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The FDA report on the study of Intercept in the PBC is not negative but we feel a strong annoyance at dawn approximations and non-compliance with requests from the FDA by the laboratory

I have carefully read (but not fully by lack of time) the 194-page report prepared by the FDA for the advisory commitee of 7 April 2016 on the accelerated marketing authorization application for OCA in Primary Biliary Cirrhosis indication (PBC).

This report will form the basis of discussions with experts gathered in public meeting on April 7. 

It shows the components that the FDA has reviewed to give (or not) its agreement .

It is good to remember that this authorization should have be given initially in November 2015, but that, given the elements transmitted by Intercept, the FDA decided to reunite an advisory commitee in April and will take its final decision in May

This can be interpreted in two ways ..

  1. FDA not very satisfied with the studies produced seeks to rely on an expert committee to justify an accelerated approval and refusal to wait for the full completion of studies to rule
  2. The FDA felt that the record is not very well put together, seeking to cover by an expert opinion before giving this accelerated approval.

By cons I can see that in the report provided to the experts, the FDA made clear its annoyance at the INTERCEPT file even if it seeks to find an ad hoc methodology to validate it.

 In commenting on the study provided by Intercept page 79, the FDA writes


Diagnostic criteria used for patient enrollment were not consistent with the meeting discussions held between the FDA and the Applicant during the drug development program, in that the FDA recommended the use of a co-primary endpoint of ALP and TB based on enrollment of a broad spectrum of PBC disease stages and the Applicant enrolled primarily only patients with early stage disease

UDCA was approved in December 1997 based on demonstration of clinical benefit (e.g., survival or need for transplant, and progression to esophageal varices, ascites, or encephalopathy), in addition to changes in histological changes at 2 years, liver biochemistries (ALP, TB, albumin),29 over a period of 2.5 years, in a high risk population. This phase 3 trial (747-301) is the first clinical trial conducted in patients with PBC with use of only biomarkers, i.e., ALP and TB as study endpoints to support efficacy for a marketing application. Most PBC patients enrolled in the clinical trial were in an early stage of disease, as observed by the biochemical profile of the patients, (i.e., 92% of patients had a normal TB at enrollment). The phase 3 trial population (early stage disease) is different from the population analyzed in the data from the Global PBC Study Group (a range of all disease stages) used to evaluate the use of the composite endpoint of ALP and TB as a surrogate for approval. Use of reductions in ALP alone has not been evaluated or agreed upon by the FDA prior to the submission of the NDA. Since PBC is a slowly progressive disease with a clinical course spanning over decades, the change in ALP seen over a 12-month trial and the magnitude of reduction in ALP and its correlation to a clinical outcome was unknown. However, the FDA approached the Applicant and the Global PBC Study Group’s principle investigator to request access to subject-level data sets from the Global PBC Study Group which would allow FDA to assess whether a reduction in ALP alone in a similar population with early stage PBC could be used as a surrogate biomarker reasonably likely to predict clinical benefit. Please see Section 4 for discussion of the results of FDA’s evaluation of the Global PBC Study Group data. "

To summarize :

FDA relied on a large study trying to identify predictors surrogates serological endpoint of improving disease.

Evolution of the disease is slow, a study on histologic improvement take years, the idea is to determine the leading indicators of the disease, wich combined, appear to be predictive of subsequent clinical improvement of the disease.

If a drug can bring, about a given period ,these indicators in the predetermined thresholds, we can statistically consider that it will improve the prognosis of the disease and we can give it a marketing authorization.

The clinical study of Intercept is the first to be based on this paradigm,  previous studies required clinical results and were therefore much longer.

So to be clear, the criteria used in the INTERCEPT study does not suggest that the disease is cured or even improved but that advanced serological parameters used as disease signals are improved in such a threshold, wich have proven to have a potential beneficial effect on the disease.

It is thus clear that to determine exactly these thresholds and criteria, a very precise statistical analysis had to be done beforehand. this comprehensive analysis can be found in the 2014 study published in Gastroenterology

This study was based on the largest study data conducted by the Global PBC Study Group located in Holland.

These data cover a range of approximately 5000 patients with PBC in different stages of the disease, the least developed to the most advanced.

The studies have concluded that , in this disparate population, acceptable  serological surrogates endoints  able to predict an improvement in long-term illness and therefore to obtain a marketing authorization were:

it is a composite endpoint:

  • Alkaline Phosphatase <1.67 times ULN (Upper Limit of Normal) e
  • Down minimum of 15%  for Alkaline Phosphatase 
  • Bilirubin levels returned to normal range and constant.

FDA in its review on the subject wrote in his report (the characters in bold are also in bold in the report)

"Several scoring systems for assessment of baseline PBC status and treatment response have been developed by different academic institutions over the years; none of these have been validated; however, they are commonly used in clinical practice and to assess treatment response in clinical trials. ALP as a stand-alone biomarker has not been validated in randomized clinical trials to predict clinical outcomes. "

We will see later why the FDA had enhanced this passage in bold !!!

So these are the endpoints which were included in the Phase 3 study INTERCEPT of the PBC

In the first reading the results are very good.

OCA reached endpoint for 40% to 50% of patients and the placebo is 10%

This might look like a total success but the FDA found a fact that annoys them greatly. Contrary to what was agreed between Intercept and FDA early in the study, Intercept has not recruited the planned patients.

Indeed one of the criterion is to reduce total bilirubin in the normal range but the FDA discovered that 94% of patients included, were already in the normal range at the start of the study .

INTERCEPT has therefore included  only little ill patients as opposed to the requests from the FDA.

The population included in the study Intercept has nothing to do with the one used to establish criteria to validate the study ..

The FDA therefore considers that the achieved criteria are not acceptable in the state as unsuitable for the study population.

the criterion bilirubin is not anymore acceptable in the ICPT study, so remained valid only the lowering of  ALP, but here as the FDA had highlighted in bold in the text 

« ALP as a stand-alone biomarker has not been validated in randomized clinical trials to predict clinical outcomes. "

One might say Game Over !!

This is not counting on the leniency of the FDA that tried to see if  they could extract in the 5000 Global PBC patients Study Group database, a sub group with the same characteristics as the population recruited by Intercept, then, Dismissing bilirubin, look if other threshold criteria based on the decline in ALP may have a predictive clinical improvements, and finally verify whether these criteria were achieved in the population of the study of ICTP.

The FDA concluded that a criterion requiring a 40% ALP brought above a threshold of 2x UNL seemed to have a predictive character ..

Fortunatly OCA appears to comply with this new ad hoc criterion 

INTERCEPT should send chocolates to the FDA

However, this corresponds to using an ad hoc criterion invented post hoc .. which is contrary to the basic principles of clinical studies.

it is understandable that the FDA could be uncomfortable with this method and seek the support of experts in an advisory commitee to validate …

Regarding the recruitment another point is very curious 

92% of the patients were under UDCA generic treatment 

but reeding ISCPT on their website

UDCA is active in only 60% of the potential patients 

It is very curious that INTERCEPT recruited 92% of their patients in the population already treated with UDCA ? 

it is not the best way to get an agreement as mono therapy as required  !!

And if they do not have an agreement as mono therapy they will stay on the UDCA market segment, a low cost generic .. ???

I can not predict the reaction of experts to the methodology used , at least questionable, especially to give an accelerated marketing authorization …but INTERCEPT and the FDA are on à slippy ground.


Since this article, the AC voted yes for an accelered agreement  (17 votes / 0)

Some points were enhanced:

A treatment starting at 5 mg for 3 month prior to dose increase at 10 mg for safety reason and monitoring of adverse effects

A limitation of the doses at 10 mg/day for safety reasons because of serious hepatic events at higher doses.  

An interrogation on MonoTherapy 

A prescription limited to early disease regarding risks and study panel.

A prescription warning on patients with advanced liver disease ( Cirrhosis, advanced Fibrosis, etc)



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