Why do cell therapy clinical trials fail?

by Alexey Bersenev on September 17, 2012 · 2 comments

in Uncategorized

This headline is a title of Greg Bonfiglio‘s presentation, which he gave at Cell Therapy Clinical Development conference. The cell therapy trials failures is a very interesting and exciting topic. Nobody talks about it at conferences, nobody collects and analyses the data. I’ll try to provide a brief summary of his talk below.

Because cell therapy is relatively new field of medicine, we don’t have a good statistical data for approval and failure rates. The “n” could be too low to calculate with significant confidence. But, based on Biotech and Pharma industry experience, we can extrapolate and predict some rates for cell therapy. Bonfiglio cited some FDA statistics: “The current clinical trials total failure rate is 84.7%, which could be breaking down by Phases as the following – Phase 1 – 53%, Phase 2 – 77% and Phase 3 – 41%”. The success rate for approval of large molecule-based drugs 32%, which is about 3 times higher than for small molecules. He thinks that success rate for cell products will fall somewhere close to large molecules. That’s where our expectations should be – about 30%.

There are 2 major groups of reasons for failure of approval for commercial medicinal products – safety and efficacy. According FDA data, cited by Bonfiglio, the safety-related failure is about 19% in Phase 2 and 21% in Phase 3. The efficacy-related failure rates is much higher – 51% in Phase 2 and 66% in Phase 3. Bonfiglio thinks that “empirical cell therapy efficacy rates should be better”. He also said that cell therapy does not represent the same safety profile. Usually cells demonstrate very low systemic toxicity, but could be associated with some rare and specific safety issues (GVHD, tumorigenicity, excessive tissue growth…). I’d agree with him. So far, the vast majority of cell therapy trials have demonstrated impressive safety profile!

Now, failure modes and examples. Bonfiglio mentioned multiple reasons of trials failures. Most of them are general for any therapeutic product. But knowledge of specific features of cell therapy trials and examples of failures are priceless.
1. Poorly chosen endpoints. It is very difficult to measure therapeutic value of cell products. They are “too noisy”. They are frequently used in “no option” or “drug-resistant” patients. Wisely chosen primary and secondary endpoint could significantly increase success rate. The example he gave – Dendreon’s “Provenge” in prostate cancer. FDA gave them very hard time on Phase 3 before market approval. The major reason – wrong endpoint (overall survival).
2. Inappropriate patients population. The business guys want to treat all patients with same disease in order to target broader market. But in reality, only some subsets of patients will benefit. So, targeted patient population is important. Example he gave – Osiris “Prochymal” in GVHD. There were good results in digestive tract GVHD, but no result in skin GVHD – mixing them up resulted in trial failure.
3. Control groups issues. Trials should be appropriately controlled, started from Phase 2. Example he gave – Intercytex “Cyzact” in venous ulcers. The control groups was added only in late-stage of trial and abolished the efficacy. Yet another example – Osiris “Prochymal” in Crohn’s disease. The reason of failure – very high unanticipated placebo effect (partially due to reporting bias).
4. Discontinuity between research and commercial process. Many great research findings simply will not translate. He said that research grade products could “lose magic” when manufacturing process is optimized.
5. Bad trial management. It’s a complex issue, which include many variables, such as lack of enrollment, lack of clinical operations experience, poor data management, biases. He said about enrollment issue: “80% of cell therapy trials fail to meet their enrollment goals”.

I’d like to conclude, that we need more discussions about failures. We don’t have many failures in cell therapy, but definitely have some. So, we have to learn and prevent the future failures. On this blog, I’ll try to highlight and, possibly, analyze recent failures in cell therapy trials. Stay tuned!

{ 2 comments… read them below or add one }

mike October 1, 2012 at 11:05 pm

thanks–very interesting write up! any comments regarding ACT’s AMD and SMD trials?

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Alexey Bersenev October 1, 2012 at 11:12 pm

I think, they are good so far. On right track.
The only thing i don’t like is frequent reporting of cases. I think Lancet paper was not timely. Report some trial result, don’t over-hype.

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