FDA guides on Covid-19 con­sid­er­a­tions in cell and gene ther­a­py

Man­u­fac­tur­ers of cell and gene ther­a­pies have a new guid­ance from the FDA that pro­vides pan­dem­ic-re­lat­ed man­u­fac­tur­ing con­sid­er­a­tions.

The guid­ance specif­i­cal­ly ad­dress­es both li­censed and in­ves­ti­ga­tion­al cell and gene ther­a­py (CGT) man­u­fac­ture, and “is in­tend­ed to sup­ple­ment the rec­om­men­da­tions to drug and bi­o­log­i­cal prod­uct man­u­fac­tur­ers pro­vid­ed in FDA’s ‘Good Man­u­fac­tur­ing Prac­tice Con­sid­er­a­tions for Re­spond­ing to COVID-19 In­fec­tion in Em­ploy­ees in Drug and Bi­o­log­i­cal Prod­ucts Man­u­fac­tur­ing; Guid­ance for In­dus­try’ is­sued in June 2020,” ac­cord­ing to the guid­ance.

In­dus­try-spe­cif­ic is­sues ad­dressed in the guid­ance in­clude cells and tis­sues re­cov­ered from donors and the par­tic­u­lar meth­ods by which a CGT prod­uct will be man­u­fac­tured, such as cell ex­pan­sion, vi­ral re­duc­tion steps, and for­mu­la­tion. The guid­ance ap­plies to CGT prod­ucts reg­u­lat­ed as drugs and bi­o­log­ic prod­ucts alike, but not to de­vices or hu­man cells, tis­sues, and cel­lu­lar- or tis­sue-based prod­ucts (HCT/Ps) reg­u­lat­ed un­der sec­tion 361 of the PHS Act.

There has been no known con­t­a­m­i­na­tion of HCT/Ps with SARS-CoV-2, the virus that caus­es COVID-19, not­ed the agency. Fur­ther, res­pi­ra­to­ry virus­es are not gen­er­al­ly con­sid­ered to be trans­mit­ted through use of HCT/Ps. “How­ev­er, as not­ed in FDA’s June 2020 GMP Guid­ance, (Ref. 1), SARS-CoV-2 is a nov­el coro­n­avirus and, to en­sure com­pli­ance with cur­rent good man­u­fac­tur­ing prac­tice (CGMP) re­quire­ments, CGT man­u­fac­tur­ers are ex­pect­ed to eval­u­ate whether it pos­es new risks in the con­text of their spe­cif­ic prod­ucts, fa­cil­i­ties, process­es, and man­u­fac­tur­ing con­trols.”

A key con­sid­er­a­tion for risk as­sess­ment is the po­ten­tial for ac­ci­den­tal ex­pan­sion of SARS-CoV-2 virus dur­ing cell cul­ture of au­tol­o­gous or al­lo­gene­ic cells, if they were in­fect­ed with the virus. This, wrote FDA, could re­sult in “a fi­nal prod­uct with am­pli­fied SAR-CoV-2 vi­ral load.” Al­lo­gene­ic prod­ucts, es­pe­cial­ly those com­ing from cell banks, may car­ry high­er risk than au­tol­o­gous prod­ucts, for ex­am­ple.

FDA ad­vis­es con­tin­u­a­tion of rou­tine screen­ing mea­sures for donor as­sess­ment. The con­sid­er­a­tions FDA puts for­ward are based on “lim­it­ed in­for­ma­tion,” but in­clude whether an al­lo­gene­ic or au­tol­o­gous donor has, in the 28 days pre­ced­ing cell or tis­sue re­cov­ery, been in close con­tact with a Covid-19-in­fect­ed in­di­vid­ual, or been di­ag­nosed with or had a pos­i­tive test for Covid-19.

FDA con­tin­ues to rec­om­mend against screen­ing asymp­to­matic donors for SAR-CoV-2. How­ev­er, an au­tho­rized, cleared, or ap­proved test may be used as part of a risk mit­i­ga­tion strat­e­gy in CGT prod­uct man­u­fac­ture. “At this time, FDA rec­om­mends that es­tab­lish­ments not screen for or de­fer HCT/P donors who have been vac­ci­nat­ed against COVID-19 with non-repli­cat­ing, in­ac­ti­vat­ed, or RNA-based COVID-19 vac­cines,” added the agency in the guid­ance.

In terms of cel­lu­lar and tis­sue source ma­te­r­i­al, FDA should con­sid­er what is known about coro­n­avirus­es in gen­er­al and SARS-CoV-2 in par­tic­u­lar, in­clud­ing its propen­si­ty to prop­a­gate in par­tic­u­lar tis­sues. This is an evolv­ing area, and man­u­fac­tur­ers should cite the sci­en­tif­ic lit­er­a­ture and pro­vide jus­ti­fi­ca­tion for risk as­sess­ment and mit­i­ga­tion.

Man­u­fac­tur­ing con­sid­er­a­tions in­clude re­duc­ing con­t­a­m­i­na­tion risk through good em­ploy­ee san­i­ta­tion and health prac­tices. The guid­ance points out that SARS-CoV-2 “has been shown to be ca­pa­ble of in­fect­ing and repli­cat­ing in cells com­mon­ly used for vec­tor pro­duc­tion (e.g., HEK293 and Vero cells),” a fact that man­u­fac­tur­ers should weigh in risk as­sess­ment and in for­mu­lat­ing mit­i­ga­tion strate­gies.

No par­tic­u­lar ma­te­r­i­al test­ing rec­om­men­da­tions are in the guid­ance, but FDA does rec­om­mend ful­ly meet­ing CGMP re­quire­ments in­clud­ing ap­proval of all eval­u­a­tions by the man­u­fac­tur­er’s qual­i­ty unit and doc­u­men­ta­tion in the qual­i­ty man­age­ment sys­tem.

FDA has made the guid­ance im­me­di­ate­ly ef­fec­tive dur­ing the pub­lic health emer­gency of the Covid-19 pan­dem­ic, but the agency is still ac­cept­ing pub­lic com­ments on the guid­ance at any point.

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BY­OD Best Prac­tices: How Mo­bile De­vice Strat­e­gy Leads to More Pa­tient-Cen­tric Clin­i­cal Tri­als

Some of the most time- and cost-consuming components of clinical research center on gathering, analyzing, and reporting data. To improve efficiency, many clinical trial sponsors have shifted to electronic clinical outcome assessments (eCOA), including electronic patient-reported outcome (ePRO) tools.

In most cases, patients enter data using apps installed on provisioned devices. At a time when 81% of Americans own a smartphone, why not use the device they rely on every day?

Voting in the 2020 election (AP Images)

The right to vote is fun­da­men­tal — a let­ter from biotech­nol­o­gy in­dus­try lead­ers

Biotech Voices is a collection of exclusive opinion editorials from some of the leading voices in biopharma on the biggest industry questions today. Think you have a voice that should be heard? Reach out to senior editors Kyle Blankenship and Amber Tong.

We oppose all attempts to introduce laws that reduce the rights of US citizens to vote or that restrict them from exercising that right. The right to vote is fundamental to democracy. States that have enacted, or are proposing to enact, legislation to restrict voting are undermining our democracy and posing a threat to our nation. As leaders of the life sciences industry, we stand for what we believe is right for our country, our enterprises, our employees and those who benefit from our work. We join the first groups of business leaders who have challenged these laws and will continue to make our collective voices heard on this matter.

UP­DAT­ED: J&J paus­es vac­cine roll­out as feds probe rare cas­es of blood clots

The FDA and CDC have jointly decided to stop administering J&J’s Covid-19 vaccine after reviewing data involving six reported US cases of a rare and severe type of blood clot in individuals after receiving the vaccine.

CDC will convene a meeting of its Advisory Committee on Immunization Practices on Wednesday to further review these cases and assess their potential significance. “FDA will review that analysis as it also investigates these cases. Until that process is complete, we are recommending a pause in the use of this vaccine out of an abundance of caution,” Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research and Anne Schuchat, Principal Deputy Director of the CDC, said in a joint statement Tuesday morning.

Pascal Soriot (AstraZeneca via YouTube)

Af­ter be­ing goad­ed to sell the com­pa­ny, Alex­ion's CEO set some am­bi­tious new goals for in­vestors. Then Pas­cal So­ri­ot came call­ing

Back in the spring of 2020, Alexion $ALXN CEO Ludwig Hantson was under considerable pressure to perform and had been for months. Elliott Advisers had been applying some high public heat on the biotech’s numbers. And in reaching out to some major stockholders, one thread of advice came through loud and clear: Sell the company or do something dramatic to change the narrative.

In the words of the rather dry SEC filing that offers a detailed backgrounder on the buyout deal, Alexion stated: ‘During the summer and fall of 2020, Alexion also continued to engage with its stockholders, and in these interactions, several stockholders encouraged the company to explore strategic alternatives.’

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Sajith Wickramasekara, Benchling via YouTube

Meet Bench­ling, the lat­est uni­corn seek­ing to rev­o­lu­tion­ize the way sci­en­tists do work with the help of the cloud

There’s another unicorn in biotech land, as Benchling and its leading R&D cloud platform pull in a $200 million Series E to help scientists accelerate drug development. In doing so, the company hit a lofty $4 billion valuation — nearly five times what it was worth around this time last year, according to Forbes.

Despite the fact that drug development is becoming significantly more complex, the industry continues to run on paper, emails and spreadsheets, co-founder and CEO Sajith Wickramasekara said in a video on Benchling’s website. The MIT grad sought to change that by creating software that allows scientists to better track, model and forecast their work.

Covid-19 roundup: No­vavax shakes up lead­er­ship with two pro­mo­tions and de­par­ture of CFO; Mod­er­na, No­vavax shots added to mix-and-match study in the UK

Novavax has had a busy month, filled with supply chain issues and manufacturing deals that have affected the rollout of its Covid-19 vaccine. Tuesday, the company announced updates to its leadership team.

CFO Greg Covino will step down from that role after just five months for personal reasons, the release said, but take on a new role as executive advisor. John Trizzino, current chief commercial officer and chief business officer, will take the CFO role over in the interim.

Amy­lyx to move for­ward with ALS pro­gram in Eu­rope, but FDA wants an­oth­er look; Hu­ma­cyte adds $50M in debt fi­nanc­ing

Amylyx is one of several companies looking to break through in the tough ALS field, and Wednesday they announced they’re moving forward with regulatory plans.

The Cambridge, MA-based biotech said they’re submitting a marketing application to the EMA for their AMX0035 program by the end of 2021. Wednesday’s news comes a few weeks after they revealed similar plans to move forward with Canadian health regulators by June 30.

Near­ly a year af­ter Au­den­tes' gene ther­a­py deaths, the tri­al con­tin­ues. What hap­pened re­mains a mys­tery

Natalie Holles was five months into her tenure as Audentes CEO and working to smooth out a $3 billion merger when the world crashed in.

Holles and her team received word on the morning of May 5 that, hours before, a patient died in a trial for their lead gene therapy. They went into triage mode, alerting the FDA, calling trial investigators to begin to understand what happened, and, the next day, writing a letter to alert the patient community so they would be the first to know. “We wanted to be as forthright and transparent as possible,” Holles told me late last month.

The brief letter noted two other patients also suffered severe reactions after receiving a high dose of the therapy and were undergoing treatment. One died a month and a half later, at which point news of the deaths became public, jolting an emergent gene therapy field and raising questions about the safety of the high doses Audentes and others were now using. The third patient died in August.

“It was deeply saddening,” Holles said. “But I was — we were — resolute and determined to understand what happened and learn from it and get back on track.”

Eleven months have now passed since the first death and the therapy, a potential cure for a rare and fatal muscle-wasting disease called X-linked myotubular myopathy, is back on track, the FDA having cleared the company to resume dosing at a lower level. Audentes itself is no more; last month, Japanese pharma giant Astellas announced it had completed working out the kinks of the $3 billion merger and had restructured and rebranded the subsidiary as Astellas Gene Therapies. Holles, having successfully steered both efforts, departed.

Still, questions about precisely what led to the deaths of the 3 boys still linger. Trial investigators released key details about the case last August and December, pointing to a biological landmine that Audentes could not have seen coming — a moment of profound medical misfortune. In an emerging field that’s promised cures for devastating diseases but also seen its share of safety setbacks, the cases provided a cautionary tale.

Audentes “contributed in a positive way by giving a painful but important example for others to look at and learn from,” Terry Flotte, dean of the UMass School of Medicine and editor of the journal Human Gene Therapy, told me. “I can’t see anything they did wrong.”

Yet some researchers say they’re still waiting on Astellas to release more data. The company has yet to publish a full paper detailing what happened, nor have they indicated that they will. In the meantime, it remains unclear what triggered the events and how to prevent them in the future.

“Since Audentes was the first one and we don’t have additional information, we’re kind of in a holding pattern, flying around, waiting to figure out how to land our vehicles,” said Jude Samulski, professor of pharmacology at UNC’s Gene Therapy Center and CSO of the gene therapy biotech AskBio, now a subsidiary of Bayer.

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Fifth Cir­cuit sides with FTC in ma­jor pay-for-de­lay set­tle­ment case

The US Court of Appeals for the Fifth Circuit on Tuesday upheld the Federal Trade Commission’s ruling that generic drugmaker Impax Laboratories should be charged with antitrust violations for accepting payments worth about $100 million to delay the entry of a generic opioid for more than two years.

The court’s opinion upheld the FTC’s anticompetitive findings on the deal between Impax (now owned by Amneal Pharmaceuticals) and Endo Pharmaceuticals, under which Endo committed to not market an authorized generic, which increased Impax’s projected profits by $24.5 million. Endo agreed to pay Impax credits for the shrunken market that Impax would inherit if, as expected, Endo made a successful hop to a reformulated Opana ER.