Tragic Patient Stories Don't Trump Weak Data, Official Says

  • Robust clinical trials needed even as patient focus grows
  • Drugs for Duchenne muscular dystrophy struggle with data

Heartrending anecdotes of sick patients in need can’t overcome the shortcomings of weak drug trial data, said one of the U.S.’s top drug regulators, as outside advocacy groups seek a larger role in the drug approval process.

The Food and Drug Administration has worked to better include patients in the development of treatments after a 2012 directive from Congress. While patient support can help a drug’s chances, the key is having evidence the FDA can trust, said Janet Woodcock, director of the agency’s Center for Drug Evaluation and Research. That includes randomized clinical trials where patients receiving an experimental drug are compared with others who don’t -- a step some drugmakers have skipped, especially when the disease is rare or particularly deadly.

“I would prefer seeing randomization very, very early” in the drug testing process, Woodcock said Thursday in a telephone interview. “Even if there’s a small, tiny effect, it may be meaningful to that patient population. If they can show there is definitely a small effect in a terrible disease, we will approve that drug.”

Patient groups have helped push drugs across the finish line, with approvals of cystic fibrosis, multiple myeloma, and low female libido treatments, even if they showed limited benefit or worked only in some cases. On the other hand, treatments for a deadly genetic condition called Duchenne muscular dystrophy have struggled.

Duchenne Failures

Despite pleas from patients, BioMarin Pharmaceutical Inc.’s drug, Kyndrisa, was rejected last month after the agency said it failed to show clear scientific evidence of helping patients. The FDA this month refused to review PTC Therapeutics Inc.’s application for its drug Translarna. The company failed to show patients getting the drug did better than those on placebo.

A third company, Sarepta Therapeutics Inc., is still waiting for its FDA review, after a snow storm canceled its advisory committee hearing scheduled for last month -- frustrating dozens of patients and family members who’d shown up in support of the drug. The company’s shares plunged by more than half after an agency staff report released in advance of the meeting said the drug hadn’t been proven to work. The agency noted the trials only randomized patients for a short time in the beginning then all patients took the drug.

Earlier guidance from the FDA has said that Duchenne drugs could be compared against how patients had done in the past, rather than a placebo group. The agency will discuss the benefit of Sarepta’s drug in a future meeting, though it hasn’t been scheduled yet.

Ian Estepan, a spokesman for Sarepta, and Debra Charlesworth, a BioMarin spokeswoman, didn’t return phone calls or e-mails seeking comment. BioMarin executives said on a call with investors Thursday that they hope to get their drug approved in Europe.

Sarepta fell 7.2 percent to $13.33 at 12:21 p.m. in New York. On Thursday, the company reported a fourth-quarter net loss that widened to $64.7 million, or $1.44 a share. In a statement, Sarepta attributed the results to an increase in operating expenses. BioMarin shares rose 3.5 percent to $79.06. The company reported fourth-quarter net income of $69 million, or 39 cents a share, compared to a net loss a year earlier, according to a statement Thursday.

Drugs Approved

In other cases, drugs that might have been -- or were -- rejected have been approved, partly in response to patients’ involvement.

Addyi is a treatment from Sprout Pharmaceuticals Inc. for low female libido. It was rejected twice before the FDA approved it last year, following a patient advocacy campaign -- partly funded by Sprout -- urging the agency to clear the drug. Now sold by Valeant Pharmaceuticals International Inc., trials showed that it provides meaningful benefit to only about 10 percent more patients than a placebo. It also carries serious risks, including low blood pressure and fainting.

With Addyi, patients’ input was critical in determining how much of a difference the drug made to individuals, and whether it was worth the risks to them, Woodcock said.

The agency is “walking a tightrope” by giving patients more of a voice, said Ira Loss, an analyst with Washington Analysis LLC who has followed the FDA for four decades. “They want to be inclusive and sympathetic without obviously compromising the standards for drug approvals.”

Matching Goals

The FDA is trying to incorporate patient and family views early in the drug development process. In the past, companies often tried to design products that led to improvements on patients’ laboratory tests, or kept patients alive longer -- features that appealed to physicians.

“We don’t want drug developers to just study what doctors think is important,” Woodcock said. “Patients often have a different focus. They want better quality of life. They may even trade off survival for a greater quality of life.”

Changes are already occurring in the muscular dystrophy realm, she said. The agency worked with Parent Project Muscular Dystrophy and other patient organizations to identify the key issues. One insight was that the six-minute walk test, a frequently used measure of experimental Duchenne drugs, doesn’t address the issues of many patients. Woodcock pointed to toddlers, who may just be learning to walk, and those in wheelchairs who could benefit from treatment that wouldn’t show up during conventional testing.

The Parent Project Muscular Dystrophy group brought in dozens of experts, patients and families to craft a draft guidance suggesting different measures, which Woodcock didn’t specify, to determine benefit.

“They related directly to drug development,” she said. “How do you measure improvement, how much risk are you willing to take? That’s where we are planning to go.”

Alzheimer’s Disease

Those considerations will be even more important for another challenging area of drug development -- Alzheimer’s disease. Drugmakers have spent billions of dollars trying and failing to bring to market a treatment that slows the progression of the neurodegenerative disease.

About 5 million Americans have Alzheimer’s, which is the sixth leading cause of death in the U.S., according to the Alzheimer’s Association. For drugs that could treat it, the agency wants to be able to capture signs of benefit, even if they’re tiny. “We don’t want to rule out drugs that only work a little bit,” she said.

Companies like Eli Lilly & Co. are using sensitive tests that measure early signs of cognitive decline, even before traditional symptoms of dementia start to appear. 

“We would do an accelerated approval if you could slow decline on these sensitive tests,” Woodcock said.

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