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.

The Fac­tors Dri­ving a Rapid Evo­lu­tion of Gene & Cell Ther­a­py and CAR-T Clin­i­cal Re­search in APAC

APAC is the fastest growing region globally for cell & gene therapy trials representing more than a third of all cell & gene studies globally, with China leading in the region. 

APAC is the leading location globally for CAR-T trials with China attracting ~60% of all CAR-T trials globally between 2015-2022. The number of CAR-T trials initiated by Western companies has rapidly increased in recent years (current CAGR of about 60%), with multiple targets being explored including CD19, CD20, CD22, BCMA, CD30, CD123, CD33, CD38, and CD138.

The End­points 11; blue­bird's $3M gene ther­a­py; Bio­gen tout new neu­ro da­ta; Harsh re­views for can­cer drugs; 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.

Reading about John Carroll’s pick of biotech’s most promising startups has become a treasured tradition. If you ever get curious about previous classes of the Endpoints 11, you can find all of them (plus a number of our other regular specials) here.

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EMA warns of short­ages of two Boehringer heart drugs due to a spike in de­mand

The EMA is putting EU member states on alert over the shortage of two drugs that counter heart attacks due to an uptick in demand.

On Friday, the EMA sent out a warning that two Boehringer Ingelheim drugs are experiencing a shortage: Actilyse and Metalyse. The drugs are used as emergency treatments for adults experiencing acute myocardial infarction, or a heart attack, by dissolving blood clots that have formed in the blood vessels.

The End­points 11: The top pri­vate biotechs in pur­suit of new drugs. Push­ing the en­ve­lope with pow­er­ful new tech­nolo­gies

Right around the beginning of the year, we got a close-up look at what happens after a boom ripples through biotech. The crash of life sciences stocks in Q1 was heard around the world.

In the months since, we’ve seen the natural Darwinian down cycle take effect. Reverse mergers made a comeback, with more burned out shells to go public at a time IPOs and road shows are out of favor. And no doubt some of the more recent arrivals on the investing side of the business are finding greener pastures.

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As­traZeneca, Mer­ck cull one Lyn­parza in­di­ca­tion in heav­i­ly pre­treat­ed ovar­i­an can­cer pa­tients

Just one day after blockbuster Lynparza got access to another indication in China, its Big Pharma owners have decided to withdraw it in certain patients after reviewing Phase III data.

The two companies that work together on Lynparza decided to recall one of the indications several weeks ago in a specific type of ovarian cancer, Lynparza’s first indication when it was first FDA-approved in 2014. Initial data showed that rates of overall survival in patients with at least three rounds of chemo before getting on the PARP inhibitor were lower than in patients with less previous chemo treatment.

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An­oth­er Cipla site lands a Form 483 over clean­ing is­sues and QC con­trols

A Cipla drug manufacturing site in India has once again landed in the crosshairs of FDA inspectors.

The facility in question is Cipla’s drug manufacturing facility in the village of Verna, in the state of Goa in India’s southwest. In a sign that foreign inspections might ramp up again, the FDA’s visit from Aug. 16 to Aug. 22 uncovered six observations.

The 11-page report noted that environmental monitoring at the site did not properly ensure that microbial contaminants were not making any impact in the aseptic filling areas. It also found that procedures meant to stop microbial contamination were not adequately conducted in aseptic areas of the facility.

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FDA ad­comm takes down Se­cu­ra Bio's leukemia drug af­ter fi­nal tri­al re­sults show po­ten­tial OS detri­ment

The FDA’s Oncologic Drugs Advisory Committee on Friday voted 8-4 against the benefit-risk profile of Secura Bio’s PI3K inhibitor Copiktra (duvelisib), which won approval in September 2018 as a third-line treatment for relapsed or refractory CLL or SLL, but updated pivotal trial results raised safety questions.

In addition to the serious and fatal toxicities of duvelisib, FDA speakers at the ODAC meeting pointed to an evolved treatment landscape for CLL and SLL, with targeted BTK or BCL2 inhibitors (front-line or second-line), and data pointing to a “potential detriment” in overall survival for duvelisib. But some ODAC members noted that the detriment was likely small and that there is some efficacy even as the data are difficult to interpret.

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FDA's out­side ex­perts vote in fa­vor of Fer­ring's fe­cal trans­plant for C. dif­fi­cile, set­ting the stage for Seres

FDA’s outside advisors voted in favor of Ferring Pharmaceuticals’ RBX2660, an experimental poop-based drug implant that the company says would be the first microbiota-based live biotherapeutic to receive an FDA green light.

That was a point repeatedly discussed during the Vaccines and Related Biological Products Advisory Committee, or VRBPAC, meeting Thursday when evaluating Ferring’s fecal microbiota transplant, or FMT, for reducing the recurrence of Clostridioides difficile infection in adults who have received antibiotics. Multiple members brought up the need for a regulated product amid a landscape of unregulated FMTs already happening in clinical care.

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Mene Pangalos (AstraZeneca via YouTube)

As­traZeneca shuts the PhI­II door for Ion­is' PC­SK9 drug de­spite pos­i­tive PhI­Ib

When Ionis and AstraZeneca unveiled the first round of mid-stage data for their antisense PCSK9 drug, Mene Pangalos, AstraZeneca’s EVP of biopharmaceuticals R&D, underscored the drug’s “potential best-in-class efficacy profile.”

But now that the second batch is in, it appears AZD8233 isn’t hitting the mark after all.

Ionis announced Friday morning that although the candidate, also dubbed ION449, met the primary endpoint in the Phase IIb SOLANO trial, its partners at AstraZeneca have decided not to move it into Phase III studies because the “results did not achieve pre-specified efficacy criteria.”

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