Corante

About this Author
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

Chemistry and Drug Data: Drugbank
Emolecules
ChemSpider
Chempedia Lab
Synthetic Pages
Organic Chemistry Portal
PubChem
Not Voodoo
DailyMed
Druglib
Clinicaltrials.gov

Chemistry and Pharma Blogs:
Org Prep Daily
The Haystack
Kilomentor
A New Merck, Reviewed
Liberal Arts Chemistry
Electron Pusher
All Things Metathesis
C&E News Blogs
Chemiotics II
Chemical Space
Noel O'Blog
In Vivo Blog
Terra Sigilatta
BBSRC/Douglas Kell
ChemBark
Realizations in Biostatistics
Chemjobber
Pharmalot
ChemSpider Blog
Pharmagossip
Med-Chemist
Organic Chem - Education & Industry
Pharma Strategy Blog
No Name No Slogan
Practical Fragments
SimBioSys
The Curious Wavefunction
Natural Product Man
Fragment Literature
Chemistry World Blog
Synthetic Nature
Chemistry Blog
Synthesizing Ideas
Business|Bytes|Genes|Molecules
Eye on FDA
Chemical Forums
Depth-First
Symyx Blog
Sceptical Chymist
Lamentations on Chemistry
Computational Organic Chemistry
Mining Drugs
Henry Rzepa


Science Blogs and News:
Bad Science
The Loom
Uncertain Principles
Fierce Biotech
Blogs for Industry
Omics! Omics!
Young Female Scientist
Notional Slurry
Nobel Intent
SciTech Daily
Science Blog
FuturePundit
Aetiology
Gene Expression (I)
Gene Expression (II)
Sciencebase
Pharyngula
Adventures in Ethics and Science
Transterrestrial Musings
Slashdot Science
Cosmic Variance
Biology News Net


Medical Blogs
DB's Medical Rants
Science-Based Medicine
GruntDoc
Respectful Insolence
Diabetes Mine


Economics and Business
Marginal Revolution
The Volokh Conspiracy
Knowledge Problem


Politics / Current Events
Virginia Postrel
Instapundit
Belmont Club
Mickey Kaus


Belles Lettres
Uncouth Reflections
Arts and Letters Daily
In the Pipeline: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

In the Pipeline

« Generex: Who Buys This Stuff, Anyway? | Main | C&E News - A Few Questions »

April 16, 2010

A Landmark In Clinical Trial Data Interpretation

Email This Entry

Posted by Derek

You know, let's just declare this "Sketchy Biotech Day" around here. A reader sends along this intriguing news item from Maryland regarding Rexahn Pharmaceuticals. They recently reported clinical data on their lead compound, Serdaxin,:

On Tuesday, the Rockville company reported the drug performed well in a phase 2a clinical trial for treating patients with one such ailment: major depressive disorder. But the announcement also said "the overall study did not achieve statistical significance," worrying investors and sending Rexahn's stock price tumbling from $3.53 to $1.76 that day.

Wednesday morning, executives felt compelled to issue a follow-up statement, offering "additional commentary, clarifications and insights" to allay investors' concerns. That apparently did the trick — at least somewhat. By the end of trading on Wednesday, the price had rebounded to $2.15. By Thursday morning, shares had climbed to $2.51; they were trading at $2.47 Thursday afternoon.

In its initial statement, Rexahn said that results from the trial, which enrolled 77 patients at several sites in the U.S., "are compelling and warrant further study in a larger phase 2 trial."

Well, to me, "compelling" clinical trial numbers are a hard thing to sell without the statistics to back them up. But that's not slowing these folks down. Here I offer you what is perhaps the most breathtaking rationalization I have yet heard about drug development - and mind you, that is saying a lot. Says Rexahn's CEO:

"Based on the feedback and reaction from our shareholders, stakeholders and other market participants, it is clear that neither the purpose of the Serdaxin trial or its results were well understood.

"The purpose of the Serdaxin Phase IIa trial was to establish, as a proof of concept, that Serdaxin can work as an antidepressant drug for patients suffering from Major Depressive Disorder," Ahn said. "I am happy to say that this is exactly what the study accomplished. The trial results unambiguously reach the conclusion that patients, especially those suffering from severe depression, respond positively to Serdaxin.

"Some market participants have asked us why our overall trial results were not statistically significant," he said. "The answer is simply that the Serdaxin study was never designed to achieve statistical significance as a primary objective, but rather to establish a positive signal among treated patients. This is exactly what the trial succeeded in accomplishing."

So here you have it: a clinical trial that was, apparently, not designed to show statistical significance. And it didn't! Champagne for everyone! Think of how many other drugs have had results just this compelling, but we've all just been too stupid to realize what we had. Throw open the pharma mausoleums and let the dead compounds come forth!

Perhaps some day we'll all look back on this event as the Day the Drug Industry Changed Forever. Or perhaps it's time to ask just what Serdaxin is. . .well, you'll never guess. It's clavulanic acid. (See, I told you that you wouldn't get it). Yep, the beta-lactamase inhibitor that's given as part of Augmentin, to overcome resistant strains of bacteria. Weirdly, it does seem to penetrate the blood-brain barrier, which is not something I would have guessed. And the Rexahn people have done some animal studies that suggest it has anxiolytic effects (as well as effects on sexual arousal, which they're not ignoring: that, friends, is the drug development candidate Zoraxel on their web site. Still clavulanic acid, though, but a rose by any other name. . .).

But none of that means a thing unless you achieve results in humans. And though I hate to contradict such a visionary mind as Dr. Ahn's, I'm afraid I'm going to have to hold out for statistical significance. And wonder, in the meantime, if any of the zillions of people who've taken clavulanate before ever noticed any elevation in their mood. Never happened to me, that's for sure. . .

Comments (53) + TrackBacks (0) | Category: Clinical Trials | Drug Development | Infectious Diseases | The Central Nervous System


COMMENTS

1. Anonymous on April 16, 2010 12:20 PM writes...

Jay Leno has never been this funny.

Permalink to Comment

2. Russ on April 16, 2010 12:24 PM writes...

When the merger of SK&F Labs with Beecham was consumated in 1990, we were intrigued to discover that 50% of Beecham's compound collection was everything they made paired with clavilinic acid.

Permalink to Comment

3. Sili on April 16, 2010 12:33 PM writes...

Seventy-seven patients? In a trial of an antidepressant? Words fail me. And I'm a bad chemist.

And they're using a last resort antibiotic for this?

Gah!

Permalink to Comment

4. Hap on April 16, 2010 12:35 PM writes...

I would have said that Leno wasn't quite so costly, but with the O'Brien snafu, I'm not sure that's correct.

Of course, given some of the complaints about statistical analysis (for example, see "Odds Are, It's Wrong"), maybe the definition of statistical significance in that study might not be right. You would, however, like to have some idea that a drug does what you claim, rather than a strong wish that your investors will continue to fund its development until you need to cash out.

Someone on Pharyngula defined science (or quoted someone else who did) as a set of techniques that make it difficult for you to fool yourself. Apparently this subset of the world of biotech finance (and maybe relevant subset of finance in general) is a set of techniques designed to foster self-delusion and fool your investors. If this is what the economy of the future is for the US, then I think we're officially screwed.

Alternatively, it's not funny enough (or probably liberal enough) for an Onion article.

Permalink to Comment

5. anon the II on April 16, 2010 12:50 PM writes...

OK, I've finally figured it out. We've all been wondering why the pharma industry is going down the tubes. Many of your readers are out of work and the patent cliff is looming large. We've speculated that there are no more targets left to hunt. I don't believe that. I've been trying to find one thing that connects all the pharma companies, in spite of what I've seen are vastly different cultures and approaches. What was "the Day the Drug Industry Changed Forever?" I believe it was the day DTC (direct-to-consumer) pharma advertising started. It marked the slow but sure descent from rational to the crap you've been talking about for the last few days on this blog. And it's not just the goofy small caps. The Novartis announcement was as bad as any. When the marketers took over, it was only a matter of time.

Rexahn Pharmaceuticals isn't quite as slick at it as the big guys, but they're all the same people. People that can look you in the eye, lie to your face and smile.

Anyhow, that's what I think.

Permalink to Comment

6. Christian Hesketh on April 16, 2010 12:54 PM writes...

I think I just threw up in my mouth a little. Ahn should be hung up by his balls.

Permalink to Comment

7. Anonymous on April 16, 2010 1:20 PM writes...

The CEO's comments are a lot more therapeutic than the drug itself for depression.

Permalink to Comment

8. Ron Bernotas on April 16, 2010 1:22 PM writes...

Note that the company name is Rex (king in Latin) and Ahn (!). Ahn is king! Long live the king!

Permalink to Comment

9. Skeptic on April 16, 2010 1:51 PM writes...

Why can't the chemists understand that all the consumer demands is:

a) NUMBER of studies backing up a claim
b) CELEBRITY to state the claim is true
c) NATURAL PRODUCT "goodness"

And if you try to contest it in court, the corporate goons will drag in "experts" from the independent statistics department of a university and in no time at all it will be "scientifically proven".

So there it is...lets shut down the physics, chemistry, etc departments because all we need for stable employment is that magical Universal Statistical Language where you can prove anything you want in a court of law.

The Consumer will be chock full of nanoparticle goodness in no time at all. Heh, solves the SS problem too.

Permalink to Comment

10. Pharma Conduct Guy on April 16, 2010 2:06 PM writes...

Some market participants have asked us why our overall trial results were not statistically significant,’ he said ‘The answer is simply that the Serdaxin study was never designed to achieve statistical significance as a primary objective, but rather to establish a positive signal among treated patients.  This is exactly what the trial succeeded in accomplishing.

Truly, this is one of the most stunning statements I have ever heard from the CEO of a pharma/biotech.  In most cases, the BS is apparent, but at least they go to some length to give the appearance of not insulting your intelligence.  Not here though.

Who in their right mind designs a study to have positive endpoint that is not statistically significant.  What does that even mean anyway?  That's like saying We designed the study not to see who would get well when treated, but to see who recovered from the illness after treatment.

Can't you just envision CEO Chang Ahn traveling the countryside in a painted wagon saying “Step right up and get yours right now!  It's available until sundown, so you better get act quickly!

Permalink to Comment

11. dearieme on April 16, 2010 2:15 PM writes...

"When the marketers took over, it was only a matter of time." Do you know, my brother says just the same thing about his industry - pensions.

Permalink to Comment

12. anchor on April 16, 2010 2:19 PM writes...

'Anti-depressing" news not withstanding, seems to me that happy days are here again for Rexhan Pharmaceuticals, if the latest information are to be believed. Rexahn plans to present data from animal studies on its oncology compound RX-8243 at the American Association for Cancer Research (AACR) 101st Annual Meeting, to be held in Washington, D.C., April 17-21, 2010, at the Walter E. Washington Convention Center. Does any one know the structure of this compound?

Permalink to Comment

13. Skeptic on April 16, 2010 2:20 PM writes...

Barry wants to bulldoze the suburbs over and get the peasant farmer thing going...thats Amerika's future. Look where the nuclear reactors are being built...it aint around here.

First, the useless F.I.R.E (Finance, Insurance, Real Estate) industry has to lay a guilt trip on the scientists and engineers...Sorry folks, you just don't cut it anymore.

It is time to learn how the banking system really operates, your very future depends on it.

Permalink to Comment

14. RandDChemist on April 16, 2010 2:46 PM writes...

An excellent example of why the pharmaceutical industry struggles and has a credibility gap.

This stuff makes my brain hurt from all of the rationalization.

Let's assume what has been stated by company is true, namely that they did not seek statistical significance.

That begs the question: "Why not?"

Psychoactives are a black box, to say the least (in my experience). But still....

Permalink to Comment

15. milkshake on April 16, 2010 2:59 PM writes...

I never noticed mood-elevating effects of Augmentin on myself. It did not elevate for me anything else anywhere else either. Which is unfortunate because being a good cheer and priapic too would make my bronchitis lot more interesting.

Permalink to Comment

16. David P on April 16, 2010 3:04 PM writes...

@8: it is good to be the king.

Plus you get to make up all sort of new rules, like what your clinical trial data shows.

Permalink to Comment

17. partial agonist on April 16, 2010 3:13 PM writes...

There ought to be a lot of placebos on their shelves that shareholders will be plenty excited about that have no statistically significant effects either.

Since the stuff is a natural product, maybe they can get Jenny McCarthy and Jim Carrey on board talking about the wonders of something coming straight from mother nature (and conveniently ignoring all of those toxic things that also come straight from mother nature).

Permalink to Comment

18. TFox on April 16, 2010 3:15 PM writes...

This is actually a nice little stats problem, interpreting their press release. (Not a real statistician, but I've done some reading. Full disclosure: I've never heard of Rexahn before.) 77 patients, in an anti-depression trial, sounds underpowered to me. So even in the best case, a wildly effective drug, I think you wouldn't be surprised to not achieve significance on the primary endpoint, since the signal in the drug group gets washed out by responders in the control group. Ideally, as I understand trial design, you first pick a minimal level of clinical significance, then you make sure your study is large enough that even a drug which is only barely clinically significant can still be demonstrated to be statistically better than placebo. This ensures that if your drug is good, you can show it's good, and if you can't show it's good, then it's not good enough to bother with anyway. An underpowered study doesn't do this -- effective drugs, tested badly, can end up indistinguishable from placebo. So why would you ever run an underpowered study? I can speculate. Maybe you're a little dubious about your hypothesis, that a beta-lactamase inhibitor could be useful for something else, and you'd like to peek at some human data first before you write the big check. You don't expect overall significance (you're underpowered, remember!) but you may still see some suggestive trends, maybe a significant subgroup, anything. However, if the numbers are about the same or worse than placebo, your hypothesis now looks less likely (in a Bayesian sense), and maybe now you can save some money by not doing the correctly powered trial. If the results look suggestive, as you hope they do, you can use them to help support the case for a properly powered trial.

So that's how you can be pleased even if your drug failed statistical significance. I guess we could call it a pilot study -- here's a review on pilots which complains about misplaced emphasis on statistical significance. They are kind of dangerous to run, though, since it's so easy for failed significance tests to be misinterpreted.

Permalink to Comment

19. partial agonist on April 16, 2010 3:31 PM writes...

Quiz: What was voted the best place to work in all of the Czech Republic?


drum roll...

Pfizer!


Hmmmm... Is that a reflection of things being really really bad over there?


go to

praguemonitor-DOT-com/2010/04/16/pfizer-nutricia-voted-best-employers-year

replacing "-DOT-" with a dot

Permalink to Comment

20. snoddas on April 16, 2010 4:00 PM writes...

People, I think you are a bit too hard on these guys.

In a small biotech company where money is tight and every day is a struggle for survival, it is necessary to stay upbeat about doomed project in order to generate some cash so that you may live to fight another day. It is not pretty, but that's the way the game is played. Don't be condescending just because you are used to being backed by the resources of a major pharma company.

The funny thing is, at a time when most pharma companies seem to be cutting early R&D and instead plan to obtain their drugs through in-licensing, small biotechs such as this one may be our only hope to get any new drugs at all in the future...

(I work in a small biotech myself, though not in the pharma area...)

Permalink to Comment

21. SteveSC on April 16, 2010 4:49 PM writes...

I agree with TFox: 77 patients is a pilot study. Don't know why they didn't use that designation, but probably their investors told them they didn't want to fund a full blown trial of a 1,000+ patients without SOME evidence that it might work.

Unlike in a big company, where you get a trial in the budget and can design intermediate assessments every year to justify further funding, these guys probably have to raise the money for the whole trial up front. You can't start a multiyear trial in a startup environment with only a year of two of funding--if the environment changes you could fail to raise new funds whether or not the trial was meeting intermediate goals, so no investor wants to put up early money for that scenario.

Permalink to Comment

22. sore arse on April 16, 2010 5:09 PM writes...

My only memory of taking large doses of clav via high dose antibiotics following dental work was sitting on the bog for hours with appalling shits - no mental wellbeing or hard ons recalled....

Permalink to Comment

23. JD on April 16, 2010 6:10 PM writes...

TFox: That is an optimistic interpretation.
You can control for antidepressant placebo responders with EEG and/or washout, but this study appears to be unpublished, so who knows what they did.

They also claim acute action in their patents. Compare to a response rate of 80-90% for true acute antidepressants like IM ketamine.

Permalink to Comment

24. milkshake on April 16, 2010 6:57 PM writes...

#22 the diarrhoea was likely an effect of microbial flora in your gut getting nuked, broad-spectrum antibiotics have this liability. Unlucky people can end up with a bad case of clostridium colitis

Permalink to Comment

25. Anonymous BMS Researcher on April 16, 2010 7:11 PM writes...

Well, at least they know their compound is safe (since zillions of people have taken augmentin we'd surely know if it's not safe).

Milkshake is right, diarrhea is a common side effect of many antibiotics because they upset the ecological balance inside your gut (with next-gen sequencing we're learning the ecology inside a person's gut is much more complex than anybody had suspected). Some years ago my mother got a bad case of Clostridium difficile that way. She lost a lot of weight and later joked about the "C diff diet plan: lose 30 pounds in six months."

Permalink to Comment

26. Anonymous on April 16, 2010 8:29 PM writes...

Re: snoddas - "People, I think you are a bit too hard on these guys..."

Look, if it don't work, it don't work. The biggest mistake investors make is looking at sunk cost to rationalize zero future value

The molecule is dog so forget about it. Regardless of what the snake-oil CEO says.

Or do you have an alternative investment strategy based on the stats?

Permalink to Comment

27. Pharma Conduct Guy on April 16, 2010 11:38 PM writes...

Just looking over the press release gives me an unsettled feeling. Anytime someone uses the phrase "but our subgroup analysis showed...," you can usually replace it with "well, we didn't find what we were looking for, so we just started looking for as many things as possible until we found something to talk about".

The article that Hap cited (see #4 Odds Are, It's wrong) gives an excellent overview of the false discovery problem to which I am alluding. Because of the work I do in systems biology, I frequently have to give people the bad news that the great result from their -omics experiment is likely a false discovery.

They don't like hearing that, especially when they've got an anxious board of directors all fired up. I try to tell them as gently as possible that the truth will come out regardless.

Permalink to Comment

28. john on April 17, 2010 9:50 AM writes...

Derek, I'm going to have to agree with TFox, I think you mis-called this one.

An analysis published in the Jan 2008 issue of the NEJM analyzed clinical trial data submitted to the FDA as part of the NDA process for 12 APPROVED antidepressants. The authors found that almost 50% of these clinical trials gave negative results, but that these negative results were extremely unlikely to be published. Coming from large companies, there was no need for a press release around these unsuccessful trials, as they were not "material" to the stock price.

There is a HUGE placebo effect in trials of CNS agents, and one does not really expect to see statistical significance in a trial of this size. But one does not need p


Permalink to Comment

29. John on April 17, 2010 9:52 AM writes...

the rest of my post above should have read:

There is a HUGE placebo effect in trials of CNS agents, and one does not really expect to see statistical significance in a trial of this size. But one does not need p

Permalink to Comment

30. John on April 17, 2010 9:54 AM writes...

OK, I think there is a technical problem here

Permalink to Comment

31. g on April 17, 2010 10:23 AM writes...

I agree with John and tFox. The company missed the mark in explaining the purpose of the trial.

While it doesn't mean this drug works, it doesn't mean that the drug doesn't work. This makes me wonder why they publicized the trial. This trial may have been designed just to figure out a reasonable dose to give in a larger trial and if adverse-effects pop up at that dose.

Antidepressant trials are notoriously difficult because of a huge placebo effects (ie 25%). It is getting even harder to show significance because it seems the placebo effect is getting LARGER.

Here is a paper where they talk about that pesky placebo effect.

Ann Pharmacother. 2003 Dec;37(12):1891-9.
Meta-analysis of placebo rates in major depressive disorder trials.
Stolk P, Ten Berg MJ, Hemels ME, Einarson TR.

Permalink to Comment

32. chris on April 17, 2010 11:07 AM writes...

Clinical trials in depression are notorious for placebo effects, as others have said this was a pilot study in 77 patients I would have been suspicious if they had seen a statistical significance.
Unfortunately it sounds like they rather over played the news.

Permalink to Comment

33. SteveM on April 17, 2010 12:06 PM writes...

The real subtext of the CNS trials is statistical significance versus clinical significance. Pharma sells stat significance when the clinical significance may be marginal.

Big Pharma pumps out dozens of me-too CNS drugs with little additional clinical value over generics and charges big bucks for them. And their rationale when selling to docs? Why "statistical significance" of course! Forget the clinical me-too-ness.

Here's a nice little tutorial on how CNS clinical numbers are gamed:

http://clinpsyc.blogspot.com/2009_12_01_archive.html

You can scroll through the guy's blog and read about other Big Pharma shenanigans that permeate the psychotropic marketing space.

Permalink to Comment

34. john on April 17, 2010 1:59 PM writes...

I think the problem here is that for a small company, the results of a phase 2a trial are material to the stock price, therefore they must publicize the results. For a larger company, this trial would not have been the subject of a press release.

Permalink to Comment

35. John Johnson on April 17, 2010 4:12 PM writes...

A failure of statistics as a profession is this obsession with reaching statistical significance. At Phase 2a (at least if it is a real Phase 2a study), there is absolutely no way to design it to achieve statistical significance, for the simple reason that it is nigh impossible to take in vitro, animal, and preliminary safety data (usually in healthy subjects) to take into account enough reliable information to design such a study. If you did, forget Phase 2a and shoot the moon for Phase 3 (I've seen people try under these conditions, and fail for various reasons often taking millions of dollars into the trashcan of R&D with it).

Phase 2a is where you start collecting the data where you can design studies to "achieve statistical significance." I guess Rexahn investigators skipped over the Phase 2a part of the press release and saw just the "didn't achieve statistical significance," where they dropped their coffee, speed-dialed their broker yelling "Sell! Sell!"

Insanity. I guess Rexahn learned a lesson here. If a study isn't designed for statistical significance (i.e not enrolling according to a statistical power calculation), don't mention significance in the press release.

Permalink to Comment

36. g on April 17, 2010 6:15 PM writes...

About the "me too" antidepressant drugs. At first blush, it is a waste to try the branded vs. generic antidepressant of the same class. However, "me too" does not mean the same as. There are differences in the side-effect profiles (although big ones stand out in the class ie SSRI's with sexual side effects). And sometimes people will respond well to escitalopram but not to fluoxetine.

Doctors are aware of pricing issues and will prescribe the generic first. If it doesn't work for the person or has intolerable side-effects, they'll consider a branded drug.

Major depression refractory to treatment is still a huge issue, especially in chronic, recurring major depression. With the current drugs, 50% don't get a benefit with monotherapy and have to go to polytherapy. Maybe 30% don't really get a benefit with that. Then you have to start messing around with antipsychotics and antiepileptics. If that doesn't work, then electroconvulsive therapy (ECT) or vagal nerve stimulation.

So for 70% of the population of depressed patients who only experience one or two lifetime major depressive episodes, generics will work. For the remaining 30%, they'd pay anything for a new, branded drug that would help them out of the pit of depression.

Permalink to Comment

37. fungus on April 18, 2010 6:53 AM writes...

There's nothing quite like watching to see where something lands and then drawing a bulls-eye around it.

Permalink to Comment

38. bbooooooya on April 18, 2010 12:05 PM writes...

"Phase 2a is where you start collecting the data where you can design studies to "achieve statistical significance.""

Wow, that is a lot of stupid. The path to FDA approval of a MDD drug is simple: show benefit in MADRS and HAMD-17. This may be challenging statistically in 77 patients, but as long as efficacy of drug is well enough separated from placebo, there is no reason for the statistics not to work.

Permalink to Comment

39. MIMD on April 18, 2010 1:24 PM writes...

Hey, we shouldn't complain! We're about to spend $1 trillion on electronic medical records, and nobody's shown them to do much to any degree of statistical significance, either...

But the P.R. is wonderful!

Permalink to Comment

40. Lou Zmyjob on April 18, 2010 10:33 PM writes...

Pfft. Preparation H for MS.

Permalink to Comment

41. cliffintokyo on April 19, 2010 3:29 AM writes...

#37 Spot on.
Is this what you get when you bring in marketing *expertise* too early in the R & D process?
(Control-freak wreaking freaking havoc!)
Spectacularious!!

Permalink to Comment

42. partial agonist on April 19, 2010 9:34 AM writes...

I assume that all of us in drug discovery have sat in on the project meeting where the pharmacologist shows an early animal study and the raw average values for the treatment group and the raw average values for the control group are clearly different in the direction that we want to to be, and yet the error bars overlap.

We all look at the data and say "Hmmm... that looks very interesting, all that we probably need to do is to get a bigger "n" to get really good data- can you use 20 rats instead of 5 and try it again, now that you have the procedure down?

This seems to be the spirit of the in-house analysis of the clinical data. I would think, however, that such data is important enough that the trial design has enough stringent patient selection criteria and sufficient "n" values that such an argument would not need to be made, even for a CNS drug. I don't think you plan a trial here a likely outcome is "hmmm... interesting, but like we expected, there is not a high enough n to tell for sure"

Permalink to Comment

43. john on April 19, 2010 12:31 PM writes...

I think john johnson nailed this question in post 35. There is absolutely no way to design an apprpriately powered study without preliminary human efficacy data of the type normally collected in a small phase 2 trial. Nor does one want to fund a 1000 patient pivotal trial without some preliminary evidence suggesting efficacy.

Permalink to Comment

44. rb on April 19, 2010 12:58 PM writes...

A typical Phase 3 trial for MDD would incorporate 100 patients or more per arm (3 doses + placebo, n=400) for the hope that 2 out of 3-4 or even 5 trials might demonstrate efficacy. So, as you see, the statement is not so absurd as it might first appear to be (although the understanding of how to communicate this reality was clearly lacking).

Permalink to Comment

45. David L on April 19, 2010 2:37 PM writes...

TFox at #18,

I agree with you from a statistical standpoint. It's possible with a high degree of variability in the signal and small size of effect you'd want to see from the control group, that the population size to statistically prove this is much larger than 77. So that means the effect is small or the noise is large (or both). But clinical data lives and dies by the satistics so talking about a nonstatistical effect still doesn't mean the drug stands a chance of surviving to the market.

Permalink to Comment

46. rjs9787 on April 19, 2010 9:53 PM writes...

From Mr Lowe's article: "In its initial statement, Rexahn said that results from the trial, which enrolled 77 patients at several sites in the U.S., "are compelling and warrant further study in a larger phase 2 trial."

That is not quite what Rexahn stated in their comments regarding the results of the trial. They said: "The results of the subgroup analysis are compelling and warrant further study in a larger phase 2 trial." To me, Mr Lowe made it look like Rexahn was talking about overall results, since he chose to omit the words "subgroup analysis".

Mr Lowe then states "Well, to me, "compelling" clinical trial numbers are a hard thing to sell without the statistics to back them up."

However, Rexahn did offer the results of the subgroup analysis in the following two paragraphs of the press release. They did not provide results for the overall population of the study- which they state "did not achieve statistical significance". But if Mr Lowe is looking for the results the company refer to as compelling, they are right there unless one again chooses to overlook them or edit them from view. ow.ly/1Ax9C

I don't own shares of RNN, but am glad they may have found a subset of patients with severe MDD they may be able to help and wish them well in the next Phase II study.

Permalink to Comment

47. biobug on April 20, 2010 8:12 AM writes...

Have to say I think this post was a rare mis-shot. While Rexahn's drug is certainly a joke, the lack of statistical significance is not the reason why.
There has been a disturbing trend the last 5 years or so to insist that all small biotech trials beyond Phase I reach statistical significance, or they are considered a massive failure. This is completely insane. Big Pharma generally runs numerous Phase IIa and even large Phase IIb programs that fail to hit a good ol' Phase IIa is an essential part of development to learn how the drug works, what kind of delta you get, and which endpoints best capture your benefits, so that you can design and properly power a successful Phase IIb or Phase III program. To begin denying this step to small biotech, and punishing them for not blowing $20 million dollars or more on a well-powered trial with absolutely no clinical efficacy information on their drug, is a great way to assure nothing gets developed going forward.

Permalink to Comment

48. JJ on April 20, 2010 9:48 AM writes...

biobug@47:

I'm not in the drug development business, but I am just curious if you cannot tell whether the signal is noise or real effect, what information does the study provide?

Permalink to Comment

49. anon on April 20, 2010 3:14 PM writes...

This seems much ado about nothing. Come on guys, haven't you seen this kind of thing before? Fer chrissakes, it's a pilot study! Over the years I have sat through zillions of presentations where the biotech guy said we saw a nice trend but in no way were we expecting to see stat. significance. The misstatement is that the study was to establish POC. Without stats, that's obviously nonsense.

Permalink to Comment

50. Hap on April 20, 2010 4:58 PM writes...

I know the article I referred to above argued against false faith in statistical significance, but how do you know that the trend you're seeing in such a small pilot study isn't just wishful thinking or a(n) (un)lucky choice of target audience? Particularly when people have a rather pronounced desire (and a strong economic motive, in this case) to find a positive where there may be none, don't you need some version of significance to make it more difficult for people to fool themselves (and their investors)?

Permalink to Comment

51. chemist on April 21, 2010 9:47 AM writes...

(Resubmission). I recall a biotech that spun its clinical trial of a treatment for psoriasis: "Our drug is effective! However, it is only as effective as the drug-free vehicle [the ointment / cream used in the formulation]. We are preparing for a new trial at a higher dose [2% vs. 1% or similar]." Nicely spun. The second trial didn't take place. The company is out of business.

Regarding antidepressants in general, see: "The Emperor's New Drugs: Exploding the Antidepressant Myth", Irving Kirsch Ph.D.. I haven't read it yet but book reviews and articles about the controversial Kirsch have been favorable.

Permalink to Comment

52. Ashritha (infoalcpl@gmail.com) on October 29, 2010 8:08 AM writes...

My colleagues and I have just concluded one of India's most in-depth studies on "Clinical Trials in India". We have looked at various areas such as:
- Market Trends
- Growth Drivers
- Regulatory Bodies and Framework
- Major Players.
-Etc.
We interviewed over 200 individuals and firms to collect the data in what we believe is one of the most detailed study on the subject in India. If you are interested in a copy, you may email me at infoalcpl@gmail.com.

Ashritha
infoalcpl@gmail.com

Permalink to Comment

53. Ashritha (infoalcpl@gmail.com) on October 29, 2010 8:18 AM writes...

My colleagues and I have just concluded one of India's most in-depth studies on "Clinical Trials in India". We have looked at various areas such as:
- Market Trends
- Growth Drivers
- Regulatory Bodies and Framework
- Major Players.
-Etc.
We interviewed over 200 individuals and firms to collect the data in what we believe is one of the most detailed study on the subject in India. If you are interested in a copy, you may email me at infoalcpl@gmail.com.

Ashritha
infoalcpl@gmail.com

Permalink to Comment

POST A COMMENT




Remember Me?



EMAIL THIS ENTRY TO A FRIEND

Email this entry to:

Your email address:

Message (optional):




RELATED ENTRIES
The Worst Seminar
Conference in Basel
Messed-Up Clinical Studies: A First-Hand Report
Pharma and Ebola
Lilly Steps In for AstraZeneca's Secretase Inhibitor
Update on Alnylam (And the Direction of Things to Come)
There Must Have Been Multiple Chances to Catch This
Weirdly, Tramadol Is Not a Natural Product After All