Robert Califf and Richard Pazdur speak at the annual Friends of Cancer Research event (Credit: Friends of Cancer Research via Twitter)

FDA lead­ers Califf and Paz­dur dish on ac­cel­er­at­ed ap­proval re­forms, sin­gle-coun­try tri­als and an emp­ty White Oak

FDA Com­mis­sion­er Rob Califf sat down for a con­ver­sa­tion on Thurs­day morn­ing with Rick Paz­dur, head of the FDA’s On­col­o­gy Cen­ter of Ex­cel­lence, with the two agree­ing that ac­cel­er­at­ed ap­proval re­forms need to hap­pen, that mul­ti-re­gion­al clin­i­cal tri­als are al­ways bet­ter than sin­gle-coun­try tri­als, and that re­turn­ing every last FDAer to the White Oak cam­pus doesn’t make sense.

The con­ver­sa­tion, con­duct­ed as part of the Friends of Can­cer Re­search’s an­nu­al meet­ing, be­gan with Califf’s ques­tions on the emp­ty space around White Oak as rou­tine staff have most­ly moved their op­er­a­tions to the more ver­sa­tile vir­tu­al set­ting, and as ad­vi­so­ry com­mit­tee and all in­dus­try meet­ings re­main vir­tu­al.

Paz­dur even went so far as to call White Oak “de­sert­ed,” not­ing that “there are more se­cu­ri­ty guards than em­ploy­ees.” But he al­so made clear that it doesn’t make sense to re­quire every­one to re­turn to an in-per­son of­fice.

“What is the pur­pose of go­ing back? To make an ad­min­is­tra­tor hap­py?” Paz­dur asked rhetor­i­cal­ly, say­ing that the clock-punch­ing men­tal­i­ty of years past needs to be rethought giv­en the work­load and work­force.

Califf not­ed that in­dus­try has been “loud and clear” about want­i­ng to re­turn to in-per­son meet­ings, but a more hy­brid en­vi­ron­ment may be what the FDA set­tles on mov­ing for­ward to re­main ag­ile.

On the top­ic of ac­cel­er­at­ed ap­proval re­forms, which De­moc­rats ini­tial­ly sought to in­clude in the user fee leg­is­la­tion but may end up deal­ing with in this lame duck ses­sion, Paz­dur re­it­er­at­ed what he wrote in the New Eng­land Jour­nal of Med­i­cine in Sep­tem­ber about clean­ing up the con­fir­ma­to­ry tri­al process.

“There’s a pe­ri­od of vul­ner­a­bil­i­ty we have to con­trol,” Paz­dur told Califf, not­ing that from ac­cel­er­at­ed ap­proval an­nounce­ment to con­fir­ma­tion of clin­i­cal ben­e­fit, “we should try to re­duce that pe­ri­od as much as pos­si­ble.”

For on­col­o­gy in­di­ca­tions that have been grant­ed AAs, the me­di­an time to be­gin­ning the with­draw­al process “was longer if the con­fir­ma­to­ry tri­al was ini­ti­at­ed af­ter the ap­proval,” Paz­dur and OCE lead­ers wrote in the NE­JM. “This dif­fer­ence was most strik­ing among with­drawn in­di­ca­tions, with a me­di­an time to with­draw­al of 3.8 years if the con­fir­ma­to­ry tri­al was on­go­ing at the time of AA, as com­pared with 7.3 years if such a tri­al had not been ini­ti­at­ed. De­layed with­drawals in this lat­ter sce­nario rep­re­sent the great­est risk to pa­tients.”

Paz­dur al­so told the con­fer­ence and Califf that larg­er com­pa­nies are large­ly ad­her­ing to the FDA’s re­quests when it comes to with­draw­ing AAs, “but we get in­to trou­ble with a com­pa­ny that may not be ad­e­quate­ly cap­i­tal­ized,” not­ing the sys­tem needs to be more nim­ble and sug­ges­tions float­ed in Con­gress on var­i­ous ways to ex­pe­dite the re­moval of these drugs, or even dif­fer­en­tial charg­ing for drugs un­der AA com­pared to prices for full ap­provals.

“When I came to the agency in 1999, I re­al­ized this was a prob­lem and with your pre­de­ces­sor, I sug­gest­ed that drugs un­der ac­cel­er­at­ed ap­proval not be con­sid­ered avail­able ther­a­py and my rea­son for that was that this would make com­pa­nies want to do these stud­ies as quick­ly as pos­si­ble. Un­for­tu­nate­ly that didn’t work,” Paz­dur said.

While not­ing that he al­so high­ly val­ues the AA path­way, Califf added that “we need more teeth,” par­tic­u­lar­ly on get­ting those con­fir­ma­to­ry tri­als start­ed pri­or to the ap­proval. “Once the ap­proval oc­curs, it’s very hard to hold back mar­ke­teers,” Califf added.

On the ques­tion of sin­gle-coun­try tri­als, fol­low­ing FDA’s re­jec­tion of Eli Lil­ly’s at­tempt to bring an­oth­er PD-1 can­cer drug with Chi­na-on­ly da­ta to the US mar­ket, Paz­dur made clear that the FDA fa­vors mul­ti-re­gion­al tri­als.

“We’re not sug­gest­ing  that all clin­i­cal tri­als have to be done in the Unit­ed States or a per­cent­age has to be done in the Unit­ed States, but we want rep­re­sen­ta­tion of all of the ICH re­gions,” in­clud­ing North Amer­i­ca, Eu­rope and Asia, Paz­dur said.

He al­so not­ed that some­times com­pa­nies move tri­als out­side the US be­cause of cost is­sues, which “might be a rea­son­able is­sue,” but “one of my prob­lems” is when com­pa­nies will use sin­gle-coun­try tri­als be­cause they can test the in­ves­ti­ga­tion­al prod­uct against an in­fe­ri­or ther­a­py and that tri­al wouldn’t be eth­i­cal­ly run in the US. He added:

I think this is par­tic­u­lar­ly prob­lem­at­ic. One of the rea­son peo­ple go on clin­i­cal tri­als is to get the best ther­a­pies. There’s no as­ter­isk that says on­ly ap­proved in your coun­try. Peo­ple are go­ing to lose con­fi­dence in the sys­tem if they know tri­als are done with in­fe­ri­or treat­ments.

“These com­pa­nies are not Moth­er There­sa here, they’re us­ing pa­tients here, and we have to al­ways make sure pa­tients aren’t con­sid­ered com­modi­ties,” Paz­dur added.

Califf said there is a prob­lem of peo­ple leav­ing the US for treat­ment and tri­als, and Paz­dur not­ed that the US clin­i­cal tri­al ecosys­tem needs to be sim­pli­fied as pa­tient con­sent forms can still run 20 pages long.

On that note, OCE is launch­ing “Pro­ject Prag­mat­i­ca” along­side the Na­tion­al Can­cer In­sti­tute to sim­pli­fy cer­tain tri­als with drugs that have known safe­ty pro­files, and can an­swer ques­tions on over­all sur­vival more rapid­ly with a prag­mat­ic tri­al that pre­serves ran­dom­iza­tion.

Both Paz­dur and Califf agreed that the key here is ran­dom­iza­tion. “Ex­ter­nal con­trols have lim­i­ta­tions and the beau­ty of ran­dom­iza­tion re­al­ly is to take and ad­dress fac­tors we don’t know about,” Paz­dur said.

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Illustration: Assistant Editor Kathy Wong for Endpoints News

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