Ques­tions pile up for No­var­tis as sen­a­tors call on FDA to take ac­tion

Why wait three months to tell the FDA about ma­nip­u­lat­ed da­ta? Why wait two months be­tween doc­u­ment­ing an ini­tial is­sue and open­ing a non­con­for­mance re­port (NCR)? And how harsh­ly will the FDA act?

These ques­tions and more are pil­ing up for No­var­tis, fol­low­ing last week’s an­nounce­ment that the FDA is in­ves­ti­gat­ing the com­pa­ny for ma­nip­u­lat­ing da­ta linked to its $2.1 mil­lion gene ther­a­py Zol­gens­ma (onasemno­gene abepar­vovec-xioi). In Eu­rope, reg­u­la­tors have al­ready pulled the gene ther­a­py’s ac­cel­er­at­ed as­sess­ment for a longer, stan­dard as­sess­ment.

There al­so seem to be dis­crep­an­cies be­tween what No­var­tis CEO Vas­ant Narasimhan has said and what the FDA has found. For in­stance, Narasimhan said in an in­vestor call that the com­pa­ny launched an in­ter­nal in­ves­ti­ga­tion in­to the da­ta ma­nip­u­la­tions as soon as it learned of them in mid-March be­fore launch­ing a “full tech­ni­cal qual­i­ty in­ves­ti­ga­tion” in May.

Wil­son Bryan

But the re­cent­ly re­leased FDA Form 483 said there is “no doc­u­men­ta­tion” as to why an NCR was not opened un­til 15 May when the ini­tial al­le­ga­tion is doc­u­ment­ed as hav­ing been re­port­ed on 14 March. FDA al­so said, “There is no doc­u­men­ta­tion in this NCR that an au­dit of all oth­er po­ten­tial­ly im­pact­ed da­ta, stud­ies, and re­ports was con­duct­ed or is planned to de­ter­mine if there was ev­i­dence of da­ta mis­man­age­ment or ma­nip­u­la­tion or a jus­ti­fi­ca­tion for not con­duct­ing or plan­ning such an au­dit.”

A Ju­ly mem­o­ran­dum from Wil­son Bryan, di­rec­tor of the FDA’s Of­fice of Tis­sues and Ad­vanced Ther­a­pies, al­so notes that this will not be re­solved in a quick man­ner and how the re­sults from the Phase III tri­al do not ap­pear to be im­pact­ed.

“A com­plete as­sess­ment of the im­pact of the da­ta ma­nip­u­la­tion will re­quire ad­di­tion­al in­ves­ti­ga­tion, dis­cus­sions both in­ter­nal­ly with­in CBER and with AveX­is, will prob­a­bly re­quire that AveX­is sub­mit and FDA re­view one or more BLA sup­ple­ments, and may take at least sev­er­al months,” Bryan wrote. “The da­ta ma­nip­u­la­tion seems like­ly to im­pact the in­ter­pre­ta­tion of the Phase 1 clin­i­cal tri­al re­sults, as well as the in­ter­pre­ta­tion of the re­sults of some, but not all, of the non­clin­i­cal stud­ies in the orig­i­nal BLA. At this time, the da­ta ma­nip­u­la­tion does not ap­pear to im­pact the in­ter­pre­ta­tion of the re­sults of the an­i­mal tox­i­col­o­gy stud­ies or the Phase 3 clin­i­cal tri­al.”

Five De­mo­c­ra­t­ic sen­a­tors (in­clud­ing pres­i­den­tial hope­fuls Bernie Sanders and Eliz­a­beth War­ren) pounced on the da­ta ma­nip­u­la­tion, say­ing this “scan­dal smacks of the phar­ma­ceu­ti­cal in­dus­try’s priv­i­lege and greed.” They al­so called on the FDA to hold No­var­tis’s AveX­is ac­count­able and they ques­tioned whether the FDA has plans to re-is­sue a fi­nal rule on fal­si­fied da­ta that the agency was plan­ning to with­draw this month.

AveX­is spokes­woman told Fo­cus: “We have and will con­tin­ue to work in close co­op­er­a­tion with the FDA to ap­pro­pri­ate­ly up­date our BLA sub­mis­sion and ad­dress any qual­i­ty gaps iden­ti­fied.”

And Zol­gens­ma aside, this is not the first time FDA has raised con­cerns about No­var­tis’s clin­i­cal tri­al op­er­a­tions in re­cent months.


RAPS: First pub­lished in Reg­u­la­to­ry Fo­cus™ by the Reg­u­la­to­ry Af­fairs Pro­fes­sion­als So­ci­ety, the largest glob­al or­ga­ni­za­tion of and for those in­volved with the reg­u­la­tion of health­care prod­ucts. Click here for more in­for­ma­tion.

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