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.

2023 Spot­light on the Fu­ture of Drug De­vel­op­ment for Small and Mid-Sized Biotechs

In the context of today’s global economic environment, there is an increasing need to work smarter, faster and leaner across all facets of the life sciences industry.  This is particularly true for small and mid-sized biotech companies, many of which are facing declining valuations and competing for increasingly limited funding to propel their science forward.  It is important to recognize that within this framework, many of these smaller companies already find themselves resource-challenged to design and manage clinical studies themselves because they don’t have large teams or in-house experts in navigating the various aspects of the drug development journey. This can be particularly challenging for the most complex and difficult to treat diseases where no previous pathway exists and patients are urgently awaiting breakthroughs.

Albert Bourla, Pfizer CEO (Efren Landaos/Sipa USA/Sipa via AP Images)

Pfiz­er makes an­oth­er bil­lion-dol­lar in­vest­ment in Eu­rope and ex­pands again in Michi­gan

Pfizer is continuing its run of manufacturing site expansions with two new large investments in the US and Europe.

The New York-based pharma giant’s site in Kalamazoo, MI, has seen a lot of attention over the past year. As a major piece of the manufacturing network for Covid-19 vaccines and antivirals, Pfizer is gearing up to place more money into the site. Pfizer announced it will place $750 million into the facility, mainly to establish “modular aseptic processing” (MAP) production and create around 300 jobs at the site.

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Yuling Li, Innoforce CEO

In­no­force opens new man­u­fac­tur­ing site in Chi­na

Innoforce is off to the races at its new site in the city of Hangzhou, China.

The Chinese CDMO announced last week that it has started manufacturing at the new facility, which was built to offer process development and manufacturing operations for RNA, plasmid DNA, viral vectors and other cell therapeutics. It will also serve as Innoforce’s corporate HQ.

The company said it’s investing more than $200 million in the 550,000-square-foot manufacturing base for advanced therapies. The GMP manufacturing facility features space for producing plasmids with three 30-liter bioreactors. For viral vector manufacturing, Innoforce also has 200- and 500-liter bioreactors at its disposal, along with eight suites to make cell therapies. The site also includes several labs and warehouse spaces.

FDA grants or­phan drug des­ig­na­tion to Al­ger­non's ifen­prodil, while ex­clu­siv­i­ty re­mains un­clear

As the FDA remains silent on orphan drug exclusivity in the wake of a controversial court case, the agency continues to hand out new designations. The latest: Algernon Pharmaceuticals’ experimental lung disease drug ifenprodil.

The Vancouver-based company announced on Monday that ifenprodil received orphan designation in idiopathic pulmonary fibrosis (IPF), a chronic lung condition that results in scarring of the lungs.  Most IPF patients suffer with a dry cough, and breathing can become difficult.

Vas Narasimhan, Novartis CEO (Thibault Camus/AP Images, Pool)

No­var­tis bol­sters Plu­vic­to's case in prostate can­cer with PhI­II re­sults

The prognosis is poor for metastatic castration-resistant prostate cancer (mCRPC) patients. Novartis wants to change that by making its recently approved Pluvicto available to patients earlier in their course of treatment.

The Swiss pharma giant unveiled Phase III results Monday suggesting that Pluvicto was able to halt disease progression in certain prostate cancer patients when administered after androgen-receptor pathway inhibitor (ARPI) therapy, but without prior taxane-based chemotherapy. The drug is currently approved for patients after they’ve received both ARPI and chemo.

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‘Catchy’ de­sign tops big ad buys on­line for grab­bing on­col­o­gists’ at­ten­tion — sur­vey

The cancer drug ads that get oncologists’ attention online are informative and use clear, eye-catching designs. That’s ZoomRx’s assessment in its most recent tracking survey, and while not necessarily surprising, the details in the research do break a few common misconceptions.

One of those is frequency, also known as the number of impressions an ad gets. No matter how many times oncologists saw a particular cancer drug ad, effectiveness prevailed in the survey across five drug brands. ZoomRx measured effectiveness as a combination of most attention-getting, relevant information and improved perception as reported by the doctors.

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Tim Walbert, Horizon Therapeutics CEO (via YouTube)

And then there were two: Janssen bows out of Hori­zon takeover ne­go­ti­a­tions

Horizon Therapeutics announced last week that it was in talks with three pharmaceutical giants that could take over the company. You can now remove one of them from the equation.

J&J’s Janssen, after Horizon reported its initial involvement in early discussions to acquire the rare disease biotech, issued a statement Saturday that said Janssen “does not intend to make an offer for Horizon,” and that Janssen is bound by restrictions set in Rule 2.8 of the Irish Takeover Rules. These rules are in place for any company interested in taking over Irish companies, with Horizon Therapeutics currently based in Dublin.

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Up­dat­ed: FDA re­mains silent on or­phan drug ex­clu­siv­i­ty af­ter last year's court loss

Since losing a controversial court case over orphan drug exclusivity last year, the FDA’s Office of Orphan Products Development has remained entirely silent on orphan exclusivity for any product approved since last November, leaving many sponsors in limbo on what to expect.

That silence means that for more than 70 orphan-designated indications for more than 60 products, OOPD has issued no public determination on the seven-year orphan exclusivity in the Orange Book, and no new listings of orphan exclusivity appear in OOPD’s searchable database, as highlighted recently by George O’Brien, a partner in Mayer Brown’s Washington, DC office.

Rick Modi, Affinia Therapeutics CEO

Ver­tex-part­nered gene ther­a­py biotech Affinia scraps IPO plans

Affinia Therapeutics has ditched its plans to go public in a relatively closed-door market that has not favored Nasdaq debuts for the drug development industry most of this year. A pandemic surge in 2020 and 2021 opened the doors for many preclinical startups, which caught Affinia’s attention and gave the gene therapy biotech confidence in the beginning days of 2022 to send in its S-1.

But on Friday, Affinia threw in the S-1 towel and concluded now is not the time to step onto Wall Street. The biotech has put out few public announcements since the spring of this year. Endpoints News picked the startup as one of its 11 biotechs to watch last year.

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