The FDA and Sarepta: a window into the real world of drug regulation

It is hard to discern the true state of drug regulation from the outside, but two recent decisions by the Food and Drug Administration — to approve one drug but reject another — offer a rare glimpse into that world.

Exondys 51 and Vyondys 53, both developed by Sarepta Therapeutics, are intended to treat a severe form of muscular dystrophy, though in different subgroups of patients. Exondys 51 gained FDA approval in 2016 amid great controversy. Agency officials were divided because evidence of the treatment’s benefits was especially thin. Its approval came with a condition requiring Sarepta to carry out a post-approval clinical trial to confirm the drug’s effectiveness.

Despite sales of $300 million in 2018 alone, however, the company has yet to begin the post-approval trial. Within days of this delay becoming public, Sarepta announced that the FDA had rejected Vyondys 53 from entering the market.

It’s precisely these sorts of decisions and how they play out inside the agency that I wanted to understand when I began interviewing senior officials at the FDA. Why does the FDA appear increasingly open to approving drugs like Exondys 51 despite weak evidence that it works? Why trust companies to study a drug after approval when the results might undercut the drug’s sales? Is a decision to reject Vyondys 53 the exception that proves the rule?

Like Exondys 51, hundreds of drugs have been given accelerated approval by the FDA since the early 1990s. As long as a drug targets a serious or life-threatening disease for which few, if any, treatments exist, approval is granted on the basis of studies that predict — rather than establish — clinical benefit. Where medical need is acute, access to a new, promising, but unproven drug is considered to outweigh the risk it might otherwise pose.

In theory, such risk is temporary: All accelerated approvals require post-market trials to confirm the effectiveness of the drug after approval. The trouble lies in getting those post-market studies done, and done well. Most are completed within four years, but delays are common. In the meantime, patients are exposed to unforeseen safety risks or, in some cases, forego other care options while taking new drugs that ultimately do not serve their intended purposes. In addition, when these studies are finally completed, they often fail to yield clinically meaningful information.

Yet the FDA seldom takes action in response to these delays. To date, only a handful of warning letters and a few strongly worded tweets from former FDA Commissioner Scott Gottlieb have been sent to companies that drag their feet. And only once has the agency ordered the withdrawal of a drug indication — Avastin for treating breast cancer. Remembered by agency leadership as “Armageddon,” the FDA is unlikely to go down that road again.

So why is the agency issuing more and more accelerated approvals and pushing off important clinical studies until after approval? Making companies do the work beforehand — denying drugs like Vyondys 53 from entering the market until there is stronger supporting evidence — is the safer play.

Welcome to the real world of drug regulation, where decisions to approve (or reject) drugs for the market are driven not just by evidence but also by resources, relationships, and politics. Sometimes these dynamics are on full display. Janet Woodcock, the senior FDA official who pushed for approval of Exondys 51 in 2016, expressed concern that Sarepta would go out of business if the drug wasn’t approved — something that had nothing to do with safety or effectiveness.

The FDA isn’t unaware of the challenges of assuring company compliance with the requirement to conduct post-approval studies; agency leaders are acutely aware that once they’ve lost the power to say “no” to market entry, the dynamics change dramatically. Rather, my conversations with FDA officials suggest that the agency is engaged in a deeper political calculus that is embedded in its interactions with key stakeholders, including industry and increasingly patient groups.

Companies generally comply (albeit slowly) with post-marketing study requirements, not because they are afraid of FDA enforcement but because they do not want to test the goodwill they’ve established with agency staff who might review the company’s next new drug submission. It is hard to imagine that Sarepta’s delays in completing Exondys 51’s post-market trial didn’t limit the agency’s appetite for approving Vyondys 53.

Patient groups, too, are being increasingly integrated into the drug regulation process, even though the agency knows those groups will make it harder to withdraw a drug like Exondys 51 if it eventually proves ineffective. The agency has nevertheless learned that bringing patients inside is key to countering the perception of a callous bureaucracy.

Politics are also visible in the type of work that gets to be a priority. FDA officials let Sarepta begin selling Exondys 51 before the study to confirm (or refute) its benefit was even designed. Why? The agency surely had insight into what kind of study would be helpful. The problem is that Congress and, in turn, FDA leaders have instructed FDA scientists to focus on the next potential breakthrough therapy in the queue.

A forward momentum within the agency prioritizes getting new drugs to market, as opposed to testing and establishing the effectiveness — and ensuring the safety — of drugs that have already been approved. But it’s more than that. Expediting reviews, delaying studies until after approval, rehearsing the benefits on “real-world evidence,” and integrating patients directly into its decision-making — all of these drug regulation activities serve as a buffer against further threats to the FDA’s authority from the administration, Congress, the courts, and beyond.

The FDA is, of course, no stranger to pressure from politicians, patients, and vested interests. Talk of a “drug lag” initiated by the pharmaceutical industry and its allies in the 1970s morphed into a cris de coeur from dying HIV/AIDS patients during the 1980s, eventually resulting in the creation of the accelerated approval review pathway that Exondys 51 went through a little less than three years ago.

The difference is that the FDA no longer organizes itself in the service of public health. If it was genuinely committed to generating and acting upon rigorous evidence, it would be distributing its resources and decision-making authority across the regulatory life cycle. Instead, those resources remain heavily allocated toward pre-approval review, and the power to issue a safety warning, alter a drug’s label, or withdraw an indication from the market is still held exclusively by those who decided to approve the drug in the first place. In other words, the FDA’s increasing reliance on real-world evidence in recent years has yet to be inscribed into the institution and its practices.

The promise of life-cycle drug regulation is that regulatory decisions will evolve along with the evidence. If a company fails to conduct a post-market study in a timely manner, or a drug’s effectiveness is not confirmed through clinical use, the FDA can withdraw its approval. The reality is that’s an empty threat. For that reason, I expect Sarepta’s Vyondys 53 to be resubmitted and approved by the FDA long before we know whether Exondys 51 really works.

Matthew Herder is the director of the Health Law Institute and associate professor in the Department of Pharmacology, Faculties of Medicine and Law, at Dalhousie University in Halifax, Nova Scotia. As a Canadian Harkness Associate in Health Care Policy and Practice, supported by The Commonwealth Fund, in 2017 and 2018, he conducted extensive research interviews with senior FDA officials. This article derives from that project, published by The Milbank Quarterly.