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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About Avance Clinical

Avance Clinical is an Australian owned Contract Research Organisation that has been providing high-quality clinical research services to the local and international drug development industry for 20 years. They specialise in working with biotech companies to execute Phase 1 and Phase 2 clinical trials to deliver high-quality outcomes fit for global regulatory standards.

As oncology sponsors look internationally to speed-up trials after unprecedented COVID-19 suspensions and delays, Australia, which has led the world in minimizing the pandemic’s impact, stands out as an attractive destination for early phase trials. This in combination with the streamlined regulatory system and the financial benefits including a very favourable exchange rate and the R & D cash rebate makes Australia the perfect location for accelerating biotech clinical programs.

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