When 15-year-old Billy Ellsworth stepped up to the microphone at a Food and Drug Administration public meeting in April, he had no way to know he was part of a historic shift in how the government considers the desires of patients and their advocates in evaluating new drugs.
Ellsworth has Duchenne muscular dystrophy, a muscle-wasting disease, that mainly affects boys. And he was taking an experimental drug that the FDA was trying to decide whether to approve.
"I'm going to beat this bloody disease but I need your help," Billy told the scientists weighing the evidence about the drug. "So please help me and my friends and do the right thing. FDA, please don't let me die early."
Applause swelled from the overflow crowd.
His testimony and other pleas like it during the 10-hour hearing clearly affected some of the scientists sitting in judgment of the experimental drug called eteplirsen. But when the scientists turned their attention to the slim evidence before them, they ultimately voted that drugmaker Sarepta had not shown that the experimental drug was effective.
Just 12 boys had been involved in the key study, and just about everybody agreed that the research was deeply flawed. But parents of some of those boys were convinced that the drug was in fact helping delay the progression of a disease that ultimately proves fatal.
"We came away really heartbroken in many ways," said Pat Furlong, a longtime advocate who founded Parent Project Muscular Dystrophy and who had lost two sons to the disease.
One similar drug had previously been rejected by the FDA, and two others were turned away before they could even get through the door. There was no approved drug to stop the progression of this disease.
But that wasn't the end of the story.
Times are changing at the FDA and other federal agencies. In recent years, legislation and regulation has pushed for a greater patient voice in decisions. The FDA's job wasn't simply to look at the science, as it has done for many years. They have "to look to what is meaningful benefit on the part of the patients," Furlong said. "What do the patients value?"
In this case, the parents were saw real promise in this drug, despite the results from the flawed study. They also noted that the drug appears to be safe, so there wasn't much risk. And the research did show that boys on the drug were producing a small amount of a potentially helpful protein called dystrophin, which could be a sign that the drug provides some benefit.
That was all part of the FDA's thinking when on Monday it approved eteplirsen, brand name Exondys 51, on a provisional basis. A letter written by FDA Commissioner Robert Califf laid out in remarkably frank terms the heated internal debate at the agency, which may have led to the departure of one key scientist who was opposed to approving the drug.
"It is inevitable that in some of these situations, highly qualified experts will disagree," Califf wrote, and he praised Dr. Janet Woodcock, the head of the FDA division that reviews new drugs, who made the call "in the face of profound changes in science and social interactions related to drugs."
Califf said Woodcock ultimately made a scientific judgment call, anchored on the observation that the drug does prompt patients to produce at least a small amount of dystrophin.
Yet the role of advocacy here was inescapable. It is, after all, the patients who face the risks and the benefits.
"You can look at this as being a potentially damaging precedent, and on the other hand you can look of this as being an innovative precedent, that could bring good things and earlier access to medicines," Eric Hoffman told NPR.
Hoffman and Louis Kunkel discovered the dystrophin gene in 1987. Hoffman is now CEO of ReveraGen, a company working on a drug for the disease, as well as associate dean of research at the University of Binghamton's pharmacy school in New York.
The FDA decision approves the drug on an accelerated basis, but that approval is contingent on follow-up studies and it can be withdrawn. In other diseases, provisional approvals have been reversed after follow-up studies failed to show the drugs were effective. (Avastin for advanced breast cancer is a notable example, despite pleas from patient groups to keep the approval intact).
The Sarepta drug addresses just one genetic mutation in muscular dystrophy, and that particular flaw only affects about 1,500 boys in the entire United States. Drugmaker Sarepta plans to use the same approach now to target other mutations related to the disease, and to use those study results to comply with the FDA's requirement for more and better studies.
In the meantime, Sarepta can start charging $300,000 per patient per year for treatment with eteplirsen.
"Yes, there was a lot of pressure," Dr. Edward Kaye, CEO of Sarepta said, "but I think the FDA demonstrated the flexibility they are allowed under the law. It took a lot of courage for them to do this. It's always easy to take the safe path and say, just give us more data."
Advocate Pat Furlong agreed. "I think the important aspect of this is maybe a new social contract," she said. Since the drug is apparently safe and possibly useful, parents wanted to make the drug available while the questions about usefulness and value are fully answered. "And at the end of five years we can reevaluate whether this really hits its mark in terms of the healthcare cost and the benefit to patients," she said.
More than a dozen potential drugs for this disease are in the pipeline now, and at the very least they now have a standard against which they can be judged.
The decision about eteplirsen would have been considerably easier, for patients and scientists alike, if the company had conducted its trials carefully and rigorously.
"Considering that a substantially flawed development program contributed to the difficulty of coming to resolution in this case, we must redouble our efforts to ... use methods that will produce high-quality evidence from the outset," Califf wrote.