Califf: He and Woodcock were Right on Duchenne Drug Approval

FDA commissioner Robert Califf says he was right in upholding her action, and by extension CDER director Janet Woodcock also was right in overruling her subordinate Center medical officers to approve Sarepta Therapeutics’ Duchenne muscular dystrophy drug Exondys 51 (eteplirsen). Addressing the same Arlington, VA meeting of the National Organization for Rare Diseases at which CDER new drug evaluation director John Jenkins criticized the approval action, Califf said the “complex process of drug and device development to provide the evidence needed to make a decision about approval and labeling has a long history replete with precedents and accumulated wisdom … While it is essential for FDA to be collaborative with the community of patients, advocates, academia, and industry during development, one of the most important issues is the preservation of independence of the FDA as a regulatory and public health agency from the vicissitudes of political influence. And for decision-making about market approval and final approval of labeling, external influence should be kept to a minimum.

“This was,” he continued, “a critical part of my decision to defer to the Center director about accelerated approval of eteplirsen.  Setting a precedent of political appointees intervening in decisions that belong in a scientific process would risk opening the door to a potentially dangerous temptation for others, including political appointees within government and other non-FDA groups to intervene more frequently. While it is true that FDA decision-making is difficult and imperfect, political meddling would undermine confidence and introduce the type of bias that is not helpful. In this regard, it is clear that the medical product center, comprised of professionals who are FDA employees and carefully vetted for financial conflicts, should make the decision. An admirable process with strong historical precedent enables the FDA to make decisions that are rational and defensible. An organized system of appeal allows those who disagree to be heard at higher administrative levels.  In the history of FDA regulation of medical products, the politically appointed Commissioner or Secretary of HHS has rarely intervened to override a decision from a medical product center.”

In his presentation, Califf said he wants FDA, industry and academia to work together to reduce the number of drug development programs that fail. “Despite the remarkable progress, the latest data continue to indicate that the vast majority of drugs entered into early phase human testing will not make it to market. This is due to a complex combination of failure to demonstrate efficacy, unexpected toxicity, and difficulty with manufacturing... Therefore, while speed to access is vital to suffering people, we also must continue to develop and implement methods that ‘separate the wheat from the chaff,’ rapidly discarding therapies that are dangerous or ineffective and speeding along therapies that truly provide clinical benefit.”

Califf’s talk focused on the accelerated approval pathway and the statute’s approval allowance related to a biomarker showing it is “reasonably likely” to predict clinical benefit. “Accordingly, the statute allows enormous latitude for FDA to consider the spectrum of evidence about biological plausibility, clinical epidemiology, and fundamental knowledge that could link the biomarker of interest to the possibility of being a valid surrogate,” he said. “In the end, the FDA must make a judgment about whether the measurement in the biomarker plus associated data and information make it ‘reasonably likely’ that the treatment will have clinical benefit.”

Califf said more work is needed to define what “reasonably likely” actually means. “It is not defined either in statute or guidance,” he said. “Although scientifically the evaluation of the totality of evidence should lead one to a quantitative or probabilistic estimate, there is no guidance on whether ‘reasonably likely’ means that there is a 50%, a 75%, or a 95% chance that the change in the biomarker will lead to a clinical benefit.  This approach necessarily vests a lot of public trust in FDA and emphasizes the clear need for the FDA to employ the very best people, and for its advisory committee system and other feedback mechanisms to enable very high quality scientific exchange. This is one of many reasons why my top priority at FDA has been to continue to develop and support our workforce, including working on the advisory committee system to assure that we get the best advice.”

Another area Califf said he is interested in is expanded access for desperate patients. He said FDA approves over 99% of such requests, but “when there is no possibility of enrolling in a trial, either because of eligibility criteria or logistics (as when the patient lives far away from the nearest study site and cannot travel), it is up to the company that manufactures the drug  to decide whether the drug can be made available. We are working with the Reagan-Udall Foundation on developing a navigator system to make it even easier to access the system to find the best avenue for the patient.  And we are following with interest efforts to increase the transparency of the policies of companies about their experimental drugs and biologics. Among many reasons to steer expanded access towards appropriate clinical trials, when possible, is the fact that, as I mentioned before, the vast majority of therapies that enter clinical trials – more than 90% – have serious toxicity or lack clinical efficacy. So it is critical that we sort out the effective therapies from those that are ineffective or dangerous through high quality clinical trials.”