Re­duc­ing risk in drug de­vel­op­ment: The im­por­tance of val­i­dat­ed MRD test­ing in lym­phoid can­cers

Ad­vances in mol­e­c­u­lar pro­fil­ing have made com­plex lab­o­ra­to­ry-de­vel­oped tests (LDTs), such as next-gen­er­a­tion se­quenc­ing (NGS) as­says, rou­tine in clin­i­cal tri­als and drug de­vel­op­ment. These tools aid in iden­ti­fy­ing bio­mark­ers or ge­net­ic vari­ants for new ther­a­peu­tic tar­gets or per­son­al­ized treat­ments; mon­i­tor­ing dis­ease pro­gres­sion and treat­ment re­sponse; and strat­i­fy­ing tri­als to en­hance the suc­cess of pre­ci­sion med­i­cine in drug de­vel­op­ment for lym­phoid ma­lig­nan­cies, among oth­er can­cers. How­ev­er, the wide­spread use of LDTs in health­care de­ci­sion-mak­ing has been met with calls for in­creased over­sight from Unit­ed States (U.S.) and Eu­ro­pean Union (EU) reg­u­la­tors.

An evolv­ing reg­u­la­to­ry land­scape for lab tests

The U.S. and EU are cur­rent­ly in vary­ing stages of reg­u­la­tion that aim to mit­i­gate their ris­ing con­cerns over ac­cu­ra­cy, re­li­a­bil­i­ty, and pa­tient safe­ty.

In 2017, the Eu­ro­pean Com­mis­sion up­dat­ed its reg­u­la­to­ry frame­work, the In Vit­ro Di­ag­nos­tic Di­rec­tive (IVDD), by in­tro­duc­ing the more strin­gent In Vit­ro Di­ag­nos­tic Med­ical De­vices Reg­u­la­tion (IV­DR), which sets high­er stan­dards for qual­i­ty, safe­ty, sup­pli­er over­sight, and risk man­age­ment. The new rules have been in ef­fect since May 2022, with a tran­si­tion­al pe­ri­od cur­rent­ly in progress for de­vice re-cer­ti­fi­ca­tion. How­ev­er, many man­u­fac­tur­ers are lag­ging due to the re­source-in­ten­sive con­for­mi­ty as­sess­ment process.

The U.S. Food & Drug Ad­min­is­tra­tion (FDA) has been ad­vo­cat­ing for greater en­force­ment dis­cre­tion over in vit­ro de­vices for some time, point­ing to the cen­tral role they play in health­care to­day. IVDs are reg­u­lat­ed through two path­ways: first, by the FDA as med­ical de­vices; and sec­ond — for the sub­set of IVDs that are LDTs — through the reg­u­la­tion of clin­i­cal labs in which they are de­vel­oped, via the Clin­i­cal Lab­o­ra­to­ry Im­prove­ment Amend­ments (CLIA) au­tho­rized by Con­gress.

In April 2024, the FDA is­sued a fi­nal rule to make ex­plic­it that LDTs are de­vices un­der the Food, Drug, and Cos­met­ic Act and reg­u­lat­ed sep­a­rate­ly from CLIA, which is spe­cif­ic to lab­o­ra­to­ry op­er­a­tions and not the clin­i­cal va­lid­i­ty of the tests.

The FDA ar­gues that this over­sight will put safe­guards in place to en­sure the ef­fec­tive­ness of LDTs used to screen and di­ag­nose pa­tients.

It’s im­por­tant to note that with the de­par­ture of med­ical de­vices head Jeff Shuren — a cham­pi­on of the leg­is­la­tion — from the FDA, the fate of this rule re­mains un­cer­tain.

Chal­lenges for drug de­vel­op­ers

For bio­phar­ma­ceu­ti­cal com­pa­nies in­vest­ing sig­nif­i­cant­ly in glob­al clin­i­cal stud­ies, it is crit­i­cal that the re­sult­ing da­ta is trust­ed and ac­cept­ed by the sci­en­tif­ic and med­ical com­mu­ni­ties.​

If U.S. drug de­vel­op­ers opt not to use a reg­u­la­tor-ap­proved as­say, ob­tain­ing an in­ves­ti­ga­tion­al de­vice ex­emp­tion (IDE) from the FDA can be cost­ly and time-con­sum­ing. On top of oth­er reg­u­la­to­ry ac­tiv­i­ties, such as in­ves­ti­ga­tion­al new drug fil­ings, us­ing an IDE re­quires sub­mit­ting a da­ta pack­age demon­strat­ing an­a­lyt­i­cal per­for­mance, un­der­go­ing FDA re­view, and re­spond­ing to spon­sor queries — a process that can take months. For glob­al stud­ies at mul­ti­ple sites, val­i­da­tion is re­quired at each site.

In the EU, man­u­fac­tur­ers must com­ply with the new reg­u­la­tions by the dead­line as­signed to their risk class, or the prod­uct can no longer be mar­ket­ed. To uti­lize an in­ves­ti­ga­tion­al prod­uct with­out IV­DR ap­proval, de­vel­op­ers may need to run an “in­ter­ven­tion­al clin­i­cal per­for­mance study.” Eval­u­a­tion for these per­for­mance stud­ies is car­ried out on a coun­try-by-coun­try ba­sis, which can make the ap­proval process some­what dif­fi­cult.

Us­ing an FDA-cleared and IV­DR-cer­ti­fied as­say helps en­sure com­pli­ance with reg­u­la­to­ry stan­dards and guide­lines, re­duc­ing the risk of da­ta be­ing re­ject­ed. This can be par­tic­u­lar­ly im­por­tant in glob­al clin­i­cal tri­als, where dif­fer­ent coun­tries may have dif­fer­ent reg­u­la­to­ry re­quire­ments.​ Reg­u­la­tor-ap­proved as­says are con­firmed to have un­der­gone rig­or­ous test­ing and val­i­da­tion to en­sure their ac­cu­ra­cy, re­li­a­bil­i­ty, and re­pro­ducibil­i­ty.

Fur­ther, the cer­ti­fi­ca­tion process ap­proves clin­i­cal use — sup­port­ing the abil­i­ty to be used in a clin­i­cal tri­al to in­form de­ci­sions to ini­ti­ate, mod­i­fy, or dis­con­tin­ue ther­a­py — with­out an IDE for sig­nif­i­cant risk stud­ies.​

Ul­ti­mate­ly, drug de­vel­op­ers need to feel con­fi­dent that the di­ag­nos­tic tools they uti­lize fol­low the high­est qual­i­ty stan­dards and don’t present ad­di­tion­al hur­dles in the ar­du­ous path to drug ap­proval.

clonoSEQ MRD test­ing

clonoSEQ® is the first and on­ly FDA-cleared as­say for min­i­mal resid­ual dis­ease (MRD) de­tec­tion in bone mar­row from pa­tients with mul­ti­ple myelo­ma and B-cell acute lym­phoblas­tic leukemia (ALL) and in blood or bone mar­row from pa­tients with chron­ic lym­pho­cyt­ic leukemia (CLL). The NGS as­say of­fers a sen­si­tiv­i­ty of 10^-6, mean­ing it can de­tect one ma­lig­nant cell among one mil­lion healthy cells re­main­ing in the body af­ter treat­ment.

clonoSEQ is now al­so the first CE-marked test un­der IV­DR that al­lows for as­sess­ment of MRD sta­tus and changes in dis­ease bur­den dur­ing and af­ter treat­ment in pa­tients di­ag­nosed with all B-cell ma­lig­nan­cies. By re­quir­ing trans­paren­cy, trace­abil­i­ty, and on­go­ing post-mar­ket sur­veil­lance, this cer­ti­fi­ca­tion pro­vides EU health­care pro­fes­sion­als, pa­tients, and clin­i­cal tri­al spon­sors with con­fi­dence and trust in the test’s re­li­a­bil­i­ty, ac­cu­ra­cy, and safe­ty.

clonoSEQ is used by drug de­vel­op­ers in clin­i­cal tri­als as an ear­ly pre­dic­tor of out­comes ahead of pro­gres­sion-free sur­vival or over­all sur­vival, and to de­ter­mine depth and ki­net­ics of treat­ment re­sponse. This can be par­tic­u­lar­ly help­ful for ac­cel­er­at­ing the pace of drug de­vel­op­ment. For mul­ti­ple myelo­ma, the FDA’s On­co­log­ic Drugs Ad­vi­so­ry Com­mit­tee re­cent­ly unan­i­mous­ly sup­port­ed the use of MRD as a pri­ma­ry end­point to sup­port ac­cel­er­at­ed drug ap­provals.

To date, da­ta demon­strat­ing the an­a­lyt­i­cal and clin­i­cal va­lid­i­ty of oth­er MRD as­says, such as next-gen­er­a­tion flow cy­tom­e­try, has not been ac­cept­ed by the FDA to sup­port a cleared prod­uct. Da­ta gen­er­at­ed us­ing clonoSEQ has rou­tine­ly been used to sup­port FDA ap­provals for sev­er­al class­es of drugs, in­clud­ing bis­pecifics and chimeric anti­gen re­cep­tor (CAR) T-cell ther­a­pies, and to treat ALL, mul­ti­ple myelo­ma, and CLL. clonoSEQ is cur­rent­ly be­ing used as a pri­ma­ry end­point in 13 stud­ies and a sec­ondary end­point in more than 70 stud­ies.

A bench­mark for qual­i­ty

The fu­ture of drug de­vel­op­ment, es­pe­cial­ly in on­col­o­gy, hinges on the abil­i­ty to gen­er­ate re­li­able, re­pro­ducible da­ta that can with­stand the scruti­ny of reg­u­la­to­ry bod­ies. As the land­scape of mol­e­c­u­lar di­ag­nos­tics con­tin­ues to evolve, en­sur­ing that the tools used in clin­i­cal tri­als meet the high­est stan­dards of ac­cu­ra­cy and safe­ty is cru­cial.

clonoSEQ stands out as the on­ly FDA-cleared MRD as­say for lym­phoid ma­lig­nan­cies that not on­ly meets but ex­ceeds the cur­rent sen­si­tiv­i­ty and stan­dard­iza­tion re­quire­ments, of­fer­ing drug de­vel­op­ers a de­pend­able part­ner in the pur­suit of ground­break­ing ther­a­pies. By choos­ing this ful­ly val­i­dat­ed and reg­u­la­tor-ap­proved as­say, bio­phar­ma com­pa­nies can con­fi­dent­ly move for­ward in their tri­als.

In the rapid­ly ad­vanc­ing world of pre­ci­sion med­i­cine, the in­te­gra­tion of NGS tech­nolo­gies such as clonoSEQ is not just a strate­gic ad­van­tage — it’s a ne­ces­si­ty. As we look to­ward the fu­ture, clonoSEQ will con­tin­ue to be a piv­otal tool in the suc­cess­ful de­vel­op­ment of tar­get­ed ther­a­pies, set­ting a bench­mark for qual­i­ty and re­li­a­bil­i­ty in the in­dus­try.

Learn more about clonoSEQ here.