On April 26, an FDA advisory committee voted 7-6 that the exon-skipping drug eteplirsen for Duchenne muscular dystrophy (DMD) failed to meet the standards needed for accelerated approval. It was widely assumed that the FDA would tell the drug's developer, Sarepta Therapeutics, to try again with better data. That, of course, did not happen. In this follow-up, we report on how it eventually did turn out for the drug and for the DMD community.
To the surprise of many, the FDA approved eteplirsen in September with the trade name Exondys 51.
While patients and families applauded the decision, believing their efforts in collaborating with industry and the agency had paid off, critics in the medical and research community questioned whether the drug really worked, and whether the FDA had made the right call. Documents later revealed internal FDA friction, and even though the agency's boss backed the approval, he also called for a key study supporting the drug to be retracted.
In addition, two recent events -- passage of the 21st Century Cures Act, a major health bill meant to spur innovation and speed the delivery of new drugs, and the surprise election of Donald Trump as president -- have sparked concerns that the FDA might inch closer to deregulation for the sake of innovation under the new administration.
Perhaps more than in previous White House transitions, confusion and uncertainty cloud the FDA's future.
Yet while consumer groups express alarm, some clinicians and policy experts believe a dramatic reversal in the FDA's core mission is unlikely. 鶹ý spoke with key stakeholders to gauge the importance of eteplirsen's approval: what it means for patients and the future of the FDA's review process.
Flash Point
In approving eteplirsen, the FDA had overruled its own advisory committee. The seven members voting against approval did not believe Sarepta had shown adequate evidence that eteplirsen triggered production of the protein dystrophin at a level that was "reasonably likely to predict clinical benefit." (DMD is caused by a genetic deficiency in dystrophin.)
Moreover, several of the FDA's senior staff members also saw evidence that patient benefit was inadequate, as documents detailing a months-long dispute between those staff members and , director of the Center for Drug Evaluation and Research (CDER), showed. She overruled their conclusions and , ultimately sided with Woodcock. Curiously, however, Califf also called for the retraction of a that aimed to demonstrate that eteplirsen produces adequate levels of dystrophin, which he called "misleading."
Insurers also appear to need more convincing that the drug is effective. The investment firm Jefferies found that three of five national payers and eight of 15 regional managed care organizations "denied or restricted coverage for the drug," according to an analyst for Jefferies. Wang told , a biopharma newsletter, the response was "in line with our expectation of pushback from private payers."
Unlike private insurers, public payers such as Medicaid do not have the option to omit FDA approved drugs from their formularies.
The ripple effect of the eteplirsen decision could prove damaging to the healthcare system, , president of the National Center for Health Research, told 鶹ý."Many drug companies will be submitting applications that they wouldn't have dreamed of submitting [before]."
Zuckerman said Woodcock's decision stemmed from sympathy for the patients.
"She approved a drug not realizing that by approving the drug based on evidence that was so obviously inadequate many health insurance companies would just refuse to pay for it."
Without insurance coverage, families have to pay $300,000 a year for the drug. "The company failed in its responsibility, the FDA failed in its responsibilities, and the patients are paying the price," Zuckerman said.
If the agency continues to move in this direction, insurers will spend more money to perform their own analyses of product data. Money that could have been better spent on coverage, she added.
On the issue of coverage determinations, , senior vice president of legislation and public policy at the (PPMD), said some insurers' refusals stemmed from a misunderstanding about the burden of the disease. Only about 2,000 U.S. patients have the specific genetic mutation making them potentially eligible for treatment.
PPMD has also pressed insurers offering narrow coverage determinations, arguing that even non-ambulatory patients can benefit from the drug. Kennedy and others have been sharing additional pulmonary data demonstrating "stability" on functional tests in treated participants compared to "a steady decline observed in the DMD natural history," according to Sarepta documents.
Kennedy anticipates that some insurers will revise their coverage determinations based on engagement with the community.
Looking Ahead
One of the FDA's advisory committee members who voted against approving eteplirsen, , of Harvard Medical School/Brigham and Women's Hospital in Boston, told 鶹ý that one of the challenges of that meeting was balancing the inconsistencies in the testimony he heard from patients and families with the data.
"How do we make sure that the patient voice is taken seriously, but at the same time also take the science seriously and come to an adequate final decision?" he said.
The newly passed "Cures Act" also has provisions that could affect the FDA's review process. It allows the agency to use "real world evidence" in deciding whether to approve expanded indications for already marketed drugs.
If Cures is given "maximum flexibility" and FDA leadership has a deregulatory agenda, said Kesselheim,"I think the future will hold a lot more products like eteplirsen that are approved on the basis of a marginal effect on a surrogate measure that does not have a clear connection to clinical endpoints."
"That's going to put a lot of pressure on physicians trying to make the decisions whether or not to use the product [and] patients deciding whether or not to take the risk ... in this context of insufficient information," he added.
Trump's election also brings the likelihood of new leadership at the FDA. Although he has made no announcement about replacing Califf as commissioner, most of his other appointees have been staunchly anti-regulation and many are coming from industry.
The possible change in agency leadership and the Cures Act together could allow the FDA to reconsider the balance between innovation and ensuring appropriate levels of safety and efficacy, said of the Johns Hopkins Bloomberg School of Public Health in a phone interview. Alexander chaired the FDA committee that voted on eteplirsen.
However, given the massive size of the FDA, whatever change does occur will be gradual, he said. "I'll be surprised if it's a total sea change."
"While cases such as Addyi (flibanserin) and eteplirsen have been quite controversial, those represent a small fraction of the reviews that FDA has performed ... I don't think that those cases are reflective of wholesale change or any deliberate decisions ... regarding a change in the evidentiary threshold for market access."
As for the worry that the "Cures Act" could encourage the use of more real world evidence, Alexander saw no conflict between leveraging patient reported outcomes, for example, and high quality science.
He added, "There's a reason the FDA has evolved toward the use of randomized controlled trials, and frankly I don't see that reliance diminishing substantially anytime soon."
Advocates Respond
In response to the backlash against the FDA's decisions and scorching criticism of Sarepta's own clinical trial, Kennedy explained that the community was "flying the plane as we were building it." For example, meetings focused on developing guidance for a protocol regarding how best to measure dystrophin happened as Sarepta's own research was already underway.
"I know there's been a lot of blame cast at this cast of characters or that cast of characters and a 152-page document released about disagreements," said Kennedy referencing the FDA's summary review.
But, she noted, "What we think happened was exactly what accelerated approval was designed for ... All of these policies and tools that so many people have pushed for, for so long ... were applied by everyone collaboratively and now we'll get to see how this plays out going forward."
"Now the onus is on Sarepta to conduct further studies to show [clinically meaningful benefit], that continues to happen in the broader subset of the community. If we don't, then the product will get pulled," she said.
Still the Watchdog
The FDA, in an emailed statement, underscored that its commitment to holding drug manufacturers, including Sarepta, accountable for confirmatory studies to determine clinical benefit will continue.
"The required study is designed to assess whether eteplirsen improves motor function of DMD patients with a confirmed mutation of the dystrophin gene amenable to exon 51 skipping. If the trial fails to verify clinical benefit, the FDA may initiate proceedings to withdraw approval," wrote Sandy Walsh, a press officer for the FDA in an email.
As for the future direction of agency, Walsh noted, "In appropriate situations, the agency exercises flexibility when evaluating treatments for serious and life-threatening conditions. However, as each situation is unique, we cannot speculate on potential decisions on other product applications."