Accelerated approval reforms need meaningful confirmatory trial improvements, professors write in Science

Richard Pazdur (via AACR)

Out­side of Covid-19, 2021 has been the year of the ac­cel­er­at­ed ap­proval.

Be­gin­ning last spring, FDA open­ly chal­lenged six ‘dan­gling’ ac­cel­er­at­ed ap­provals (hadn’t con­firmed their clin­i­cal ben­e­fit yet), three of which were lat­er pulled by the com­pa­nies.

Then in June, FDA pulled out the ac­cel­er­at­ed ap­proval path­way, seem­ing­ly out of nowhere, to sign off on Bio­gen’s con­tro­ver­sial Alzheimer’s drug Aduhelm. It hadn’t even been men­tioned at the drug’s ad­comm.

And just this week, the FDA can­celled an­oth­er ad­comm to re­view two more dan­gling AAs, one of which was pulled by Se­cu­ra Bio.

The rain of crit­i­cism con­tin­ues to pour on­to FDA, as two pro­fes­sors from the Uni­ver­si­ty of Penn­syl­va­nia and Boston Uni­ver­si­ty on Thurs­day af­ter­noon pub­lished a new per­spec­tive in Sci­ence ar­gu­ing that the ear­ly ac­cess to these new med­i­cines un­der the AA path­way is not be­ing fol­lowed up with the ap­pro­pri­ate proof in the con­fir­ma­to­ry tri­als.  They said that the Aduhelm ap­proval al­so risks FDA’s rep­u­ta­tion and un­der­mines ‘its core role in keep­ing the mar­ket free of worth­less or dan­ger­ous med­ical prod­ucts.’

As the alarm bells sound, Rick Paz­dur’s On­col­o­gy Cen­ter for Ex­cel­lence at FDA 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 that ac­cel­er­at­ed OK for Aduhelm.

‘One ap­proach OIG should con­sid­er is ex­am­in­ing the de­tails of tri­als that have fur­ther eval­u­at­ed a drug’s ap­proved in­di­ca­tion af­ter mar­ket­ing ap­proval, look­ing to dis­tin­guish the fea­tures of tri­als that were more ver­sus less suc­cess­ful,’ pro­fes­sors Hol­ly Fer­nan­dez Lynch and Christo­pher Robert­son wrote, adding:

Ac­cel­er­at­ed ap­proval is an im­por­tant reg­u­la­to­ry path­way worth try­ing to save, if the ev­i­dence sug­gests that mean­ing­ful im­prove­ments in con­fir­ma­to­ry tri­als are pos­si­ble. While this ev­i­dence is gath­ered, com­pa­nies, pa­tients, and pol­i­cy-mak­ers should pri­or­i­tize ef­forts to mean­ing­ful­ly im­prove ac­cess to in­ves­ti­ga­tion­al prod­ucts in the preap­proval pe­ri­od, with­out fur­ther push­ing the bound­aries of ac­cel­er­at­ed ap­proval.

Lynch and Robert­son al­so ex­plained how once a drug is mar­ket­ed via the AA path­way, the com­pa­ny’s in­cen­tives to per­form a speedy con­fir­ma­tion tri­al ‘drop off pre­cip­i­tous­ly,’ and pa­tients may al­so be un­will­ing to par­tic­i­pate in a con­fir­ma­to­ry tri­al in which they may be ran­dom­ized to some­thing oth­er than the drug that won ap­proval.

Lynch added via email to End­points that ‘mean­ing­ful im­prove­ments in con­fir­ma­to­ry clin­i­cal tri­als could be sev­er­al-fold: faster time­lines and stricter dead­lines for com­ple­tion, in­sis­tence on more rig­or­ous de­signs (blind­ing, ran­dom­iza­tion, con­cur­rent con­trols, re­jec­tion of fur­ther use of sur­ro­gate end­points), re­quir­ing con­fir­ma­to­ry tri­al de­sign to be agreed up­on (and per­haps even re­quir­ing the tri­als to be un­der­way) at the time of grant­i­ng ac­cel­er­at­ed ap­proval, and stronger abil­i­ty and will­ing­ness on the part of FDA to rapid­ly pull prod­ucts if post-ap­proval tri­als fail to con­firm ben­e­fit.’

But she said, the ‘main point of the piece, though, is that pol­i­cy changes need to be in­formed by ad­di­tion­al ev­i­dence about why con­fir­ma­to­ry tri­als are fail­ing to live up to ex­pec­ta­tions. For ex­am­ple, if the is­sue is that not enough pa­tients are will­ing to en­roll in rig­or­ous con­fir­ma­to­ry tri­als, it won’t mat­ter for FDA to in­sist on them and we’ll need to fig­ure out al­ter­na­tive ways to en­cour­age par­tic­i­pa­tion or bet­ter ways to pro­cure ac­cess pri­or to mar­ket­ing ap­proval while still gath­er­ing rig­or­ous da­ta.’

An­na Kaltenboeck, health econ­o­mist and pol­i­cy re­searcher at Memo­r­i­al Sloan Ket­ter­ing Can­cer Cen­ter, and ICER’s Aman­da Mehlman and Steven Pear­son al­so pub­lished an ar­ti­cle in the Jour­nal of Com­par­a­tive Ef­fec­tive­ness Re­search in Au­gust out­lin­ing 10 pos­si­ble ways to re­form the ac­cel­er­at­ed ap­proval path­way.

The re­searchers point­ed to sim­i­lar re­forms in the pre­mar­ket and post­mar­ket tri­als, 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 cre­at­ing a new la­bel alert for ac­cel­er­at­ed drugs and bet­ter en­forc­ing the com­ple­tion of con­fir­ma­to­ry tri­als.

An­oth­er re­view of ac­cel­er­at­ed ap­provals, pub­lished in JA­MA Open Net­work last month, al­so raised ques­tions about the use of AA path­way for cer­tain drugs, ‘es­pe­cial­ly if postap­proval con­fir­ma­to­ry tri­als nei­ther con­sis­tent­ly eval­u­ate clin­i­cal out­comes nor are much longer than piv­otal tri­als us­ing sur­ro­gate end­points,’ the au­thors wrote.

While oncology researchers have long pursued the potential of cellular immunotherapies for the treatment of cancer, it was unclear whether these therapies would ever reach patients due to the complexity of manufacturing and costs of development. Fortunately, the recent successful development and regulatory approval of chimeric antigen receptor-engineered T (CAR-T) cells have demonstrated the significant benefit of these therapies to patients.

Merck’s new antiviral molnupiravir (Quality Stock Arts / Shutterstock)

After South African scientists reported a new Covid-19 variant — dubbed Omicron by the WHO  — scientists became concerned about how effective vaccines and monoclonal antibodies might be against it, which has more than 30 mutations in the spike protein.

‘I think it is super worrisome,’ Dartmouth professor and Adagio co-founder and CEO Tillman Gerngross told Endpoints News this weekend. Moderna CEO Stéphane Bancel echoed similar concerns, telling the Financial Times that experts warned him, ‘This is not going to be good.’

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AstraZeneca has reportedly tanked a deal that would have taken high-profile rare disease company Sobi private over fears its respiratory drugs would fall into the hands of rivals.

The Big Pharma withheld its 8% stake in Sobi after a $7.6 billion offer from Advent International and Singapore’s sovereign wealth fund closed in September, Bloomberg reported early Friday morning, effectively blocking the buyout. Sobi, also known as Swedish Orphan Biovitrum, possessed certain assets AstraZeneca itself was interested in acquiring, the report said.

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Novartis is plopping down $150 million in cash to pick up an experimental Parkinson’s drug and grab an option to another, a move that puts it on an increasingly popular path in the field’s search for disease-modifying therapies.

Belgium’s UCB is its partner of choice, supplying two small molecule alpha-synuclein misfolding inhibitors in a deal that can add up to nearly $1.5 billion.

Out of the pair, UCB0599 is already in Phase II trials, making Novartis confident enough to pull the trigger on co-development and commercialization, including to foot half of the R&D bill. The pharma giant will make a decision on UCB7853 once UCB wraps the ongoing Phase I program.

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Joseph Arron is sometimes referred to as the black sheep of his family. While everyone else is a professional musician, he was always more interested in science.

‘I played music, but I was never that keen on pursuing that as a career,’ Arron says, adding that his dad played in orchestras, his mom was the director of Carnegie Hall, and his brother is a professional cellist.

Arron is a maestro in a different kind of field — and now, genetic data will be the music to his ears as he leaves a 15-year career at Genentech to become 23andMe’s new CSO.

Lan Huang, BeyondSpring CEO

BeyondSpring shocked investors in early August after its once-marginal lead drug suddenly showed a lot of promise in a common form of lung cancer. With hopes high, the FDA has now slammed the door on that drug in another indication — does that spell bad news for BeyondSpring’s Cinderella story?

The FDA issued BeyondSpring a complete response letter for its plinabulin in combination with granulocyte colony-stimulating factor (G-CSF) for the prevention of chemotherapy-induced neutropenia, effectively shutting down the drug’s immediate chances at a marketing approval, the biotech said Wednesday.

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Common performs onstage, December 2020 (Getty Images)

Healthcare screenings and clinical trial enrollment were battered by the pandemic. But the well-known celebrity-backed Stand Up To Cancer non-profit, along with pharma and advocacy partners, has been working to reverse that and make up lost ground, by stepping up awareness campaigns.

Twelve campaigns launched in 2020 and another five in 2021 amplify the need for cancer screening and care, especially for underserved communities. While pharma companies have long been donors to the cancer research group, Covid brought new support — and increased awareness efforts.

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The former CFO of Immunomedics, who helped steer the company to its $21 billion buyout by Gilead last year, has been charged with insider trading, the Department of Justice announced Thursday.

Usama Malik tipped off his then-girlfriend and four others that a Phase III study for Trodelvy would be stopped early four days before Immunomedics publicly announced the result in April 2020, DoJ alleged in its complaint. The individuals then purchased Immunomedics shares, selling them after the news broke and Immunomedics’ stock price doubled.

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A press release referred to it as simply, ‘the incident.’ But a fire at an Olainfarm site in Latvia last week has left one person dead, and injured another, the company announced Monday.

Just before midnight Nov. 26, a fire broke out in the production building of JSC Olainfarm,  as the result of an ‘accident,’ a company spokesperson said in an email to Endpoints News. The two victims were both company employees, and the causes of the accident are still being determined.
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