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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

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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September 14, 2010

A New Way to Approve Drugs

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Posted by Derek

Who are our customers in this drug business? Well, sick patients, naturally. But their physicians, too, since they're the ones who will be writing the prescriptions. And the insurance companies, of course, since in most cases they're the ones who will be paying at least some of the bill. But the customer before we get to all that is the FDA.

Not many other industries have a gatekeeper that absolute. Every product has to be submitted and given an explicit, detailed review, with a thumbs-up or thumbs-down at the end of it. Imagine a car maker putting together a New Model Authorization package for each new model of light truck for Approval To Sell in the fall, or waiting for the Committee On SUVs to define the review criteria for Truck-Like Four-Door Crossovers before any of them can be sent to the dealers. A fast food chain wants to offer a new Double Taco Burger? Fine - submit the paperwork, and the agency will get right on it. The review committee on Fake Mexican Entrees meets in March.

The reasons for all this are no mystery. Anything that can directly affect a person's health, in either direction, is going to have a lot more oversight than the new Double Taco Burger, which will probably not kill you, although you may wonder about that forty minutes later. But given that we're going to have a large, complicated regulatory regime for new drugs, do we have the right large, complicated regulatory regime?

Steve Usdin and the team at BioCentury have a good article out that asks just this question. Since we were talking around here about the conditional approval for Avastin in metastatic breast cancer, that's a good example of how this new system might work: instead of binary decisions, the whole thing is adaptive.
Adaptive%20regulation.jpg
The idea is to set things up so that decision-making data can be generated more quickly, and so that these decisions can be modified based on later findings. The big push in the early phases of the clinic would involve biomarkers - and yes, I know that everyone's been trying to do that, with rather mixed success. But the plan here is not to add on biomarker work, but to make it an integral part of every clinical program, with stored samples (and incentives to share them), and a clear regulatory framework for what the FDA wants to see in each case.

But since biomarkers aren't easy to come by, the next part of the plan is wider use of conditional approval and adaptive clinical trials. Another way to speed things up with adaptive designs would be to run several new therapies in a given space simultaneously, re-assigning patients as the more effective candidates show themselves. If the trials are going on continuously, the barriers to getting in on them would be lower than they are under the current system, where everyone has to start their own work from the ground up. Again, the idea is to be able to make some sort of decision as early as feasible, with the option of going back if later data don't pan out. (That's the key mental adjustment in the whole thing, actually - the willingness to act on the belief that, if done well, enough of these early decisions will turn out to be the right ones to outweigh the ones that aren't).

Conditional approval would have to be coupled with restrictions on marketing until more data came in - you couldn't just go crazy as soon as possible. But it would work both ways - a company would get wider authorization as the numbers got better, or would have to narrow things down or even pull a compound altogether. This would be a big adjustment for the public to make, frankly - I can already see the editorials going on about making the entire American public a group of test subjects, and so on. But you know, they already are: every compound that makes it to market is still an investigational drug, no matter what anyone might think.

There's more at that BioCentury link, and I encourage anyone who's interested to read it all. I think that there's a lot of merit in these ideas myself, although getting them implemented in the real world won't be easy. There's also the worry that half-implementing them would leave us with a system that's no better (or subtly worse) than the one we have now. Thoughts?

Comments (13) + TrackBacks (0) | Category: Regulatory Affairs


COMMENTS

1. Dennis on September 14, 2010 9:18 AM writes...

Do Double Taco Burgers exist? If so, where can I obtain one?

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2. eCurmudgeon on September 14, 2010 10:25 AM writes...

Imagine a car maker putting together a New Model Authorization package for each new model of light truck for Approval To Sell in the fall, or waiting for the Committee On SUVs to define the review criteria for Truck-Like Four-Door Crossovers before any of them can be sent to the dealers. A fast food chain wants to offer a new Double Taco Burger? Fine - submit the paperwork, and the agency will get right on it. The review committee on Fake Mexican Entrees meets in March.

Actually, I can imagine such a thing, and surprised that the EPA, DOT and FDA aren't actively pushing for it...

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3. barry on September 14, 2010 11:44 AM writes...

without re-inventing the whole approval structure, we could (and should)see more conditional approvals in the current FDA. Every time a drug goes to market based on a surrogate clinical endpoint, approval should be conditional on finding real clinical benefit in Phase IV.

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4. DylanE on September 14, 2010 12:17 PM writes...

I'm doing some work with a small IT company that is focused on designing software for clinical trials that tries to address these problems. The idea is to take all these different silos of data that spring up during a clinical trial and standardize it (using CDISC standards) so that it can all be integrated and analyzed much more quickly, and also hopefully allow you to see things that you might have otherwise missed (or at least not seen until it was too late).

They are not the only ones working on this of course, and it really isn't my area of expertise, but I am interested in the potential for IT to make even marginal improvements in clinical trial efficiency.

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5. Todd on September 14, 2010 12:58 PM writes...

Dennis: Thanks for Google, I've found a chain called Taco Mayo in Oklahoma that will sell you a Double Taco Burger. :) For locations, visit http://www.tacomayo.com.

As for the adaptive clinical trial issue, I think it could work very well. I also think it would have the salutatory effect of getting drugs with smaller markets or limited indications on the market, if only so companies can try to push this into wider markets through clinical trial success. Also, I think it would avoid a lot of the major damage that's done when big drugs hit patent cliffs, if only because you have more drugs providing revenues and ultimately funding R&D work.

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6. S. Pelech - Kinexus on September 14, 2010 1:40 PM writes...

A more adaptive system for regulatory approval of drugs has clear merit. However, it is possible that drugs used for treatment of chronic conditions might have much wider dispersion before it is realized that they can have very serious longer-term side-effects in a significant portion of users. The story with the eventually withdrawal from the market of COX-2 inhibitors like Vioxx (rofecoxib) exemplifies such a problem.

Personalized medicine is becoming more of a reality with improved genomic and proteomic tests with the discovery of larger panels of robust and reliable biomarkers. However, it will also become increasingly important to test combinations of complementary drugs that can simultaneously address the multiple defects that arise in cancer and other diseases. Monotherapy appears to produce only a transient relief for most forms of cancer, and eventual drug resistance is a common result. It appears that the opportunity for drug resistance is effectively mitigated with combination therapy, as has been so well demonstrated for the treatment of AIDS with three drugs used together.

Clinical testing of drug combinations will be extremely difficult as the number of possibilities escalates with the appearance of promising new drugs and the number of available patients for a specific trial declines with the identification of more specific genomic/proteomic profiles in which to stratify them. It may make sense for pharmaceutical companies to continue testing their drugs in large patient groups, but submit their drugs for approval with the data from those patients that shared biomarkers where there are clear efficacious results without deleterious effects.

Whatever changes in regulatory drug approvals may be forthcoming, they will need to permit a better assessment of combination therapy. Foremost, it should be clear that individual drugs are proven safe in healthy volunteers and cause no harm to intended patients. Thereafter, the beneficial synergistic effects of drug combinations applied in a rational manner can be determined.

While individual patients would still need to be tested for their unique responses to a combination of drugs, at least they can be treated based on their unique circumstances and not on findings for the general population.

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7. MLBpitcher_and_MedicinalChemist on September 14, 2010 1:50 PM writes...

Good job Derek, you got 12 strikeouts against the Nationals yesterday while pitching 8 innings of four hit, no walk, no run baseball.

How many medicinal chemists or organic chemistry PhDs can claim they struck out 12 Major League batters in game, pitched a no-hitter, and won a World Series? Only Derek Lowe! Most medicinal chemists, unlike yourself, are losers who didn't discover a drug that made it to market.

Returning to the actual topic, I remember reading about nine months ago an article by Bernard Munos which cited something that claimed that strict regulation from the FDA is beneficial to drug companies and makes them more competitive globally. The imprimatur of the FDA is valued because it is selective and drugs that have not passed through a strict regulatory regime would not be consumed globally. FDA regulation imposes a barrier to entry to bring a drug to market, since many firms do not have the capital necessary to invest in trials that have high statistical power.

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8. Hap on September 14, 2010 3:32 PM writes...

Please tell that the McRib can get an accelerated approval, or that it's grandfathered in.

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9. Fake Name on September 14, 2010 6:24 PM writes...

Just came across this article (hagiography?) in the NYT about Frances Kelsey

http://www.nytimes.com/2010/09/14/health/14kelsey.html

Though she did pioneering work regarding elixir sulfanilamide and thalidomide is the legacy of FDA approval of every drug (or even the process of approval) an unalloyed good? The tone of the article suggests that every FDA regulation is good and any deregulation or even change is bad. Since you are a practicing industrial chemist I would like to hear your thoughts on the article.

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10. Kevin on September 14, 2010 11:37 PM writes...

I would rather FDA approve drugs based on safety and quality. Thereafter, physicians and insurers can decide whether the drugs are efficacious by paying for what works. If a drug doesn't make it to a formulary, then it dies.

Obviously, the system would not be as simple as I've described it.

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11. Yawn on September 15, 2010 3:58 AM writes...

Please give it up #7 - you are painfully boring and not in the slightest bit amusing.

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12. ole ginger on September 15, 2010 4:57 AM writes...

I guess some recent experience in the biomarkers field could be relevant in this context. Take a look at http://www.nature.com/nbt/journal/v28/n5/full/nbt.1625.html for an interesting paper by the Predictive Safety Testing Consortium and the FDA discussing how progressive
(‘incremental’, ‘rolling’) biomarker qualification could work in practice. Similar principles might be applicable with respect to drugs, too.

Permalink to Comment

13. Anonymous BMS Researcher on September 15, 2010 6:21 AM writes...

7. MLBpitcher_and_MedicinalChemist on September 14, 2010 1:50 PM wrotes...

...strict regulation from the FDA is beneficial to drug companies and makes them more competitive globally. The imprimatur of the FDA is valued because it is selective and drugs that have not passed through a strict regulatory regime would not be consumed globally. FDA regulation imposes a barrier to entry to bring a drug to market, since many firms do not have the capital necessary to invest in trials that have high statistical power...

This is an important and under-appreciated point. Some years ago at an industry meeting I heard an extremely interesting talk by a patent lawyer about how FDA approval is really another type of intellectual property, but that greater transparency by FDA could increase the social benefit of this IP. Her main point was that most forms of IP are social bargains of some type. For instance the fundamental purpose of patents is to encourage prompt publication of inventions, because in societies without effective patent systems inventors keep their ideas secret and much knowledge dies with its inventors (there are many ancient technologies about which we know very little precisely because their makers kept them secret). In the case of FDA regulation, the purpose is to protect patients from unsafe drugs -- before we had such regulations there were some very dangerous drugs on the market. But she said an equally important consequence of FDA regulation was forcing companies to generate high-quality scientific data that would pass muster with skeptical experts. So, she said, we need to change our thinking: the social tradeoff is "drugmakers, you get the FDA imprimatur in return for generating high-quality data." Therefore, she argued, the data submitted to FDA represent a major portion of the social benefit from our current regulatory regime.

However, she said, there is one major flaw in the current system: much of the data provided to FDA by drug companies are currently proprietary and therefore not available for outside researchers to mine. Of course, she acknowledged, some data do need to be confidential to protect the rights of companies. But she felt the current system is out of balance, and shifting that balance towards releasing more data sooner would have social benefits vastly exceeding the cost to companies of greater transparency.

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