In a live­ly and some­times con­tentious hear­ing, the FDA’s On­co­log­ic Drugs Ad­vi­so­ry Com­mit­tee (ODAC) near­ly unan­i­mous­ly rec­om­mend­ed against ap­prov­ing Eli Lil­ly and In­novent’s an­ti-PD-1 an­ti­body sin­til­imab, deal­ing a blow to “me-too” can­cer drug­mak­ers hop­ing to reach the mar­ket based sole­ly on da­ta from Chi­na.

But the pan­el’s con­cerns were large­ly over­shad­owed by FDA of­fi­cials tear­ing in­to Lil­ly over not mak­ing good on its promis­es to in­crease tri­al di­ver­si­ty, sub­mit­ting the ap­pli­ca­tion with­out con­sult­ing reg­u­la­tors be­fore the tri­al con­clud­ed and mis­rep­re­sent­ing in­ter­ac­tions with the agency dur­ing its pre­sen­ta­tion.

The top two FDA reps at the hear­ing, on­col­o­gy chief Richard Paz­dur and Di­rec­tor Di­vi­sion of On­col­o­gy 2 Harpreet Singh, both said the study did not meet “good clin­i­cal prac­tice” stan­dards and suf­fered da­ta in­tegri­ty is­sues. They both asked re­peat­ed­ly whether there were any in­stances of fraud­u­lent da­ta re­port­ing, giv­en how a 2016 in­ves­ti­ga­tion found about 80% of da­ta from tri­als con­duct­ed in Chi­na are coun­ter­feit.

In the wake of the news, Lil­ly is­sued a some­what apolo­getic state­ment to End­points News, which read in full:

While we are dis­ap­point­ed with the out­come of to­day’s ODAC as it re­lates to the in­ves­ti­ga­tion­al prod­uct sin­til­imab, we ap­pre­ci­at­ed the op­por­tu­ni­ty to pub­licly dis­cuss the ap­pli­ca­tion and broad­er is­sues re­lat­ed to sin­gle-coun­try clin­i­cal tri­als. We had hoped that sin­til­imab could have played a pos­i­tive role for pa­tients and the U.S. health­care sys­tem through an ag­gres­sive pric­ing strat­e­gy. We ac­knowl­edge that the land­scape has changed dra­mat­i­cal­ly on a num­ber of fronts since the ORI­ENT-11 study was con­duct­ed and the sin­til­imab ap­pli­ca­tion was ini­ti­at­ed. Lil­ly whole­heart­ed­ly agrees with the im­por­tance of ethics in clin­i­cal tri­al con­duct and clin­i­cal tri­al di­ver­si­ty. We have long-stand­ing ini­tia­tives in place to ad­vance di­ver­si­ty and in­clu­sion in Lil­ly-con­duct­ed clin­i­cal tri­als. Along with In­novent, we will con­tin­ue to work with the FDA as it com­pletes its re­view of the sin­til­imab ap­pli­ca­tion.

Lil­ly re­mains com­mit­ted to bring­ing for­ward med­i­cines with the po­ten­tial to mean­ing­ful­ly im­prove treat­ment par­a­digms for pa­tients with can­cer.

Ear­li­er Thurs­day, the pan­elists were os­ten­si­bly sup­posed to dis­cuss whether or not Lil­ly’s tri­al, dubbed ORI­ENT-11, could be ap­plic­a­ble and gen­er­al­iz­able to the US pop­u­la­tion. ORI­ENT-11 was con­duct­ed en­tire­ly in Chi­na, rais­ing ques­tions at the FDA about if the pos­i­tive da­ta seen would re­main the same in a more het­ero­ge­neous set­ting.

Dis­cus­sion soon de­volved in­to a pub­lic flog­ging, how­ev­er, with Paz­dur and Singh tak­ing Lil­ly to task over not just the di­ver­si­ty is­sues, but the na­ture of the study it­self. Lil­ly and In­novent used pro­gres­sion-free sur­vival as their pri­ma­ry end­point, but most of the pre­vi­ous PD-1 drug stud­ies have nabbed ap­proval based on over­all sur­vival.

In ad­di­tion, while Lil­ly and In­novent were con­duct­ing the study, Paz­dur and Singh con­tend­ed that the stan­dard of care for non-small cell lung can­cer — the in­di­ca­tion in which Lil­ly is seek­ing ap­proval — changed to Mer­ck’s Keytru­da plus chemother­a­py. The reg­u­la­tors point­ed to one Keytru­da study in par­tic­u­lar, KEYNOTE-189, they said was par­a­digm-shift­ing in lung can­cer. Lil­ly and In­novent did not up­date their in­formed con­sent guid­ance to al­low pa­tients in the con­trol arm to take Keytru­da, with Singh ac­cus­ing the drug­mak­ers of pre­vent­ing pa­tients from get­ting the best avail­able drugs.

Harpreet Singh

Lil­ly, for its part, not­ed the ORI­ENT-11 tri­al was orig­i­nal­ly de­signed to ob­tain ap­proval in Chi­na. Once the com­pa­ny saw the da­ta, it ap­proached the FDA with the study, Lil­ly VP of gas­troin­testi­nal on­col­o­gy strat­e­gy David Fer­ry told the pan­el.

This, too, drew the ire of FDA of­fi­cials. In both its pre­sen­ta­tion to the com­mit­tee and while clar­i­fy­ing ques­tions for the pan­el mem­bers, reg­u­la­tors crit­i­cized Lil­ly for not con­sult­ing with the FDA at all un­til the study read out topline da­ta. Com­pet­ing nar­ra­tives emerged dur­ing the pre­sen­ta­tions about the time­line of the in­ter­ac­tions be­tween the two par­ties, with Lil­ly claim­ing it met three times be­fore sub­mit­ting its BLA.

Af­ter Singh cas­ti­gat­ed Lil­ly for mis­rep­re­sent­ing its con­ver­sa­tions with the FDA, she threat­ened to re­lease all pri­vate cor­re­spon­dences to the pub­lic. Singh said that some fed­er­al reg­u­la­tions may al­low for flex­i­bil­i­ty on for­eign da­ta in cer­tain in­stances, but on­ly when the FDA can val­i­date the da­ta through in­spec­tions and train­ing in­ves­ti­ga­tors.

“I find this in­cred­i­bly mis­lead­ing,” Singh said to Lil­ly at one point. “We used much stronger lan­guage in in­vok­ing the reg­u­la­tions, and would be hap­py to pro­vide all the in­fo in­to the pub­lic record.”

Com­pa­ny ex­ecs apol­o­gized mul­ti­ple times dur­ing the hear­ing, with one say­ing, “It’s cer­tain­ly not our in­tent to mis­char­ac­ter­ize our in­ter­ac­tions with the agency.”

Pan­elists vot­ed 14-1 that a new tri­al should be re­quired for ap­proval. Most of the pan­elists agreed more so that the da­ta and ORI­ENT-11 pro­to­col were not good enough to rec­om­mend an OK, but split over how to bet­ter de­sign an ap­pro­pri­ate study. Through­out the meet­ing, FDA vouched to be­gin in­clud­ing more Chi­nese da­ta in mul­ti-re­gion­al clin­i­cal stud­ies.

A pos­i­tive rec­om­men­da­tion — and po­ten­tial ap­proval — were like­ly to be dif­fi­cult for Lil­ly. Late last week, FDA on­col­o­gy chief Richard Paz­dur wrote in The Lancet that drug ap­pli­ca­tions seek­ing ap­proval based on da­ta from a “sin­gle for­eign coun­try” need to be rep­re­sen­ta­tive of the US pop­u­la­tion in or­der for reg­u­la­tors to be flex­i­ble (gen­er­al­ly, the FDA re­quires com­pa­nies to con­duct piv­otal stud­ies at least in part in the US).

Paz­dur’s ar­ti­cle proved to be an about-face from ear­li­er pub­lic com­ments made at a med­ical con­fer­ence in 2019 when, while re­count­ing a re­cent trip to Chi­na, he said the FDA would ac­cept ap­pli­ca­tions based sole­ly on Chi­nese da­ta. In an in­ter­view with STAT News on Tues­day, Paz­dur de­fend­ed the flip, de­clar­ing, “I have a right to change my mind.”

While dis­cussing the is­sues with the pan­elists, Paz­dur al­so took a step fur­ther, ad­dress­ing that for­mer AACR com­ments “should not be viewed as reg­u­la­to­ry pol­i­cy.” He al­so de­scribed how treat­ment land­scapes have changed in the last three years, both due to im­prove­ments in sur­vival da­ta and how the Covid-19 pan­dem­ic has changed the pub­lic’s de­sire for di­ver­si­ty in all as­pects of life.

“Sin­gle coun­try sub­mis­sions are a step back­ward in achiev­ing the racial di­ver­si­ty we need in the Unit­ed States,” Paz­dur said, “and we want peo­ple to un­der­stand this is a ma­jor goal not just in on­col­o­gy sub­mis­sions but through­out all sub­mis­sions at the FDA.”

Lil­ly is un­like­ly to be the on­ly com­pa­ny af­fect­ed by this rul­ing, as sev­er­al oth­ers are at­tempt­ing to get drugs on the Amer­i­can mar­ket through Chi­nese-on­ly da­ta. Paz­dur said in his Lancet ar­ti­cle — and the FDA said in its pre­sen­ta­tion — that there are about 25 such ap­pli­ca­tions ei­ther un­der re­view, planned to be sub­mit­ted or cur­rent­ly un­der de­vel­op­ment.

Most no­tably, the biotech EQRx is de­vel­op­ing a large suite of drugs in-li­censed from Chi­nese com­pa­nies with the goal of dis­rupt­ing pric­ing mod­els in the US. One of its two lead pro­grams is an an­ti-PD-L1 an­ti­body, known as sug­e­mal­imab, which EQRx has said it could price at a 40% to 50% dis­count.

Lil­ly had at­tempt­ed a sim­i­lar price dis­rup­tion strat­e­gy, with on­col­o­gy head Ja­cob Van Naar­den say­ing Wednes­day the com­pa­ny had plans to dis­count the drug by as much as 40% com­pared to oth­er PD-1s on the mar­ket. So far, each of the sev­en an­ti-PD-1 and an­ti-PD-L1 drugs ap­proved by the FDA has been priced the same at $150,000 per year.

But the FDA does not take pric­ing in­to ac­count when re­view­ing drugs, a point ham­mered re­peat­ed­ly in Paz­dur’s 2019 com­ments, his Lancet ar­ti­cle and the FDA pre­sen­ta­tion Thurs­day. Reg­u­la­tors told pan­elists that all dis­cus­sion of pric­ing would not be al­lowed.

David Fredrick­son

Even be­fore ODAC made its rec­om­men­da­tion and the FDA had thor­ough­ly tongue-lashed Lil­ly and In­novent, the ram­i­fi­ca­tions of the po­ten­tial “no” vote were be­ing felt in the in­dus­try. Dur­ing As­traZeneca’s fourth-quar­ter and FY2021 earn­ings call ear­li­er Thurs­day, ex­ec­u­tive VP of on­col­o­gy David Fredrick­son said he feels more con­fi­dent now about the com­pa­ny’s Tagris­so fran­chise, es­sen­tial­ly telling Lil­ly, “I told you so.”

Un­like sin­til­imab, Tagris­so is an EGFR-TKI in­hibitor ap­proved for EGFR-mu­tat­ed NSCLC in the first-line set­ting.

“I’ve been fair­ly con­sis­tent­ly want­i­ng to raise the fact that Chi­na-on­ly stud­ies that don’t have over­all sur­vival, and that com­pare against an old stan­dard of care, bring with them some reg­u­la­to­ry risks,” he said, adding lat­er, “I do think that cer­tain­ly, the ODAC from to­day, the brief­ing doc­u­ments do give me more con­fi­dence that there is reg­u­la­to­ry hur­dles in front of the com­pe­ti­tion that’s seek­ing to come in from some of the com­peti­tors that we’ve seen.”

CEO Pas­cal So­ri­ot piled on, not­ing, “I’m not sure that de­clar­ing a price be­fore an ODAC is a good strat­e­gy.”

This ar­ti­cle has been up­dat­ed to in­clude com­ment from Eli Lil­ly as well as ad­di­tion­al con­text on the land­scape of Chi­nese-on­ly da­ta, in­clud­ing com­ments from As­traZeneca ex­ec­u­tives David Fredrick­son and Pas­cal So­ri­ot. 

It was great getting back to a live ESMO conference/webinar in Paris followed by a live pop-up event for the Endpoints 11 in Boston. We’re staying on the road in October with our return for a live/streaming EUBIO22 in London.

Silicon Valley Bank’s Nooman Haque and I are once again jumping back into the thick of it with a slate of virtual and live events on October 12. I’ll get the ball rolling with a virtual fireside chat with Novo Nordisk R&D chief Marcus Schindler, covering their pipeline plans and BD work.