Rep. Frank Pallone (D-NJ) (Photo by Michael Brochstein/Sipa USA)(Sipa via AP Images)

Over­haul­ing FDA's ac­cel­er­at­ed ap­proval path­way: Key House com­mit­tee chair pens new bill

House En­er­gy & Com­merce Com­mit­tee Chair Frank Pal­lone (D-NJ) late Mon­day in­tro­duced new leg­is­la­tion that would re­vamp the way the FDA can tight­en its reigns around ac­cel­er­at­ed ap­provals, which have seen ris­ing num­bers over the years, but no re­al way for the agency to quick­ly pull ones that have failed to con­firm clin­i­cal ben­e­fit in a time­ly man­ner.

Specif­i­cal­ly, the bill pro­vides the FDA with a lot more dis­cre­tion on how it can man­age the ac­cel­er­at­ed ap­proval pro­gram. The FDA’s On­col­o­gy Cen­ter of Ex­cel­lence, which re­views the bulk of the ac­cel­er­at­ed ap­provals that come in­to the agency, held an ad­vi­so­ry com­mit­tee meet­ing last spring and has been work­ing to move for­ward on ei­ther pulling or re­quir­ing fur­ther stud­ies for some of these “dan­gling” ac­cel­er­at­ed ap­provals.

To pre­vent such dan­gling, Pal­lone’s bill would set time lim­its around ac­cel­er­at­ed ap­provals, such as re­quir­ing the ap­provals to ex­pire one year af­ter post-ap­proval stud­ies are sched­uled to be com­plete, and nev­er lat­er than five years af­ter an ac­cel­er­at­ed ap­proval, un­less the post-mar­ket­ing study has been com­plet­ed and ver­i­fied the clin­i­cal ben­e­fit, or the HHS Sec­re­tary de­ter­mines that ad­e­quate progress has been made.

Pal­lone said in a state­ment that “un­der the cur­rent sys­tem, some prod­ucts have been al­lowed to stay on the mar­ket for far too long with­out clin­i­cal tri­als that demon­strate a re­al clin­i­cal ben­e­fit for pa­tients. Pa­tients de­serve to know that the drugs they are tak­ing are safe and ef­fec­tive.”

Un­der such a sys­tem, if the leg­is­la­tion wins sup­port in the Sen­ate and White House, ac­cel­er­at­ed ap­provals like No­var­tis’ in 2015 for Fary­dak (panobi­no­s­tat) in com­bi­na­tion with borte­zomib and dex­am­etha­sone for the treat­ment of pa­tients in third-line mul­ti­ple myelo­ma may have been pulled two years ago, rather than last No­vem­ber. The drug was pulled by Se­cu­ra Bio, which ac­quired the drug in 2019.

Sim­i­lar­ly, Seagen’s Ad­cetris (bren­tux­imab ve­dotin), which won an ac­cel­er­at­ed ap­proval in 2011 for sys­temic anaplas­tic large cell lym­phoma af­ter the fail­ure of at least one mul­ti-agent chemo, might not have been able to take un­til 2018 to fin­ish its con­fir­ma­to­ry tri­al and win a full ap­proval.

Bio­gen’s con­tro­ver­sial new Alzheimer’s drug Aduhelm ⁠— like­ly one of the main rea­sons this bill was writ­ten ⁠— al­so wouldn’t be al­lowed to take un­til 2030 (the FDA’s dead­line) to com­plete its con­fir­ma­to­ry tri­al un­der Pal­lone’s bill, al­though Bio­gen has said it will fin­ish its tri­al clos­er to 2026.

Ju­lia Beaver

An­oth­er way the bill aims to stop bad ac­tors from slow-play­ing a con­fir­ma­to­ry tri­al is by re­quir­ing man­u­fac­tur­ers to en­ter in­to an agree­ment with the FDA on how the stud­ies will be con­duct­ed be­fore the agency can grant an ac­cel­er­at­ed ap­proval. The FDA has sought to shore up those agree­ments pri­or to sign­ing off on the ex­pe­dit­ed OKs.

Ju­lia Beaver, chief of med­ical on­col­o­gy at the FDA’s On­col­o­gy Cen­ter of Ex­cel­lence, not­ed in Jan­u­ary that half of all ac­cel­er­at­ed ap­proval in­di­ca­tions have con­firmed ben­e­fit in a me­di­an of 3 years, and the re­main­der of those that have not yet con­firmed ben­e­fit have been those grant­ed AA in the last few years. Less than 10% of these in­di­ca­tions have been with­drawn ei­ther due to failed tri­als or be­cause the tri­als weren’t con­duct­ed, she said.

Pal­lone’s bill would al­so re­quire more fre­quent up­dates from spon­sors on post-ap­proval stud­ies, in­clud­ing up­dates on en­roll­ment tar­gets, mile­stones, and study de­sign.

On the specifics of when the FDA can ex­pe­dite the with­draw­al of an ac­cel­er­at­ed ap­proval, which would re­quire due no­tice to the spon­sor and an op­por­tu­ni­ty for a writ­ten ap­peal, the text of the bill gives the agency a lot of lee­ways, not­ing such cas­es when:

  • the spon­sor fails to con­duct any re­quired post ap­proval study of the prod­uct with due dili­gence;
  • the spon­sor fails to achieve agreed up­on en­roll­ment tar­gets, mile­stones, or time­ly study com­ple­tion;
  • the spon­sor dis­sem­i­nates false or mis­lead­ing pro­mo­tion­al ma­te­ri­als with re­spect to the prod­uct.

“The chal­lenge for ac­cel­er­at­ed ap­proval re­form is build­ing in enough flex­i­bil­i­ty for chal­lenges aris­ing in dif­fer­ent dis­ease ar­eas (esp. rare dis­ease) while si­mul­ta­ne­ous­ly min­i­miz­ing FDA dis­cre­tion,” Hol­ly Fer­nan­dez Lynch, as­sis­tant pro­fes­sor of med­ical ethics at the Uni­ver­si­ty of Penn­syl­va­nia’s Perel­man School of Med­i­cine, wrote on Twit­ter.

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.

Illustration: Assistant Editor Kathy Wong for Endpoints News

As mon­ey pours in­to dig­i­tal ther­a­peu­tics, in­sur­ance cov­er­age crawls



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Vi­a­tris with­draws ac­cel­er­at­ed ap­proval for top­i­cal an­timi­cro­bial 24 years lat­er

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Lynn Baxter, Viiv Healthcare's head of North America

Vi­iV dri­ves new cor­po­rate coali­tion in­clud­ing Uber, Tin­der and Wal­mart, aimed at end­ing HIV

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Matt Gline, Roivant Sciences CEO (Photo by John Sciulli/Getty Images for GLG)

Pfiz­er and Roivant team up again for an­oth­er 'Van­t', set­ting up an­ti-in­flam­ma­to­ry show­down with Prometheus

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Roche HQ in Basel, Switzerland. (Image credit: Kyle LaHucik/Endpoints News)

As com­peti­tors near FDA goal­post, Roche spells out its re­peat Alzheimer's set­back

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