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.

Mi­no­ryx and Sper­o­genix ink an ex­clu­sive li­cense agree­ment to de­vel­op and com­mer­cial­ize lerigli­ta­zone in Chi­na

September 23, 2020 – Hong Kong, Beijing, Shanghai (China) and Mataró, Barcelona (Spain)  

Minoryx will receive an upfront and milestone payments of up to $78 million, as well as double digit royalties on annual net sales 

Sperogenix will receive exclusive rights to develop and commercialize leriglitazone for the treatment of X-linked adrenoleukodystrophy (X-ALD), a rare life-threatening neurological condition

Secretary of health and human services Alex Azar speaking in the Rose Garden at the White House (Photo: AFP)

Trump’s HHS claims ab­solute au­thor­i­ty over the FDA, clear­ing path to a vac­cine EUA

The top career staff at the FDA has vowed not to let politics overrule science when looking at vaccine data this fall. But Alex Azar, who happens to be their boss’s boss, apparently won’t even give them a chance to stand in the way.

In a new memorandum issued Tuesday last week, the HHS chief stripped the FDA and other health agencies under his purview of their rule making ability, asserting all such power “is reserved to the Secretary.” Sheila Kaplan of the New York Times first obtained and reported the details of the September 15 bulletin.

FDA commissioner Stephen Hahn at the White House (AP Images)

Un­der fire, FDA to is­sue stricter guid­ance for Covid-19 vac­cine EUA this week — re­port

The FDA has been insisting for months that a Covid-19 vaccine had to be at least 50% effective – a measure of transparency meant to shore public trust in the agency and in a vaccine that had been brought forward at record speed and record political pressure. But now, with concerns of a Trump-driven authorization arriving before the election, the agency may be raising the bar.

The FDA is set to release new guidance that would raise safety and efficacy requirements for a vaccine EUA above earlier guidance and above the criteria used for convalescent plasma or hydroxychloroquine, The Washington Post reported. Experts say this significantly lowers the odds of an approval before the election on November 3, which Trump has promised despite vocal concerns from public health officials, and could help shore up public trust in the agency and any eventual vaccine.

Vas Narasimhan (AP Images)

UP­DAT­ED: Still held down by clin­i­cal hold, No­var­tis' Zol­gens­ma falls fur­ther be­hind Bio­gen and Roche as FDA asks for a new piv­otal study

Last October, the FDA slowed down Novartis’ quest to extend its gene therapy to older spinal muscular atrophy patients by slapping a partial hold on intrathecal administration. Almost a year later, the hold is still there, and regulators are adding another hurdle required for regulatory submission: a new pivotal confirmatory study.

The new requirement — which departs significantly from Novartis’ prior expectations — will likely stretch the path to registration beyond 2021, when analysts were expecting a BLA submission. That could mean more time for Biogen to reap Spinraza revenues and Roche to ramp up sales of Evrysdi in the absence of a rival.

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Scoop: ARCH’s Bob Nelsen is back­ing an mR­NA up­start that promis­es to up­end the en­tire man­u­fac­tur­ing side of the glob­al busi­ness

For the past 2 years, serial entrepreneur Igor Khandros relied on a small network of friends and close insiders to supply the first millions he needed to fund a secretive project to master a new approach to manufacturing mRNA therapies.

Right now, he says, he has a working “GMP-in-a-box” prototype for a new company he’s building — after launching 3 public companies — which plans to spread this contained, precise manufacturing tech around the world with a set of partners. He’s raised $60 million, recruited some prominent experts. And not coincidentally, he’s going semi-public with this just as a small group of pioneers appears to be on the threshold of ushering in the world’s first mRNA vaccines to fight a worldwide pandemic.

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Isaac Veinbergs, Libra CEO

With $29M in Se­ries A, Boehringer-backed Li­bra looks to tack­le neu­rode­gen­er­a­tion through cel­lu­lar clean­ing

Can the natural process by which cells clean out toxic proteins be harnessed to create potential treatments for neurodegenerative disorders?

That’s the question Libra Therapeutics will be trying to answer, as the new biotech officially launched Wednesday morning with $29 million in Series A financing. The company has three preclinical programs at the ready, with its lead candidate targeting ALS and frontotemporal dementia. But CEO Isaac Veinbergs said he hopes to develop therapies for a wide range of diseases, including Parkinson’s, Alzheimer’s and Huntington’s.

Patrick Enright, Longitude co-founder (Longitude)

As its biotechs hit the pan­dem­ic ex­it, Lon­gi­tude rais­es $585M for new neu­ro, can­cer, ag­ing and or­phan-fo­cused fund

The years have been kind to Longitude Capital. This year, too.

A 2006 spinout of Pequot Capital, its founders started their new firm just four years before the parent company would go under amid insider trading allegations. Their first life sciences fund raised $325 million amid the financial crisis, they added a second for $385 million and then in, 2016, a third for $525 million. In the last few months, the pandemic biotech IPO boom netted several high-value exits from those funds, as Checkmate, Vaxcyte, Inozyme and Poseida all went public.

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Gene Wang, Immetas co-founder and CEO (file photo)

Im­metas Ther­a­peu­tics nabs $11M Se­ries A to nar­row their bis­pe­cif­ic work tar­get­ing in­flam­ma­tion in age-re­lat­ed dis­eases

How does a biotech celebrate its two-year anniversary? For Immetas Therapeutics, it’s with an $11 million Series A round and a game plan to fight age-related disease.

Co-founders Gene Wang and David Sinclair came together years ago around the idea that inflammation is the ultimate process driving age-related illnesses, including cancer. The duo launched Immetas in 2018 and packed the staff with industry experts. Wang, who says he’s always had an entrepreneurial spirit, has held lead roles at Novartis, GSK, Bristol Myers Squibb and Merck. He’s worked on blockbuster drugs like Humira, Gardasil, Varubi and Zolinza. And now, he’s channeling that spirit as CEO.

#ES­MO20: Push­ing in­to front­line, Mer­ck and Bris­tol My­ers duke it out with new slate of GI can­cer da­ta

Having worked in parallel for years to move their respective PD-1 inhibitors up to the first-line treatment of gastrointestinal cancers, Merck and Bristol Myers Squibb finally have the data at ESMO for a showdown.

Comparing KEYNOTE-590 and CheckMate-649, of course, comes with the usual caveats. But a side-by-side look at the overall survival numbers also offer some perspective on a new frontier for the reigning checkpoint rivals, both of whom are claiming to have achieved a first.