The pharmaceuticals are not sure themselves

And now the cold spin. Finally, Indevus managed to get an investor Teva in who will foot the bill for further clinical trials and thereby bets on Pagoclone being effective. Why did it take so long?

Indevus previously announced promising data from its 8-week, placebo controlled, double-blind, multi-center Phase II trial in patients with persistent stuttering which showed that pagoclone produced a statistically significant benefit in multiple primary and secondary stuttering endpoints compared to placebo. 

The text is a bit misleading in my view as it looks as if it is a significant effect. Don't confuse statistically significant with significant! Statistically significant means that with a high probability there is a difference in effect between the group that took Pagoclone and those who received a placebo. However, it does not say anything about how large this effect is! In fact, as I mentioned before. The reduction of stuttering in comparison to placebo was only about 10% in week 8. On the other hand, you can argue that you don't care about this fact, and only look at the absolute effect because it is the relevant measure for a person who stutters. However, it does show that the compound itself does not seem to be very effective at all! The open label phase (where everyone could choose to take the compound) was more successful. It is also possible that only a subgroup responds positively to Pagoclone and the other not at all, so the mean effect is not a good measure and does not show the large improvement on a sub group! Finally, it has not been published in a journal yet, as far as I know.

Under the terms of the Agreement, which is subject to applicable regulatory clearances and customary conditions, Indevus will conduct and Teva will reimburse Indevus for its expenses for a Phase IIb study. The placebo-controlled study will involve approximately 300 patients with stuttering in the U.S. treated for a period of six months and is expected to commence enrollment by Q1 2009.

I am also not exactly clear on what a Phase IIb study is. Wikipedia says: "Phase II trials are performed on larger groups (20-300) and are designed to assess how well the drug works, as well as to continue Phase I safety assessments in a larger group of volunteers and patients. Phase II studies are sometimes divided into Phase IIA and Phase IIB. Phase IIA is specifically designed to assess dosing requirements (how much drug should be given), whereas Phase IIB is specifically designed to study efficacy (how well the drug works at the prescribed dose(s))." I have the suspicion that in this case Phase IIb simply means "let's do it again to be sure before doing Phase III but let's do it a bit larger, longer and fine-tune", see above.

The main difference to the last Phase II trial is probably three-fold. First, 300 instead of 132 people will participate so the statistical error will be lower. Second, they will fine-tune their methodology from the last trial. Third, they observe them for 6 months. The open label was more successful, and they probably want to collect placebo-controlled data to confirm their suspicion that the full effect comes out over several months.

But the real reason might well be, because Tera and Indevus are not 100% convinced about the efficacy of Pagoclone. Stuttering is a very tricky disorder, and they might even have read my blog! ;-) So they probably want to play it safe, and re-do the last trial but with a bigger sample size and fine-tuned methodology. And the calculation is simple: if you do a real Phase III with 1000s of people, the costs are a multiple of the 300, and probably too high a risk. Wikipedia writes on Phase III: "Phase III studies are randomized controlled multicenter trials on large patient groups (300–3,000 or more depending upon the disease/medical condition studied) and are aimed at being the definitive assessment of how effective the drug is, in comparison with current 'gold standard' treatment. Because of their size and comparatively long duration, Phase III trials are the most expensive, time-consuming and difficult trials to design and run, especially in therapies for chronic medical conditions." I may add that medication can get approved after a successful Phase IIb and Phase III runs while the medication is already on the market.

We are excited that we have partnered pagoclone with a leading pharmaceutical company with a focus on central nervous system conditions,"said Glenn L. Cooper, M.D., chief executive officer and chairman of Indevus."There are currently no approved drugs anywhere in the world for patients with stuttering. Pagoclone has tremendous potential to become a highly significant commercial product, as well as to provide a ground-breaking therapy to then early three million Americans and millions of patients around the world who are afflicted with this condition. The deal we have negotiated with Teva allows us to conduct a definitive Phase IIb trial, funded by our partner. If the trial is positive, we believe that both companies will have a unique opportunity to commercialize the first pharmaceutical product for the millions of patients who stutter.

Typical CEO-bla bla bla! He doesn't really say anything, but it sounds good! For example, "tremendous potential" but of course potential might not translate into a real medication. So it is safe to say it anyway!

Watch the phrase "to conduct a definitive Phase IIb trial". Why use "definitive"? I think it is a slip of the hand, which reveals the mood they are in: They are not really sure themselves about the "tremendous potential" but this second trial will definitively give us a clear result. And any way Teva is footing the bill. And if it works fine, we just take 50% of the profits which is still millions.