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.”

Stephen Hahn, FDA commissioner (AP Images)

As FDA sets the stage for the first Covid-19 vac­cine EUAs, some big play­ers are ask­ing for a tweak of the guide­lines

Setting the stage for an extraordinary one-day meeting of the Vaccines and Related Biological Products Advisory Committee this Thursday, the FDA has cleared 2 experts of financial conflicts to help beef up the committee. And regulators went on to specify the safety, efficacy and CMC input they’re looking for on EUAs, before they move on to the full BLA approval process.

All of this has already been spelled out to the developers. But the devil is in the details, and it’s clear from the first round of posted responses that some of the top players — including J&J and Pfizer — would like some adjustments and added feedback. And on Thursday, the experts can offer their own thoughts on shaping the first OKs.

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Bio­gen spot­lights a pair of painful pipeline set­backs as ad­u­canum­ab show­down looms at the FDA

Biogen has flagged a pair of setbacks in the pipeline, spotlighting the final failure for a one-time top MS prospect while scrapping a gene therapy for SMA after the IND was put on hold due to toxicity.

Both failures will raise the stakes even higher on aducanumab, the Alzheimer’s drug that Biogen is betting the ranch on, determined to pursue an FDA OK despite significant skepticism they can make it with mixed results and a reliance on post hoc data mining.

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A new chap­ter in the de­cen­tral­ized clin­i­cal tri­al ap­proach

Despite the promised decentralized trial revolution, we haven’t yet moved the needle in a significant way, although we are seeing far bolder commitments to this as we continue to experience the pandemic restrictions for some time to come. The vision of grandeur is one thing, but operationalizing and execution are another and recognising that change, particularly mid-flight on studies, is worthy of thorough evaluation and consideration in order to achieve success. Here we will discuss one of the critical building blocks of a Decentralized and Remote Trial strategy: TeleConsent; more than paper under glass, it is a paradigm change and key digital enabler.

Covid-19 roundup: As­traZeneca could soon re­sume US vac­cine tri­als; Pfiz­er's dis­tri­b­u­tion plan in­volves spe­cial ship­ping box­es, no whole­salers 

AstraZeneca’s Covid-19 vaccine trial could resume in the US later this week, according to a Reuters report.

Experimental dosing of the candidate came screeching to a halt in September, when a participant in the UK suffered what’s believed to be the spinal inflammatory condition transverse myelitis. Trials have already resumed in the UK, Brazil, India, Japan and South Africa — and four anonymous sources told Reuters that a green light from the US could come as early as this week.

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CRISPR Ther­a­peu­tics gets a snap­shot of off-the-shelf CAR-T suc­cess in B-cell ma­lig­nan­cies — marred by the death of a pa­tient

Just days after scientific founder Emmanuelle Charpentier shared the Nobel prize for her work on CRISPR/Cas9, CRISPR Therapeutics $CRSP is showing off a snapshot of success in their early-stage study for an off-the-shelf CAR-T approach to CD19+ B cell malignancies — a snapshot marred by the death of a patient who had been given a high dose of the treatment.

Using their gene editing tech, researchers for CRISPR engineered cells from healthy donors into an attack vehicle aimed at cancer, something that has been achieved with great success using patients’ own cells — the autologous approach. But autologous CAR-T is hampered by the more complex vein-to-vein requirement that delays treatment, and now CRISPR Therapeutics along with other players like Allogene are determined to replace the pioneers with CAR-T 2.0.

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CEO Grace Colón (InCarda)

Look­ing to re­pur­pose an old drug to treat ir­reg­u­lar heart­beats, In­Car­da rais­es $30M in first Se­ries C close

A little less than two years after completing its $42 million Series B round, InCarda has returned to the venture well.

The San Francisco-based biotech announced the first portion of its Series C on Wednesday, pulling in $30 million in new funding. Most of the money will give enough runway for InCarda’s InRhythm program, an inhaled therapeutic aiming to treat sudden episodes of irregular heartbeats, through its Phase II trials and prepare it for Phase III.

Un­fazed by PhII miss, Roche ush­ers Prothena's Parkin­son's drug in­to late-stage tri­al — a $60M move

Prothena’s prasinezumab may not have met the primary endpoint in Phase II, but its partners at Roche are seeing enough to move it into a late-stage trial for Parkinson’s disease.

The Phase IIb will build on the Phase II PASADENA study, adding a subgroup of early Parkinson’s patients on stable levodopa therapy to the population.

It’s a significant milestone for a $600 million deal that dates back to 2013, as dosing of the first patient — expected next year — will trigger a $60 million milestone payment to Prothena.

Steve Chen, Cellis Therapeutics president and CMO (Cellics)

UC San Diego spin­out award­ed up to $15M for nanosponge de­signed to soak up sep­sis-caus­ing tox­ins

CARB-X, a global partnership looking to spur the development of new antibacterial drugs, is awarding Cellics Therapeutics $3.94 million to do what president and CMO Steve Chen calls “looking at traditional drug development upside down.”

Instead of going after a target directly — in this case bacterial toxins and inflammatory cytokines that cause sepsis — Cellics researchers “flip it around” to examine the host cells being attacked. The UC San Diego spinout then creates what it calls “nanosponges” — nanoparticles cloaked in the fragments of macrophage cell membranes. Chen says the “sponges” are designed to trap the sepsis-causing endotoxins and cytokines on their cell membranes, neutralizing them.

Derek Chalmers, Cara Therapeutics CEO

Cara lines up a $440M deal for US rights to its late-stage drug for se­vere itch, with $150M cash on the ta­ble

With plans afoot to file an NDA for what could be its first approved drug, Cara Therapeutics is pivoting its focus to commercialization. And Swiss company Vifor Pharma is willing to surrender up to $440 million to market the candidate in the US.

Cara $CARA CEO Derek Chalmers said an NDA submission is coming this quarter for their intravenous drug Korsuva in chronic kidney disease-associated pruritus (CKD-aP), a severe itching condition. The Stamford, CT-based biotech read out positive topline data from a Phase III pivotal study back in April, and announced plans to approach EMA regulators shortly after filing with the FDA.

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