FDA is­sues draft guid­ance on NASH drug de­vel­op­ment

The FDA on Mon­day is­sued draft guid­ance on de­vel­op­ing drugs to treat pa­tients who have non­cir­rhot­ic non­al­co­holic steato­hep­ati­tis (NASH) with liv­er fi­bro­sis.

“Cur­rent­ly, there are no ap­proved drugs for the treat­ment of NASH. Giv­en the high preva­lence of NASH, the as­so­ci­at­ed mor­bid­i­ty, the grow­ing bur­den of end-stage liv­er dis­ease, and the lim­it­ed avail­abil­i­ty of liv­ers for or­gan trans­plan­ta­tion, FDA be­lieves that iden­ti­fy­ing ther­a­pies that will slow the progress or, halt, or re­verse NASH and NAFLD will ad­dress an un­met med­ical need,” FDA writes.

How­ev­er, FDA ac­knowl­edges that there are knowl­edge gaps that present chal­lenges to de­vel­op­ing drugs to treat NASH. One par­tic­u­lar chal­lenge is that there are cur­rent­ly no cri­te­ria for iden­ti­fy­ing which pa­tients with non­al­co­holic fat­ty liv­er (NAFL) will progress to NASH.

Be­cause of this, FDA says that spon­sors should fo­cus on de­vel­op­ing treat­ments non­cir­rhot­ic NASH with liv­er fi­bro­sis un­til there are meth­ods for iden­ti­fy­ing the sub­set of pa­tients who are at risk of pro­gres­sion.

FDA al­so en­cour­ages spon­sors to de­vel­op and val­i­date bio­mark­ers for di­ag­nos­ing and grad­ing NASH and liv­er fi­bro­sis, as liv­er biop­sy is cur­rent­ly the on­ly re­li­able method for di­ag­nos­ing the dis­ease.


The guid­ance it­self pro­vides rec­om­men­da­tions for pre­clin­i­cal and clin­i­cal de­vel­op­ment as well as tri­al de­sign and end­point se­lec­tion to sup­port ap­proval of drugs to treat non­cir­rhot­ic NASH with liv­er fi­bro­sis.

FDA notes that the guid­ance is not meant to cov­er the de­vel­op­ment of drugs to treat cir­rho­sis caused by NASH or the de­vel­op­ment of in vit­ro di­ag­nos­tics that may be used in de­vel­op­ing drugs to treat the dis­ease.

For Phase 3 stud­ies, FDA says that spon­sors should en­roll pa­tients with a his­to­log­i­cal di­ag­no­sis of NASH with liv­er fi­bro­sis made with­in six months of en­roll­ment, tak­ing in­to con­sid­er­a­tion pa­tients’ stan­dard of care and back­ground ther­a­py for oth­er chron­ic con­di­tions. FDA al­so says that pa­tients’ weight should be sta­ble for three months pri­or to en­roll­ment.

FDA al­so says that Phase 3 stud­ies for NASH should be dou­ble-blind and place­bo-con­trolled with the goal of slow­ing, halt­ing or re­vers­ing dis­ease pro­gres­sion and im­prov­ing clin­i­cal out­comes.

“Be­cause of the slow pro­gres­sion of NASH and the time re­quired to con­duct a tri­al that would eval­u­ate clin­i­cal end­points such as pro­gres­sion to cir­rho­sis or sur­vival, the FDA rec­om­mends spon­sors con­sid­er … liv­er his­to­log­i­cal im­prove­ments as end­points rea­son­ably like­ly to pre­dict clin­i­cal ben­e­fit to sup­port ac­cel­er­at­ed ap­proval,” FDA writes.

Those end­points in­clude res­o­lu­tion of steato­hep­ati­tis on over­all histopatho­log­i­cal read­ing and no wors­en­ing of liv­er fi­bro­sis on NASH Clin­i­cal Re­search Net­work (CRN) fi­bro­sis score and/or im­prove­ment in liv­er fi­bro­sis greater than or equal to one stage (NASH CRN fi­bro­sis score) and no wors­en­ing of steato­hep­ati­tis.

For NASH treat­ments grant­ed ac­cel­er­at­ed ap­proval on the ba­sis of liv­er his­tol­ogy, FDA says that ran­dom­ized, dou­ble-blind, place­bo-con­trolled tri­als to ver­i­fy clin­i­cal ben­e­fits should be un­der­way when the mar­ket­ing ap­pli­ca­tion is sub­mit­ted.

The guid­ance al­so pro­vides some caveats for pe­di­atric de­vel­op­ment, as “Pe­di­atric NASH ap­pears to have dif­fer­ent his­to­log­i­cal char­ac­ter­is­tics as well as a dif­fer­ent nat­ur­al his­to­ry when com­pared to adult NASH. For rea­sons that are cur­rent­ly un­known, dis­ease char­ac­ter­is­tics and pro­gres­sion in pe­di­atric pa­tients may be dif­fer­ent.”

As such, FDA says that ex­trap­o­la­tion of ef­fi­ca­cy from adults “is not ap­pro­pri­ate at this time,” and that lon­gi­tu­di­nal nat­ur­al his­to­ry da­ta for pe­di­atric pa­tients are need­ed.

FDA says it plans to fur­ther ad­dress is­sues re­lat­ed to pe­di­atric non­cir­rhot­ic NASH in an up­com­ing guid­ance.

Draft Guid­ance, Fed­er­al Reg­is­ter No­tice

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.

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