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.

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.

NYU surgeon transplants an engineered pig kidney into the outside of a brain-dead patient (Joe Carrotta/NYU Langone Health)

No, sci­en­tists are not any clos­er to pig-to-hu­man trans­plants than they were last week

Steve Holtzman was awoken by a 1 a.m. call from a doctor at Duke University asking if he could put some pigs on a plane and fly them from Ohio to North Carolina that day. A motorcyclist had gotten into a horrific crash, the doctor explained. He believed the pigs’ livers, sutured onto the patient’s skin like an external filter, might be able to tide the young man over until a donor liver became available.

UP­DAT­ED: Agenus calls out FDA for play­ing fa­vorites with Mer­ck, pulls cer­vi­cal can­cer BLA at agen­cy's re­quest

While criticizing the FDA for what may be some favoritism towards Merck, Agenus on Friday officially pulled its accelerated BLA for its anti-PD-1 inhibitor balstilimab as a potential second-line treatment for cervical cancer because of the recent full approval for Merck’s Keytruda in the same indication.

The company said the BLA, which was due for an FDA decision by Dec. 16, was withdrawn “when the window for accelerated approval of balstilimab closed,” thanks to the conversion of Keytruda’s accelerated approval to a full approval four months prior to its PDUFA date.

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Marty Duvall, Oncopeptides CEO

On­copep­tides stock craters as it pulls can­cer drug Pepax­to from the mar­ket

Shares of Oncopeptides crashed more than 70% in early Friday trading after the company said it’s pulling its multiple myeloma drug Pepaxto (melphalan flufenamide) from the US market after failing a confirmatory trial. The move will force the company to close its US and EU business units and enact significant layoffs.

The FDA had scheduled an adcomm meeting next Thursday to discuss Pepaxto, which first won accelerated approval in February and costs about $19,000 per course of treatment. The committee was to weigh in on whether the confirmatory trial demonstrated a worse overall survival in the treatment arm compared to the control arm.

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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 are 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 are 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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David Livingston (Credit: Michael Sazel for CeMM)

Renowned Dana-Far­ber sci­en­tist, men­tor and bio­phar­ma ad­vi­sor David Liv­ingston has died

David Livingston, the Dana-Farber/Harvard Med scientist who helped shine a light on some of the key molecular drivers of breast and ovarian cancer, died unexpectedly last Sunday.

One of the senior leaders at Dana-Farber during his nearly half century of work there, Livingston was credited with shedding light on the genes that regulate cell growth, with insights into inherited BRCA1 and BRCA2 mutations that helped lay the scientific foundation for targeted therapies and earlier detection that have transformed the field.

Pfiz­er pitch­es its Covid-19 vac­cine for younger chil­dren ahead of ad­comm next week

Pfizer will present its case to the FDA’s vaccine adcomm next week, seeking authorization for a lower-dose version of its Covid-19 vaccine for kids ages 5 through 12, which the Biden administration said will likely begin rolling out early next month.

Two primary doses of the 10 µg vaccine (the dose for those ages 12 and up is 30 μg) given 3 weeks apart in this group of children “have shown a favorable safety and tolerability profile, robust immune responses against all variants of concern including Delta, and vaccine efficacy of 90.7% against laboratory-confirmed symptomatic COVID-19,” the company said in briefing documents ahead of next Tuesday’s meeting of the FDA’s Vaccines and Related Biological Products Advisory Committee.

David Sabatini (MIT)

For­mer MIT sci­en­tist David Saba­ti­ni fires back at ac­cuser, White­head In­sti­tute for 'false' ha­rass­ment al­le­ga­tions

David Sabatini, the prominent biotech founder who was ousted by the Whitehead Institute and the Howard Hughes Medical Institute this summer over sexual harassment allegations, has filed a lawsuit claiming he was falsely accused by a “former lover” looking to “exact revenge.”

In court documents filed Wednesday, Sabatini claimed he had a consensual sexual relationship with a fellow at the Whitehead Institute, which was “effectively over” by 2019. The suit, which refers to Sabatini as a “brilliant” and “world renowned” scientist, was filed against his accuser, the Whitehead Institute, and director Ruth Lehmann.

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Jay Flatley, new Zymergen CEO

Fol­low­ing Au­gust melt­down, Zymer­gen hints at sal­vage plans — cut­ting jobs and rene­go­ti­at­ing loans

Two months after a spectacular implosion that saw its founding CEO leave his post amid customer reports its only product didn’t work, Zymergen provided the first peek behind the curtain for its plans moving forward.

In an SEC filing Wednesday, Zymergen told regulators it would slash about 100 jobs and had renegotiated a $100 million loan from Perceptive that loomed like a storm cloud over the company, moving up the maturity date 18 months to June 30, 2022. Jed Dean, one of Zymergen’s three co-founders and VP of operations, will also step down at the end of the month.

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