FDA un­veils 5 guid­ances on broad­en­ing can­cer clin­i­cal tri­al el­i­gi­bil­i­ty

As part of a push to trans­form clin­i­cal tri­al el­i­gi­bil­i­ty cri­te­ria that have been ac­cept­ed over time with­out a clear sci­en­tif­ic or clin­i­cal ra­tio­nale, the FDA on Tues­day pub­lished four draft guid­ance doc­u­ments on can­cer clin­i­cal tri­al el­i­gi­bil­i­ty cri­te­ria and one fi­nal guid­ance on in­clud­ing ado­les­cents in adult on­col­o­gy tri­als.

The four drafts, de­vel­oped by the FDA with in­put from the Amer­i­can So­ci­ety of Clin­i­cal On­col­o­gy and Friends of Can­cer Re­search, fo­cus on min­i­mum age for pe­di­atric pa­tients; pa­tients with HIV, he­pati­tis B or C virus­es; pa­tients with or­gan dys­func­tion or pri­or or cur­rent ma­lig­nan­cies; and pa­tients with brain metas­tases.

“Over­ly re­stric­tive el­i­gi­bil­i­ty cri­te­ria may slow pa­tient ac­cru­al, lim­it pa­tients’ ac­cess to clin­i­cal tri­als and lead to tri­al re­sults that don’t ful­ly rep­re­sent treat­ment ef­fects in the pa­tient pop­u­la­tion that will ul­ti­mate­ly re­ceive the drug,” FDA Com­mis­sion­er Scott Got­tlieb said, not­ing how the draft guid­ances of­fer new rec­om­men­da­tions for broad­en­ing can­cer tri­al el­i­gi­bil­i­ty cri­te­ria.

Min­i­mum Age for Pe­di­atric Pa­tients

This sev­en-page draft guid­ance ex­plains how spon­sors seek­ing to in­clude pe­di­atric pa­tient pop­u­la­tions in adult can­cer tri­als should eval­u­ate pe­di­atric for­mu­la­tions, tak­ing in­to ac­count the age, size, phys­i­o­log­ic con­di­tion and the treat­ment needs of pe­di­atric pa­tients.

The draft notes the types of ev­i­dence that could sup­port in­clu­sion of pa­tients from two years of age to un­der age twelve, clar­i­fy­ing that chil­dren un­der the age of two “may be par­tic­u­lar­ly vul­ner­a­ble to ex­pect­ed and unan­tic­i­pat­ed tox­i­c­i­ty due to de­vel­op­men­tal con­cerns and age-de­pen­dent mat­u­ra­tion of meta­bol­ic en­zyme sys­tems and or­gan func­tion, chil­dren < 2 years should not be in­clud­ed in adult can­cer tri­als. In rare in­stances, in­fants be­yond the neona­tal pe­ri­od may be ap­pro­pri­ate can­di­dates for se­lect new drugs. How­ev­er, en­roll­ment of chil­dren < 2 years of age is best re­served for ex­cep­tion­al cas­es and on­ly af­ter con­sul­ta­tion with the FDA.”

In ad­di­tion, the draft fea­tures po­ten­tial ways to in­clude pe­di­atric pa­tients in ear­ly phase tri­als af­ter a suf­fi­cient num­ber of adult pa­tients have been eval­u­at­ed to pro­vide ad­e­quate safe­ty and tox­i­c­i­ty da­ta.

For late-phase tri­als, the draft says: “The min­i­mum age of el­i­gi­bil­i­ty spec­i­fied in late-phase tri­als should be tai­lored to the bi­ol­o­gy of the dis­ease un­der study, the sci­en­tif­ic ob­jec­tives of the tri­al, and the ex­ist­ing da­ta re­gard­ing the mech­a­nism of ac­tion and safe­ty pro­file of the drug.”

Pa­tients with HIV, He­pati­tis B Virus or He­pati­tis C Virus In­fec­tions

This eight-page draft guid­ance ex­plains how ex­pand­ing can­cer clin­i­cal tri­al el­i­gi­bil­i­ty to be more in­clu­sive of pa­tients with HIV, HBV, or HCV in­fec­tions “is jus­ti­fied in many cas­es, and may ac­cel­er­ate the de­vel­op­ment of ef­fec­tive ther­a­pies in can­cer pa­tients with these chron­ic in­fec­tions.”

The rec­om­men­da­tions in the draft for el­i­gi­bil­i­ty cri­te­ria for pa­tients with can­cer and con­cur­rent HIV in­fec­tion “are fo­cused on eval­u­a­tion of im­mune func­tion and HIV ther­a­py,” while the rec­om­men­da­tions for those “with can­cer who have ev­i­dence of chron­ic HBV or with cur­rent or his­to­ry of HCV are fo­cused on liv­er-re­lat­ed lab­o­ra­to­ries and HBV/HCV ther­a­py.”

Or­gan Dys­func­tion or Pri­or or Con­cur­rent Ma­lig­nan­cies

This six-page draft guid­ance fea­tures rec­om­men­da­tions for el­i­gi­bil­i­ty cri­te­ria for pa­tients with or­gan dys­func­tion in can­cer clin­i­cal tri­als, fo­cus­ing on re­nal func­tion, car­diac func­tion and he­pat­ic func­tion, in ad­di­tion to rec­om­men­da­tions for el­i­gi­bil­i­ty cri­te­ria for pa­tients with can­cer who have a his­to­ry of pri­or or con­cur­rent sec­ond pri­ma­ry ma­lig­nan­cies.

“By ex­clud­ing in­di­vid­u­als from can­cer clin­i­cal tri­als who have ma­jor or­gan dys­func­tion or pre­vi­ous or con­cur­rent can­cers, tri­al re­cruit­ment fa­vors younger pa­tients, which may not be ful­ly rep­re­sen­ta­tive of the pop­u­la­tion for whom the drug will be in­di­cat­ed,” the FDA ex­plains.

“For ex­am­ple, in ini­tial dose find­ing or pre­lim­i­nary ac­tiv­i­ty-es­ti­mat­ing or proof-of-con­cept stud­ies, pa­tients with a his­to­ry of pri­or or con­cur­rent sec­ond pri­ma­ry ma­lig­nan­cies should not be ex­clud­ed,” the draft says.

Brain Metas­tases

As about 70,000 pa­tients liv­ing with can­cer in the US are di­ag­nosed with brain metas­tases, this six-page draft guid­ance ex­plains how such pa­tients should be in­clud­ed in clin­i­cal tri­als to cre­ate a bet­ter un­der­stand­ing of the ef­fi­ca­cy and safe­ty pro­file of the in­ves­ti­ga­tion­al drug while main­tain­ing pa­tient safe­ty.

“The in­ci­dence of brain metas­tases is in­creas­ing in pa­tients with cer­tain ma­lig­nan­cies such as melanoma, lung can­cer, and breast can­cer. How­ev­er, pa­tients with brain metas­tases have his­tor­i­cal­ly been ex­clud­ed from clin­i­cal tri­als due to con­cerns of poor func­tion­al sta­tus, short­ened life ex­pectan­cy, or in­creased risk of tox­i­c­i­ty,” the guid­ance says.

It al­so ex­plains how pa­tients with can­cers that metas­ta­size to the brain should be in­clud­ed in ear­ly phase tri­als “ei­ther in sep­a­rate co­horts or in co­horts with planned sub­set analy­ses to as­sess pre­lim­i­nary ef­fi­ca­cy and tox­i­c­i­ty in pa­tients with brain metas­tases. In cas­es where there is a strong ra­tio­nale for ex­clu­sion, the ra­tio­nale should be de­scribed in the tri­al pro­to­col.”

In­clud­ing Ado­les­cent Pa­tients in Adult On­col­o­gy Clin­i­cal Tri­als

This four-page fi­nal guid­ance pro­vides rec­om­men­da­tions for the ap­pro­pri­ate in­clu­sion cri­te­ria, dos­ing and phar­ma­co­ki­net­ic (PK) eval­u­a­tions, safe­ty mon­i­tor­ing, and eth­i­cal re­quire­ments for en­rolling ado­les­cent pa­tients in adult on­col­o­gy tri­als.

The FDA says that ado­les­cents should on­ly be en­rolled in first-in-hu­man or dose-es­ca­la­tion tri­als af­ter ini­tial adult PK and tox­i­c­i­ty da­ta are ob­tained. The agency al­so says that ado­les­cent pa­tients should on­ly be en­rolled in ear­ly phase tri­als when they have re­lapsed or re­frac­to­ry can­cer, or a can­cer with no cu­ra­tive stan­dard treat­ment avail­able.

As far as changes be­tween the draft and fi­nal, the FDA said: “All the pub­lic com­ments re­ceived on the draft guid­ance have been con­sid­ered and the guid­ance has been re­vised as ap­pro­pri­ate.”


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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