Does the FDA’s ‘break­through’ drug pro­gram need to be re­formed? Har­vard skep­tics say yes

Of all the ex­pe­dit­ed re­view pro­grams that the FDA has set up, none are as pop­u­lar as the “break­through” ther­a­py des­ig­na­tion. And a group of high-pro­file skep­tics says that has cre­at­ed some prob­lems that need to be ad­dressed.

Jonathan Dar­row

Writ­ing in the New Eng­land Jour­nal of Med­i­cine, Har­vard’s Jonathan Dar­row, Jer­ry Avorn and Aaron Kessel­heim spell out how the BTD pro­gram has tak­en hold in the near­ly 6 years since it was cre­at­ed by Con­gress, with each pass­ing year scor­ing high­er on the per­cent­age of new drug ap­provals go­ing to a break­through ther­a­py.

It’s not hard to see why. They write:

In car­ry­ing out its di­rec­tions from Con­gress, the FDA de­vel­oped poli­cies that were ap­plic­a­ble to break­through-des­ig­nat­ed ther­a­pies: the agency cre­at­ed well-de­fined staff re­spon­si­bil­i­ties, short­ened its re­sponse times, and of­fered in­ten­sive guid­ance to cor­po­rate ap­pli­cants. For ex­am­ple, un­der this pro­gram, the FDA has ad­vised spon­sors about in­ter­im analy­ses, meth­ods for da­ta bridg­ing be­tween stud­ies, study-size re­duc­tion, and cus­tom-de­signed end points. The FDA re­sponse time­lines are 60 days or less for many break­through-re­lat­ed sub­mis­sions, and dis­cus­sion of cer­tain top­ics, such as pro­pri­etary names, man­u­fac­tur­ing in­spec­tions, and post­mar­ket­ing stud­ies, can be­gin ear­li­er in the de­vel­op­ment process.

Jer­ry Avorn

And that ap­proach has de­liv­ered big gains for bio­phar­ma com­panuies. In a field where shav­ing off a few months in the de­vel­op­ment cy­cle can be a big ad­van­tage — worth well over $100 mil­lion for the com­pa­nies that buy pri­or­i­ty re­view vouch­ers — the BTD pro­gram can slice years off the process. The au­thors cite one re­port un­der­scor­ing an av­er­age 4.8-year de­vel­op­ment pe­ri­od for break­through drugs, com­pared to 8 years for non-ex­pe­dit­ed ther­a­pies.

In­creas­ing­ly, the crit­ics note, the agency is ap­prov­ing break­through drugs on less and less da­ta, leav­ing their rel­a­tive val­ue over cur­rent ther­a­pies untest­ed and un­cer­tain. (This is some­thing I wrote about ear­li­er re­lat­ed to the FDA’s in­creased ea­ger­ness to stamp an OK on a drug af­ter a sin­gle study, rather than re­ly on the twin study stan­dard that has been the hall­mark of an R&D gold stan­dard.)

Over­all, of the 31 break­through-des­ig­nat­ed ther­a­pies, 16 (52%) (in­clud­ing 12 [75%] of 16 on­col­o­gy drugs) were ap­proved on the ba­sis of phase 1 or phase 2 da­ta, 14 (45%) (in­clud­ing 12 [75%] of 16 on­col­o­gy drugs) were sup­port­ed by on­ly a sin­gle piv­otal tri­al, and 13 (42%) (in­clud­ing 10 [63%] of 16 on­col­o­gy drugs) were ap­proved on the ba­sis of ei­ther non–con­cur­rent­ly con­trolled or dose-com­par­i­son tri­als.

Aaron Kessel­heim

And the au­thors say that call­ing these drugs break­throughs has spurred the pop­u­lar press to seize on these new ther­a­pies as ground­break­ing game-chang­ers, even cures, when they are any­thing but. In fact, giv­en that the agency of­ten hands out these des­ig­na­tions ear­ly on, the drugs they deem wor­thy of VIP ser­vice don’t mea­sure up.

Case in point: Aca­dia’s pi­ma­vanserin.

The “break­through” drug was ap­proved af­ter it failed two stud­ies, then bare­ly passed muster in a piv­otal pro­gram. The pri­ma­ry re­view­er turned thumbs down on the drug. But it was ap­proved in any case af­ter a ma­jor­i­ty of FDA ex­perts on the ad­vi­so­ry com­mit­tee felt the ben­e­fits out­weighed the risks. That’s not much of a break­through, and they cite oth­er ex­am­ples of the same stripe.

So the three say it’s time to call the “break­through” pro­gram some­thing else that won’t be so eas­i­ly mis­in­ter­pret­ed.

But that’s not go­ing to hap­pen. 

Jacque­line Cor­ri­g­an-Cu­ray

In an ac­com­pa­ny­ing let­ter, FDA of­fi­cials led by Jacque­line Cor­ri­g­an-Cu­ray, di­rec­tor of the Of­fice of Med­ical Pol­i­cy with­in the Cen­ter for Drug Eval­u­a­tion and Re­search, con­clud­ed that while not every BTD lives up to its promise, the agency has not set the bar too low — and they warn against set­ting it too high.

The FDA needs the tools to iden­ti­fy and ac­cel­er­ate the ap­proval of drugs that can sub­stan­tial­ly im­prove the lives of pa­tients with se­ri­ous or life-threat­en­ing dis­eases who have in­ad­e­quate op­tions. Fast-track and break­through-ther­a­py des­ig­na­tions have done just that — while not with­out chal­lenges, cer­tain­ly with­out com­pro­mis­ing the thor­ough­ness of our re­view or the stan­dards of ev­i­dence to sup­port ap­proval. 

The dis­cus­sion goes on. But FDA com­mis­sion­er Scott Got­tlieb has made it clear that he wants all of the agency to em­brace the break­through pro­gram with the same fer­vor that the on­col­o­gy group has shown. And the pres­i­dent has en­dorsed faster ap­provals, not high­er stan­dards.

For now, BTD isn’t go­ing any­where.

Tal Zaks, Moderna CMO (Moderna via YouTube)

UP­DAT­ED: NI­AID and Mod­er­na spell out a 'ro­bust' im­mune re­sponse in PhI coro­n­avirus vac­cine test — but big ques­tions re­main to be an­swered

The NIAID and Moderna have spelled out positive Phase I safety and efficacy data for their Covid-19 vaccine mRNA-1273 — highlighting the first full, clear sketch of evidence that back-to-back jabs at the dose selected for Phase III routinely produced a swarm of antibodies to the virus that exceeded levels seen in convalescent patients — typically in multiples indicating a protective response.

Moderna execs say plainly that this first stage of research produced exactly the kind of efficacy they hoped to see in humans, with a manageable safety profile.

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Trans­port Sim­u­la­tion Test­ing for Your Ther­a­py is the Best Way to As­sure FDA Ex­pe­dit­ed Pro­gram Ap­proval

Modality Solutions is an ISO:9001-registered biopharmaceutical cold chain engineering firm with unique transport simulation capabilities that support accelerated regulatory approval for biologics and advanced therapeutic medicinal products (ATMP). Our expertise combines traditional validation engineering approaches with regulatory knowledge into a methodology tailored for the life sciences industry. We provide insight and execution for the challenges faced in your cold chain logistics network.

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Who are the women blaz­ing trails in bio­phar­ma R&D and lead­ing the fight against Covid-19? Nom­i­nate them for End­points' spe­cial re­port

One of the many inequalities the pandemic has laid bare is the gender imbalance in biomedical research. A paper examining Covid-19 research authorship wondered out loud: Where are the women?

It’s a question that echoes beyond our current times. In the biopharma world, not only are women under-represented in R&D roles (particularly at higher levels), their achievements and talents could also be undermined by stereotypes and norms of leadership styles. The problem is even more dire for women of color.

Jeff Albers, Blueprint CEO

Di­ag­nos­tic champ Roche buys its way in­to the RET ti­tle fight with Eli Lil­ly, pay­ing $775M in cash to Blue­print

When Roche spelled out its original $1 billion deal — $45 million of that upfront — with Blueprint to discover targeted therapies against immunokinases, the biotech partner’s RET program was still preclinical. Four years later, pralsetinib is on the cusp of potential approval and the Swiss pharma giant is putting in much more to get in on the commercial game.

Roche gains rights to co-develop and co-commercialize the drug, with sole marketing responsibility for places outside the US and China (where CStone has staked its claim).

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Stéphane Bancel, Moderna CEO (Andrew Harnik/AP Images)

A top an­a­lyst turns the spot­light on Mod­er­na, fu­el­ing a fast-and-fu­ri­ous Street race over the fu­ture of mR­NA

Bioregnum Opinion Column by John Carroll

Four months ago, one of the favorite talking points on the biopharma social media wave length was whether Moderna shares $MRNA were priced right or were wildly inflated.

After all, said the naysayers, the company had never actually pushed a treatment to an approval. Did messenger RNA really work, coding cells to make a drug or a vaccine? And how about all that chatter about how ‘secretive’ they are, or were?

Now, as CEO Stéphane Bancel and the top execs push the company to the forefront of a frantic race to develop the first vaccine to fight against the reignited wildfire spread of Covid-19, all those questions have been magnified — along with the stock price.

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Andrew Allen, Gritstone Oncology CEO

A neoanti­gen pi­o­neer says its tech is work­ing great. So what wrecked the share price?

Gritstone Oncology was one of the original neoantigen upstarts, raising cash and planning to disrupt the immuno-oncology field with a bold new approach to fighting cancer with a new brand of vaccines.

On Monday, the crew in charge ran out a full display of what they’ve been seeing in a Phase I study. And everything seems to be working perfectly with one big exception: It didn’t significantly shrink tumors, let alone eradicate them.

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Mene Pangalos, AstraZeneca R&D chief (AstraZeneca via YouTube)

A day af­ter Mod­er­na vac­cine re­sults, ru­mors swirl of pend­ing As­traZeneca da­ta

A day after Moderna and the NIH published much-anticipated data from their Phase I Covid-19 vaccine trial, attention is turning to AstraZeneca which, according to a UK report, is expected to publish its own early data tomorrow.

ITV’s Robert Peston reported that AstraZeneca will publish the Phase I data in The Lancet. 

AstraZeneca and Moderna represent the two most ambitious Covid-19 vaccine efforts, having set the quickest timelines for approval (though they were recently joined in that regard by the Pfizer-BioNTech partnership) and some of the loftiest goals in total doses. Yet there is even less known about AstraZeneca’s vaccine’s effect on humans than there was about Moderna’s before yesterday. Although, in a controversial move, Moderna released some statistics from its Phase I in May, AstraZeneca has yet to say anything about what it saw in its Phase I trial — a move consistent with the scientific convention to withhold data until it can be published in a peer-reviewed journal.

Stéphane Bancel, Moderna CEO (Steven Ferdman/Getty Images)

‘Plan­ning to vac­ci­nate every­one in the US,’ Mod­er­na out­lines ef­forts to sup­ply their Covid-19 vac­cine as man­u­fac­tur­ing ramps up ahead of PhI­II

Twelve days from the planned start of their Phase III pivotal trial, the executive crew at Moderna has set up the manufacturing base needed to begin production of the first 500,000 doses of their Covid-19 vaccine with plans to feed it into a global supply chain. But the initial batches will likely be ready in the US first, where company CEO Stéphane Bancel plans to be able to vaccinate everyone.

“We have started making commercial product at-risk, and will continue to do so every day and every week of the month,” Bancel told analysts during their morning call on the Phase I data just published in the New England Journal of Medicine.

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Covid-19 roundup: Vac­cine by end of 2020? Ken Fra­zier warns hype do­ing 'grave dis­ser­vice'

When it comes to setting expectations about a Covid-19 vaccine, Ken Frazier does not mince words.

Over a month after first casting doubts on the aggressive 12- to 18-month timeframe championed by the US government and his biopharma peers, the Merck CEO again cautioned against any hype around a quick vaccine approval.

In a wide-ranging interview with Harvard Business School professor Tsedal Neeley that touched other big topics such as race, Frazier emphasized that vaccines take a long time to develop. He would know: Out of the seven new vaccines introduced around the world in the past 25 years, four came from Merck.

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