Four ex­perts from the FDA’s On­col­o­gy Cen­ter of Ex­cel­lence took to the New Eng­land Jour­nal of Med­i­cine yes­ter­day to make the case for not on­ly im­prov­ing the agency’s abil­i­ty to ex­pe­di­tious­ly pull dan­gling ac­cel­er­at­ed ap­provals when, on the rare oc­ca­sion, con­fir­ma­to­ry tri­als fail, but al­so bet­ter build­ing “qual­i­ty and ef­fi­cien­cy in­to the AA on-ramp.”

The time­ly per­spec­tive ar­rives as Con­gress has ex­act­ly one week left to draft, re­lease and sign off on the reau­tho­rized user fee deals be­fore lay­off no­tices will be sent to drug re­view­ers. That pack­age, which is like­ly to hitch a ride with the con­tin­u­ing res­o­lu­tion, may or may not in­clude sev­er­al pol­i­cy rid­ers (op­posed by Re­pub­li­cans), in­clud­ing one that would al­low the FDA to re­quire con­fir­ma­to­ry tri­als to be un­der­way be­fore an AA is grant­ed, and would im­prove the process by which FDA can with­draw AAs.

The FDA au­thors make clear the need for such an AA rid­er as for on­col­o­gy in­di­ca­tions that have been grant­ed AAs, the me­di­an time to be­gin­ning the with­draw­al process “was longer if the con­fir­ma­to­ry tri­al was ini­ti­at­ed af­ter the ap­proval (see fig­ure). This dif­fer­ence was most strik­ing among with­drawn in­di­ca­tions, with a me­di­an time to with­draw­al of 3.8 years if the con­fir­ma­to­ry tri­al was on­go­ing at the time of AA, as com­pared with 7.3 years if such a tri­al had not been ini­ti­at­ed. De­layed with­drawals in this lat­ter sce­nario rep­re­sent the great­est risk to pa­tients.”

OCE’s Lo­la Fashoyin-Aje, Gau­tam Mehta, Ju­lia Beaver, and Richard Paz­dur al­so of­fer sev­er­al up­front op­tions for those pur­su­ing AAs.

For in­stance, spon­sors could pur­sue a sin­gle ran­dom­ized tri­al, po­ten­tial­ly in an ear­li­er treat­ment set­ting, that could both sup­port AA and ver­i­fy clin­i­cal ben­e­fit, they say, with the ac­cel­er­at­ed ap­proval com­ing on the ba­sis of a planned in­ter­im analy­sis of ORR, and a con­ver­sion to full ap­proval grant­ed on the ba­sis of clin­i­cal ben­e­fit (OS im­prove­ment) at the tri­al’s con­clu­sion.

“This ap­proach would pro­vide a more thor­ough safe­ty as­sess­ment and ear­li­er de­fin­i­tive ev­i­dence of the ben­e­fit–risk bal­ance. It would al­so re­duce the risk of pre­ma­ture­ly halt­ing de­vel­op­ment of a drug with a lim­it­ed over­all re­sponse rate that might nev­er­the­less im­prove over­all sur­vival,” they wrote.

An­oth­er po­ten­tial strat­e­gy for spon­sors would be to agree in ad­vance on the cri­te­ria for at­tain­ing AA, and the cri­te­ria for with­draw­ing the in­di­ca­tion. Spon­sors could then run two con­cur­rent stud­ies: a sin­gle-group AA study ex­am­in­ing the ORR in pa­tients with­out oth­er avail­able ther­a­pies, and a ran­dom­ized tri­al fo­cused on clin­i­cal ben­e­fit in pa­tients who have re­ceived few­er treat­ments.

“If these stud­ies en­rolled pa­tients around the same time, an in­ter­im analy­sis of safe­ty and over­all re­sponse rate in the con­fir­ma­to­ry tri­al could pro­vide sup­port­ive ev­i­dence and greater con­fi­dence for the AA based on the sin­gle-group study,” they ex­plain.

Mov­ing for­ward, OCE’s Fashoyin-Aje et. al. ex­plain how both the at-times de­layed with­draw­al process (the fo­cus on Con­gres­sion­al ef­forts) should not over­shad­ow the lead-up to an ap­proval.

“Pub­lic dis­cus­sion has fo­cused on im­prov­ing the AA off-ramp, sug­gest­ing spe­cif­ic time lim­its for com­plet­ing con­fir­ma­to­ry tri­als, pa­tient en­roll­ment mile­stones for eval­u­at­ing time­ly tri­al com­ple­tion, and al­ter­na­tive pro­ce­dures for with­draw­ing in­di­ca­tions. But equal­ly im­por­tant are pro­ce­dures to build qual­i­ty and ef­fi­cien­cy in­to the AA on-ramp, which should in­clude a prospec­tive com­pre­hen­sive strat­e­gy de­tail­ing plans for AA and the ver­i­fi­ca­tion of clin­i­cal ben­e­fit, with the aim of ex­pe­dit­ing ther­a­peu­tic ad­vances and short­en­ing this pe­ri­od of un­cer­tain­ty,” they con­clud­ed.

Beginning tomorrow, biopharma companies can be charged rebates for any new drug price increases rising faster than the rate of inflation.

The new rebates are part of the newly signed Inflation Reduction Act, which introduces this new requirement that manufacturers pay rebates to Medicare for Part D drugs whose price increases exceed inflation, and in January 2023, the same will occur with Part B drugs.

The WTO’s TRIPS Council in mid-October is expected to debate whether to extend the IP waiver for Covid-19 vaccines to therapeutics and diagnostics too.

While the Biden administration backed the original vaccine waiver, which critics note has not done much to expand access to vaccines as demand has dried up, US trade officials haven’t offered any perspective yet on whether to expand the waiver to Covid treatments.

It was great getting back to a live ESMO conference/webinar in Paris followed by a live pop-up event for the Endpoints 11 in Boston. We’re staying on the road in October with our return for a live/streaming EUBIO22 in London.

Silicon Valley Bank’s Nooman Haque and I are once again jumping back into the thick of it with a slate of virtual and live events on October 12. I’ll get the ball rolling with a virtual fireside chat with Novo Nordisk R&D chief Marcus Schindler, covering their pipeline plans and BD work.