10 ways to re­form the FDA's ac­cel­er­at­ed ap­proval path­way: ICER and MSKCC of­fer op­tions

The FDA’s top can­cer doc­tor Rick Paz­dur re­cent­ly called the FDA’s ac­cel­er­at­ed ap­proval path­way “un­der at­tack,” and three top drug pric­ing ex­perts from Memo­r­i­al Sloan Ket­ter­ing Can­cer Cen­ter and ICER are now call­ing the path­way “in flux, and many would say, in cri­sis.”

As the alarm bells sound, Paz­dur’s On­col­o­gy Cen­ter for Ex­cel­lence ini­ti­at­ed a re­view of the ac­cel­er­at­ed ap­proval path­way about a year ago, while more re­cent­ly, HHS’ In­spec­tor Gen­er­al said it al­so will re­view the path­way, fol­low­ing a quick ac­cel­er­at­ed OK for Bio­gen Alzheimer’s drug Aduhelm. The lat­ter re­view came in the face of con­flict­ing da­ta over whether the drug could ac­tu­al­ly slow pa­tients’ men­tal de­cline.

“There’s two ma­jor is­sues here: How do we re­move these drugs if their ac­cel­er­at­ed ap­proval stud­ies do not pan out, and the oth­er one is how the leg­is­la­tion is writ­ten,” Paz­dur said in a Pre­vi­sion Pol­i­cy we­bi­nar ear­li­er this sum­mer. At the time, he not­ed some dis­ap­point­ments from the re­cent mul­ti-day ODAC meet­ing in April on so-called “dan­gling” ac­cel­er­at­ed ap­provals, where a drug that fails a con­fir­ma­to­ry tri­al stays on the mar­ket.

The oth­er ma­jor is­sue is what should be con­sid­ered con­fir­ma­to­ry stud­ies, Paz­dur said, ques­tion­ing if it should just be ad­di­tion­al in­for­ma­tion from an on­go­ing, sin­gle-arm tri­al, or some­thing more.

“We’re caught in the mid­dle many times with on­col­o­gy prod­ucts of a sub­op­ti­mal de­vel­op­ment pro­gram yet a ter­rif­ic un­met need,” Paz­dur said. Over­all, how­ev­er, the ac­cel­er­at­ed path­way has “been very, very suc­cess­ful,” he added, not­ing, “but that doesn’t mean there isn’t room for im­prove­ment.”

Tak­ing that cue on what im­prove­ments can be made, An­na Kaltenboeck, health econ­o­mist and pol­i­cy re­searcher at Memo­r­i­al Sloan Ket­ter­ing Can­cer Cen­ter, and ICER’s Aman­da Mehlman and Steven Pear­son pub­lished an ar­ti­cle in the Jour­nal of Com­par­a­tive Ef­fec­tive­ness Re­search on Wednes­day out­lin­ing 10 pos­si­ble ways to re­form the ac­cel­er­at­ed ap­proval path­way.

The re­searchers point to sev­en pol­i­cy re­forms that the FDA could make and an­oth­er three for pay­ers and the life sci­ence in­dus­try.

For the FDA, ICER and MSKCC, au­thors point to re­forms in the pre­mar­ket space, such as by strength­en­ing the se­lec­tion and use of sur­ro­gate end­points, de­vel­op­ing stan­dard­ized re­view tem­plates and re­quir­ing greater use of ran­dom­ized con­trolled tri­als, as well as oth­er rec­om­men­da­tions in the post­mar­ket space, such as cre­at­ing a new la­bel alert for ac­cel­er­at­ed drugs and bet­ter en­forc­ing the com­ple­tion of con­fir­ma­to­ry tri­als.

On sur­ro­gate end­points, the re­searchers call for FDA to re­lease for pub­lic com­ment a pre­lim­i­nary jus­ti­fi­ca­tion for why such an end­point could be used, in­clud­ing what cri­te­ria FDA has al­ready es­tab­lished to sup­port that end­point. The pub­lic com­ment pe­ri­od could al­low clin­i­cal ex­perts and oth­er stake­hold­ers with ex­per­tise in a par­tic­u­lar area to see the FDA’s think­ing and con­tribute to the fi­nal de­ci­sion on us­ing that end­point.

While RCTs are in­fea­si­ble in some sit­u­a­tions, such as with some very rare dis­eases, Kaltenboeck, Mehlman and Pear­son al­so say FDA “should adopt a for­mal shift in pos­ture to­ward re­quir­ing ran­dom­ized con­trolled tri­als.” This ap­proach could do more of the work up­front, ahead of an ac­cel­er­at­ed ap­proval, re­ly­ing less on the con­fir­ma­to­ry work.

Once a drug is mar­ket­ed un­der the ac­cel­er­at­ed path­way, the re­searchers say FDA could help pa­tients un­der­stand the un­con­firmed ben­e­fits of the drug by in­clud­ing a new vi­su­al for its la­bel, such as a yel­low tri­an­gle or a gray box.

On in­creas­ing the FDA’s en­force­ment of com­pa­nies that have dragged their feet in com­plet­ing con­fir­ma­to­ry tri­als, the re­searchers echo what Paz­dur men­tioned about how the path­way on­ly works if the FDA has the abil­i­ty to pull drugs when the fol­low-ups are mov­ing too slow or fail. One of the ma­jor is­sues with more en­force­ment, how­ev­er, is that it’s like­ly to trig­ger push­back from in­dus­try and pa­tient groups, rais­ing the risk that Con­gress would lean on the FDA to cool its jets on en­force­ment, as it did with the Right to Try leg­is­la­tion.

The re­searchers al­so pro­pose two more ideas that might re­quire Con­gres­sion­al ac­tion and are fur­ther re­moved from the sta­tus quo: Sun­set­ting ac­cel­er­at­ed ap­provals that lack con­fir­ma­to­ry ev­i­dence and cre­at­ing a sep­a­rate “safe­ty-on­ly” ap­proval path­way, which could po­ten­tial­ly put pa­tients at even more risk, es­pe­cial­ly if it waives pub­lic or pri­vate in­sur­ance cov­er­age re­quire­ments.

They write:

A law or reg­u­la­tion could be changed to au­to­mat­i­cal­ly with­draw mar­ket­ing au­tho­riza­tion for an ac­cel­er­at­ed ap­proval drug should its con­fir­ma­to­ry ev­i­dence not be avail­able for the FDA re­view by a pre­de­ter­mined date set at the time of ap­proval. This kind of for­mal ‘sun­set’ pol­i­cy would give the clear­est sig­nal to in­dus­try of what is re­quired, and pro­tect the FDA from pres­sure to change de­ci­sions when it makes them at its dis­cre­tion.

As far as poli­cies for life sci­ence com­pa­nies and pay­ers, the MSKCC and ICER re­searchers call to in­crease manda­to­ry fed­er­al re­bate lev­els un­til a drug shifts from ac­cel­er­at­ed to full ap­proval, use pric­ing to in­cen­tivize com­ple­tion of con­fir­ma­to­ry tri­als, and re­quire pay­ments un­der Medicare and Med­ic­aid for ac­cel­er­at­ed ap­proval drugs to be based on out­comes-based con­tracts.

For in­stance, the Med­ic­aid Drug Re­bate Pro­gram could be mod­i­fied for drugs with ac­cel­er­at­ed ap­proval, they note, to re­quire a high­er re­bate dur­ing the time be­tween ac­cel­er­at­ed and full ap­proval. The Med­ic­aid and CHIP Pay­ment and Ac­cess Com­mis­sion re­cent­ly vot­ed 16-1 to rec­om­mend to Con­gress that they in­crease Med­ic­aid re­bates for ac­cel­er­at­ed ap­proval drugs be­fore con­fir­ma­to­ry tri­als are com­plet­ed.

M&A: a crit­i­cal dri­ver for sus­tain­able top-line growth in health­care

2021 saw a record $600B in healthcare M&A activity. In 2022, there is an anticipated slowdown in activity, however, M&A prospects remain strong in the medium to long-term. What are future growth drivers for the healthcare sector? Where might we see innovations that drive M&A? RBC’s Andrew Callaway, Global Head, Healthcare Investment Banking discusses with Vito Sperduto, Global Co-Head, M&A.

15 LGBTQ lead­ers in bio­phar­ma; Paul Stof­fels’ Gala­pa­gos re­vamp; As­traZeneca catch­es up in AT­TR; and more

Welcome back to Endpoints Weekly, your review of the week’s top biopharma headlines. Want this in your inbox every Saturday morning? Current Endpoints readers can visit their reader profile to add Endpoints Weekly. New to Endpoints? Sign up here.

A return to in-person conferences also marks a return to on-the-ground reporting. My colleagues Beth Synder Bulik and Nicole DeFeudis were on-site at Cannes Lions, bringing live coverage of pharma’s presence at the ad festival — accompanied by photos from Clara Bui, our virtual producer, that bring you right to the scene. You can find a recap (and links to all the stories) below.

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Abortion-rights protesters regroup and protest following Supreme Court's decision to overturn Roe v. Wade. (AP Photo/Gemunu Amarasinghe)

Fol­low­ing SCO­TUS de­ci­sion to over­turn abor­tion pro­tec­tions, AG Gar­land says states can't ban the abor­tion pill

Following the Supreme Court’s historic decision on Friday to overturn Americans’ constitutional right to an abortion after almost 50 years, Attorney General Merrick Garland sought to somewhat reassure women that states will not be able to ban the prescription drug sometimes used for abortions.

Following the decision, the New England Journal of Medicine also published an editorial strongly condemning the reversal, saying it “serves American families poorly, putting their health, safety, finances, and futures at risk.”

Joe Wiley, Amryt Pharma CEO

Am­ryt Phar­ma sub­mits a for­mal dis­pute res­o­lu­tion to the FDA over re­ject­ed skin dis­ease drug

The story of Amryt Pharma’s candidate for the genetic skin condition epidermolysis bullosa, or EB, will soon enter another chapter.

After the Irish drugmaker’s candidate, dubbed Oleogel-S10 and marketed as Filsuvez, was handed a CRL earlier this year, the company announced in a press release that it plans to submit a formal dispute resolution request for the company’s NDA for Oleogel-S10.

Sen. Thom Tillis (R-NC) (J. Scott Applewhite/AP Images)

Phar­ma-friend­ly sen­a­tor calls on FDA for a third time to show patent pro­tec­tions should­n't be blamed for high drug prices

North Carolina Republican Sen. Thom Tillis made a name for himself in the 2020 election cycle as the darling of the pharma industry, accepting hundreds of thousands in campaign contributions, even from the likes of Pfizer CEO Albert Bourla.

Those contributions have led Tillis to attempt to re-write patent laws in pharma’s favor, a move which failed to gain steam in 2019, and request for a third time since January that the FDA should help stop “the false narrative that patent protections are to blame for high drug prices.”

EMA signs off on 3 drugs re­cent­ly re­ject­ed by FDA, in­clud­ing Bio­Mar­in's new he­mo­phil­ia gene ther­a­py

The EMA’s human medicines committee on Friday recommended three new drugs for approval or conditional approval, even as their US counterparts have rejected these three for various reasons.

In a major move, CHMP offered a thumbs-up to a conditional marketing authorization for the first gene therapy to treat severe hemophilia A, although the agency cautioned that it’s so far unknown how long the effects of infusion will last.

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Sanofi, GSK tout 72% Omi­cron ef­fi­ca­cy in PhI­II tri­al of next-gen, bi­va­lent shot — with an eye to year-end roll­out

Sometimes, being late can give you an advantage.

That’s what Sanofi and GSK are trying to say as the Big Pharma partners report positive results from a late-stage trial of their next-gen bivalent Covid-19 vaccine, which was designed to protect against both the original strain of the SARS-CoV-2 virus and the Beta variant. Specifically, against Omicron, they note, the vaccine delivered 72% efficacy in all adults and 93.2% in those previously infected.

Alarmed by side ef­fect, FDA slaps clin­i­cal hold on Sarep­ta's next-gen Duchenne drug

Sarepta Therapeutics’ next-gen Duchenne muscular dystrophy drug has been hit with a clinical hold after investigators flagged a serious case of low magnesium levels in one patient’s blood.

Screening and dosing will be halted in what is known as Part B of the Phase II MOMENTUM study, which has enrolled about half of the planned patients. Sarepta said it will be submitting information on all cases of the condition, known as hypomagnesemia, per the FDA’s request and proposing some changes to the risk mitigation and safety monitoring plan.

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GSK says its drug for chron­ic hep B could ‘lead to a func­tion­al cure’ — but will it be alone or in com­bi­na­tion?

GSK, newly branded and soon-to-be demerged, shared interim results from its Phase II trial on its chronic hepatitis B treatment, one that it says has the “potential to lead to a functional cure.”

At a presentation at the EASL International Liver Congress, GSK shared that in around 450 patients who received its hep B drug bepirovirsen for 24 weeks, just under 30% had hepatitis B surface antigen and viral DNA levels that were too low to detect.