FDA of­fi­cials: There was “no sci­en­tif­ic ba­sis” for Duchenne drug OK as Sarep­ta com­plained of “dire fi­nan­cial” con­di­tion

Janet Wood­cock

Two se­nior FDA of­fi­cials mount­ed a ve­he­ment as­sault on Janet Wood­cock’s de­ci­sion to push through an ap­proval of Sarep­ta’s Duchenne mus­cu­lar dy­s­tro­phy drug Ex­ondys 51. New doc­u­ments post­ed by the FDA, in­clud­ing a round of mem­os on the is­sue in Sep­tem­ber, warned FDA Com­mis­sion­er Robert Califf that he was al­low­ing an ap­proval even though Wood­cock had not con­sid­ered all the analy­sis they had done to un­der­score the com­pa­ny’s weak case, adding that there was no sci­en­tif­ic ba­sis to con­clude that the drug was rea­son­ably like­ly to ben­e­fit pa­tients.

The agency has al­ready post­ed some of the mem­os of­fered up in the lead-up to the ap­proval de­ci­sion, along with Califf’s de­ci­sion that he would de­fer to Wood­cock, who over­ruled the agency’s re­view­ers as well as Lu­ciano Bo­rio and El­lis Unger, the act­ing chief sci­en­tist and di­rec­tor of the Of­fice of Drug Eval­u­a­tion at the FDA. But these mem­os from Sep­tem­ber hit hard on their con­clu­sion that Wood­cock was de­vi­at­ing wide­ly from the agency’s stan­dards for an ap­proval in al­low­ing Ex­ondys 51 on the mar­ket af­ter the biotech had pro­vid­ed on­ly a “mere scin­til­la” of ev­i­dence of ef­fi­ca­cy.

Robert Califf

In a memo to Califf on Sep­tem­ber 14, Unger wrote that he had con­duct­ed an analy­sis of the ev­i­dence on dy­s­trophin pro­duc­tion, which Wood­cock did not take in­to con­sid­er­a­tion be­fore reach­ing her de­ci­sion:

I think it will be im­por­tant for the reg­u­la­to­ry record to re­flect that there was no sci­en­tif­ic ba­sis un­der­ly­ing the con­clu­sion of “rea­son­ably like­ly” in this case. This was sim­ply a judg­ment call by Dr. Wood­cock. (Dr. Wood­cock might have al­so tak­en the po­si­tion that, in this des­per­ate pa­tient pop­u­la­tion, any dy­s­trophin pro­duc­tion would suf­fice as a ba­sis for ac­cel­er­at­ed ap­proval, but she didn’t state this.)

In Unger’s opin­ion, the FDA al­so need­ed to more care­ful­ly con­sid­er the im­pact the de­ci­sion on eteplirsen would have on oth­er rare dis­ease drug ap­pli­ca­tions:

We all agree that each sit­u­a­tion must be eval­u­at­ed on its own mer­its; how­ev­er, I fail to see how DMD dif­fers in­trin­si­cal­ly from oth­er rare neu­ro­log­i­cal dis­eases, e.g., Alexan­der dis­ease, Cana­van dis­ease, Ear­ly in­fan­tile GM1 gan­gliosi­do­sis, Krabbe dis­ease, Metachro­mat­ic leukody­s­tro­phy, Nie­mann–Pick dis­ease, Pelizaeus–Merzbach­er dis­ease, Pompe dis­ease, Sand­hoff dis­ease, and X- linked adrenoleukody­s­tro­phy. Based on what you have writ­ten in your draft memo, it is not clear to me why a stan­dard of any in­crease in the sur­ro­gate end­point wouldn’t ap­ply for these dis­eases.

“Per­haps grant­i­ng ac­cel­er­at­ed ap­proval to drugs that show a mere scin­til­la of an ef­fect on a sur­ro­gate end­point rep­re­sents a stroke of bril­liance – one that will stim­u­late in­vest­ment in the de­vel­op­ment of drugs for these dis­or­ders. But in my opin­ion, this ap­proach should re­ceive broad­er pub­lic (and FDA) in­put be­fore be­ing im­ple­ment­ed.

Unger al­so not­ed:

Her (Wood­cock’s) is­suance of a de­ci­sion­al mem­o­ran­dum pri­or to care­ful con­sid­er­a­tion of my fi­nal re­view rep­re­sents a crit­i­cal de­vi­a­tion from pro­to­col….

Un­aware of my fi­nal con­clu­sions on this mat­ter, Dr. Wood­cock did not re­but the above rea­son­ing. As I not­ed (and the SDR Board ap­peared to agree), she pro­vid­ed no co­gent ra­tio­nale for her de­ci­sion that the bare­ly de­tectable amount of dy­s­trophin pro­duced is “rea­son­ably like­ly to pre­dict clin­i­cal ben­e­fit.

Calif, though, had al­ready made up his mind the day be­fore:

I have con­clud­ed that al­though I be­lieve that both views are ra­tio­nal and re­flect ex­tra­or­di­nary ded­i­ca­tion to the top­ic, there is no ba­sis up­on which I should over­rule Dr. Wood­cock’s de­ci­sion, and that ad­di­tion­al ex­ter­nal re­view is not in­di­cat­ed.

Lu­ciano Bo­ria, the act­ing chief sci­en­tist, al­so crit­i­cized Califf for fail­ing to grap­ple with the “mi­nus­cule” amount of da­ta that Sarep­ta had of­fered. In a memo dat­ed Sep­tem­ber 14, Bo­rio wrote Califf:

(Y)our draft de­ci­sion­al memo seems to down­play the sig­nif­i­cance of the very small amount of dy­s­trophin re­port­ed in the eteplirsen NDA (see, e.g., pages 4-5 of your draft de­ci­sion­al memo). In fact, your draft de­ci­sion­al memo nev­er once cites the 0.3% in­crease in dy­s­trophin pro­duc­tion shown by Study 301 (or the 0.93% de­tect­ed in Stud­ies 201/202). In­stead, your draft de­ci­sion­al memo at­trib­ut­es the sci­en­tif­ic dis­agree­ment to: (1) a lack of con­sen­sus on the ap­pro­pri­ate thresh­old for clin­i­cal ben­e­fit both with­in CDER and in the sci­en­tif­ic lit­er­a­ture, and (2) con­cerns re­gard­ing the cor­re­la­tion be­tween dy­s­trophin pro­duc­tion and clin­i­cal out­comes in Study 201/202. To me, the crux of the dis­agree­ment is not whether there is an ap­pro­pri­ate thresh­old, but whether such a minis­cule (sic) amount of dy­s­trophin is rea­son­ably like­ly to pre­dict clin­i­cal ben­e­fit. Your draft de­ci­sion­al memo does not ad­dress that is­sue. In my view, it is not suf­fi­cient to say that no thresh­old has been es­tab­lished and that, there­fore, any in­crease in dy­s­trophin pro­duc­tion is rea­son­ably like­ly to pre­dict clin­i­cal ben­e­fit.

In the months ahead of the show­down in­side the FDA, reg­u­la­tors re­peat­ed­ly ex­pressed their will­ing­ness to help speed the work they asked for to pro­vide ad­di­tion­al ev­i­dence of dy­s­trophin pro­duc­tion, which pro­voked Sarep­ta’s Shamim Ruff, their head of reg­u­la­to­ry af­fairs, to fret about the “dire fi­nan­cial con­straints” the com­pa­ny was forced to deal with as a re­sult of the de­lays at the FDA.

“We must start the process by June 6, 2016,” Ruff wrote.”There is no room for flex­i­bil­i­ty with this date due to our dire fi­nan­cial con­straints as a re­sult of the on­go­ing de­lays.”

Here’s a look at all the doc­u­ments re­leased by the FDA:

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Paul Biondi (File photo)

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Arie Belldegrun at UKBIO 2019. Shai Dolev for Endpoints News

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