FDA cites litany of er­rors at Lon­za Hous­ton plant at the cen­ter of Bris­tol My­ers CVR de­ba­cle

In­vestors’ some­what long­shot bet on a $9 CVR tied to Bris­tol My­ers Squibb’s ac­qui­si­tion of Cel­gene came to a screech­ing halt last month af­ter the FDA took too long to de­cide on CAR-T can­di­date liso-cel. One of the po­ten­tial cul­prits in that de­lay, a De­cem­ber in­spec­tion of a con­tract man­u­fac­tur­er, now ap­pears to have played a big role af­ter the FDA cit­ed a num­ber of is­sues at that plant.

In a Form 483  pub­lished on­line this week, the FDA blast­ed Lon­za Hous­ton, one of the con­tract man­u­fac­tur­ers for liso-cel, for a litany of er­rors, in­clud­ing mis­la­bel­ing, prod­ucts for the US and EU drug mar­kets stored in the same bins, “poor­ly main­tained” freez­er units, and ex­pired batch­es of in­gre­di­ents that weren’t prop­er­ly dis­posed of.

Those is­sues were found dur­ing an ear­ly De­cem­ber in­spec­tion and out­lined in the four-ob­ser­va­tion Form 483. De­spite Bris­tol re­spond­ing to con­cerns at the site with­in eight days, it wasn’t enough to get liso-cel on track for an ap­proval by year-end — one of the key check­points for the $9 CVR.

De­spite those is­sues, Lon­za ul­ti­mate­ly be­lieves a de­lay in the planned in­spec­tion at its site due to Covid-19 may have ul­ti­mate­ly tor­pe­doed the ap­proval. In a state­ment Wednes­day, Lon­za spokesper­son San­na Fowler said the com­pa­ny is “rapid­ly ad­dress­ing” the FDA’s ob­ser­va­tions from the De­cem­ber site in­spec­tion, and isn’t aware of any rea­sons that would fur­ther de­lay the ap­proval of the drug in ques­tion—Bris­tol My­ers Squibb’s liso-cel CAR-T ther­a­py.

“Lon­za reg­u­lar­ly re­ceives vis­its from in­ter­na­tion­al reg­u­la­to­ry bod­ies, in­clud­ing the FDA and in a typ­i­cal year we host around ten FDA in­spec­tions,” Fowler wrote in an email. “We take com­pli­ance very se­ri­ous­ly and do every­thing we can to en­sure that all cus­tomers and stake­hold­ers, in­clud­ing reg­u­la­tors, are sat­is­fied. When is­sues come to our at­ten­tion, we ad­dress them ex­pe­di­tious­ly and ef­fec­tive­ly, as is the case here.”

Lon­za, Fowler said, re­mains com­mit­ted to sup­port­ing Bris­tol My­ers Squibb “in their goal of bring­ing liso-cel to pa­tients with re­lapsed or re­frac­to­ry large B-cell lym­phoma.”

A week­long in­spec­tion of the Lon­za site was part of the liso-cel drug ap­pli­ca­tion re­view. Due to Covid-19 re­stric­tions, though, an in­spec­tion ini­tial­ly sched­uled for April was sig­nif­i­cant­ly de­layed to Dec. 3-10.

This de­lay, ob­ser­va­tions aside, had dras­tic and ex­pen­sive ram­i­fi­ca­tions for Bris­tol in­vestors, who were re­ly­ing on a PDU­FA ap­proval for liso-cel by Dec. 31, 2020 to cash in on a $6.4 bil­lion pay­day linked to the com­pa­ny’s Cel­gene merg­er. While the Form 483 it­self isn’t a death nail to an even­tu­al liso-cel ap­proval, it fur­ther de­layed those reg­u­la­to­ry process­es and firm­ly shut the door on any hopes those in­vestors had of the ad­di­tion­al pay­day.

When the FDA fi­nal­ly did come to in­spect Lon­za’s site, it clear­ly wasn’t quite pre­pared.

The Form 483 notes that among the afore­men­tioned ob­served is­sues, fa­cil­i­ty work­ers ap­par­ent­ly failed to ver­i­fy the iden­ti­ty of each new batch of raw ma­te­ri­als be­fore they were re­leased to the man­u­fac­tur­ing process­es. Writ­ten pro­ce­dures weren’t al­ways fol­lowed, and the in­spec­tors said they ob­served one case of asep­tic op­er­a­tion con­trol that was in­ad­e­quate.

On Jan. 1, Bris­tol My­ers Squibb is­sued a brief and some­what cryp­tic press re­lease up­dat­ing the sta­tus of the liso-cel ap­pli­ca­tion, and said that both Lon­za and the com­pa­ny “re­spond­ed ex­pe­di­tious­ly” to ob­ser­va­tions from the Dec. 3-10 in­spec­tion, but didn’t men­tion the Form 483.

Bris­tol My­ers Squibb hasn’t pub­licly com­ment­ed on the liso-cel ap­pli­ca­tion process since. In a state­ment, a com­pa­ny spokesper­son said the work to get the drug ap­proved con­tin­ues but didn’t specif­i­cal­ly ad­dress its part­ner­ship with Lon­za, the Form 483 ob­ser­va­tions or the CVR loss­es im­posed by the de­lay.

“The com­pa­ny con­tin­ues to work close­ly with the FDA to sup­port the on-go­ing re­view of the BLA for liso-cel, the tim­ing of which is set by the FDA,” the spokesper­son said. “We are com­mit­ted to bring­ing liso-cel to pa­tients with re­lapsed or re­frac­to­ry large B-cell lym­phoma who still have sig­nif­i­cant un­met needs.”

Biotech Half­time Re­port: Af­ter a bumpy year, is biotech ready to re­bound?

The biotech sector has come down firmly from the highs of February as negative sentiment takes hold. The sector had a major boost of optimism from the success of the COVID-19 vaccines, making investors keenly aware of the potential of biopharma R&D engines. But from early this year, clinical trial, regulatory and access setbacks have reminded investors of the sector’s inherent risks.

RBC Capital Markets recently surveyed investors to take the temperature of the market, a mix of specialists/generalists and long-only/ long-short investment strategies. Heading into the second half of the year, investors mostly see the sector as undervalued (49%), a large change from the first half of the year when only 20% rated it as undervalued. Around 41% of investors now believe that biotech will underperform the S&P500 in the second half of 2021. Despite that view, 54% plan to maintain their position in the market and 41% still plan to increase their holdings.

How to col­lect and sub­mit RWD to win ap­proval for a new drug in­di­ca­tion: FDA spells it out in a long-await­ed guid­ance

Real-world data is messy. There can be differences in the standards used to collect different types of data, differences in terminologies and curation strategies, and even in the way data is exchanged.

While acknowledging this somewhat controlled chaos, the FDA is now explaining how biopharma companies can submit study data derived from real-world data (RWD) sources in applicable regulatory submissions, including new drug indications.

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Sen. Richard Durbin (D-IL, foreground) and Sen. Richard Blumenthal (D-CT) (Patrick Semansky/AP Images)

Sen­a­tors back FDA's plan to re­quire manda­to­ry pre­scriber ed­u­ca­tion for opi­oids

Three Senate Democrats are backing an FDA plan to require mandatory prescriber education for opioids as overdose deaths have risen sharply over the past decade, with almost 97,000 American opioid-related overdose deaths in the past year alone.

While acknowledging a decline in overall opioid analgesic dispensing in recent years, the FDA said it’s reconsidering the need for mandatory prescriber training through a REMS given the current situation with overdoses, and is seeking input on the aspects of the opioid crisis that mandatory training could potentially mitigate.

David Lockhart, ReCode Therapeutics CEO

Pfiz­er throws its weight be­hind LNP play­er eye­ing mR­NA treat­ments for CF, PCD

David Lockhart did not see the meteoric rise of messenger RNA and lipid nanoparticles coming.

Thanks to the worldwide fight against Covid-19, mRNA — the genetic code that can be engineered to turn the body into a mini protein factory — and LNPs, those tiny bubbles of fat carrying those instructions, have found their way into hundreds of millions of people. Within the biotech world, pioneers like Alnylam and Intellia have demonstrated just how versatile LNPs can be as a delivery vehicle for anything from siRNA to CRISPR/Cas9.

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Some can­cer pa­tients now have to find oth­er op­tions as Bris­tol My­er­s' Abrax­ane falls in­to short­age from man­u­fac­tur­ing woes

When Beth Hogan, a metastatic pancreatic cancer patient, showed up for her infusion at Yale’s Smilow Cancer Hospital in New Haven, CT on Oct. 11, she said she was informed that day that she would not be receiving Bristol Myers Squibb’s Abraxane, part of her combo treatment, because of a shortage.

“I was told we don’t know when you can have it,” she told Endpoints News via email, adding that she doesn’t expect to receive any Abraxane this coming Monday at her treatment appointment either, and she doesn’t know when things will change.

Man­u­fac­tur­ing woes for No­vavax’s Covid jab bad­ly dis­rupt plans for roll­out to the poor — re­port

Production problems at a Novavax facility in Maryland have led to delays in the Covax vaccine sharing program. Now, a shortage of 1 billion doses is expected, as the supplier tries to navigate producing a shot up to regulators’ standards, Politico reported Tuesday.

The company has run into trouble with the purity of the vaccine. Novavax has had trouble proving it can produce a shot consistently up to standards, and it has caused significant delays in the rollout to low- and middle-income countries. This follows several delays at Novavax that has put the executive crew on the defensive.

Leen Kawas (L) has resigned as CEO of Athira and will be replaced by COO Mark Litton

Ex­clu­sive: Athi­ra CEO Leen Kawas re­signs af­ter in­ves­ti­ga­tion finds she ma­nip­u­lat­ed da­ta

Leen Kawas, CEO and founder of the Alzheimer’s upstart Athira Pharma, has resigned after an internal investigation found she altered images in her doctoral thesis and four other papers that were foundational to establishing the company.

Mark Litton, the company’s COO since June 2019 and a longtime biotech executive, has been named full-time CEO. Kawas, meanwhile, will no longer have ties to the company except for owning a few hundred thousand shares.

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House pass­es two bills on con­tin­u­ous man­u­fac­tur­ing, stock­pil­ing ahead of fu­ture pan­demics

The House of Representatives this week passed two bills to strengthen America’s national stockpile of medical supplies and to allow the FDA to designate colleges and universities as National Centers of Excellence in Advanced and Continuous Pharmaceutical Manufacturing.

The stockpile bill, known as HR 3635, passed by a vote of 397-22. Introduced by Rep. Elissa Slotkin (D-MI) and 15 other cosponsors, the bill would improve America’s ability to respond to future pandemics, as well as handle the ongoing Covid-19 pandemic too.

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Martine Rothblatt (AP Photo/Jack Plunkett)

FDA re­jects Unit­ed's po­ten­tial PAH drug due to a man­u­fac­tur­ing is­sue

United Therapeutics said Monday that it received a complete response letter for its potential pulmonary arterial hypertension drug Tyvaso DPI, due to an issue with a third-party facility that performs drug substance testing. The company said it expects an approval will come by next summer.

The inspection issue appears to be the only problem the FDA took notice of, according to United. There were no issues with packaging, manufacturing or testing Tyvaso DPI at the MannKind Corporation facility, the company said.