The Sarep­ta dilem­ma: Bioethics ex­pert Arthur Ca­plan says it’s time to re­think how to reg­u­late com­pas­sion

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.

Martin Shkreli [via Getty]

Pris­on­er #87850-053 does not get to add drug de­vel­op­er to his list of cred­its

Just days after Retrophin shed its last ties to founder Martin Shkreli, the biotech is reporting that the lead drug he co-invented flopped in a pivotal trial. Fosmetpantotenate flunked both the primary and key secondary endpoints in a placebo-controlled trial for a rare disease called pantothenate kinase-associated neurodegeneration, or PKAN.

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We­bi­nar: Re­al World End­points — the brave new world com­ing in build­ing fran­chise ther­a­pies

Several biopharma companies have been working on expanding drug labels through the use of real world endpoints, combing through the data to find evidence of a drug’s efficacy for particular indications. But we’ve just begun. Real World Evidence is becoming an important part of every clinical development plan, in the soup-through-nuts approach used in building franchises.

I’ve recruited a panel of 3 top experts in the field — the first in a series of premium webinars — to look at the practical realities governing what can be done today, and where this is headed over the next few years, at the prodding of the FDA.

ZHEN SU — Merck Serono’s Senior Vice President and Global Head of Oncology
ELLIOTT LEVY — Amgen’s Senior Vice President of Global Development
CHRIS BOSHOFF — Pfizer Oncology’s Chief Development Officer

A premium subscription to Endpoints News is required to attend this webinar. Please upgrade to either an Insider or Enterprise plan for access. Already have Endpoints Premium? Please sign-in below. You can contact our Subscriptions team at help@endpointsnews.com with any issues.

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Brian Kaspar. AveXis via Twitter

AveX­is sci­en­tif­ic founder fires back at No­var­tis CEO Vas Narasimhan, 'cat­e­gor­i­cal­ly de­nies any wrong­do­ing'

Brian Kaspar’s head was among the first to roll at Novartis after company execs became aware of the fact that manipulated data had been included in its application for Zolgensma, now the world’s most expensive therapy.

But in his first public response, the scientific founder at AveXis — acquired by Novartis for $8.7 billion — is firing back. And he says that not only was he not involved in any wrongdoing, he’s ready to defend his name as needed.

I reached out to Brian Kaspar after Novartis put out word that he and his brother Allen had been axed in mid-May, two months after the company became aware of the allegations related to manipulated data. His response came back through his attorneys.

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Hal Barron. GSK

GSK's Hal Bar­ron her­alds their sec­ond pos­i­tive piv­otal for cru­cial an­ti-BC­MA ther­a­py, point­ing to a push for quick OKs in a crowd­ed field

Hal Barron has his second positive round of Phase III data in hand for his anti-BCMA antibody drug conjugate belantamab mafodotin (GSK2857916). And GSK’s research chief says the data paves the way for their drive in search of an FDA approval for treating multiple myeloma.

It’s hard to overestimate the importance of this drug for GSK, a cornerstone of Barron’s campaign to make a dramatic impact on the oncology market and provide some long-lost excitement for the pharma giant’s pipeline. They’re putting this BCMA program at the front of that charge — looking to lead a host of rivals all aimed at the same target.

We don’t know what the data are yet, but DREAMM-2 falls on the heels of a promising set of data delivered 5 months ago for DREAMM-1. There investigators noted that complete responses among treatment-resistant patients rose to 15% in the extra year’s worth of data to look over, with a median progression-free survival rate of 12 months, up from 7.9 months reported earlier. The median duration of response was 14.3 months.

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UP­DAT­ED: An em­bold­ened As­traZeneca splurges $95M on a pri­or­i­ty re­view vouch­er. Where do they need the FDA to hus­tle up?

AstraZeneca is in a hurry.

We learned this morning that the pharma giant — not known as a big spender, until recently — forked over $95 million to get its hands on a priority review voucher from Sobi, otherwise known as Swedish Orphan Biovitrum.

That marks another step down on price for a PRV, which allows the holder to slash 4 months off of any FDA review time.

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Bob Smith, Pfizer

Pfiz­er is mak­ing a $500M state­ment to­day: Here’s how you be­come a lead play­er in the boom­ing gene ther­a­py sec­tor

Three years ago, Pfizer anted up $150 million in cash to buy Bamboo Therapeutics in Chapel Hill, NC as it cautiously stuck a toe in the small gene therapy pool of research and development.

Company execs followed up a year later with a $100 million expansion of the manufacturing operations they picked up in that deal for the UNC spinout, which came with $495 million in milestones.

And now they’re really going for it.

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Video: Putting the AI in R&D — with Badhri Srini­vasan, Tony Wood, Rosana Kapeller, Hugo Ceule­mans, Saurabh Sa­ha and Shoibal Dat­ta

During BIO this year, I had a chance to moderate a panel among some of the top tech experts in biopharma on their real-world use of artificial intelligence in R&D. There’s been a lot said about the potential of AI, but I wanted to explore more about what some of the larger players are actually doing with this technology today, and how they see it advancing in the future. It was a fascinating exchange, which you can see here. The transcript has been edited for brevity and clarity. — John Carroll

As­traZeneca’s Imfinzi/treme com­bo strikes out — again — in lung can­cer. Is it time for last rites?

AstraZeneca bet big on the future of their PD-L1 Imfinzi combined with the experimental CTLA-4 drug tremelimumab. But once again it’s gone down to defeat in a major Phase III study — while adding damage to the theory involving targeting cancer with a high tumor mutational burden.

Early Wednesday the pharma giant announced that their NEPTUNE study had failed, with the combination unable to beat standard chemo at overall survival in high TMB cases of advanced non-small cell lung cancer. We won’t get hard data until later in the year, but the drumbeat of failures will call into question what — if any — future this combination can have left.

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Why would Am­gen want to buy Alex­ion? An­a­lysts call hot­ly ru­mored takeover un­like­ly, but seize the mo­ment

A rumor that Amgen is closing in on buyout deal for Alexion has sparked a guessing game on just what kind of M&A strategy Amgen is pursuing and how much Alexion is worth.

Mizuho analyst Salim Syed first lent credence to the report out of the Spanish news outlet Intereconomía, which said Amgen is bidding as much as $200 per share. While the source may be questionable, “the concept of this happening doesn’t sound too crazy to me,” he wrote.