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Sarepta's AdCom Needs FDA's Permission To Speak Freely

This article is more than 7 years old.

On April 25, 2016, an FDA Advisory Committee (AdCom) voted against accelerated approval for eteplirsen. However, the panel was given instructions that are inconsistent with those used for other drugs, and the wording of the voting questions may have led two panelists to incorrectly ignore evidence provided by patients, parents, and experts in Duchenne. To restore the integrity of the drug approval process, the FDA needs to give the AdCom members permission to speak freely about whether they want to change their vote in light of these errors.

In criminal cases prosecutors have to prove guilt beyond a reasonable doubt. In civil cases, the standard of proof is the preponderance of the evidence. What is the standard of proof for a drug seeking FDA approval?

In the case of pimavanserin, the FDA’s Dr. Mitchel Mathis writes that if a "... drug is completely without safety signals, then we need not spend too much time defining clinical meaningfulness because benefit, however small, outweighs zero risk, and even a small benefit in a disabling disease is valuable.”

For eteplirsen, The FDA’s Dr. Ronald Farkas writes “Although approvability of a drug reflects a benefit-risk assessment, the decision about approvability is necessarily stepwise, requiring first that the drug be found effective, prior to consideration of benefit-risk.”

For Mathis, the evidentiary standard of proof increases with the safety risks of the drug. In other words, efficacy does not have to be proven beyond a reasonable doubt in the case of a drug that is safe because a benefit however small outweighs zero risk. In contrast, Dr. Farkas requires all drugs to be proven effective beyond a reasonable doubt regardless of their safety profile.

The FDA should be embarrassed that the standard of proof required to approve a new drug varies so much between these two cases. If this process is to have any integrity, the FDA must apply the rules for drug approval consistently. Therefore, Farkas and Mathis cannot both be right.

The FDA needs to clearly say whether it is Mathis or Farkas who has stated the correct evidentiary standard for drug approvals.

If Farkas is right, then the pimavanserin AdCom should be advised that their briefing documents contained information that was inconsistent with FDA policy. If Mathis is right, then it is the Sarepta AdCom that was instructed to use an evidentiary standard that is inconsistent with FDA policy.

Every member of the Sarepta AdCom who voted against accelerated approval used the fact that the clinical trial did not meet the gold standard for proof of efficacy to explain their vote. However, if Mathis is right, eteplirsen’s clean safety profile should have justified a lower evidentiary standard for proof of efficacy than beyond a reasonable doubt. Before the FDA renders its decision on May 26, the AdCom members need to say whether Sarepta’s clinical trial met this standard and also whether it would affect their vote for or against accelerated approval.

In addition, there is the separate question of whether the panelists could consider evidence presented by patients, family members, and world renowned DMD experts.

In Sarepta AdCom’s Potential Swing Votes, I reported that there are two panelists who believed that the wording of the approval questions required them to ignore any evidence except for the clinical trial data.

Here is the wording of the question on accelerated approval:

Has the Applicant provided substantial evidence from adequate and well controlled studies that eteplirsen induces production of dystrophin to a level that is reasonably likely to predict clinical benefit?

It is the phrase “from adequate and well controlled studies” that made two panelists believe they could not consider any other evidence. When they asked for clarification, the answer they got back from the FDA did not overcome their reservations and both voted no.

After reviewing the questions other AdComs were asked to vote on for other drugs, it seems that the phrase “from adequate and well controlled studies,” is unique to eteplirsen. Here are four examples, but there are many more.

Acadia's Pimavanserin: "Has the applicant provided substantial evidence of the effectiveness for pimavanserin for the treatment of psychosis associated with Parkinson’s disease?"

Mannkind's Afrezza: "Based on data in both the briefing materials and presented at today’s meeting, has the applicant demonstrated that Afrezza is safe and effective for the treatment of adult patients with type 1 diabetes mellitus to support approval?"

Merck's Vytorin: "Do the efficacy and safety data from the IMPROVE-IT trial provide substantial evidence to support approval of a claim that adding ezetimibe to statin therapy reduces the risk of cardiovascular events?"

Fabre-Kramer's Gepirone: "Has the sponsor provided substantial evidence of effectiveness for gepirone extended-release (ER) in the treatment of major depressive disorder (MDD)?"

I found no other instance where the phrasing of the approval question gave any member of an FDA AdCom any doubt about whether they could consider all of the evidence presented at the meeting. It is clear that the panelists for every other AdCom are allowed, even encouraged, to consider the testimony presented at the meetings in addition to the trial data.

This view is also supported by 24 Senators who signed a letter to the FDA. Here is the relevant paragraph:

FDASIA launched the Patient Focused Drug Development (PFDD) initiative and charged the agency to take into account the views and experiences of patients as part of the review process…In addition, the experiences of patient representatives on the advisory committee and testimony of patients at the advisory committee meetings offer important perspectives and information. We urge the FDA to ensure that all of these perspectives are considered in regulatory review.

Based on questions the FDA has asked other AdComs to vote on, and the letter from the 24 Senators, I fail to see why the FDA's Janet Woodcock could not answer with a straightforward yes when two of the panelists asked if they could consider the testimony they heard that day.

The members of the Sarepta AdCom and the public need to know the FDA's answers to two questions:

  1. Is it Dr. Farkas, or Dr. Mathis who has accurately described the FDA's evidentiary standard for approving a new drug?
  2. When voting, are AdCom members permitted to consider evidence presented at the meetings in addition to clinical trial data?

I cannot see how any panelist on any AdCom can make an informed vote about whether a drug should be approved when there is disagreement on something so basic as the proper evidentiary standard. As things currently stand, it appears that the Sarepta AdCom voted on whether Sarepta's clinical trial met the FDA's gold standard, when in fact a different standard may have been appropriate given eteplirsen's safety profile. In addition, at least two panelists incorrectly disregarded the evidence provided by over 50 presenters at the meeting.

If the FDA's answers to these questions would change the votes of any of the AdCom members, it needs to be taken into consideration before the final decision is announced on May 26. When the NY Times asked one of the panelists to explain his no vote, he said “Based on all I heard, the drug definitely works, but the question was framed differently.” There may be others who would want to change their vote after these two questions are cleared up but so far no one seems willing to speak on the record unless the FDA grants them permission. 

Making a decision based on a flawed AdCom vote would have consequences that go far beyond eteplirsen.

What investor in their right mind would invest in any biotech stock if the FDA can arbitrarily change the rules from one company to the next? By increasing the risks biotech investors face, for no good reason, the FDA would reduce the amount of capital available to develop new drugs and thereby hurt everyone who now has, or may ever have, a disease for which there is currently no cure.

About my column.

Disclosure: I am the portfolio manager for a mutual fund advised by Marketocracy Capital Management, an SEC registered investment advisor. Before relying on the opinions expressed in this article, you should assume that Marketocracy, its affiliates, clients, and I have material financial interests in these stocks and may hold or trade them contrary to these opinions when, in our view, market conditions change.