Arthur Caplan was never enthusiastic about the idea of an FDA approval for Exondys 51 (eteplirsen) for Duchenne muscular dystrophy. When it came through, the noted NYU bioethics expert saw it as a deviation from the FDA’s policies on how drugs should be studied and reviewed, focusing on safety and a clear signal of efficacy.
But there were a lot of things wrong with it.
“The trial was poor,” Caplan tells me, “and even with small numbers I think it could have been done better.” The vehement public lobbying by Duchenne families to get it across the finish line also didn’t convince him that the agency needed to make it available.
“Sometimes, people see what they want to see,” he says. “And sometimes they’re right. It’s an iffy basis for approving things.”
But this isn’t a story about a prominent bioethicist objecting to the FDA’s controversial ruling, which hinged entirely on Janet Woodcock’s willingness to override her colleagues.
At this point, says Caplan, debating over whether the FDA should or should not have approved the drug is distracting from the real issues at hand. Sarepta, he says, was a shot across the bow of the FDA and biopharma.
“Let’s use the Sarepta battle to revisit where we are with compassionate use, what constitutes evidence, what will be accepted as evidence and who pays for collection of the evidence and ultimately early access,” says Caplan.
Because the next Sarepta will be right around the next corner. Followed by the next, the next and.…
“The FDA should be thinking hard about this,” says Caplan. “This is the first in what will be a long parade of diseases that affects small numbers of patients.
“We’re trying to balance the challenge of compassionate use against approval and I think we have to revisit the whole subject,” says Caplan. “This is a trigger to re-examine what are we going to do down the road. Are expanded access guidelines adequate? Is it time to start rethinking what sort of information can be provided as evidence? What about ultra rare diseases, where the numbers are small? What should regulators expect in terms of ‘evidence’”
Just consider gene therapy, which is targeting pathways where the numbers are often tiny.
“We have to start to rethink what constitutes ‘adequate’ and ‘sufficient’ evidence,” do we need more mandatory extensive Phase 4 monitoring than now occurs he says.
How should developers and the FDA think about evaluating hopeful early signs of efficacy? What targets should you go after? Where should surrogate endpoints play a big role?
“Today’s trial designs are not up to what has been expected in terms of evidence,” says Caplan, “and doing this on the fly doesn’t make a lot of sense.”
The FDA is behind the curve on where the science is and where consumer pressures are being applied. If they had been up to speed, says Caplan, Sarepta could have been guided much earlier to provide more relevant data with what they had.
“I don’t think they collected enough systematic information,” says the ethicist. “The FDA might have demanded more earlier. The company could have done more.”
And how can you even run trials when a drug is made available early to small patient groups with very rare diseases through compassionate use, which might be a better way to go for patients than a placebo trial?
Under the old social contract between drug companies and patients, says Caplan, if patients were willing to run the risk of being in the control arm, they could sign up for a trial to help prove if a drug worked or not — and might get it. In the process, they were willing to take a big risk to gain access and help the process of drug development.
That kind of arrangement no longer works for patients.
“The new deal is, I want the drug,” says Caplan, “I want to help me. So patient groups praise these new drugs, saying everything is great, I want the drug.”
And they don’t want to be left paying for it out of pocket, either, especially if you’re talking about a $300,000 a year bill for a rare disease therapy like Exondys 51. But then, neither do insurers like Anthem, which announced late last week that they wouldn’t reimburse for a drug the insurer has determined is still experimental.
“Of course it’s an experimental drug,” Caplan responds. “They’re not going to be bound by that kind of an FDA decision until they think there’s adequate evidence. And this is especially true since it’s very expensive.”
So who does pay for these? Often, small biotechs like Sarepta can’t afford to pay. So when Caplan hears state and Federal lawmakers talk about the right to try, he wonders why they don’t immediately start discussing how they propose to provide the funds to pay for it.
That’s another part of the discussion that’s missing in action in this debate, says the ethicist. And it’s past time for the industry, the FDA, lawmakers and patient groups to grapple with the reality of cost and all the scientific issues now.
Time has run short for taking a comprehensive look at one of the most difficult topics in the industry—how best to regulate compassion.
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