Top FDA of­fi­cial ac­cused CDER chief Wood­cock of ap­pear­ing bi­ased, brow­beat­ing re­view­ers in de­mand­ing eteplirsen OK

While FDA com­mis­sion­er Rob Califf was try­ing to nav­i­gate an in­ter­nal civ­il war at the agency over its con­tro­ver­sial de­ci­sion to pro­vide an ac­cel­er­at­ed ap­proval for Sarep­ta’s eteplirsen, John Jenk­ins, then head of the Of­fice of New Drugs, sent him a memo which de­tailed a blis­ter­ing at­tack on CDER chief Janet Wood­cock.

Janet Wood­cock

It was Wood­cock who de­mand­ed, and won, the ar­gu­ment in fa­vor of an ac­cel­er­at­ed OK of the Duchenne mus­cu­lar dy­s­tro­phy drug.

But Jenk­ins, who sided with oth­er top of­fi­cials at the FDA in op­pos­ing the ap­proval, says that Wood­cock cre­at­ed an “ap­pear­ance of bias” in push­ing for the ap­proval from an ear­ly point. Wood­cock, he wrote Califf in a memo dat­ed Sep­tem­ber 14, 2016, left the FDA re­view team feel­ing pres­sured to come over to her side. And she by­passed the usu­al chain of com­mand to get what she want­ed, in­sist­ing on an ap­proval even be­fore the re­view team had com­plet­ed its task and leav­ing them dis­trust­ful of her role and man­ner.

Not on­ly did Jenk­ins ob­ject to Wood­cock’s han­dling of eteplirsen, a drug which had the vo­cal sup­port of the Duchenne com­mu­ni­ty, he al­so told Califf that he had de­layed his re­tire­ment specif­i­cal­ly be­cause Wood­cock in­tend­ed to take his place af­ter he left. And that is ex­act­ly what she did.

The memo was high­light­ed in a re­port by Charles Seife on Un­dark, an on­line site that al­so in­clud­ed a copy of the full let­ter. You can read the whole doc­u­ment here.

While Califf pub­lished much of the doc­u­men­ta­tion around the dis­pute, this par­tic­u­lar memo did not sur­face un­til Seife’s FOIA law­suit forced it out. And it in­cludes the re­mark­able sug­ges­tion that Califf should coun­sel the pow­er­ful CDER chief on her man­ner and her meth­ods.

Jenk­ins has since re­tired from the FDA, but he de­clined to talk to Seife, as did Wood­cock. But his memo de­serves care­ful at­ten­tion. One ex­cerpt:

John Jenk­ins

On page 4, you state “there is al­so abun­dant ev­i­dence that Dr. Wood­cock heard and read FDACDER0001 all the sci­en­tif­ic ev­i­dence…” This im­plies she took these ac­tions BE­FORE reach­ing a de­ci­sion on the ap­pli­ca­tion, which is clear­ly not cor­rect giv­en her state­ment to the re­view team of her in­ten­tion to over­rule them and ap­prove the drug BE­FORE they had com­plet­ed their re­views. Keep in mind this oc­curred af­ter an AC (ad­vi­so­ry com­mit­tee) meet­ing at which the ma­jor­i­ty of the pan­el vot­ed against both AA and full ap­proval. It is al­so clear that she was pre­pared to ap­prove the drug over the team’s ob­jec­tions by the orig­i­nal PDU­FA goal date and on­ly re­luc­tant­ly agreed to press the spon­sor for ad­di­tion­al da­ta on dy­s­trophin pro­duc­tion from the on­go­ing open-la­bel tri­al. While I am glad she agreed to go along with that re­quest, con­vinc­ing her to take what seemed like a very log­i­cal ac­tion was not easy. So, I find it hard to rec­on­cile your state­ments about the process with the ac­tions tak­en. Keep in mind that the usu­al course of ac­tion would be for the Of­fice to is­sue a CR let­ter and then the spon­sor could sub­mit a FDRR that would first come to me and on­ly if I sup­port­ed the Of­fice would an FDRR go to the Cen­ter Di­rec­tor. In this case that process was by­passed.

His memo goes on to out­line his con­cerns about the com­plete lack of da­ta on ef­fi­ca­cy as well as con­cerns that ac­cel­er­at­ed ap­proval would clear­ly low­er the bar at the agency on a new drug OK.

Al­so on page 9 it is iron­ic that you at­tribute to Janet the idea of ran­dom­iz­ing ear­ly in or­der to gen­er­ate good ev­i­dence. That is ex­act­ly what the re­view team planned to re­quire of Sarep­ta af­ter the re­sults of the 12-pa­tient study be­came avail­able, but it was Janet that pressed that a new ran­dom­ized tri­al not be re­quired. So, if Janet had fol­lowed the nor­mal CDER process in this case the re­view team would have re­quired place­bo-con­trolled tri­als, as they did for dris­apersen and we would have bet­ter da­ta on which to make a de­ci­sion.

Jenk­ins stops one step short of ac­cus­ing Wood­cock of bul­ly­ing the staff.

While I un­der­stand your de­sire not to un­der­cut her role as Cen­ter Di­rec­tor, her ac­tions have at best cre­at­ed a serous …ap­pear­ance of bias among the re­view team mem­bers and that has cre­at­ed dis­trust and a sense of un­due pres­sure to “come around” to her way of think­ing. Even if you up­hold her de­ci­sion I would think you should coun­sel her about how her be­hav­ior and ac­tions have un­der­mined her cred­i­bil­i­ty among the re­view staff and should be avoid­ed in fu­ture sim­i­lar cas­es. Ef­fec­tive lead­ers must have the trust and re­spect of their staff.

Lat­er, just be­fore he re­tired, Jenk­ins gave a speech in which he tried to warn oth­er drug de­vel­op­ers to avoid try­ing to fol­low the same path that Sarep­ta took. But he was clear­ly con­cerned about the fu­ture:

As you know, I had planned to re­tire from FDA last spring. I have de­layed my de­par­ture for a va­ri­ety of rea­sons, but one of the most im­por­tant rea­sons is that Janet has told me she plans to serve as act­ing in my place as head of OND once I leave. I am very con­cerned about the im­pact of that de­ci­sion on the fu­ture of the new drugs re­view pro­gram and would be hap­py to dis­cuss those con­cerns fur­ther.

Regeneron CEO Leonard Schleifer speaks at a meeting with President Donald Trump, members of the Coronavirus Task Force, and pharmaceutical executives in the Cabinet Room of the White House (AP Photo/Andrew Harnik)

OWS shifts spot­light to drugs to fight Covid-19, hand­ing Re­gen­eron $450M to be­gin large scale man­u­fac­tur­ing in the US

The US government is on a spending spree. And after committing billions to vaccines defense operations are now doling out more of the big bucks through Operation Warp Speed to back a rapid flip of a drug into the market to stop Covid-19 from ravaging patients — possibly inside of 2 months.

The beneficiary this morning is Regeneron, the big biotech engaged in a frenzied race to develop an antibody cocktail called REGN-COV2 that just started a late-stage program to prove its worth in fighting the virus. BARDA and the Department of Defense are awarding Regeneron a $450 million contract to cover bulk delivery of the cocktail starting as early as late summer, with money added for fill/finish and storage activities.

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UP­DAT­ED: Bio­gen shares spike as ex­ecs com­plete a de­layed pitch for their con­tro­ver­sial Alzheimer's drug — the next move be­longs to the FDA

Biogen is stepping out onto the high wire today, reporting that the team working on the controversial Alzheimer’s drug aducanumab has now completed their submission to the FDA. And they want the agency to bless it with a priority review that would cut the agency’s decision-making time to a mere 6 months.

The news drove a 10% spike in Biogen’s stock $BIIB ahead of the bell.

Part of that spike can be attributed to a relief rally. Biogen execs rattled backers and a host of analysts earlier in the year when they unexpectedly delayed their filing to the third quarter. That delay provoked all manner of speculation after CEO Michel Vounatsos and R&D chief Al Sandrock failed to persuade influential observers that the pandemic and other factors had slowed the timeline for filing. Actually making the pitch at least satisfies skeptics that the FDA was not likely pushing back as Biogen was pushing in. From the start, Biogen execs claimed that they were doing everything in cooperation with the FDA, saying that regulators had signaled their interest in reviewing the submission.

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Donald and Melania Trump watch the smoke of fireworks from the South Lawn of the White House on July 4, 2020 (via Getty)

Which drug de­vel­op­ers of­fer Trump a quick, game-chang­ing ‘so­lu­tion’ as the pan­dem­ic roars back? Eli Lil­ly and Ab­Cellera look to break out of the pack

We are unleashing our nation’s scientific brilliance and will likely have a therapeutic and/or vaccine solution long before the end of the year.

— Donald Trump, July 4

Next week administration officials plan to promote a new study they say shows promising results on therapeutics, the officials said. They wouldn’t describe the study in any further detail because, they said, its disclosure would be “market-moving.”

— NBC News, July 3

Something’s cooking. And it’s not just July 4 leftovers involving stale buns and uneaten hot dogs.

Over the long weekend observers picked up signs that the focus in the Trump administration may swiftly shift from the bright spotlight on vaccines being promised this fall, around the time of the election, to include drugs that could possibly keep patients out of the hospital and take the political sting out of the soaring Covid-19 numbers causing embarrassment in states that swiftly reopened — as Trump cheered along.

So far, Gilead has been the chief beneficiary of the drive on drugs, swiftly offering enough early data to get remdesivir an emergency authorization and into the hands of the US government. But their drug, while helpful in cutting stays, is known for a limited, modest effect. And that won’t tamp down on the hurricane of criticism that’s been tearing at the White House, and buffeting the president’s most stalwart core defenders as the economy suffers.

We’ve had positive early-stage vaccine data, most recently from Pfizer and BioNTech, playing catchup on an mRNA race led by Moderna — where every little sign of potential trouble is magnified into a lethal threat, just as every advance excites a frenzy of support. But that race still has months to play out, with more Phase I data due ahead of the mid-stage numbers looming ahead. A vaccine may not be available in large enough quantities until well into 2021, which is still wildly ambitious.

So what about a drug solution?

Trump’s initial support for a panacea focused on hydroxychloroquine. But that fizzled in the face of data underscoring its ineffectiveness — killing trials that aren’t likely to be restarted because of a recent population-based study offering some support. And there are a number of existing drugs being repurposed to see how they help hospitalized patients.

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Daniel O'Day, Gilead CEO (Kevin Dietsch/UPI/Bloomberg via Getty Images)

A new study points to $6.5B in pub­lic sup­port build­ing the sci­en­tif­ic foun­da­tion of Gilead­'s remde­sivir. Should that be re­flect­ed in the price?

By drug R&D standards, Gilead’s move to repurpose remdesivir for Covid-19 and grab an emergency use authorization was a remarkably easy, low-cost layup that required modest efficacy and a clean safety profile from just a small group of patients.

The drug OK also arrived after Gilead had paid much of the freight on getting it positioned to move fast.

In a study by Fred Ledley, director of the Center for Integration of Science and Industry at Bentley University in Waltham, MA, researchers concluded that the NIH had invested only $46.5 million in the research devoted to the drug ahead of the pandemic, a small sum compared to the more than $1 billion Gilead expected to spend getting it out this year, all on top of what it had already cost in R&D expenses.

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FDA bars the door — for now — against Mer­ck’s star can­cer drug af­ter Roche beat them to the punch

Merck has been handed a rare setback at the FDA.

After filing for the accelerated approval of a combination of their star PD-1 drug Keytruda with Eisai’s Lenvima as a first-line treatment for unresectable hepatocellular carcinoma, the FDA nixed the move, handing out a CRL because Roche beat them to the punch on the same indication by a matter of weeks.

According to Merck:

Ahead of the Prescription Drug User Fee Act action dates of Merck’s and Eisai’s applications, another combination therapy was approved based on a randomized, controlled trial that demonstrated overall survival. Consequently, the CRL stated that Merck’s and Eisai’s applications do not provide evidence that Keytruda in combination with Lenvima represents a meaningful advantage over available therapies for the treatment of unresectable or metastatic HCC with no prior systemic therapy for advanced disease. Since the applications for KEYNOTE-524/Study 116 no longer meet the criteria for accelerated approval, both companies plan to work with the FDA to take appropriate next steps, which include conducting a well-controlled clinical trial that demonstrates substantial evidence of effectiveness and the clinical benefit of the combination.

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Covid-19 roundup: Mod­er­na sticks to Ju­ly for its Phase III as ru­mors swirl; Fol­low­ing US lead, EU buys up Covid-19 treat­ments

The Phase III might be delayed from its original early July goal, but Moderna says it will still kick off the pivotal study for what could ultimately be the first Covid-19 vaccine before the end of the month.

A day after Reuters reported that squabbling between the Cambridge biotech and government regulators had held up the trial by about two weeks, Moderna released a statement saying that they had completed enrollment of their 650-person Phase II trial and were on track to begin Phase III by the end of the month. The protocol for that study, which is meant to prove whether or not the vaccine can prevent people from becoming sick, has been finalized, they said.

Stephen Hahn, AP

Trump and Navar­ro press again for hy­drox­y­chloro­quine. Can the FDA stay in­de­pen­dent?

Tuesday morning, economist and Trump advisor Peter Navarro walked onto the White House driveway and promptly brought a political cloud back onto the FDA.

Speaking to a White House pool reporter, Navarro said that four Detroit doctors were, based on a single disputed study, filing for the FDA to again issue an emergency authorization for hydroxychloroquine, the anti-malarial pill that President Trump hyped for months as a Covid-19 treatment over the objections of his own scientists. Then, while avoiding directly calling for the FDA to OK the drug, blasted the agency. He said its decision to pull an earlier authorization “was based on bad science” and “had a tremendously negative effect” on doctors and patients.

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Noubar Afeyan, Flagship CEO and Tessera chairman (Victor Boyko/Getty Images)

Flag­ship ex­ecs take a les­son from na­ture to mas­ter ‘gene writ­ing,’ launch­ing a star-stud­ded biotech with big am­bi­tions to cure dis­ease

Flagship Pioneering has opened up its deep pockets to fund a biotech upstart out to revolutionize the whole gene therapy/gene editing field — before gene editing has even made it to the market. And they’ve surrounded themselves with some marquee scientists and execs who have crowded around to help shepherd the technology ahead.

The lead player here is Flagship general partner Geoff von Maltzahn, an MIT-trained synthetic biologist who set out in 2018 to do CRISPR — a widely used gene editing tool — and other rival technologies one or two better. Von Maltzahn has been working with Sana co-founder Jake Rubens, another synthetic biology player out of MIT who he describes as his “superstar,” who’s taken the CSO role.

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Covid-19 roundup: Squab­bles with gov­ern­ment de­lay Mod­er­na’s PhI­II — re­ports; No­vavax se­cures largest Warp Speed deal yet: $1.6B

A much-anticipated Phase III trial for Moderna’s Covid-19 vaccine is being held up as the company delayed submitting trial protocols and sparred with government scientists on how to run the study and even what the benchmark for success should be, Reuters reported.

Moderna, the first US company to put their vaccine into human testing, was supposed to enter a 30,000-person study this month in partnership with the NIH to determine whether it can prevent infection. STAT reported last week that the trial was facing delays over the protocol, but that a July start was still possible. Neither the NIH nor Moderna ever disclosed a specific date the trial should start, but Reuters reported that the agency had hoped to begin on July 10.

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