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.

RWE chal­lenges for to­day's bio­phar­ma

The rapid development of technology — and the resulting avalanche of data — are catalysts for significant change in the biopharmaceutical industry. This translates into urgent pressures for today’s biopharma, including a need to quickly and affordably develop products with proven therapeutic efficacy and value. This urgency is expedited by the growth of value-based contracting, where access to reimbursement and profit depends on these abilities.

UP­DAT­ED: In a stun­ning turn­around, Bio­gen says that ad­u­canum­ab does work for Alzheimer's — but da­ta min­ing in­cites con­tro­ver­sy and ques­tions

Biogen has confounded the biotech world one more time.

In a stunning about-face, the company and its partners at Eisai say that a new analysis of a larger dataset on aducanumab has restored its faith in the drug as a game-changer for Alzheimer’s and, after talking it over with the FDA, they’ll now be filing for an approval of a drug that had been given up for dead.

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As shares suf­fer from a lin­ger­ing slump, a bruised Alk­er­mes slash­es 160 jobs in R&D re­struc­tur­ing

With its share price in a deep slump after suffering through a regulatory debacle over their depression drug ALKS 5461, Alkermes CEO Richard Pops is taking the ax to its R&D organization in a restructuring aimed at cutting costs ahead of its next attempt at a rollout in a tough field.

Richard Pops, Endpoints via Youtube

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Acor­da's Ron Co­hen brings the ax back out as new drug sales on­ly trick­le in while cash cow is led to the slaugh­ter

With its new drug earning meager sums and its one-time cash cow reduced to a bony shadow of its former self, Acorda Therapeutics today is rolling out a new restructuring aimed at slashing the staff and cutting costs to get through the hard times ahead.

The biotech is chopping a quarter of its staff today, carving back R&D as well as SG&A expenses. And CEO Ron Cohen is cutting deep.

Under the new austerity budget, Acorda’s R&D expenses for the full year 2019 are expected to be $55 – $60 million, reduced from $70 – $80 million. SG&A expenses for the full year 2019 are expected to be $185 – $190 million, reduced from $200 – $210 million. R&D expenses for the full year 2020 are expected to be $20 – $25 million and SG&A
expenses for the full year 2020 are expected to be $160 – $165 million.

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RAPT Ther­a­peu­tics re­turns to Wall Street to re­vive IPO bid

On May 24, FLX Bio, a small cancer and inflammation biotech with backing from GV, changed its name to RAPT Therapeutics and filed confidentially for an IPO. On July 5th, they filed to raise up to $86 million. On July 22, they announced the IPO with a $75 million goal.  And on August 1, they abruptly and without explanation called it all off.

Now, without explanation, they’re reviving the bid, filing again for a $75 million IPO, this time with a new bookrunner and a new drug candidate in the clinic. The terms will be the same: 5 million shares at $14-$16 per share. It would give them a diluted market value of $351 million.

EY vet set to re­place re­tir­ing Am­gen CFO Meline

Ahead of its third-quarter results next week, Amgen on Tuesday disclosed the planned retirement of David Meline, who has served as the company’s chief financial officer since 2014.

Meline will be replaced by Ernst & Young vet, Peter Griffith, as CFO come January 1, 2020 — but until then Griffith will serve as executive vice president, finance.

“Over the last 5 years at Amgen, Meline instituted many major changes that led to operational efficiencies and margin expansion while successfully returning cash to shareholders. Now that Amgen is on solid footing, it was a good time to step away,” Cowen’s Yaron Werber wrote in a note. “We do not anticipate any major changes to strategy or operations immediately due to this transition as Amgen is on solid footing.”

Eli Lil­ly’s USA, di­a­betes chief En­rique Con­ter­no is head­ing out af­ter 27 years, and he’s be­ing re­placed by a com­pa­ny in­sid­er

Close to 3 years after Eli Lilly CEO Dave Ricks added the title of president of the US operations to Enrique Conterno’s resume, which included his helmsmanship of the diabetes franchise, the Peruvian born exec is set to retire after a 27-year run at the pharma giant.

Lilly put out the news just as it was posting Q3 results, with a mix of upbeat and downbeat results in the latest set of numbers from Lilly.
Conterno — a grizzled, deeply experienced and sometimes gruff veteran of the pharma world — was a high-profile figure at Lilly, stepping up to expanded duties as the company was forced to deal with intense pricing pressure on the diabetes side of the business. He had replaced outgoing US president Alex Azar, who later popped up as head of Health and Human Services in the Trump administration.
As head of the diabetes unit, Conterno had to deal with an extraordinarily competitive field as payers demanded bigger discounts. Trulicity’s success helped generate new revenue for the company, but Q3’s miss on revenue had a lot to do with the need for discounting the drug ahead of Novo Nordisk’s rival therapy, Rybelsus, which was priced on the wholesale level at an almost identical rate.

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No­var­tis hands off $80M in cash to part­ner up with a top biotech play­er in the fi­bro­sis sec­tor

Never underestimate the power of a good showing at a scientific conference.
In a presentation late last year, the researchers at Pliant Therapeutics launched a series of discussions about the preclinical data they were pulling together around their work on their small-molecule integrin inhibitor aimed at transforming growth factor beta, or TGF-β, a key pathway involved in fibrosis.
And they got some serious attention for the work.
“We got interest from pharma partners and at the end Novartis basically made it,” says Pliant CEO Bernard Coulie.

Is there a recipe for M&A suc­cess? The best and worst buy­out deals in the past decade of­fer some keys to suc­cess — and fail­ure

It’s not easy achieving a solid win in M&A in this industry. But if you follow a few simple guidelines, you may be able to increase your odds of success.
Geoffrey Porges and the team at SVB Leerink went about the “notoriously difficult” task of scoring the biopharma buyout of 2009 to 2019. Sizing up current and expected revenue from the products that were gained, they came up with the 5 winners:
Merck/Schering Plough
Bristol/Medarex
Gilead/Pharmasset
Sanofi/Genzyme
AstraZeneca/Acerta
It says a lot about the field that it’s much easier sorting out the 5 worst deals, though there’s also a lot more competition for that title, notes Porges. As picked by the analysts:
J&J/Actelion
Merck/Cubist
Alexion/Synageva
AbbVie/Stemcentrx
Gilead/Kite

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