Se­nior FDA of­fi­cials warned that ap­prov­ing $300,000 Duchenne drug will low­er agency stan­dards

In the end, Sarep­ta did many things wrong when it came to de­vel­op­ing a new drug for Duchenne mus­cu­lar dy­s­tro­phy. But it got one very im­por­tant part right. The biotech, with the sup­port of a le­gion of ad­vo­cates in the pa­tient com­mu­ni­ty, won over Janet Wood­cock to their side ear­ly on.

The pow­er­ful CDER di­rec­tor pushed for an ap­proval even in the face of a heat­ed de­bate in­side the FDA, as se­nior of­fi­cials weighed in in op­po­si­tion to her stand. The act­ing chief sci­en­tist at the agency, Lu­ciana Bo­rio, ar­gued that an ap­proval would low­er the agency’s stan­dards and en­cour­age oth­er de­vel­op­ers to pur­sue the same kind of lob­by­ing cam­paigns em­ployed at Sarep­ta. And she ac­cused Sarep­ta of act­ing ir­re­spon­si­bly by know­ing­ly push­ing “mis­lead­ing” in­for­ma­tion about the drug. El­lis Unger, di­rec­tor of the of­fice of drug eval­u­a­tion, scoffed at the da­ta Sarep­ta of­fered, call­ing the drug a “sci­en­tif­i­cal­ly el­e­gant place­bo.”

But FDA Com­mis­sion­er Robert Califf re­fused to over­rule Wood­cock’s de­ci­sion to OK eteplirsen, de­spite shar­ing some of the ma­jor ob­jec­tions raised by of­fi­cials who op­posed putting this drug on the mar­ket at Sarep­ta’s price of $300,000 a year.

Califf’s sum­ma­ry re­view of the ex­tra­or­di­nary show­down over eteplirsen point to prob­lems that would have eas­i­ly killed prac­ti­cal­ly any oth­er mar­ket­ing ap­pli­ca­tion. But with the cen­ter di­rec­tor tak­ing a pas­sion­ate stand in fa­vor of the drug, the com­mis­sion­er says he de­cid­ed that he would de­fer to Wood­cock in view of his lack of tech­ni­cal ex­per­tise in the mat­ter and a suf­fi­cient record of ev­i­dence to war­rant its move in­to the mar­ket.

Both Unger and Bo­rio op­posed Wood­cock’s de­ci­sion to grant an ac­cel­er­at­ed ap­proval for eteplirsen, ac­cord­ing to the Sep­tem­ber 16 memo from Califf as well as their own mem­os. Califf set out to de­ter­mine if the FDA was sig­nif­i­cant­ly low­er­ing the bar for an ap­proval, but ul­ti­mate­ly de­cid­ed that Wood­cock was pur­su­ing a well es­tab­lished track record for be­ing will­ing to take tough, eth­i­cal stands in­side the agency, rather than buck­ling to a lob­by­ing cam­paign.

Ac­cord­ing to Bo­rio, who says that Wood­cock was lean­ing to­ward an OK in 2014, an ap­proval of this flawed ap­pli­ca­tion may set a dan­ger­ous prece­dent that will en­cour­age des­per­ate pa­tients to mount a fu­ri­ous as­sault in fa­vor of oth­er drug ap­provals. Her po­si­tion, out­lined in the memo:

Grant­i­ng ac­cel­er­at­ed ap­proval here on the ba­sis of the da­ta sub­mit­ted could make mat­ters worse for pa­tients with no ex­ist­ing mean­ing­ful ther­a­pies — both by dis­cour­ag­ing oth­ers from de­vel­op­ing ef­fec­tive ther­a­pies for DMD and by en­cour­ag­ing oth­er de­vel­op­ers to seek ap­proval for se­ri­ous con­di­tions be­fore they have in­vest­ed the time and re­search nec­es­sary to es­tab­lish whether a prod­uct is like­ly to con­fer clin­i­cal ben­e­fit. If we were to ap­prove eteplirsen with­out sub­stan­tial ev­i­dence of ef­fec­tive­ness, or on the ba­sis of a sur­ro­gate end­point with a triv­ial treat­ment ef­fect, we would quick­ly find our­selves in the po­si­tion of hav­ing to ap­prove a myr­i­ad of in­ef­fec­tive treat­ments for groups of des­per­ate pa­tients.

Unger, who warned that the safe­ty pro­file of eteplirsen is not yet known and that pa­tients tak­ing the drug could die from treat­ment, was scathing in his as­sess­ment of the ther­a­py.

By al­low­ing the mar­ket­ing of an in­ef­fec­tive drug, es­sen­tial­ly a sci­en­tif­i­cal­ly el­e­gant place­bo, thou­sands of pa­tients and their fam­i­lies would be giv­en false hope in ex­change for hard­ship and risk. I ar­gue that this would be un­eth­i­cal and coun­ter­pro­duc­tive. There could al­so be sig­nif­i­cant and un­jus­ti­fied fi­nan­cial costs – if not to pa­tients, to so­ci­ety.

And the re­view doc­u­ments in­clud­ed Wood­cock’s ex­tra­or­di­nary ar­gu­ment that Sarep­ta need­ed an ac­cel­er­at­ed ap­proval to help its stock price, so it could fund ad­di­tion­al work.

She opined that Sarep­ta in par­tic­u­lar “need­ed to be cap­i­tal­ized.” She not­ed that the spon­sor’s stock went down af­ter the AC meet­ing and went up af­ter FDA sent the June 3, 2016 let­ter. Dr. Wood­cock cau­tioned that, if Sarep­ta did not re­ceive ac­cel­er­at­ed ap­proval for eteplirsen, it would have in­suf­fi­cient fund­ing to con­tin­ue to study eteplirsen and the oth­er sim­i­lar drugs in its pipeline. She stat­ed that, with­out an ap­proval in cas­es such as eteplirsen, pa­tients would aban­don all hope of ap­proval for these types of prod­ucts and would “lapse in­to a po­si­tion of” self-treat­ment.

Sig­nif­i­cant de­fi­cien­cies in the eteplirsen pro­gram, says Califf, in­clude a con­sen­sus that “the poor qual­i­ty of many of the biop­sies and the fail­ure of the spon­sor to im­ple­ment a high-qual­i­ty pro­ce­dure for as­say val­i­da­tion” made it im­pos­si­ble to con­sid­er much of the da­ta in the ap­pli­ca­tion. They all agreed that the drug pro­duced lev­els of dy­s­trophin that were “small com­pared with ex­pec­ta­tions at the out­set of tri­als in hu­mans.”

Sarep­ta “tout­ed” a study that used un­re­li­able mea­sures of the as­say, lead­ing the com­pa­ny to over­state pro­tein ex­pres­sion in fol­low-up biop­sies. That study was de­bunked by FDA ex­perts, Califf says, and should be cor­rect­ed or re­tract­ed. Bo­rio was much more crit­i­cal of Sarep­ta. Her memo states:

I would be re­miss if I did not note that the spon­sor has ex­hib­it­ed se­ri­ous ir­re­spon­si­bil­i­ty by play­ing a role in pub­lish­ing and pro­mot­ing se­lec­tive da­ta dur­ing the de­vel­op­ment of this prod­uct. Not on­ly was there a mis­lead­ing pub­lished ar­ti­cle with re­spect to the re­sults of Study 201/202147 –which has nev­er been re­tract­ed—but Sarep­ta al­so is­sued a press re­lease re­ly­ing on the mis­lead­ing ar­ti­cle and its find­ings.

There is a dis­tinct pos­si­bil­i­ty, the FDA feels, that in­creas­ing the dose would pro­vide enough dy­s­trophin ex­pres­sion, the key bio­mark­er for this dis­ease, to make it work as hoped. But it’s on­ly been test­ed in an­i­mals, nev­er in hu­mans — at least not yet.

And if Sarep­ta had done what the FDA was telling the com­pa­ny to do, says Califf, then they would prob­a­bly al­ready have enough com­pelling da­ta in hand to make a de­ci­sion based on the mer­its of the drug.

Wood­cock ac­tu­al­ly de­cid­ed in fa­vor of an ap­proval on May 4, af­ter tak­ing an “ex­ten­sive and ear­ly in­volve­ment” on the drug, which raised con­cerns about in­ter­fer­ence with “the in­tegri­ty of sci­en­tif­ic re­views” at low­er lev­els in the FDA. Wood­cock com­plet­ed her fi­nal mem­o­ran­dum be­fore Unger had had a chance to com­plete his own.

Once she de­ter­mined her po­si­tion, Wood­cock nev­er budged. Ul­ti­mate­ly, that was enough. What­ev­er else hap­pens, Wood­cock was proved right about Sarep­ta’s stock price. Shares are up 86% in mid-af­ter­noon trad­ing. In a call with an­a­lysts Mon­day af­ter­noon, com­pa­ny of­fi­cials say they will file for an ear­ly ap­proval in Eu­rope be­fore the end of this year.

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