FDA, EMA ad­vise on risk-based mon­i­tor­ing in clin­i­cal tri­als

US and EU of­fi­cials ex­plained on Wednes­day what their re­spec­tive reg­u­la­to­ry agen­cies look for in clin­i­cal tri­al risk-based mon­i­tor­ing (RBM) and how RBM can im­pact re­view times.

Un­der a co­op­er­a­tive agree­ment with the FDA, the Duke-Mar­go­lis Health Pol­i­cy Cen­ter con­vened the pub­lic work­shop in Wash­ing­ton, DC for a de­bate on im­prov­ing the im­ple­men­ta­tion of RBM in clin­i­cal tri­als by iden­ti­fy­ing how reg­u­la­tors can help with some of the cur­rent bar­ri­ers to wide­spread adop­tion of RBM. Par­tic­i­pants looked for clar­i­fi­ca­tion around how reg­u­la­tors’ ap­proach­es to RBM dif­fer.

The FDA Of­fice of Sci­en­tif­ic In­ves­ti­ga­tions (OSI) Di­rec­tor David Bur­row stressed that “ter­mi­nol­o­gy is crit­i­cal.” Hav­ing rec­og­nized that the FDA and the EMA “may slight­ly dif­fer in the ter­mi­nol­o­gy that we use in the risk-based qual­i­ty man­age­ment (RBQM) con­ver­sa­tion,” Bur­row iden­ti­fied com­mon el­e­ments in RBM.

The el­e­ments com­prise a three-part process to plan and de­vel­op RBM sys­tems such that the end re­sults align with the ex­pec­ta­tions of agency re­view teams, per Bur­row. It be­gins with what Bur­row refers to as “a nec­es­sary com­po­nent for an ef­fec­tive RBM”—a risk as­sess­ment, fol­lowed by a “well-ar­tic­u­lat­ed, clean, crisp clear, ap­pro­pri­ate pro­to­col based on that risk as­sess­ment.” The risk-based mon­i­tor­ing plan can then be built on an ap­pro­pri­ate risk as­sess­ment to be ef­fec­tive.

Bur­row placed em­pha­sis on in­clud­ing a plan that spec­i­fies the in­tent of an RBM sys­tem as the FDA would not oth­er­wise con­sid­er it to be “true RBM.” No plan could re­sult in ap­pli­ca­tion de­lays fol­low­ing com­plete re­sponse let­ters or re­quests for ad­di­tion­al in­for­ma­tion, among oth­er reg­u­la­to­ry ac­tions at the agency’s dis­pos­al. De­lays cost time and time is mon­ey, Bur­row not­ed, high­light­ing an analy­sis OSI con­duct­ed of 334 clin­i­cal in­ves­ti­ga­tion sum­maries (CISs) over a three-year pe­ri­od. A CSI pro­vides rec­om­men­da­tions to the FDA’s Of­fice of New Drugs.

The analy­sis un­der­scored the im­pact on re­view times by sep­a­rat­ing OSI rec­om­men­da­tions in­to two buck­ets, with pas­sive rec­om­men­da­tions be­ing those that con­clude the da­ta are re­li­able in sup­port of the sub­mit­ted ap­pli­ca­tion and ac­tive rec­om­men­da­tions be­ing those that pro­long re­views. OSI found that 62 out of 334 (19%) had at least one ac­tive rec­om­men­da­tion, most of which were dri­ven by no ac­tion in­di­cat­ed in­spec­tions and vol­un­tary ac­tion in­di­cat­ed in­spec­tions. The re­sults con­verse­ly meant that RBM was ef­fec­tive for most (81%).

Bur­row ex­plained that a spon­sor who claims to have used RBM may be at adds with what the FDA be­lieves to be RBM, which is a chal­lenge for the agency to as­sess and track RBM out­comes. But in “some in­stances where we have seen true RBM be im­ple­ment­ed, we have seen a great cor­re­la­tion be­tween the is­sues that were iden­ti­fied in the risk-based mon­i­tor­ing sys­tem and the is­sues we see in the ap­pli­ca­tion re­view on the back end.”

EMA Sci­en­tif­ic Ad­min­is­tra­tor Camelia Mi­haes­cu al­so stressed that a RBM plan should be based on the da­ta of the risk as­sess­ment as well as be tri­al-spe­cif­ic. Mi­haes­cu fo­cused more heav­i­ly on the pair­ing of a risk as­sess­ment with a mit­i­ga­tion plan. “There should al­ways be a con­nec­tion be­tween a mon­i­tor­ing plan and a risk as­sess­ment and mit­i­ga­tion plan,” she said. “Risk adap­ta­tion al­lows a shift in fo­cus from the cor­rect­ness of in­di­vid­ual da­ta points to try and re­solve re­li­a­bil­i­ty, which, of course, is the ba­sis for reg­u­la­to­ry de­ci­sion-mak­ing.”

Mi­haes­cu fur­ther ex­plained that the EMA con­sid­ers RBM in clin­i­cal tri­als to be an ef­fec­tive tool for ad­dress­ing ar­eas of risk, whether high or low, ear­ly in and through­out the drug de­vel­op­ment process and thus al­low the spon­sor to be bet­ter po­si­tioned when seek­ing to sub­mit an ap­pli­ca­tion and bring a new prod­uct to the mar­ket.

The slight de­vi­a­tions in how the FDA ver­sus the EMA ap­proach RBM should not be a de­ter­rent to RBM adop­tion be­cause reg­u­la­tors share the same in­ter­est as in­dus­try to have an ab­sence of er­rors that mat­ter, ac­cord­ing to Bur­row. Both the FDA and the EMA view RBM, if used cor­rect­ly, and qual­i­ty as two sides of the same coin.

Im­prov­ing the Im­ple­men­ta­tion of RBM Ap­proach­es


RAPS: 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.

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