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.

Over the past three years, Endpoints News has spotlighted 60 women who have blazed trails and supercharged R&D across the biopharma world. And judging from the response we’ve received, to both our special reports and live events, telling their stories — including any obstacles they may have had to overcome — has inspired our readers in many different ways.

But change takes time, and the fact remains that women are still underrepresented at the upper ranks of the drug-making world.

After making it clear that the US’ current monkeypox vaccine supply is insufficient, the FDA on Tuesday authorized a new route of administration that should increase the number of available doses by five-fold.

Regulators cleared Bavarian Nordic’s Jynneos vaccine for intradermal injection in adults older than 18. Unlike subcutaneous injection — the current method by which vaccine is delivered under the skin — an intradermal jab goes directly into the skin. It’s believed that this method requires less vaccine, since the dermis is rich in dendritic cells which specialize in taking up foreign antigens and presenting them to the immune system, according to Daniel Kuritzkes, chief of infectious diseases at Brigham and Women’s Hospital in Boston.

The FDA’s Center for Drug Evaluation and Research on Tuesday released a warning letter sent last week to Amazon CEO Andy Jassy in Seattle for selling mole removal products over-the-counter, or, as the FDA explains, “introducing, delivering, or causing the introduction or delivery into interstate commerce of products that are unapproved new drugs.”

“There are no over-the-counter (OTC) drugs that can be legally sold for mole or skin tag removal, and FDA has safety concerns about drugs marketed OTC directly to consumers for these uses,” the agency said in its Aug. 4 warning.

Pfizer is launching its second-ever rebate program, this time for Panzyga, its treatment for a rare neurological disease of the peripheral nerves.

The program began last month, according to STAT which first reported the news, and offers a refund of out-of-pocket costs for patients who must discontinue their course before the fifth treatment for “clinical reasons.”

Panzyga was approved back in 2018 to treat primary immunodeficiency (PI) in patients two years and older and chronic immune thrombocytopenia (cITP) in adults. It has since picked up an indication in chronic inflammatory demyelinating polyneuropathy (CIDP), a condition that’s characterized by weakness of the arms or legs, tingling or numbness, and a loss of deep tendon reflexes, according to the NIH.