FDA drafts guid­ance on demon­strat­ing sub­stan­tial ev­i­dence of ef­fec­tive­ness

The FDA on Thurs­day is­sued draft guid­ance on demon­strat­ing “sub­stan­tial ev­i­dence” of ef­fec­tive­ness for drugs and bi­o­log­ics, ex­pand­ing on decades-old guid­ance is­sued to ad­dress statu­to­ry changes brought on by the Food and Drug Ad­min­is­tra­tion Mod­ern­iza­tion Act of 1997 (FDAMA).

Specif­i­cal­ly, the 18-page draft guid­ance builds on the FDA’s 1998 guid­ance Pro­vid­ing Clin­i­cal Ev­i­dence of Ef­fec­tive­ness for Hu­man Drug and Bi­o­log­i­cal Prod­ucts, which de­tailed the FDA’s ex­pec­ta­tions for ev­i­dence to sup­port the ap­proval of new drugs and bi­o­log­ics or ap­pli­ca­tions for sup­ple­men­tal in­di­ca­tions in light of FDAMA’s clar­i­fi­ca­tion that a sin­gle ad­e­quate and well-con­trolled clin­i­cal tri­al and con­fir­ma­to­ry ev­i­dence can be used to sup­port ap­proval.

While the FDA says its “stan­dard for demon­strat­ing ef­fec­tive­ness has not changed” since the 1998 guid­ance, the agency says that new guid­ance is nec­es­sary to keep up with sci­en­tif­ic ad­vance­ments and changes in drug de­vel­op­ment over the last two decades.

Amy Aber­nethy

“As our sci­en­tif­ic knowl­edge ad­vances, and drugs and bi­o­log­ics with nov­el mech­a­nisms are be­ing de­vel­oped to treat con­di­tions that were pre­vi­ous­ly with­out treat­ments, there is a need for ad­di­tion­al guid­ance on the flex­i­bil­i­ty in the amount and type of ev­i­dence need­ed to es­tab­lish their ef­fec­tive­ness,” said FDA Prin­ci­pal Deputy Com­mis­sion­er Amy Aber­nethy.

With­in the guid­ance, the FDA dis­cuss­es the lev­el of qual­i­ty and the quan­ti­ty of clin­i­cal ev­i­dence need­ed to demon­strate ef­fec­tive­ness and pro­vides ex­am­ples of “cir­cum­stances where ad­di­tion­al flex­i­bil­i­ty may be war­rant­ed,” such as for treat­ments for rare dis­eases or life-threat­en­ing or se­vere­ly de­bil­i­tat­ing con­di­tions where there is an un­met med­ical need.

“There are cir­cum­stances where ev­i­dence gen­er­at­ed us­ing a va­ri­ety of clin­i­cal tri­al de­signs, end­points and sta­tis­ti­cal method­ol­o­gy can sup­port ef­fec­tive­ness, such as in cer­tain drug de­vel­op­ment pro­grams for rare dis­eases,” Aber­nethy said.

In ad­di­tion to the “gold stan­dard” ran­dom­ized, dou­ble-blind­ed, con­trolled su­pe­ri­or­i­ty tri­als, which the FDA says are “re­gard­ed as the most rig­or­ous de­sign,” the guid­ance al­so dis­cuss­es oth­er types of de­signs, in­clud­ing place­bo con­cur­rent con­trol, dose-com­par­i­son con­cur­rent con­trol, no treat­ment con­cur­rent con­trol, ac­tive treat­ment con­cur­rent con­trol and his­tor­i­cal con­trol de­signs.

The guid­ance al­so dis­cuss­es when dif­fer­ent amounts of ev­i­dence are ap­pro­pri­ate to sup­port ap­proval, in­clud­ing two ad­e­quate and well-con­trolled clin­i­cal in­ves­ti­ga­tions or a sin­gle ad­e­quate and well-con­trolled large mul­ti­cen­ter tri­al.

Ad­di­tion­al­ly, the guid­ance pro­vides ex­am­ples of ap­proach­es based around a sin­gle ad­e­quate and well-con­trolled study:

  • One ad­e­quate and well-con­trolled clin­i­cal in­ves­ti­ga­tion on a new in­di­ca­tion for an ap­proved drug, sup­port­ed by ex­ist­ing ad­e­quate and well-con­trolled clin­i­cal in­ves­ti­ga­tion(s) that demon­strat­ed the ef­fec­tive­ness of the drug for its oth­er, close­ly re­lat­ed ap­proved in­di­ca­tion(s);
  • One ad­e­quate and well-con­trolled clin­i­cal in­ves­ti­ga­tion sup­port­ed by da­ta that pro­vide strong mech­a­nis­tic sup­port;
  • One ad­e­quate and well-con­trolled clin­i­cal in­ves­ti­ga­tion with com­pelling re­sults, sup­port­ed by ad­di­tion­al da­ta from the nat­ur­al his­to­ry of the dis­ease; and
  • One ad­e­quate and well-con­trolled clin­i­cal in­ves­ti­ga­tion of the new drug, sup­port­ed by sci­en­tif­ic knowl­edge about the ef­fec­tive­ness of oth­er drugs in the same phar­ma­co­log­i­cal class.

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