FDA Approves First Muscular Dystrophy Drug Despite Thumbs Down by Scientific Panel

Federal regulators granted tentative approval to the first drug for muscular dystrophy, following an intense public campaign from patients and doctors who pushed for the largely unproven medication.

Federal regulators granted tentative approval to the first drug for #musculardystrophy Click To Tweet

The approval comes nearly five months after the Food and Drug Administration and a panel of outside advisers panned the drug, saying there was little evidence that it helped. But regulators faced a public backlash from patients’ families, politicians and physicians, says The Associated Press.

The FDA cleared Sarepta Therapeutics Inc.’s (Cambridge MA) Exondys 51 (pdf) for a rare form of Duchenne muscular dystrophy, a deadly inherited disease that affects boys. It’s the first FDA approval for the degenerative condition, which causes muscle weakness, loss of movement and eventually death.

The approval was based on a company study of just 12 boys. The agency is requiring Sarepta to conduct a larger study examining whether Exondys 51 results in improved movement and function for patients. If the study fails to shows it helps, the FDA said it could withdraw the drug.

Duchenne’s muscular dystrophy is a rare disease, affecting about 1 of every 3,600 boys worldwide and usually causing death by age 25, according to the National Institutes of Health. The new drug targets a genetic mutation that affects about 13% of Duchenne’s patients. Previously there were no US-approved drugs to fight the disease, though steroid drugs have been used to slow the loss of muscle strength.

Pat Furlong, a patient advocate who lost two sons to the disease, called the announcement “an extraordinary win.” Furlong is founder and president of Parent Project Muscular Dystrophy, a nonprofit that helped fund travel and other expenses related to the study.

She added, “I think this is a collaborative effort that shows the FDA, companies and the patient community can work together toward a single goal, and that is improving the lives of patients.”

The FDA cleared Sarepta’s drug under its accelerated approval program, reserved for drugs that show promising early results that have not been confirmed. The drug acts on a protein called dystrophin, which plays a role in the growth of muscle fibers.

The 12-patient study showed an increase in dystrophin “that is reasonably likely to predict” benefit in some patients, the FDA said in its announcement.

“Accelerated approval makes this drug available to patients based on initial data, but we eagerly await learning more about the efficacy of this drug through a confirmatory clinical trial,” said Dr. Janet Woodcock, director of the FDA’s drug center.

FDA staff said at a public meeting in April that they “strongly encouraged” Sarepta to conduct a larger, more comprehensive study of its drug with a randomly selected control group of patients receiving a placebo–considered the gold standard of study design.

An outside panel of experts voted 7-3 at the meeting that the drug did not show effectiveness in treating the disease. The FDA is not required to follow the advice of its advisory panels, though it often does.

Shares of Sarepta Therapeutics closed Tuesday at $55.73, nearly double their close Friday.

Steve’s Take: Having worked for the federal government decades ago as a lawyer in the National Office of the IRS, I can well imagine the titanic furor this particular FDA ruling caused inside those walls as scientific egos and administrative rank flexed their muscle to come up this extraordinary ruling.

I’ve covered the FDA for a long time and the drama surrounding this rarest-of-rare overrule by the Agency of its own, hand-picked science panel is unprecedented. I’ll get to some mind-boggling stats to validate my “rare” label for this bare-knuckle brouhaha a bit later.

Let’s begin with the aspects of this case that make it stand apart from the usual SOP at the agency:

First, the ultimate decision to approve Exondys 51 was predicated on reasons that were not just scientific. Janet Woodcock, the director of the FDA’s Center for Drug Evaluation and Research (she’s the drugs overlord), overruled the protests of her own staff to approve the drug, according to Forbes.

One of her division’s top officials appealed the ruling, and the agency’s chief scientist largely backed his conclusions, saying that “by any meaningful objective standard” the medicine is unlikely to improve patients.

But the FDA’s commissioner, Robert Califf, decided not to overturn Woodcock’s decision, citing Woodcock’s long record of independence and arguing that her differences with other FDA scientists were a matter of honest scientific disagreement, and the decision was within Woodcock’s authority.

For the FDA, the decision represents an intramural conflagration that could have unforeseen consequences. Ronald Farkas, the FDA reviewer charged with reviewing the Exondys new drug application, has already left the agency to take a job in industry. The contention between Woodcock and Dr. Ellis Unger, who is in charge of reviews of heart, kidney, neurology and psychiatric drugs, are prickly, to say the least.

And some outside experts are already arguing that Unger was correct. Eric Topol, chief academic officer at Scripps Research Institute in La Jolla, CA, says the decision is “compromising reasonable approval standards.” Walid Gellad, an associate professor of medicine at the University of Pittsburgh who frequently serves on FDA panels tweeted:

“Let me summarize: a drug the FDA says has no clinical benefit will cost four times as much as a drug that cures hepatitis C.”

Gellad’s got a point.

In an email to staff on Monday and released by Reuters, Woodcock said the approval,

“reflects FDA’s ability to apply flexibility to address challenges we often see with rare, life-threatening diseases–while remaining within our statutory framework.”

FDA scientists, including Dr. Unger, have appealed Woodcock’s planned decision to an internal disputes board, according to a publicly available summary of the dispute written by FDA Commissioner Robert Califf on Sept. 16.

The agency’s acting chief scientist, Dr. Luciana Borio, also did not believe Sarepta’s data but still supported approval, Califf’s summary stated. Nonetheless, Califf decided to:

“defer to Dr. Woodcock’s judgment and authority to make the decision.”  He added, “I find no basis for a view that Dr. Woodcock was unduly influenced by involvement with the patient community or other external pressures.” He added, however, that “serious shortcomings present in the eteplirsen development program should not be allowed to establish a broad precedent for therapeutic development in rare diseases.”

Simos Simeonidis, an analyst at RBC Capital Markets, described the approval as “one of the most perplexing regulatory decisions in recent history.” The FDA approved Sarepta’s drug under its so-called “accelerated” approval pathway in which a product is approved based on data believed to predict a clinical benefit.

That benefit must be proven by the company in a subsequent clinical trial. “It will be years before we find out the outcome of that trial,” Simeonidis said, adding that Sarepta “now becomes one of the most attractive mergers and acquisitions targets in biopharma.”

Finally, Mark Senak, a lawyer and 20-year veteran of these regulatory turf wars at public relations firm FleishmanHillard’s Washington, D.C. office, got down and dirty with his sharp, No. 2 pencil (okay, I’m making that up). He went back to 2011 and looked at every advisory committee meeting and found that there had been a total since then of 231 (data at eyeonfda.com). Of those, 145 of were held to consider a treatment candidate for approval. Of those 145, decisions have been reached in 136 of them while the balance are still under consideration.

What is the track record of recommendations for or against approval? Although I’m not 100% surprised, get this: Senak found that FDA Advisory Committees offered negative assessments and voted not to approve a drug 30% of the time (41 meetings). They voted to approve the drug 70% of the time (95 meetings).

So if a new drug application gets approved by the advisory committee, what are the chances that FDA will act against the recommendation? Since 2011, Senak found that there were 7 times that a panel had voted against approval of a product where the FDA went ahead and gave the product an approval. And there were six times that panels recommended approval, but FDA decided not to do so.

In the aggregate that means that about 10% of the time, overall–at least using meetings since and including 2011 through 2016–FDA decides ultimately on a different course than was recommended by its advisers.

Steve's Take: A remarkable tale of #FDA intramural war over bringing vital drugs to market Click To Tweet

So this is the truly remarkable tale of how a federal agency, even today, can wage intramural, nuclear war over approving bringing a drug to market–to give to patients, remember, not study volunteers–even with its hand-picked scientific advisors unwilling to sign off on that. And we’re talking about the advisors’ consensus about the safety and efficacy of the drug. (They are unquestionably the top people in this field, by the way.)

Anyone see a book or made-for-TV movie springing out of this?