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

Another big drug approval came through on Friday afternoon as the FDA OK’d AbbVie’s upadacitinib — an oral JAK1 inhibitor that is hitting the rheumatoid arthritis market with a black box warning of serious malignancies, infections and thrombosis reflecting fears associated with the class.

It will be sold as Rinvoq — at a wholesale price of $59,000 a year — and will likely soon face competition from a drug that AbbVie once controlled, and spurned. Reuters reports that a 4-week supply of Humira, by comparison, is $5,174, adding up to about $67,000 a year.

After a “hot” period of rapid growth between 2009 and 2012, and a relatively “cooler” period of slower growth from 2013 to 2015, China has once again become a top-of-mind priority for the CEOs of most large, multinational pharmaceutical companies.

At the International Pharma Forum, hosted in March in Beijing by the R&D Based Pharmaceutical Association Committee (RDPAC) and the Pharmaceutical Research and Manufacturers of America (PhRMA), no fewer than seven CEOs of major multinational pharmaceutical firms participated, including GSK, Eli Lilly, LEO Pharma, Merck KGaA, Pfizer, Sanofi and UCB. A few days earlier, the CEOs of several other large multinationals attended the China Development Forum, an annual business forum hosted by the research arm of China’s State Council. It’s hard to imagine any other country, except the US, having such drawing power at CEO level.

ICER has some strong words for PTC, Sarepta and the FDA as the US drug price watchdog concludes that as currently priced, their respective new treatments for Duchenne muscular dystrophy are decidedly not cost-effective.

The final report — which cements the conclusions of a draft issued in May — incorporates the opinion of a panel of 17 experts ICER convened in a public meeting last month. It also based its analysis of Emflaza (deflazacort) and Exondys 51 (eteplirsen) on updated annual costs of $81,400 and over $1 million, respectively, after citing “incorrect” lower numbers in the initial calculations.