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.

Nick Leschly via Getty

UP­DAT­ED: Blue­bird shares sink as an­a­lysts puz­zle out $1.8M stick­er shock and an un­ex­pect­ed de­lay

Blue­bird bio $BLUE has un­veiled its price for the new­ly ap­proved gene ther­a­py Zyn­te­glo (Lenti­Glo­bin), which came as a big sur­prise. And it wasn’t the on­ly un­ex­pect­ed twist in to­day’s sto­ry.

With some an­a­lysts bet­ting on a $900,000 price for the β-tha­lassemia treat­ment in Eu­rope, where reg­u­la­tors pro­vid­ed a con­di­tion­al ear­ly OK, blue­bird CEO Nick Leschly said Fri­day morn­ing that the pa­tients who are suc­cess­ful­ly treat­ed with their drug over 5 years will be charged twice that — $1.8 mil­lion — on the con­ti­nent. That makes this drug the sec­ond most ex­pen­sive ther­a­py on the plan­et, just be­hind No­var­tis’ new­ly ap­proved Zol­gens­ma at $2.1 mil­lion, with an­a­lysts still wait­ing to see what kind of pre­mi­um can be had in the US.

Ted Love. HAVERFORD COLLEGE

Glob­al Blood Ther­a­peu­tics poised to sub­mit ap­pli­ca­tion for ac­cel­er­at­ed ap­proval, with new piv­otal da­ta on its sick­le cell dis­ease drug

Global Blood Therapeutics is set to submit an application for accelerated approval in the second-half of this year, after unveiling fresh data from a late-stage trial that showed just over half the patients given the highest dose of its experimental sickle cell disease drug experienced a statistically significant improvement in oxygen-wielding hemoglobin, meeting the study's main goal.

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Turns out, Rudy Tanzi did­n't see much of a sto­ry about a hid­den link be­tween En­brel and Alzheimer's ei­ther

The Wash­ing­ton Post man­aged to whip up the quick­est in­dus­try con­sen­sus I’ve ever seen that one of its re­porters was pur­vey­ing overblown non­sense with a sto­ry that Pfiz­er was sit­ting on da­ta sug­gest­ing that En­brel could be an ef­fec­tive treat­ment for Alzheimer’s. 

In cov­er­ing that bit of an­ti-Big Phar­ma fan­ta­sy — there are lots of rea­sons to go af­ter phar­ma, but this piece was lu­di­crous — I not­ed com­ments in the sto­ry from some promi­nent peo­ple in the field crit­i­ciz­ing Pfiz­er for not pub­lish­ing the da­ta. I sin­gled out Rudy Tanzi at Har­vard and then ap­plied some added crit­i­cism for the things he’s done to hype — in my opin­ion — high­ly ques­tion­able as­sump­tions. You can see it in the link. 

News­mak­ers at #EHA19: Re­gen­eron, Ar­Qule track progress on re­sponse rates

Re­gen­eron’s close­ly-watched bis­pe­cif­ic con­tin­ues to ring up high re­sponse rates

Re­gen­eron’s high-pro­file bis­pe­cif­ic REGN1979 is back in the spot­light at the Eu­ro­pean Hema­tol­ogy As­so­ci­a­tion sci­en­tif­ic con­fab. And while the stel­lar num­bers we saw at ASH have erod­ed some­what as more blood can­cer pa­tients are eval­u­at­ed, the re­sponse rates for this CD3/CD20 drug re­main high.

A to­tal of 13 out of 14 fol­lic­u­lar lym­phomas re­spond­ed to the drug, a 93% ORR, down from 100% at the last read­out. In 10 out of 14, there was a com­plete re­sponse. In dif­fuse large B-cell lym­phoma the re­sponse rate was 57% among pa­tients treat­ed at the 80 mg to 160 mg dose range. They were all com­plete re­spons­es. And 2 of these Cars were for pa­tients who had failed CAR-T ther­a­py.

Neil Woodford, Woodford Investment Management via YouTube

Un­der siege, in­vest­ment man­ag­er Wood­ford faces an­oth­er in­vest­ment shock

Em­bat­tled UK fund man­ag­er Neil Wood­ford — who has con­tro­ver­sial­ly blocked in­vestors from pulling out from his flag­ship fund to stem the blood­let­ting, af­ter a slew of dis­ap­point­ed in­vestors fled fol­low­ing a se­ries of sour bets — is now pay­ing the price for his ac­tions via an in­vestor ex­o­dus on an­oth­er fund.

Har­g­reaves Lans­down, which has in the past sold and pro­mot­ed the Wood­ford funds via its re­tail in­vest­ment plat­form, has re­port­ed­ly with­drawn £45 mil­lion — its en­tire po­si­tion — from the in­vest­ment man­ag­er’s In­come Fo­cus Fund.

Gene ther­a­pies seize the top of the list of the most ex­pen­sive drugs on the plan­et — and that trend has just be­gun

Anyone looking for a few simple reasons why the gene therapy field has caught fire with the pharma giants need only look at the new list of the 10 most expensive therapies from GoodRx.

Two recently approved gene therapies sit atop this list, with Novartis’ Zolgensma crowned the king of the priciest drugs at $2.1 million. Right below is Luxturna, the $850,000 pioneer from Spark, which Roche is pushing hard to acquire as it adds a gene therapy group to the global mix.

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Ab­b­Vie touts new da­ta for Hu­mi­ra suc­ces­sor; Gilead inks dis­cov­ery deal

→ Ab­b­Vie is tout­ing new pos­i­tive da­ta com­par­ing their ag­ing block­buster Hu­mi­ra with their hoped-for block­buster upadac­i­tinib. Over 48 weeks a larg­er pro­por­tion of pa­tients tak­ing the ex­per­i­men­tal drug ex­pe­ri­enced clin­i­cal re­mis­sion than in the con­trol arm with Hu­mi­ra. Their drug brought in $20 bil­lion last year, top­ping the scales in the num­ber 1 slot.

→ Gilead has turned to Van­cou­ver-based Ab­Cellera for its lat­est dis­cov­ery deal. Ab­Cellera will use its know-how in “sin­gle-cell screen­ing of nat­ur­al im­mune sources” to find an­ti­body can­di­dates for Gilead to pur­sue in the in­fec­tious dis­ease field. The deal in­cludes an up­front and mile­stones.

In a boost to Rit­ux­an fran­chise, Roche nabs quick ap­proval for po­latuzum­ab ve­dotin

Roche’s lat­est an­ti­body-drug con­ju­gate has crossed the FDA fin­ish line, gain­ing an ac­cel­er­at­ed ap­proval a full two months ahead of sched­ule.

Po­livy, or po­latuzum­ab ve­dotin, is a first-in-class drug tar­get­ing CD79b — a pro­tein promi­nent in B-cell non-Hodgkin lym­phoma. It will now be mar­ket­ed for dif­fuse large B-cell lym­phoma as part of a reg­i­men that al­so in­cludes the chemother­a­py ben­damus­tine and a ver­sion of rit­ux­imab (Rit­ux­an).

Sil­i­con Val­ley's most an­tic­i­pat­ed slide deck just dropped. What does it mean for bio­phar­ma's dig­i­tal teams?

These aren’t the typ­i­cal slides you’d see at End­points — no mol­e­cules, clin­i­cal pro­grams, or p-val­ues. In­stead, we’ll talk dig­i­tal and in­ter­net trends, fac­tors that elite glob­al brands — re­gard­less of in­dus­try — must first mea­sure and un­der­stand be­fore de­ploy­ing prod­ucts in­to the world. That’s a con­cept that most of our Big Phar­ma au­di­ence is in tune with. Dig­i­tal aware­ness is key to suc­cess in the dis­cov­ery, de­vel­op­ment, and mar­ket­ing of new bio­phar­ma­ceu­ti­cals, and most of the ma­jors now have a chief dig­i­tal of­fi­cer: No­var­tis, Sanofi, and Pfiz­er, just to name a few.