FDA commissioner Stephen Hahn at the White House (AP Images)

Un­der fire, FDA to is­sue stricter guid­ance for Covid-19 vac­cine EUA this week — re­port

The FDA has been in­sist­ing for months that a Covid-19 vac­cine had to be at least 50% ef­fec­tive – a mea­sure of trans­paren­cy meant to shore pub­lic trust in the agency and in a vac­cine that had been brought for­ward at record speed and record po­lit­i­cal pres­sure. But now, with con­cerns of a Trump-dri­ven au­tho­riza­tion ar­riv­ing be­fore the elec­tion, the agency may be rais­ing the bar.

The FDA is set to re­lease new guid­ance that would raise safe­ty and ef­fi­ca­cy re­quire­ments for a vac­cine EUA above ear­li­er guid­ance and above the cri­te­ria used for con­va­les­cent plas­ma or hy­drox­y­chloro­quine, The Wash­ing­ton Post re­port­ed. Ex­perts say this sig­nif­i­cant­ly low­ers the odds of an ap­proval be­fore the elec­tion on No­vem­ber 3, which Trump has promised de­spite vo­cal con­cerns from pub­lic health of­fi­cials, and could help shore up pub­lic trust in the agency and any even­tu­al vac­cine.

“This step should help re­as­sure Amer­i­cans that FDA’s ca­reer sci­en­tists with re­spon­si­bil­i­ty for reg­u­lat­ing vac­cines have their back and are mak­ing de­ci­sions based on sound sci­ence,” for­mer FDA chief sci­en­tist Lu­ciana Bo­rio told End­points News in an email, adding they “en­sure that on­ly vac­cines with ad­e­quate safe­ty and mean­ing­ful ef­fec­tive­ness da­ta are grant­ed an EUA.”

Most no­table among the new reg­u­la­tions is a pro­vi­sion that calls for vac­cine man­u­fac­tur­ers seek­ing an EUA fol­low sub­jects for a me­di­an of at least 60 days fol­low­ing the sec­ond dose of the vac­cine. It al­so asks them to ac­crue at least 5 cas­es of se­vere Covid-19 in the place­bo group, a mea­sure that will be sig­nif­i­cant­ly hard­er to hit than the met­rics in the cur­rent tri­al pro­to­cols.

CBER chief Pe­ter Marks had point­ed to some of these mea­sures in pri­or ap­pear­ances, but they were not part of pub­lic guide­lines.

The Post re­port says the guide­lines could come as soon as this week.

Al­though the orig­i­nal FDA guid­ance called for long-term fol­lowup of tri­al par­tic­i­pants, as is rou­tine in vac­cine stud­ies, it did not set a bar for how long vol­un­teers had to be mon­i­tored be­fore de­vel­op­ers filed for an EUA. And while it called for the vac­cine to be 50% ef­fec­tive, the agency left open to man­u­fac­tur­ers whether they would de­fine that as ef­fec­tive in pre­vent­ing in­fec­tion or pre­vent­ing dis­ease.

The new­ly re­leased Phase III pro­to­col for Pfiz­er, whose CEO Al­bert Bourla has been the most vo­cal of any phar­ma­ceu­ti­cal ex­ec­u­tive in promis­ing Covid-19 vac­cine da­ta be­fore No­vem­ber, re­vealed that the com­pa­ny was us­ing a rel­a­tive­ly low bar for ef­fi­ca­cy com­pared to Mod­er­na, count­ing any of a long list of symp­toms as “dis­ease.” Mod­er­na and As­traZeneca al­so did not re­quire in­stances of se­vere dis­ease.

News of the new guide­lines came on the same day that well-known sci­en­tists – al­beit not vac­ci­nol­o­gists – raised con­cerns in The New York Times and The Post opin­ion sec­tions that the cri­te­ria Mod­er­na and Pfiz­er picked were not strin­gent enough. Oth­ers ar­gue bar for ef­fi­ca­cy was al­so in line with WHO guid­ance, al­lows for faster an­swers and is not un­com­mon in vac­cine de­vel­op­ment.

The new guide­lines, though, al­most cer­tain­ly in­crease the amount of time need­ed to de­ter­mine safe­ty and ef­fi­ca­cy.

“It’s hard to imag­ine how an EUA could pos­si­bly oc­cur be­fore De­cem­ber,” Paul Of­fit, a promi­nent vac­ci­nol­o­gist and mem­ber of the FDA’s vac­cines Ad­Comm, told The Post.

Er­ic Topol, who called in The Times for hard­er ef­fi­ca­cy stan­dards and was a crit­ic of the FDA’s con­duct on the EUA for con­va­les­cent plas­ma, praised the move.

Still, it’s not clear who will have fi­nal de­ci­sion mak­ing pow­er on these vac­cines. Ear­li­er this week in a memo panned by one for­mer FDA as­so­ciate com­mis­sion­er as a “pow­er grab,” HHS chief Alex Azar stripped the FDA’s abil­i­ty to make rules with­out his sig­na­ture. An HHS spokesper­son said con­cerns were overblown and called the memo an ex­am­ple of “good gov­er­nance” and had noth­ing to do with vac­cines.

FDA com­mis­sion­er Stephen Hahn, vest­ed with the au­thor­i­ty as fi­nal de­ci­sion mak­er on the na­tion’s drugs, re­ports di­rect­ly to HHS Sec­re­tary Alex Azar. The FDA com­mis­sion­er doesn’t have to fol­low agency ad­vice and it while it would be an ex­tra­or­di­nary breach of prece­dent, ex­perts say the HHS sec­re­tary could is­sue an ap­proval him­self.

Rachel Sachs, a law pro­fes­sor at Wash­ing­ton Uni­ver­si­ty at St Louis, said fed­er­al statutes make clear that the fi­nal de­ci­sion rests with the HHS sec­re­tary, not­ing that in one high-pro­file in­stance dur­ing the Oba­ma Ad­min­is­tra­tion, the sec­re­tary over­ruled FDA com­mis­sion­er Mar­garet Ham­burg on ac­cess rules for “Plan B.” But she called that case the “ex­cep­tion that proves the rule” of the agency’s in­de­pen­dence and said she was skep­ti­cal Azar would over­rule Hahn.

“It would be very dif­fi­cult for the sec­re­tary of HHS to au­tho­rize the vac­cines over ob­jec­tions of FDA, pro­ce­du­ral­ly as well as po­lit­i­cal­ly,” she told End­points News, not­ing Marks’ promise to re­sign if the agency okayed an un­proven vac­cine.

A for­mer FDA of­fi­cial, though, said there’s yet a chance these guide­lines don’t be­come pol­i­cy.  It hasn’t been re­leased and of­fi­cials could yet stop them.

“Want­i­ng to see at least some se­vere cas­es, and want­i­ng 2 months safe­ty da­ta sound like rea­son­able pre­cau­tions,” for­mer FDA chief sci­en­tist Jesse Good­man told End­points in an email. “I am con­cerned that now that this is leaked some­one may try to stop it.”

At the In­flec­tion Point for the Next Gen­er­a­tion of Can­cer Im­munother­a­py

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.

All about Omi­cron; We need more Covid an­tivi­rals; GSK snags Pfiz­er’s vac­cine ex­ec; Janet Wood­cock’s fu­ture at FDA; 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.

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

As Omi­cron spread looms, oral an­tivi­rals ap­pear to be one of the best de­fens­es — now we just need more

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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Pfiz­er, Am­gen and Janssen seek fur­ther clar­i­ty on FDA's new ben­e­fit-risk guid­ance

Three top biopharma companies are seeking more details from the FDA on how the agency conducts its benefit-risk assessments for new drugs and biologics.

While Pfizer, Amgen and Janssen praised the agency for further spelling out its thinking on the subject in a new draft guidance, including a discussion of patient experience data as part of the assessment, the companies said the FDA could’ve included more specifics in the 20-page draft document.

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Re­searchers move clos­er to de­ci­pher­ing blood clots from As­traZeneca, J&J's Covid-19 vac­cines

Researchers may be nearing an answer for the mysterious and life-threatening blood clots that appeared on very rare occasions in people who received the J&J or AstraZeneca Covid-19 vaccine.

The new work builds on an early hypothesis researchers in Norway put forward last spring, when the cases first cropped up. They proposed the events were similar to blood clots that can occur in a small subset of patients who receive heparin, one of the most commonly used blood thinners.

Janet Woodcock (AP Images)

Janet Wood­cock plots her fu­ture at FDA, with se­nior ad­vi­sor role to fall back on if Califf wins con­fir­ma­tion

Acting FDA commissioner Janet Woodcock has been the face of just about every drug approval decision at the agency since the turn of the century. Since the pandemic began, she’s moved between the top of the drugs center to the head of therapeutics at Operation Warp Speed, leading the drive for work on Covid-targeted mAbs and antivirals.

Looking forward — and pending a quick Senate confirmation to cement Rob Califf’s return to the top of FDA early next year — Woodcock’s role at the agency will again be in flux.

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Richard Pazdur (via AACR)

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

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.

Lisa Deschamps, AviadoBio CEO

Ex-No­var­tis busi­ness head hops over to a gene ther­a­py start­up — and she's reeled in $80M for a dash to the clin­ic

Neurologist and King’s College London professor Christopher Shaw has been researching neurodegenerative diseases like ALS and collaborating with drugmakers for the last 25 years in the hopes of pushing new therapies forward. But unfortunately, none of those efforts have come anywhere close to fruition.

“So, you know, after 20 years in the game, I said, ‘Let’s try and do it ourselves,’” he told Endpoints News. 

In­cor­po­rat­ing Ex­ter­nal Da­ta in­to Clin­i­cal Tri­als: Com­par­ing Dig­i­tal Twins to Ex­ter­nal Con­trol Arms

Most drug development professionals are familiar with the nerve-racking wait for the read-out of a large trial. If it’s negative, is the investigational therapy ineffective? Or could the failure result from an unforeseen flaw in the design or execution of the protocol, rather than a lack of efficacy? The team could spend weeks analyzing data, but a definitive answer may be elusive due to insufficient power for such analyses in the already completed trial. These problems are only made worse if the trial had lower enrollment, or higher dropout than expected due to an unanticipated event like COVID-19. And if a trial is negative, the next one is likely to be larger and more costly — if it happens at all.