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.

Illustration: Assistant Editor Kathy Wong for Endpoints News

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