EMA fi­nal­izes clin­i­cal de­vel­op­ment guide­line for new gout treat­ments

The EMA on Thurs­day is­sued a guide­line set­ting its ex­pec­ta­tions for the clin­i­cal de­vel­op­ment of new urate-low­er­ing ther­a­pies (ULT) and an­ti-in­flam­ma­to­ry drugs to treat gout.

The 14-page guide­line comes less than a year af­ter the EMA’s Com­mit­tee for Med­i­c­i­nal Prod­ucts for Hu­man Use (CHMP) re­leased the draft ver­sion for con­sul­ta­tion and sev­en years af­ter the agency pub­lished a con­cept pa­per high­light­ing the need for such guid­ance.

While there are a hand­ful of ULTs avail­able in Eu­rope, the EMA notes that there are some is­sues with ex­ist­ing treat­ments. “Al­lop­uri­nol, a xan­thine-ox­i­dase in­hibitor in­ter­fer­ing with the pro­duc­tion of uric acid, is con­sid­ered as a first-line ULT treat­ment op­tion … how­ev­er, al­lop­uri­nol hy­per­sen­si­tiv­i­ty syn­drome with skin re­ac­tions is quite com­mon,” the EMA writes, not­ing that dos­es must al­so be low­ered in re­nal­ly im­paired pa­tients.

Clin­i­cal De­vel­op­ment

With­in the guide­line, the EMA pro­vides rec­om­men­da­tions for pa­tient se­lec­tion, safe­ty and ef­fi­ca­cy as­sess­ments and clin­i­cal tri­al de­sign, as well as dis­cussing con­sid­er­a­tions for stud­ies in el­der­ly, pe­di­atric and re­nal­ly im­paired pa­tients.

How­ev­er, the EMA points out that “the study de­sign, in­clu­sion cri­te­ria, pri­ma­ry end­points and tri­al du­ra­tion large­ly de­pend on the treat­ment goal and mode of ac­tion of the new drug.”

The EMA notes that treat­ment guide­lines in both the US and EU do not en­dorse the treat­ment of asymp­to­matic hy­pe­r­uricemia and says that its clin­i­cal de­vel­op­ment guide­line does not ad­dress the treat­ment or pro­phy­lax­is of acute hy­pe­r­uricemia caused by oth­er con­di­tions.

When se­lect­ing pa­tients for en­roll­ment in clin­i­cal tri­als, the EMA rec­om­mends that spon­sors use es­tab­lished di­ag­nos­tic cri­te­ria, such as those de­vel­oped by the Eu­ro­pean League Against Rheuma­tism (EU­LAR) and Amer­i­can Col­lege of Rheuma­tol­ogy (ACR).

The EMA says that spon­sors may dis­tin­guish “be­tween pa­tients with in­ter­mit­tent flar­ing dis­ease, with symp­tom free in­ter­vals, or ad­vanced pa­tients with chron­ic arthropa­thy man­i­fes­ta­tions,” and rec­om­mends that stud­ies for ULTs se­lect pa­tients with hy­pe­r­uricemia above 7mg/dl as a base­line.

The agency al­so en­cour­ages spon­sors to en­roll pa­tients with com­mon co­mor­bidi­ties, such as obe­si­ty, di­a­betes, hy­per­ten­sion and re­nal im­pair­ment … de­pend­ing on the safe­ty pro­file of the drug.”

The EMA points out that there are dif­fer­ent po­ten­tial treat­ment goals for gout which re­quire dif­fer­ent clin­i­cal de­vel­op­ment plans and tri­al de­signs, such as the re­duc­tion of hy­pe­r­uricemia and urate crys­tal load or the symp­to­matic treat­ment of acute gouty arthri­tis flares.

The EMA rec­om­mends that for ULTs, spon­sors con­duct par­al­lel, ran­dom­ized dou­ble-blind place­bo-con­trolled tri­als for at least six months. For first line treat­ments, the EMA says that at least one study should use al­lop­uri­nol as an ac­tive con­trol, while the agency pro­vides dif­fer­ent op­tions for study de­sign for sec­ond line treat­ments de­pend­ing on whether the drug will be used as monother­a­py or in com­bi­na­tion with a xan­thine ox­i­dase in­hibitor (XOI).

The EMA rec­om­mends us­ing serum uric acid (SUA) as a sur­ro­gate end­point to eval­u­ate the ef­fi­ca­cy of ULTs. “As it takes time for the body to be cleared of uric acid crys­tals, and as uric acid lev­els fluc­tu­ate over time de­pend­ing on food and flu­id in­take, the pri­ma­ry end­point should not con­sist of SUA lev­els at a sin­gle time-point, but should re­flect a sus­tained SUA re­sponse be­low a crit­i­cal tar­get lev­el. SUA should, there­fore, be fre­quent­ly mon­i­tored in the tri­als (at least every 4 weeks),” the EMA writes.

The pri­ma­ry end­point for con­fir­ma­to­ry tri­als for ULTs should be sus­tained SUA lev­els be­low 6mg/dl for three con­sec­u­tive months or < 5 mg/dl for pa­tients with topha­ceous gout.

For an­ti-in­flam­ma­to­ry drugs, the EMA al­so rec­om­mends par­al­lel, dou­ble-blind ran­dom­ized place­bo-con­trolled tri­als, though the agency says that “no place­bo-con­trol is need­ed if the study ob­jec­tive is demon­strat­ing su­pe­ri­or­i­ty to­wards an ac­tive con­trol.” For non-in­fe­ri­or­i­ty stud­ies, the EMA says a three-arm study in­clud­ing a place­bo is gen­er­al­ly nec­es­sary.

For an­ti-in­flam­ma­to­ry drugs, the EMA of­fers dif­fer­ent end­points de­pend­ing on the goal of treat­ment, such as acute treat­ment of flares or pro­phy­lax­is at the start of ULT.

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