NASH CLINICAL TRIAL PARTICULARISMS

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 This note is a reaction to the several article presenting NASH clinical trials as success or failure.  

It is characteristic of journalists to move towards simplification, they have few words to enhance their point of view. However it is often inappropriate to take firm positions on the clinical study results and this is especially true in NASH.

Declare that a clinical trial is a success or a failure simply because the endpoint defined at the beginning of the study was not achieved without taking into account all the parameters and context of the study is a big mistake.

A success in a poorly conducted study, not respecting the elementary rules of non-interaction with other drugs, having been prematurely ended and the results are absolutely not reproduced in a subsequent study, much like a success in trompe l ' oeuil.

Conversely, an apparent failure can turn into success when the disease-defining criteria defined by the regulatory agencies operate retrospectively.

It is please I invite you to read the following lines to realize a Manichean approach to reading clinical trial in NASH can lead you to make bad investments.


Many analysts don’t understand what is special in the NASH clinical trials.

It is an emerging disease, not a well defined one, so the definition of the disease is smoothly modified every year and the regulatory endpoints are also modified to follow the scientific knowledge.

A first example, INTERCEPT in FLINT.

Despite they didn't followed the basic standards rules of clinical studies (26% of patients started medication (statins) impacting the disease DURING the study and were not removed from the results), It was announced that they reached their primary endpoint (2 points decrease of NAS score without fibrosis worsening). 

Following basic analysis, it is a success, but in the real world it is not so evident because : 

- The FLINT study’s bias are numerous.

- The FLINT results have been contradicted by the Japanese study

- The target they reached is not anymore the target to reach.

The FDA announced clearly that NASH reversion without fibrosis worsening was now the target to reach and ICPT who had this endpoint as secondary in the FLINT trial was unable to reach it despite they counted patients who did not have NASH at the beginning of the trial as cured patients in their results. (Read:  INTERCEPT'S STUDY CURIOSITIES)


A second example, GENFIT in GOLDEN

The primary endpoint of the GOLDEN study was NASH reversion without worsening of fibrosis, an endpoint harder to reach. The study included patients  with a NAS score of 3 to 8 inclusive while Intercept trial excluded the NAS score <4. 

Indeed the NAS 3 group of patients (15%) who got a reversion under placebo  prevented GENFIT to have a statistically significant result in the entire population. This effect could have been anticipated because the false positives biopsy results are mathematically high in less advanced disease population. ( to see why, please read, BIOPSY IN QUESTION ! FALSE NEGATIVES  - FALSE POSITIVES ! A POPULARIZATION !)

Following basic analysis, it is a failure, but In July 2015, a new and stricter definition of the NASH reversion was proposed by the NASH Key opinion leaders and endorsed by the FDA. (To see the difference between the two definitions, please read, THE NEW DEFINITION OF NASH STRIKE THE NASH PLAYERS)

It is for now the definition to be used in Phases 3 trials.

Logically, as the publication of the results was about to be published, Genfit was asked by the authors of the publication to let them use this more strict definition on the GOLDEN data in the publication analysis, witch make sense.

Stricto sensu it is a' post hoc’ analysis and some analysts mention it as not relevant, but they are wrong because it is not an 'ad hoc’ analysis with criteria chosen post hoc to present positives results.

In this case GENFIT did not interfere in the new definition parameters, the new definition grid promoted by the FDA and unknown at the beginning of the study, was applied by the authors on GOLDEN raw data, including the NAS 3 patients who perturbed the previous study results.

Surprise!  The result of the study with this new consensual endpoint was clear!  The GOLDEN study reached this endpoint on ITT population without any statistical treatment ... 

ICPT was supposed to do the same on FLINT raw data, but they didn’t, to my opinion it would have been a fiasco, but no one can know! 

It shows clearly why it is not easy to have a definite position on NASH trial results just reading abstracts.

In a few months, what seemed evident at the beginning?

FLINT = Success and GOLDEN = Failure,

Was totally inversed by the evolution of scientific knowledge of the disease.

▪   FLINT reached the wrong target and missed the good one 

   GOLDEN missed the wrong target but reached the good one

It was the same for Tobira’s results, annonced as a failure, but showing promising results on the secondary endpoint. despite that, investors sold the lab and its stock dropped by 60%

Again they were very ill-advised to do a quick reading without addressing the subject as should do real investors, They surely bite their fingers now.

Thats why clinical trial results are not black and white and should be analysed finely before investing by following the main herd .


G. DIVRY

NASHtargets



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