FDA-EMA work­shop dis­cuss­es qual­i­ty chal­lenges for PRIME, break­through ther­a­pies

Last No­vem­ber, of­fi­cials from the EMA and FDA met with in­dus­try rep­re­sen­ta­tives in Lon­don to dis­cuss the var­i­ous qual­i­ty chal­lenges that arise when the de­vel­op­ment of in­ves­ti­ga­tion­al prod­ucts is ac­cel­er­at­ed.

The EMA’s launch of its pri­or­i­ty med­i­cines (PRIME) scheme and the FDA’s break­through ther­a­py des­ig­na­tion have en­abled com­pa­nies to speed cer­tain treat­ments to mar­ket, al­though there have been dif­fi­cul­ties in iden­ti­fy­ing pos­si­ble sci­en­tif­ic and reg­u­la­to­ry ap­proach­es to fa­cil­i­tate the type of ro­bust qual­i­ty da­ta pack­ages nec­es­sary to en­sure that pa­tient safe­ty and prod­uct qual­i­ty and ef­fi­ca­cy are not com­pro­mised, ac­cord­ing to a re­port re­leased Wednes­day on the work­shop.

Ramesh Sood

In ad­di­tion to the fo­cus on ear­ly ac­cess ap­proach­es, the work­shop dis­cussed process val­i­da­tion, con­trol strate­gies, good man­u­fac­tur­ing prac­tice (GMP) com­pli­ance, com­pa­ra­bil­i­ty, sta­bil­i­ty and reg­u­la­to­ry tools.

Ramesh Sood, se­nior sci­en­tif­ic ad­vi­sor at the FDA’s Of­fice of New Drugs, dis­cussed the agency’s break­through pro­gram, not­ing the chal­lenges faced by ap­pli­cants col­lect­ing the nec­es­sary man­u­fac­tur­ing da­ta and pro­vid­ing an ad­e­quate man­u­fac­tur­ing con­trol strat­e­gy.

“It be­comes im­por­tant for the Agency re­view­ers to do a risk-ben­e­fit as­sess­ment re­gard­ing [the] risk of less man­u­fac­tur­ing in­for­ma­tion ver­sus pa­tient ben­e­fit,” the work­shop re­port says of Sood’s pre­sen­ta­tion. “This re­quires in­no­v­a­tive risk-mit­i­ga­tion strate­gies to en­sure prod­uct qual­i­ty and re­duce the qual­i­ty-re­lat­ed prod­uct risk to an ac­cept­able lev­el.”

Veroni­ka Jek­er­le

Veroni­ka Jek­er­le of the EMA’s qual­i­ty of­fice al­so dis­cussed the sci­en­tif­ic chal­lenges for PRIME can­di­dates, which in­clude ab­bre­vi­at­ed time­lines that add con­straints to set­ting up com­mer­cial man­u­fac­tur­ing sites.

“An analy­sis ex­am­in­ing sci­en­tif­ic is­sues most com­mon­ly iden­ti­fied by PRIME ap­pli­cants (as in­di­cat­ed by SA [sci­en­tif­ic ad­vice] re­quests) re­vealed the fol­low­ing ar­eas as the most crit­i­cal: start­ing ma­te­ri­als, com­pa­ra­bil­i­ty, process val­i­da­tion, an­a­lyt­i­cal con­trol strat­e­gy, spec­i­fi­ca­tions and sta­bil­i­ty,” the re­port says.

Stu­art Finnie, di­rec­tor of reg­u­la­to­ry CMC at As­traZeneca, al­so pre­sent­ed on a small mol­e­cule prod­uct that earned the FDA’s break­through des­ig­na­tion but ran in­to process val­i­da­tion prob­lems that meant sup­plies of the drug would come four months af­ter ap­proval.

As­traZeneca ap­proached the FDA and dis­cussed de­cou­pling the val­i­da­tion of drug sub­stance and drug prod­uct, and dis­cussed plans to use drug sub­stance man­u­fac­tured in the clin­i­cal fa­cil­i­ty to sup­ply drug prod­uct val­i­da­tion.

“Three key el­e­ments lead to the suc­cess of this pro­pos­al,” the re­port says of the As­traZeneca work. “First­ly, the ap­pli­cant pro­vid­ed the Agency with sig­nif­i­cant ev­i­dence of sim­i­lar­i­ty in terms of qual­i­ty, man­u­fac­tur­ing process and qual­i­ty sys­tem be­tween the clin­i­cal cam­paigns and the pro­posed com­mer­cial cam­paign. Sec­ond­ly, dur­ing the site in­spec­tion there was open and close en­gage­ment be­tween the in­spec­tors, re­view­ers, sub­ject mat­ter ex­perts and qual­i­ty de­part­ments en­sur­ing that ques­tions raised were an­swered swift­ly lead­ing to a bal­anced and aligned view on risk as­sess­ment. Fi­nal­ly, and most im­por­tant­ly, it was clear that through­out the in­ter­ac­tions all par­ties were fo­cused on en­sur­ing sup­ply to the pa­tient.”

Oth­er in­dus­try pre­sen­ta­tions in­volved rep­re­sen­ta­tives from Pfiz­er, Am­gen, Cel­gene, MSD (known as Mer­ck in the US), Bio­gen and sev­er­al vac­cine man­u­fac­tur­ers, among oth­ers.

As far as fu­ture joint EMA-FDA ac­tions, the re­port points to the use of mod­els for sta­bil­i­ty and shelf life de­ter­mi­na­tions, in­no­v­a­tive process val­i­da­tion ap­proach­es and al­low­ing launch­es from clin­i­cal man­u­fac­tur­ing sites.

Ned Sharp­less NIH

“In ad­di­tion, the or­ga­niz­ing com­mit­tee pro­pos­es to de­vel­op a ‘Tool­box- guid­ance’ for PRIME prod­ucts, which shall sum­marise the iden­ti­fied sci­en­tif­ic el­e­ments/reg­u­la­to­ry tools that are al­ready avail­able in the EU to ad­dress some of the chal­lenges faced dur­ing the de­vel­op­ment of prod­ucts un­der PRIME and gen­er­a­tion of ro­bust qual­i­ty pack­ages for MAA [mar­ket­ing au­tho­riza­tion ap­pli­ca­tion] re­view,” the re­port says.

Act­ing FDA Com­mis­sion­er Ned Sharp­less added in a state­ment: “We will con­tin­ue to work with our EMA col­leagues and in­dus­try to dis­cuss ways to ad­dress qual­i­ty chal­lenges as­so­ci­at­ed with ex­pe­dit­ed de­vel­op­ment pro­grams to help en­sure pa­tients re­ceive safe, ef­fec­tive drugs.”

Work­shop Re­port

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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