FDA drafts rec­om­men­da­tions for study­ing can­cer drugs in pa­tients with CNS metas­tases

The FDA on Wednes­day is­sued draft guid­ance pro­vid­ing rec­om­men­da­tions to drug­mak­ers on eval­u­at­ing can­cer drugs in pa­tients with cen­tral ner­vous sys­tem (CNS) metas­tases. FDA says the guid­ance is meant to in­form clin­i­cal tri­al de­signs to sup­port prod­uct la­bel­ing that de­scribes an­ti­tu­mor ac­tiv­i­ty of drugs or bi­o­log­ics in pa­tients with CNS metas­tases from sol­id tu­mors orig­i­nat­ing in oth­er parts of the body.

Richard Paz­dur

“There are few ef­fec­tive treat­ments for pa­tients with cen­tral ner­vous sys­tem (CNS) metas­tases — a type of can­cer that has spread from the orig­i­nal tu­mor to the CNS and is as­so­ci­at­ed with a high­er risk of death. In ad­di­tion, there are al­so few clin­i­cal tri­als test­ing ther­a­pies for CNS metas­tases. More at­ten­tion is war­rant­ed to ad­dress this un­met med­ical need,” said Richard Paz­dur, di­rec­tor of FDA’s On­col­o­gy Cen­ter of Ex­cel­lence.

When look­ing to en­roll pa­tients with brain metas­tases in clin­i­cal tri­als, FDA di­rects spon­sors to its re­cent­ly fi­nal­ized guid­ance, Can­cer Clin­i­cal Tri­al El­i­gi­bil­i­ty Cri­te­ria: Brain Metas­tases.

In the guid­ance, FDA ex­plains some of the chal­lenges present in eval­u­at­ing treat­ments for CNS metasta­t­ic dis­ease. “The po­ten­tial for ben­e­fit of a drug as as­sessed by tu­mor shrink­age of CNS le­sions is un­in­ter­pretable with­out in­for­ma­tion re­gard­ing tu­mor shrink­age at ex­tra-CNS dis­ease sites. Fur­ther­more, eval­u­a­tion of an­ti-tu­mor ac­tiv­i­ty, par­tic­u­lar­ly dura­bil­i­ty of tu­mor re­sponse in the CNS may not be at­trib­ut­able sole­ly to the in­ves­ti­ga­tion­al drug, as treat­ment would gen­er­al­ly be changed at the time of ex­tra CNS dis­ease pro­gres­sion in pa­tients with ev­i­dence of sta­ble or re­spond­ing CNS le­sions,” FDA writes.

FDA al­so notes that CNS dis­ease should not be eval­u­at­ed in iso­la­tion from metasta­t­ic dis­ease in the rest of the body. As such, FDA says that “ef­fi­ca­cy claims based on end­points mea­sur­ing CNS ac­tiv­i­ty alone may not be ap­pro­pri­ate.”

To de­ter­mine whether an ex­pe­dit­ed pro­gram for ther­a­pies with­out avail­able ther­a­peu­tic al­ter­na­tives, FDA says it con­sid­ers, “an avail­able ther­a­py for a metasta­t­ic sol­id tu­mor [to] be an avail­able ther­a­py for CNS metas­tases of that sol­id tu­mor, un­less oth­er­wise spec­i­fied in the la­bel­ing for that ther­a­py.”

When it comes to de­sign­ing clin­i­cal tri­als, FDA says spon­sors should take con­sid­er­a­tion of pri­or ther­a­pies sub­jects may have re­ceived. FDA notes that spon­sors should cap­ture in­for­ma­tion on all pri­or CNS-di­rect­ed treat­ments and that pro­to­cols should spec­i­fy an in­ter­val, typ­i­cal­ly of at least 12 weeks, be­tween com­ple­tion of CNS ra­di­a­tion ther­a­py and study en­try, “to al­low at­tri­bu­tion of treat­ment ef­fects to the study in­ter­ven­tion.”

Ad­di­tion­al­ly, pro­to­cols, “Should spec­i­fy ap­pro­pri­ate strat­i­fi­ca­tion fac­tors for ran­dom­iza­tion to min­i­mize bias based on pri­or ther­a­py(ies).”

FDA al­so pro­vides guid­ance on as­sess­ing CNS metas­tases, not­ing that mag­net­ic res­o­nance imag­ing (MRI) with gadolin­i­um con­trast is pre­ferred and that pro­to­cols should re­quire base­line imag­ing eval­u­a­tion of the CNS in all en­rolled pa­tients with CNS dis­ease. Oth­er rec­om­men­da­tions in­clude ap­ply­ing ac­cept­ed stan­dard re­sponse cri­te­ria for eval­u­at­ing CNS dis­ease and re­quir­ing on-study imag­ing as­sess­ments for CNS dis­ease at the same time points as those for ex­tra-CNS dis­ease.

As for end­points, FDA says the se­lec­tion of an ap­pro­pri­ate end­point will de­pend on the study pop­u­la­tion and whether the study is eval­u­at­ing on­ly pa­tients with CNS metas­tases. Some of the end­points FDA says may be con­sid­ered in­clude time-to-event end­points in ran­dom­ized con­trolled tri­als, over­all sur­vival or end­points based on tu­mor as­sess­ment such as over­all re­sponse rate or pro­gres­sion-free sur­vival.

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