FDA kicks off GDU­FA III reau­tho­riza­tion process

In a pub­lic meet­ing held via we­b­cast, of­fi­cials of the FDA kicked off the process for reau­tho­riz­ing the Gener­ic Drug User Fee Amend­ments (GDU­FA). The meet­ing, which in­clud­ed pre­sen­ta­tions by mem­bers of in­dus­try and the pub­lic, is the first of many that will shape the agency’s third GDU­FA pro­gram.

GDU­FA II, au­tho­rized in 2017, ex­pires at the end of Sep­tem­ber 2022. The GDU­FA II agree­ment had two ma­jor ob­jec­tives in speed­ing ac­cess to gener­ic drugs, said Maryll To­ufan­ian, di­rec­tor of the Of­fice of Gener­ic Drug Pol­i­cy at CDER’s Of­fice of Gener­ic Drugs (OGD) at the meet­ing. The first was to re­duce the num­ber of re­view cy­cles to ap­proval, and the sec­ond was to in­crease the num­ber of gener­ic drugs ap­proved while main­tain­ing safe­ty and qual­i­ty stan­dards.

To that end, GDU­FA II in­clud­ed a new pre-ab­bre­vi­at­ed new drug ap­pli­ca­tion (AN­DA) pro­gram de­signed to smooth de­vel­op­ment and re­view of AN­DAs for com­plex gener­ics; new re­view goals were al­so set for pri­or­i­ty AN­DA sub­mis­sions. Oth­er up­dates in GDU­FA II in­clud­ed more ac­count­abil­i­ty and re­port­ing re­quire­ments, a mod­i­fi­ca­tion of the user fee struc­ture, and pro­vi­sions for small busi­ness re­lief.

GDU­FA II by the num­bers

Maryll To­ufan­ian

Div­ing in­to the “num­bers be­hind the num­bers,” said To­ufan­ian, re­veals that the to­tal num­ber of com­mu­ni­ca­tions with ap­pli­cants ex­ceeds 20,000. In all, 264 pre-AN­DA pro­gram meet­ings have been held, with 113 pre-AN­DA re­quests re­ceived in FY 2019 alone. “Use of the pre-AN­DA meet­ing pro­gram con­tin­ues to grow,” said Robert Li­on­berg­er, PhD, di­rec­tor of the Of­fice of Re­search and Stan­dards at OGD, adding that FDA has ex­ceed­ed its GDU­FA II goals in this area.

Sal­ly Choe, PhD, OGD Di­rec­tor, not­ed on FDA’s web­site  that prod­uct-spe­cif­ic guid­ances can in­crease the ef­fi­cien­cy and cost-ef­fec­tive­ness of gener­ic drug de­vel­op­ment “by iden­ti­fy­ing the most ap­pro­pri­ate method­ol­o­gy and ev­i­dence need­ed to sup­port a spe­cif­ic gener­ic drug’s com­par­i­son with the brand name drug dur­ing FDA’s as­sess­ment process, which can stream­line prod­uct ap­provals.” Over 1,900 such prod­uct-spe­cif­ic guid­ances have been pub­lished by FDA as of June 2020.

Dur­ing GDU­FA II, said To­ufan­ian, OGD re­ceived 8,450 items of con­trolled cor­re­spon­dence. Li­on­berg­er not­ed that about 40% of con­trolled cor­re­spon­dence re­gards com­plex prod­ucts, and about 7% of con­trolled cor­re­spon­dence re­gards “com­plex con­trols;” with a goal date of 120 rather than 60 days.

To­ufan­ian char­ac­ter­ized GDU­FA II as hav­ing achieved “a healthy gener­ic pro­gram” that has achieved “the most pre­dictable and trans­par­ent as­sess­ment process to date.” Still, she said, “There is still work to be done to fur­ther en­hance ef­fi­cien­cy, trans­paren­cy, and gain more first-cy­cle ap­provals” in the next cy­cle of GDU­FA au­tho­riza­tion.

Michael Kopcha

A key area of fo­cus for OGD will be the grow­ing are­na of com­plex gener­ic drug prod­ucts which, said Michael Kopcha, di­rec­tor of CDER’s Of­fice of Phar­ma­ceu­ti­cal Qual­i­ty, “are hard­er to ‘gener­i­cize’ and of­ten have less mar­ket com­pe­ti­tion.” Li­on­berg­er point­ed out that it is key to con­tin­ue mov­ing com­plex gener­ic drug ap­pli­ca­tions through the sys­tem, with an eye to keep­ing pace with prod­uct de­vel­op­ments that add com­plex­i­ty. “Pre-AN­DA meet­ings sup­port in­no­v­a­tive ap­proach­es to bioe­quiv­a­lence that can ac­cel­er­ate ac­cess to com­plex gener­ics,” he said.

In­dus­try seeks cer­tain­ty – with flex­i­bil­i­ty

When it came time for in­dus­try pre­sen­ta­tions, Scott Tom­sky, Te­va’s vice pres­i­dent of reg­u­la­to­ry af­fairs and ge­net­ics for North Amer­i­ca, found am­ple room for im­prove­ment in the gener­ics ap­proval process. In GDU­FA III, FDA needs to take ad­di­tion­al steps to in­crease the num­ber of first-cy­cle ap­provals, es­pe­cial­ly for com­plex gener­ics. Tom­sky cit­ed a 2019 Gov­ern­ment Ac­count­abil­i­ty Of­fice re­port find­ing a 12%  av­er­age rate of first-cy­cle ap­provals, with “most ap­pli­ca­tions tak­ing at least three re­view cy­cles to reach ap­proval.”

Scott Tom­sky

“One of the biggest chal­lenges Te­va still en­coun­ters is with FDA’s reg­u­la­to­ry un­cer­tain­ty; it’s pret­ty de­bil­i­tat­ing,” said Tom­sky. “This has a tremen­dous im­pact on Te­va fore­casts and busi­ness de­ci­sions re­lat­ed to plan­ning for launch as well as prod­uct se­lec­tion.

“Why is it this way? Does it have to be? Com­plex gener­ics may be more akin to their new drug coun­ter­parts in the type of re­view re­quired. It’s no­table that the FDA of­fice of new drugs is able to ap­prove over 90% of ap­pli­ca­tions even for new mol­e­c­u­lar en­ti­ties on the first round of re­view.”

Tom­sky sug­gest­ed that the goal date should be set from the date of fil­ing, rather from the sub­mis­sion date for com­plex gener­ic ap­pli­ca­tions, as is the case with new mol­e­c­u­lar en­ti­ties. That, he said, “would pro­vide the agency a bit more time to do a sub­stan­tive re­view.”

Ad­just­ments should have the ef­fect of keep­ing an ap­pli­ca­tion in play even if the goal date is missed: “This would al­low the Of­fice of Gener­ic Drugs the flex­i­bil­i­ty to miss a goal date when they feel they can work to­ward an ap­proval. It can on­ly work if spon­sors have more in­sight in­to their re­view process, and con­fi­dence and clar­i­ty to where an ap­pli­ca­tion re­view stands if the goal date is missed. The ap­pli­ca­tion can­not fall in­to obliv­ion, as of­ten is the case to­day when the goal date is missed,” said Tom­sky.

Tom­sky called the cre­ation of the pre-AN­DA process “one of the best re­sults of GDU­FA II,” since it gives spon­sors ear­ly in­sight in­to agency think­ing. In con­trast, mid-cy­cle re­view meet­ings, he said, “are cur­rent­ly a lost op­por­tu­ni­ty” that con­sti­tute a poor use of FDA and in­dus­try re­sources and a “lost op­por­tu­ni­ty to re­duce the like­li­hood or need for a sub­se­quent re­view cy­cle.” ac­cord­ing to Tom­sky, the meet­ings cur­rent­ly don’t have the back-and-forth ex­change that was en­vi­sioned.

Through­out, Tom­sky asked for more flex­i­bil­i­ty from the agency and a more cer­tain and re­li­able path to first-cy­cle ap­proval. “My com­mer­cial col­leagues walk a tightrope of pos­si­bil­i­ty which is made even more treach­er­ous by the con­stant shift­ing wind of FDA reg­u­la­tion for gener­ic med­i­cines,” he said. “You of­ten hear FDA ask­ing why the num­ber of launch­es doesn’t cor­re­late with the num­ber of ap­provals. When the ap­proval process drags on or be­comes too un­pre­dictable to sup­port the busi­ness case, the prod­uct won’t launch. It’s that sim­ple.”

GDU­FA ne­go­ti­a­tion meet­ings are not open for pub­lic view­ing or at­ten­dance, though pub­licly post­ed meet­ing min­utes are made avail­able af­ter stake­hold­er meet­ings, Kopcha not­ed. “Af­ter ne­go­ti­a­tions with the gener­ic drug in­dus­try, FDA will send the agreed-up­on rec­om­men­da­tions to Con­gress, and Con­gress will hold hear­ings that in­clude tes­ti­mo­ny from FDA ex­perts, the gener­ic drug in­dus­try, and oth­er in­ter­est­ed par­ties,” he said.

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