Up to 9 months for Q/A protocols? Doesn't sound right as they would/should have been working on these over the past two years and with manufacturing being done by CMO's, this should have been a nonissue. It makes more sense there are problems regarding manufacture and/or issues with their CMO's. The company's explanation and timeline just doesn't make sense.
The company first announced the NDA delay on November 10, 2014 with no concrete reasons given for the delay. Three-plus months later they announce another delay with a few vague reasons regarding manufacturing processes. Assuming the reasons given for the delay in the second announcement are the reasons for the original delay, one has to question whether it would take 6-12 months to work on processes. Processes are generally boilerplate when it comes to small molecule drugs. That leaves efficacy/safety data issues (which I don’t want to believe), drug-drug interaction problems or manufacturing stability issues. And since they are going with manufacturing processes as their excuse, I’m leaning toward manufacturing stability issues – contrary to their claim in the November 10th release that their stability testing had been successfully completed. And yes, this is fixable.
crecy et al.,
Ignore me at your own risk. Check my ACAD posts back in November 2012 when I was correctly predicting the P-value’s achieved in the pimavanserin Phase III were so low that a comfirmatory Phase III would not be necessary – contrary to everything Uli was telling analysts at that time.
What the company is currently telling analysts makes no sense. Scaling up production is never the problem. Scaling up production while maintaining compositional integrity and stability is always a challenge. Had the company been made to run the confirmatory Phase III as originally anticipated, these issues would unlikely have arisen as the company would have had the entire 2nd Phase III period to work on the scale-up. It’s been two years since the company publicly announced the FDA would allow them to submit the NDA without the confirmatory Phase III. Scaling up is not easy. I’m pretty sure it’s the stability issue.
ACAD’s delay is almost assuredly the result of failures in stability testing. The NDA requires stability testing of all drugs, meaning the company must prove the drug will remain stable and not degrade over time as it is stored in the normal course of use (shelf life). The company would be required to produce commercial size batches of pimavanserin, the formulation of which must be identical to the formulation used in the trials, and then see how the quality of the drug varies over time under the influence of a variety of environmental of factors such as, temperature, humidity and light. Companies are normally required to test stability up to 12 months under a variety of storage conditions on three separate commercial-sized production batches.
Some drugs, due to their chemical formulation, are by their nature highly unstable and make production in commercial size a real challenge. I’m not a chemist, so I don’t know this to be the case with pimavanserin. However, while all drugs can be produced to some scale, achieving stability over time is often a major challenge. And the more complex the compound, the greater the challenge.
Almost two years have passed since the company announced they could move forward with an NDA without having to run a second Phase III. They've had two years to work on this. Something's not right.
What you bid for is the right to receive 20% of the gross revenue stream of a drug that could potentially be used in a large number of oncology indications generating billions of dollars.
Don't read too much into the transfer of the IND. It's strictly procedural. If Janssen is to have control of the trial regarding filings and contact with the FDA, it needs to be in control of the IND's.
I wish it were as easy as that. Comparing results across trials or to other outcomes retrospectively, such as the results normally achieved with current standards of therapy, is great for hypothesis testing, but it is not statistically satisfactory as far as the FDA is concerned. It's wonderful the results your husband and the others achieved, but those results must be reproduced. I'm confident they will, but only time will tell.
Probably zero. But that's why they run prospectively designed trials that need to show statistical significance, to prove that your husband's response was not a random event.