Billy Ellsworth, a teenager with an inexorable and devastating degenerative muscle disease, will bring a football with him to a Maryland hotel conference center on Monday. For months, he has been brainstorming a way to prove to a panel of scientists and physicians that the experimental drug he has been taking for more than four years has kept him strong and well — and he’d like to punctuate his brief testimony in the clearest possible way: by throwing them the ball.
When he was 4¼, Billy was diagnosed with Duchenne muscular dystrophy, a rare and lethal disease that typically forces boys to use wheelchairs by their teens and kills them in their 20s or 30s. His mother, Terri, has always measured her son’s life in fractions; Billy is 15¼ now, and the reason he isn’t in a wheelchair yet, they believe, is the experimental drug eteplirsen.
On Monday, the panel of scientists and physicians who catch Billy’s pass — if he’s allowed to throw it — will vote on whether the drug is effective. It is more than just a major make-it-or-break-it milestone for the Massachusetts drug company Sarepta Therapeutics and the families who support approval. The meeting also provides a window into the growing sophistication of grass-roots patient groups, whose well-organized lobbying efforts are exerting intense pressure on the drug-approval process. The Duchenne parent groups are orchestrating webinars on how to participate in the meeting, providing travel grants to help families attend, gathering their own data on the risks families are willing to accept and lobbying Congress.
The disease affects 1 in 3,500 boys, and it works only on a gene mutation carried by 13 percent of boys with Duchenne. A dozen boys were included in the key trial under scrutiny at the FDA meeting. But close to 900 community members are expected to attend, revealing the tensions that arise when patients adamantly believe that a drug works but the evidence is far less clear.
“It can, I think, at times border on patients putting a lot of pressure on the agency that’s inappropriate — to make decisions that aren’t based on science,” said Sarah Sorscher, of the consumer watchdog Public Citizen. “Really, I’ve never seen a drug that was even considered for approval with this poor quality of data. . . . If the drug is really a miracle, why don’t they have the data?”
The FDA has been working to incorporate the patient perspective into the drug-approval process, especially over the past five years, under growing pressure from advocacy groups and Congress. The Duchenne parent groups have been especially active on this front, running studies of the benefits and risks patients and caregivers are willing to accept — to try to “quantify the tears” for regulators as Pat Furlong, president of the Parent Project Muscular Dystrophy, says.
The parent group led a coalition that drafted a paper to help guide companies on best practices for successfully creating drugs for the disease that the FDA credited and drew from when it published its own guidance last summer — a first that other disease groups are working to follow. This month, they have worked to get two dozen senators to sign a letter reminding the FDA to prioritize the patient perspective when considering drugs for diseases with no treatments.
The Duchenne parent groups “have been an active leader. They have a strategy they call ‘aggressive engagement’: We’re going to the FDA on this, and we’re not going to stop,” said John F.P. Bridges, a researcher at the Johns Hopkins Bloomberg School of Public Health who works with advocacy groups and pharmaceutical companies to quantify and rigorously measure patient preference.
The meeting may reveal the limitations of the patient perspective for regulators. In the run-up to it, the FDA released documents that are critical of the way Sarepta’s small trial of just a dozen boys has been designed, saying “there are significant concerns regarding the ability to draw valid conclusions.” The FDA’s documents show that although the agency views the drug as safe, there is clear skepticism that it works: They say the ability of boys on the drug to walk declines over time, consistent with natural disease progression. And a crucial protein called dystrophin missing in people with Duchenne was present at less than 1 percent of normal levels after patients took the drug for three and a half years.
A group of 36 experts — some of whom with ties to the company — sent a letter in February rebutting FDA critiques of the evidence, stating that they have observed 5,000 patients over 15 years and that the boys on the drug are “clearly performing better than our collective clinical experience and the published literature would predict.”
The patient view can be extremely valuable: Patients know better than anyone what a meaningful benefit would be or what risks they would accept. But the patient’s view on whether the drug works may be influenced by hope.
“I think a lot of it is the desire — that people really want the drug to work, because there is nothing else,” said Richard Klein, director of the FDA’s patient liaison program, who said he was not speaking about any particular drug. “The downside is that people don’t understand the scientific rigors of what needs to be done, and they want the drug to be approved on extremely small bits of data.”
Contrast that with a parent’s experience:
“We’re not asking for something that’s not worthy or didn’t prove itself; we’re asking for flexibility for a rare disease,” Terri Ellsworth said. “My son gets himself to bed, gets himself out of bed every morning, dresses himself . . . eats breakfast and carries his dishes to the sink. Most boys are losing upper-body strength at [Billy’s] age. Here’s my son, and we don’t even own a wheelchair.”
Parents like Ellsworth say that since the FDA agrees that there are no known risks to eteplirsen and the disease is fatal, parents should be able to decide whether to give the drug, even if the benefit is unclear to regulators. The outcome for their sons, otherwise, is tragic and unavoidable.
Thomas Rando, a neurologist at Stanford University School of Medicine, said in an email that it’s hard to fault the FDA for being critical — and yet, it’s also hard to fault parents for pushing for approval of a drug that appears safe even if it has only subtle benefits in a clinical trial.
“Essentially, the question is should the FDA lower the bar for devastating disease, which is not a scientific question, it’s a policy question — an ethical question, too,” Rando said.
The agency’s attempt to consider the patient’s point of view was jump-started by HIV and AIDS activists in the late 1980s. But the effort to incorporate the patient viewpoint has been accelerated by recent law. Since 2013, the FDA has held “patient-focused drug development” meetings that are listening sessions for the agency to hear from patients suffering from various diseases. In 2015, the agency approved an obesity device called the Maestro Rechargeable System — something Bridges, the Johns Hopkins researcher, said was a watershed.
In that case, the device fell short of its endpoint: that people with the device would lose at least 10 percent more weight than a comparison group. But the agency, in its approval, cited a survey of patient preferences that showed patients would accept risk for the degree of benefit the device was expected to provide.
More recently, Diana Zuckerman, president of the National Center for Health Research, pointed to last year’s controversial drug approval of a female libido drug, flibanserin, as a milestone that might have emboldened Sarepta.
“In that case, a campaign by patients persuaded an FDA Advisory Committee and the FDA to approve a drug they knew had little benefit and substantial risk,” Zuckerman wrote. “Sarepta probably assumed a campaign by desperate parents would be even more persuasive.”
Ron Cohen, chairman of the Biotechnology Innovation Organization, a trade group for biotech drug companies, said that listening to patients is essential for companies and for regulators.
But he also noted that clinical trials remain critically important — something he learned personally years ago, when his company, Acorda Therapeutics, tested a therapy for spinal-cord injury. During a trial in which patients and medical practitioners were blind to who was getting the drug and who was getting the placebo, there were four excited calls from nurses, saying they thought the drug was working: Partially paralyzed patients were moving their legs.
“We were high-fiving back at the office and the lab — we were so thrilled,” Cohen said.
But the company then found that half of the patients that had seen marked improvements were on a placebo. “You’d never think someone with a spinal-cord injury would spontaneously move their leg when they haven’t moved it in years,” Cohen said. “And yet there it was.”