FDA drafts guid­ance on seam­less clin­i­cal tri­als for can­cer drug de­vel­op­ers

The FDA on Fri­day re­leased draft guid­ance to help spon­sors de­sign and con­duct first in hu­man (FIH) clin­i­cal tri­als that speed the clin­i­cal de­vel­op­ment of can­cer drugs through mul­ti­ple ex­pan­sion co­hort study de­signs.

The guid­ance pro­vides the FDA’s thoughts on the char­ac­ter­is­tics of drugs and bi­o­log­ics ap­pro­pri­ate­ly suit­ed for such an ex­pe­dit­ed plan, in­for­ma­tion to in­clude in such in­ves­ti­ga­tion­al new drug (IND) ap­pli­ca­tion sub­mis­sions, when to in­ter­act with the FDA and safe­guards to pro­tect pa­tients en­rolled in FIH ex­pan­sion co­hort stud­ies.

FDA Com­mis­sion­er Scott Got­tlieb ex­plained how the draft guid­ance dis­cuss­es ways spon­sors can com­press the tra­di­tion­al three phas­es of tri­als in­to one con­tin­u­ous tri­al, called an ex­pan­sion co­hort tri­al. “A lot of the time and cost of clin­i­cal de­vel­op­ment is spent wait­ing in be­tween the start and end of the phas­es of tri­als. Ex­pan­sion co­hort tri­als can bring ef­fi­cien­cy to drug de­vel­op­ment, po­ten­tial­ly re­duc­ing de­vel­op­ment costs and time,” he said.

Back­ground

Phase I clin­i­cal tri­als, which are ex­pect­ed to in­clude be­tween 20 and 80 pa­tients, are de­signed to de­ter­mine the me­tab­o­lism and phar­ma­co­log­ic ac­tions of an in­ves­ti­ga­tion­al drug, the side ef­fects as­so­ci­at­ed with in­creased dos­es, and, if pos­si­ble, to gain ear­ly ev­i­dence of ef­fec­tive­ness, ac­cord­ing to the FDA.

FIH mul­ti­ple ex­pan­sion co­hort tri­als, de­fined as tri­als with a sin­gle pro­to­col with an ini­tial dose-es­ca­la­tion phase that al­so con­tains three or more ad­di­tion­al pa­tient co­horts with co­hort-spe­cif­ic ob­jec­tives, are in­tend­ed to ex­pe­dite de­vel­op­ment by pro­ceed­ing from ini­tial de­ter­mi­na­tion of a po­ten­tial­ly ef­fec­tive dose to in­di­vid­ual co­horts that have tri­al ob­jec­tives typ­i­cal of Phase II tri­als (i.e., to es­ti­mate an­ti-tu­mor ac­tiv­i­ty), the FDA says.

The ob­jec­tives of these ex­pan­sion co­horts can in­clude “as­sess­ment of an­ti-tu­mor ac­tiv­i­ty in a dis­ease-spe­cif­ic set­ting, as­sess­ment of a rea­son­ably safe dose in spe­cif­ic pop­u­la­tions (e.g., pe­di­atric or el­der­ly pa­tients or pa­tients with or­gan im­pair­ment), eval­u­a­tion of al­ter­na­tive dos­es or sched­ules, es­tab­lish­ment of dose and sched­ule for the in­ves­ti­ga­tion­al drug ad­min­is­tered with an­oth­er on­col­o­gy drug, or eval­u­a­tion of the pre­dic­tive val­ue of a po­ten­tial bio­mark­er,” the draft says.

But chal­lenges are to be ex­pect­ed be­cause of the na­ture of these tri­als.

“Be­cause of the rapid en­roll­ment and evolv­ing na­ture of the in­for­ma­tion ob­tained in these tri­als, large num­bers of pa­tients are ex­posed to drugs with un­known ef­fi­ca­cy and min­i­mal­ly char­ac­ter­ized tox­i­c­i­ty pro­files,” the FDA ex­plains. “To mit­i­gate such risks and to pro­tect pa­tients, it is im­per­a­tive that spon­sors es­tab­lish an in­fra­struc­ture to stream­line tri­al lo­gis­tics, fa­cil­i­tate da­ta col­lec­tion, and in­cor­po­rate plans to rapid­ly as­sess emerg­ing da­ta in re­al time and to dis­sem­i­nate in­ter­im re­sults to in­ves­ti­ga­tors, in­sti­tu­tion­al re­view boards (IRBs), and reg­u­la­tors.”

Chal­lenges

FIH mul­ti­ple ex­pan­sion co­hort stud­ies pose unique chal­lenges and risks, ac­cord­ing to the FDA, in­clud­ing ex­pos­ing pa­tients across mul­ti­ple, si­mul­ta­ne­ous­ly ac­cru­ing, co­horts to po­ten­tial­ly sub­op­ti­mal or tox­ic dos­es of an in­ves­ti­ga­tion­al drug or ex­pos­ing more pa­tients than re­quired to achieve cer­tain ob­jec­tives.

“In­ef­fi­cient drug de­vel­op­ment based on pos­si­bly missed in­ter­pre­ta­tion of pre­lim­i­nary tri­al” was al­so cit­ed as a po­ten­tial chal­lenge in the draft.

To en­sure such stud­ies are worth the added risk, the FDA says, “The pa­tient pop­u­la­tion should be lim­it­ed to pa­tients with se­ri­ous dis­eases for which no cu­ra­tive ther­a­pies are avail­able.”

The 14-page draft guid­ance al­so fea­tures sec­tions on con­sid­er­a­tions based on co­hort ob­jec­tives, sta­tis­ti­cal and safe­ty con­sid­er­a­tions, as well as pro­to­col con­tent and com­mu­ni­ca­tions and in­ter­ac­tions with the FDA.

“Spon­sors should re­quest a pre-IND meet­ing to dis­cuss their plans to con­duct an FIH mul­ti­ple ex­pan­sion co­hort tri­al,” the draft says.


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. 

Author

Zachary Brennan

managing editor, RAPS

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