A half-dozen bio­phar­ma com­pa­nies are seek­ing fur­ther clar­i­ty from the FDA re­gard­ing draft guid­ance from Au­gust on us­ing a place­bo in cer­tain on­col­o­gy tri­als.

The draft fea­tures the FDA’s thoughts on the eth­i­cal chal­lenges of us­ing a place­bo in ran­dom­ized con­trolled clin­i­cal tri­als for ther­a­pies to treat hema­to­log­ic ma­lig­nan­cy and on­co­log­ic dis­ease. The draft al­so dis­cuss­es blind­ing and un­blind­ing, pa­tient re­port­ed out­comes (PROs) and prac­ti­cal and eth­i­cal con­cerns.

Com­ments

Roche’s Genen­tech said that it be­lieves the draft could be “fur­ther re­fined to ful­ly re­flect” the FDA’s in­creased recog­ni­tion of the val­ue of pa­tient in­put re­gard­ing their ex­pe­ri­ences with dis­ease and treat­ment.

“We urge the Agency to clar­i­fy that, al­though col­lec­tion of PROs from pa­tients blind­ed to treat­ment may be pre­ferred to re­move the risk of as­ses­sor bias, there are in­her­ent dif­fi­cul­ties in on­col­o­gy and hema­tol­ogy set­tings to de­sign tri­als as dou­ble-blind­ed stud­ies. For in­stance, when treat­ments are be­ing com­pared to ac­tive en­ti­ties with dif­fer­ing sched­ules or routes of ad­min­is­tra­tion, par­tic­u­lar­ly in­tra­venous (IV), ad­di­tion of place­bo is not eth­i­cal and blind­ing of the pa­tients not achiev­able.”

Mer­ck, mean­while, notes that the draft in­di­cates that a place­bo-con­trolled tri­al would be ap­pro­pri­ate in cir­cum­stances, such as where sur­veil­lance is stan­dard of care (SOC), or with cer­tain tri­al de­sign fea­tures, for ex­am­ple, if the tri­al us­es an add-on de­sign or when the end­point in­tend­ed to sup­port a la­bel­ing claim has a high de­gree of sub­jec­tiv­i­ty, such as with PROs. How­ev­er, Mer­ck cau­tions that the use of a place­bo con­trol “may raise prob­lems of ethics, ac­cept­abil­i­ty and fea­si­bil­i­ty in sub­se­quent tri­als or oth­er sce­nar­ios, and may not be ac­cept­able once some ben­e­fit has been shown.”

Mer­ck al­so says that it would be help­ful if the FDA could pro­vide ad­di­tion­al guid­ance on what a suit­able com­para­tor would be in sit­u­a­tions where there is no stan­dard of care (SOC) and a place­bo con­trol would be in­ap­pro­pri­ate.

“We al­so ask that FDA clar­i­fy when/which type of ex­ter­nal con­trols might be ad­e­quate to sub­stan­ti­ate the rel­e­vance of sin­gle-arm tri­al da­ta. For ex­am­ple, would re­al world ev­i­dence (RWE)-gen­er­at­ed his­tor­i­cal con­trols or mod­el-based meta-analy­ses of lit­er­a­ture be ac­cept­able, and in what sit­u­a­tions?” Mer­ck ques­tions.

Re­gen­eron al­so notes that the draft of­fers ad­vice on the im­pact of un­blind­ing on study de­sign, end­points and sta­tis­ti­cal analy­sis.

“Specif­i­cal­ly, if pa­tients are un­blind­ed and re­ceive al­ter­na­tive treat­ment up­on pro­gres­sion as sug­gest­ed in the draft guid­ance, eval­u­a­tion of over­all sur­vival (OS) may be con­found­ed by post-study treat­ments, and us­ing OS as a pri­ma­ry end­point may not be fea­si­ble. There­fore, we rec­om­mend that the Agency con­sid­er al­ter­na­tive pri­ma­ry end­points to sup­port reg­is­tra­tion for on­col­o­gy drugs and in­cor­po­rate these dis­cus­sions in the fi­nal ver­sion of this guid­ance,” Re­gen­eron said.

Bris­tol-My­ers Squibb, mean­while, said the draft is “a pos­i­tive step” in rec­om­mend­ing the use of place­bos in blind­ed ran­dom­ized con­trolled stud­ies for the treat­ment of hema­to­log­ic ma­lig­nan­cies and on­co­log­ic dis­eases, but the com­pa­ny called for the scope of the guid­ance to be re­fined to in­clude con­sid­er­a­tions for blind­ing in place­bo con­trol stud­ies on­ly.

“In cer­tain sec­tions of the pro­posed guid­ance, it is vague whether the rec­om­men­da­tions ap­ply to any blind­ed ran­dom­ized con­trolled study or just the ones that use place­bos,” B-MS says.

And As­traZeneca not­ed that the draft pro­vides guid­ance on the con­sid­er­a­tions for pa­tient and in­ves­ti­ga­tor blind­ing, but it does not ad­dress con­sid­er­a­tions for spon­sor-lev­el blind­ing of place­bo-con­trolled tri­als. “It would be help­ful if the Agency could pro­vide in­for­ma­tion to be con­sid­ered for main­te­nance of the spon­sor blind and/or un­blind­ing of the spon­sor,” the com­pa­ny says.

As pro­gres­sion-free sur­vival is a com­mon pri­ma­ry end­point in on­col­o­gy tri­als, As­traZeneca fur­ther says that the draft does not ad­dress con­cerns with bias in “some­what sub­jec­tive” end­points. “It would be help­ful for the FDA to pro­vide guid­ance on whether blind­ed cen­tral ad­ju­di­ca­tion is re­quired for end­points oth­er than over­all sur­vival,” the com­pa­ny adds.

Ab­b­Vie al­so sought more de­tail on the risks of un­blind­ing/run­ning open la­bel stud­ies, with de­scrip­tions on how po­ten­tial bi­as­es should be man­aged, “in­clud­ing how much bias is ac­cept­able.”

First pub­lished here. Reg­u­la­to­ry Fo­cus is the flag­ship on­line pub­li­ca­tion of the Reg­u­la­to­ry Af­fairs Pro­fes­sion­als So­ci­ety (RAPS), the largest glob­al or­ga­ni­za­tion of and for those in­volved with the reg­u­la­tion of health­care and re­lat­ed prod­ucts, in­clud­ing med­ical de­vices, phar­ma­ceu­ti­cals, bi­o­log­ics and nu­tri­tion­al prod­ucts. Email news@raps.org for more in­for­ma­tion.

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