The Cen­ter for Drug Eval­u­a­tion and Re­search (CDER) at the FDA is­sued draft rec­om­men­da­tions for spon­sors look­ing to de­vel­op drugs to treat non­al­co­holic steato­hep­ati­tis (NASH) with com­pen­sat­ed cir­rho­sis.

NASH is as­so­ci­at­ed with a range of com­mon dis­eases, in­clud­ing type 2 di­a­betes, hy­per­ten­sion and obe­si­ty, among oth­ers. “It is a grow­ing pub­lic health con­cern and is an­tic­i­pat­ed to be the lead­ing cause of liv­er trans­plan­ta­tion with­in a decade,” the agency says. But “no stan­dard treat­ment ex­ists for NASH.”

The guid­ance fol­lows a sep­a­rate draft guid­ance is­sued in De­cem­ber that pro­vides rec­om­men­da­tions for ear­ly NASH drug de­vel­op­ment and de­vel­op­ing drugs to treat non­cir­rhot­ic NASH.

Guid­ance

To aid spon­sors of drugs to treat com­pen­sat­ed NASH cir­rho­sis dur­ing clin­i­cal de­vel­op­ment, the draft guid­ance de­tails the agency’s cur­rent rec­om­men­da­tions re­gard­ing com­po­nents of Phase III pro­grams.

Specif­i­cal­ly, the guid­ance de­tails pa­tient en­roll­ment cri­te­ria, clin­i­cal tri­al de­sign, ef­fi­ca­cy end­points and safe­ty con­sid­er­a­tions for Phase III tri­als.

The FDA em­phases that spon­sors should on­ly en­roll pa­tients in Phase III clin­i­cal tri­als whose cir­rho­sis is sec­ondary to NASH and should rule out oth­er caus­es of chron­ic liv­er dis­ease, such as al­co­holic liv­er dis­ease, vi­ral he­pati­tis and Wil­son’s dis­ease.

The guid­ance al­so pro­vides rec­om­men­da­tions for di­ag­nos­ing pa­tients with com­pen­sat­ed cir­rho­sis and for ex­clud­ing pa­tients with de­com­pen­sat­ed cir­rho­sis, among oth­er en­roll­ment cri­te­ria.

The FDA says that spon­sors should eval­u­ate drugs to treat com­pen­sat­ed NASH cir­rho­sis in ran­dom­ized, place­bo-con­trolled, dou­ble-blind clin­i­cal tri­als, and rec­om­mends that spon­sors should dis­cuss pro­posed strat­i­fi­ca­tion fac­tors with the agency be­fore be­gin­ning Phase III tri­als.

For ef­fi­ca­cy end­points, the FDA says spon­sors should “eval­u­ate the ef­fect of the in­ves­ti­ga­tion­al drug rel­a­tive to place­bo on the com­pos­ite end­point of time from ran­dom­iza­tion to the first of any one of” six out­comes, in­clud­ing com­pli­ca­tion of as­cites, variceal he­m­or­rhage, he­pat­ic en­cephalopa­thy, wors­en­ing in the Mod­el for End-State Liv­er Dis­ease (MELD) score, liv­er trans­plan­ta­tion or death from any cause.

The agency says it “strong­ly rec­om­mends clin­i­cal out­come tri­als to sup­port a mar­ket­ing ap­pli­ca­tion.” Yet a drug for the treat­ment of NASH cir­rho­sis will like­ly un­der­go FDA eval­u­a­tion through the tra­di­tion­al ap­proval path­way due to a cur­rent lack of ev­i­dence to sup­port an FDA ac­cel­er­at­ed ap­proval.

Draft guid­ance

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.

Im­age: An­drew Harnik AP

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