitis.) It's a pretty decent surrogate for the disease, brought on by deliberate (and heavy) immunization with peptides that are close enough to myelin's surface composition to set off the autoimmune response. There are several recipes for doing that, some of which only work in specific strains of mice, which cause different types of impairment (more or less severe, chronic versus repeating, and so on.)
The statin used was atorvastatin (known to the world, and to nearby planets if Pfizer's marketing department has anything to do with it, as Lipitor.) I note without comment that one of the paper's authors was the recipient of an "Atorvastatin Research Award" from Pfizer, but their choice of this particular compound was justified. Two years ago, it was found to be more potent on immune targets in vitro.
Giving the drug before symptoms set in was effective at lessening them. In fact, the statin even helped after waiting until the peak of the illness, which is a pretty severe test. All this was confirmed on the tissue and molecular levels; the results look very solid indeed.
So how does it work? Probably not through cholesterol lowering per se. But the HMG-CoA reductase enzyme that the statins inhibit produces mevalonate, which is a molecule that does seem to have some effects on immune function. Outside of that whole pathway, statins seem to affect production (although it's not clear how) of a regulatory protein called CIITA. That one's involved in presenting antigens to helper T cells, a process very close to presenting a pack of bloodhounds with someone's dirty sock. So it could be that the T-cell attack on myelin is thrown off at the very beginning.
There are other mechanisms, not mutually exclusive. Statins have also been shown to affect a protein called LFA-1, which is known to be important for T-cell migration. Perhaps even if they're on the scent, they get diverted at the last minute by this pathway. (One way to check would be to use pravastain, which doesn't seem to affect LFA-1, interestingly.)
Unraveling all this is going to keep a of people up late in the lab for some time to come. For now, atorvastatin is going into human trials on MS patients. You can bet that as the mechanism comes more into focus that drug companies will be ready to screen their compound banks again, though. Statins are a very good start in this area, but they don't have to be the last word.
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August 26, 2002
Posted by Derek
I've been meaning to comment on some recent reports in the Wall Street Journal about the lengths that stock analysts have gone to get information on clinical trials. The main example was one David Risk of Sterling Financial (primarily a short-selling outfit, and quite sceptical of official company information.) Back in February, he signed on as a patient in a trial of a sleep-disorder drug from Neurocrine Bioscience, saying that he fit the profile that they were looking for. After his acceptance, he spent his time quizzing everyone he could buttonhole, then bailed and issued a "sell" on the stock. This was based on one verbal report of a bad reaction in one patient.
Other examples in the article had analysts calling the physician in charge of a trial, pretending to be fellow MDs, and asking for details on enrolling patients (while really trolling for inside data.) One Boston outfit, Leerink Swann & Co., pays physicians involved in clinical trials to have "discussions" with analysts (who pay Leerink Swann, of course.) These discussions supposedly don't violate confidentiality agreements, but I'd like to know what useful information could change hands in a conversation that didn't.
This sort of thing strikes me as being over the line. And the thing is, I like selling stocks short. I'm a bear by temperament; my facial expression in the stock market is a permanently raised eyebrow. Investors should view company press releases with suspicion, because most of the time it's fully deserved. Biotech drips with hype and falsely raised expectations. But that doesn't justify this behavior, which is indefensible on several grounds. Legally, the Sterling analyst entered the trial under false pretences, and he had to violate his non-disclosure agreements to write the report he did. If someone wants to make a case out of that, they probably could. I could add that he wasted the time of the administrators of the trial, and that these things are hard enough to run without jokers joining in.
On the scientific side, it's really idiotic to grab onto individual data points the way he did. As it turned out, the patient with the bad reaction to the Neurocrine test drug also tested positive for opiates, and was kicked out of the trial for violating its protocol. His case probably had no bearing on whether the drug was working or not, or how safe it was. It's a recurring pattern, though: the same analyst put out a strongly negative report on a Regeneron clinical candidate for obesity because one patient came down with Guillain-Barre syndrome during the trials. Did this have anything to do with the drug? Causality's a tough question, but the patient had had a recent flu vaccination and an upper-respiratory infection (both of which are risk factors for G-B.) No other patients have had the syndrome. There seems to be no reason to assume a connection between the two.
I can't stress this enough: finding out if a drug is safe is very difficult. Finding out if a drug is effective is very difficult. And that's if you're the one running the clinical trials.The only data that mean anything are those from rigorously controlled studies, done on as many patients as possible. And once the numbers come in, you have to sit down for an extended session of head-banging statistics to be sure that you know what they mean. Sure, you can go around picking out tiny bits of positive news (like some companies do) or tiny bits of negative data (as these examples have done.) But both of these are dangerous, stupid, and irresponsible. The people in the WSJ's article go on about how they're just trying to "uncover the truth." The truth is, they're just as bad as any deceptive PR department.
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June 18, 2002
Posted by Derek
Having unloaded on the Weekly Standardlast week, I now find myself taking aim at the Wall Street Journal. Pretty soon, I'm going to be in the pundit equivalent of Albania (as was,) having ditched my every natural ally.
But it has to be done. The Journal has an editorial today on the Imclone situation - an long impassioned one that starts from false premises and draws incorrect conclusions from them. Let's excerpt the thing:
After starting off by expressing sympathy for cancer patients (and no sympathy for Sam Waksal or Martha Stewart, all perfectly defensible positions,) the editorial calls for "focusing on the FDA's role in this fiasco. . .while Imclone has not produced a study of the size and type the FDA appears to want, the larger truth is that Erbitux continues to show promising results iin small trials."
Note the "appears." Actually, it "appears" that the FDA made its requirements for clinical trials very clear, and it was Imclone that obfuscated. The dispute, which came to light during the recent congressional hearings, centers on the Phase II trial, a combination therapy of Imclone's Erbitux and the current chemotherapy agent irinotecan for colorectal cancer. Originally, as of August 1999, patients were going to get the combination of the two drugs only if their disease had still progressed after two cycles of irinotecan alone. Imclone amended this in October to allow combination therapy after any irinotecan treatment at all, and it appears that the FDA didn't completely catch on. And as it turned out, this plan muddied eventually the data thoroughly enough to make it hard to see if Imclone's drug did anything at all. But it sure did speed things up, which seems to have been what really mattered.
Harlan Waksal of Imclone maintained that they didn't mislead anyone. Minutes of a key meeting in August of 2000, though, showed that the FDA was still under the impression that the original rules applied, and no one from Imclone bothered to correct them. Even when Imclone got "Fast Track" approval in January of 2001, the FDA letter shows their decision was based on the original clinical protocol. No one from Imclone said a word.
And the "larger truth" is that small trials don't mean much. You want meaning, you run a large trial, and you run it the right way, with a design that's capable of distinguishing your drug's effects from random clinical noise. Imclone set everything up to run the fastest, cheapest trial they thought they could possibly get away with, putting the approval of their drug at risk by doing so.
Back to the editorial: "Apparently, the FDA would like Erbitux to show "single-agent activity," even though there is good reason to believe it may work better in combination with traditional chemotherapy drugs." Well, these good reasons turn out to be largely propaganda. Imclone's colorectal cancer trial, as detailed above, relied on giving Erbitux as a combination therapy. When they asked for fast-track approval status, the FDA did indeed get recommendations to turn them down, since the drug had never been tried as a stand-alone therapy. Imclone made great protestations that their drug was not effective by itself, that it had synergistic effects with irinotecan, and that it would be downright unethical to run a trial as a monotherapy. The FDA bought it, and gave them fast-track.
But the data that Imclone backed all this up with wasn't from colorectal cancer patients - it was from renal cancer, which is a very different disease. In January 2001, the FDA (feeling that they'd been had) told Imclone that they needed a monotherapy trial, which they ran. You wouldn't know that from the Journal's editorial, would you? But they ran it in the quickest, shoddiest way possible, with a total of only 57 patients. Six of them responded to Erbitux as a single therapy, but the small number of data points made the results a statistical hairball. Maybe it worked, maybe it didn't.
Sam Waksal told Bristol-Meyers Squibb that this was good news, and that the FDA was pleased with it - but the agency has no record of ever having seen the data at that point, and "pleased" wasn't the right word when it finally showed up. Remember, this study could have shown that Erbitux worked by itself, which would have surprised people after Imclone's earlier statements, but would have been strong data for approval nonetheless. Or it could have confirmed their contention that the drug wouldn't work solo. It did neither, undermining both arguments.
"Too often," the Journal says as the editorial goes into the home stretch, "the FDA simply isn't clear about what a drug like Erbitux has to do to prove itself effective. . ." On the contrary, at least in this case. The record shows that the FDA was quite clear about what it wanted, and informed Imclone in a timely manner. The record also shows that Imclone misled the FDA, their partners at Bristol-Meyers Squibb, and their stockholders at almost every opportunity.
I understand the Journal's reflexive small-government postion, and I sympathize with it most of the time. But this isn't the big regulatory agency beating up on a poor company that only wants to help sick cancer patients. This is a company with their eye on their own stock options, playing games with the data to try to get their drug through as quickly as possible. They took stupid, unacceptable risks by doing so. To use the Journal's formulation, they played these games with the health and hopes of the terminally ill. I've no sympathy for Imclone at all. No one should.
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