CLINICAL TRIALS IN NASH AND PROBABILITY OF SUCCESS.


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Releved in Nature : Link 

In 2010–2012, only 20% of compounds from a cohort of 40 large and mid-sized pharmaceutical companies advanced from phase II to phase III, whereas in 2013–2014 the proportion of compounds advancing from phase II had increased to 25%. The corresponding rates for progression from phase III also increased slightly, from 55% in 2010–2012 to 58% in 2013–2014. Finally, the rates of success at the regulatory review stage also increased, from 84% in 2010–2012 to 91% in 2013–2014. 

I just wanted to pin some particularisms of NASH studies 

Currently, clinical trial success rate is based on statistical rate of previous studies. 

However we must consider certain particularities for non adressed diseases and for which no treatments exists, particularly for Phase 3.

A drug in phase 3, targeting a competitive market must not only prove its effectiveness, but also to propose improvements compared to already marketed drugs.

Therefore, the task is doubly complicated and statistical success rates published for phases 3 reflect this dual requirement.

In the case of NASH, the expectation for any solution to treat patients is high and , to date, approved drug does not already exist on the market, therefore, the expected improvements                       criteria are more complacent and there is no need to demonstrate greater efficiency than competitor. Side effects, although important, can be tolerated because there is no other drug to treat patients.

But analysts in their risk calculations rarely consider this arrangement.

This is even truer regarding the examination stage by regulatory agencies to obtain authorization.

In a recent article in Nature (auth :Richard K. Harrison) that analyzes the evolution of rates and causes of failure of clinical trials, it is given, for the most recent period (2013-2014), an average success rate of 58% for phases 3 and 91% for the regulatory review stage.

Regarding this study, a lambda drug entering phase 3 get statistically 53% of chances to reach the market.

Is this true for a drug targeting and NASH in Phase 3 as the OCA or Elafibranor?

I do not think so because finding a drug to treat NASH has become a priority for health agencies and there is no treatment approved to date.

Any medication finishing its phase 3 with positive results on the disease, however small, will be considered favorably by health agencies. The main risk is the occurrence of side effects making the ratio profit / risk unbalanced for patients.

This does not prejudge possible decommissioning in the future of these drugs if other more effective or safer medicines reach the market, but it ensures that both drugs currently the most advanced (OCA and Elafibranor) have a high probability of getting an approval.

At what level of probability could we estimate the chances of success in this configuration? 

it's hard to say !

However, in a second article published in 2014 in Nature (Clinical development success rates for investigational drugs Michael Hay, David W Thomas, John L Craighead, Celia Economides & Jesse Rosenthal), the results included smaller biotechs and differed between specialties’ giving a specific success rate for drugs treating major specialties such as oncology, infectious diseases, endocrinology, respiratory diseases, cardiovascular diseases, autoimmune diseases and neurology

Phase-3 success rate for other drug was 71%. Orphan diseases (excluding oncology) had a phase-3 success rate even higher, 72.9%

Since NASH does not enter directly into any of these categories but that can be the considered as orphan disease drug, we could take this figure of 73% for phase 3 success.

To be more accurate, we could have different figures for OCA and Elafibranor, knowing that OCA didn’t show significant NASH reversion( new definition of reversion as validated endpoint in Phases 3) in previous phases as Elafibranor did, but as the both Phases 2b had used post hoc studies on that criteria, we’ll keep a balanced approach.

Regarding the rate of success for the preliminary review by regulatory agencies, my opinion is that a health agency who asked labs to work on the treatment of NASH, which receives a request for reviewing a drug succeeding in its phase 3 and whose Phase 3 design was approved, has no reason to refuse agreement.

So I would fix the success rate to 95% because of the ratio profit / risk of side effects.

 

This would give to NASH drugs in phase 3 clinical trials an overall probability of success of 69%, which seems more realistic to me.



 


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