NASH TRIAL RECRUITMENT BASICS

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I read a lot of contradictory remarks about the progress of the recruitment of clinical studies in NASH. The figures published give rise to sometimes fanciful interpretations, speculations and projections.

I wanted to take a closer look at what they might mean.

We will start with figures announced by the two leaders in the drug race, Intercept Pharma and Genfit Pharma.

INTERCEPT 

May 4, 2017 Intercept pharmaceuticals issued a press release on the results of the first quarter of 2017. In this press release, an announcement is made by Mark Pruzansky saying: "In our NASH program, we achieved a major milestone with the completion of our interim analysis cohort in REGENERATE, the first and largest Phase 3 trial in NASH, "

No figures are given, only those who had followed the previous events can deduce from the conference of February 10, 2017 given by Intercept reducing the cohort of intermediate results (750 vs 1400), that the number of patients recruited must therefore be 750 as of May 4, 2017.

It should be noted that this announcement on the reduction of the cohort was done in conference but did not give rise to an announcement published by the company.

GENFIT

On October 27, 2017, in a letter to the individual shareholders, GENFIT writes:

"At the invitation of GENFIT, the researchers involved in the RESOLVE-IT trial, evaluating elafibranor in NASH, gathered at the invitation of GENFIT and were very satisfied with the increasing recruitment of patients, particularly of the net acceleration he has experienced in recent months, with a view to having completed the recruitment of the ~ 1000 first patients to the end of Q1 2018. Thus, 762 patients are already randomized. The first patient of the study was already finished his treatment. "

The figure is accurate, 762 patients are recruited, probably at the beginning of October.

Does this mean that there are only 238 patients to recruit to complete the cohort of 1000 patients that will be analyzed for intermediate outcomes?, The answer is clearly no!


Global Recruitment vs Balanced Recruitment

There is a clear difference between the overall recruitment of the 2000 patients in the study and that of the first 1000 patients. Both must be balanced, which means that they must be representative of the population selected in the design of the study and negotiated with the FDA.

This is very important, the closer the study population will be to the one chosen in the design, the more reliable the statistical analyzes will be and, above all, the more the regulatory authorities will be able to make a quick decision on an approval. 

In the opposite case, complex satistic studies and retreatments will have to be carried out to correct, if possible, the distortions of the study population compared to the initial choices.


A very good example against us was given by the Intercept POISE study in the PBC, the final population of the study was absolutely not in conformity with that retained initially, which forced the FDA to make statistical reprocessings complex and even to modify the post hoc criteria to make it possible to validate the study (see HERE), the entire process was lengthened by almost a year, delaying the placing on the market of OCALIVA in the PBC.

In addition to respecting the statistical profile of the population, the laboratories must also ensure that they have balanced centers, each with at least one patient per arm. We know that the Genfit Phase 2b GOLDEN trial has been weakened considerably for not having met this criterion.

We can therefore understand that it is very complex to balance all these parameters, especially since each center presents  the patients it preselects without having a global vision of this breakdown.

What makes a patient even conforming to the medical criteria of the study can, according to its ethnic categorization, its sex, or the progress of its disease, not to be retained in the study because its segment is already provided, either to be retained in the cohort of 2000 patients not yet fully provided, but not in the cohort of 1000 patients who, on this segment, is already provided.

This is why 762 patients may have been recruited globally in the cohort of 2000 patients, but, in fact, fewer patients are included in the cohort of 1000 intermediate patients.

This is why the announcement of Genfit does not mean that there are only 238 patients to recruit to complete the intermediate cohort of 1000 patients.


Regarding Intercept, it is possible that on May 4, 2017 they had recruited more than 750 patients including 750 balanced for their intermediate cohort, as it is possible that they recruited only 750 patients, not really balanced, relying on the months to rebalance their cohorts.

As they have not given any details on this point, we remain in the assumptions, hope that they will do better than in POISE!


More to come ...

G Divry


Notice that I am neither a physician nor a biologist, my point of view is only that of an enlightened amateur, so it must be taken for what it is, a questionable point of view!



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