In­spec­tions: GAO calls on FDA to plan for back­log, re­view al­ter­na­tives

In a near­ly 350-page re­port to Con­gress on the fed­er­al gov­ern­ment’s Covid-19 re­sponse, the Gov­ern­ment Ac­count­abil­i­ty Of­fice (GAO) calls on the FDA to re­view its in­spec­tions ap­proach and come up with a plan to ad­dress its loom­ing back­log.

Pan­dem­ic in­spec­tion al­ter­na­tives

In the ear­ly days of the pan­dem­ic, FDA halt­ed non-mis­sion-crit­i­cal for­eign and do­mes­tic in­spec­tions and re­lied on al­ter­na­tive tools, such as in­spec­tion re­ports from for­eign reg­u­la­tors, records re­quests and prod­uct sam­pling, to com­ple­ment its over­sight ac­tiv­i­ties. The agency has since re­sumed some pri­or­i­tized do­mes­tic in­spec­tions based on a rat­ing sys­tem and, ac­cord­ing to Act­ing Cen­ter for Drug Eval­u­a­tion and Re­search Di­rec­tor Pa­trizia Cavaz­zoni’s re­cent Twit­ter post, “FDA has be­gun con­duct­ing pri­or­i­tized in­spec­tions by in­ves­ti­ga­tor staff in Chi­na and is plan­ning to ini­ti­ate pri­or­i­tized in­spec­tions in In­dia short­ly.”

Un­sur­pris­ing­ly, the pan­dem­ic has tak­en its toll on FDA’s in­spec­tions pro­gram, cut­ting the num­ber of drug es­tab­lish­ment in­spec­tions the agency car­ried out in FY2020 to less than half of what it had done in the pre­vi­ous two fis­cal years. GAO says the drop in in­spec­tions has added to its “long-stand­ing con­cerns about FDA’s abil­i­ty to over­see drugs man­u­fac­tured over­seas.”

“Pri­or to COVID-19, FDA typ­i­cal­ly con­duct­ed more than 1,600 in­spec­tions of for­eign and do­mes­tic drug man­u­fac­tur­ing es­tab­lish­ments each year, but in­spec­tions have been re­duced sig­nif­i­cant­ly. Al­ter­na­tive tools have helped FDA con­tin­ue its over­sight, but are not a com­pre­hen­sive or long-term sub­sti­tute for FDA in­spec­tions,” GAO writes.

More than half of fa­cil­i­ties that man­u­fac­ture drugs for the US are lo­cat­ed in oth­er coun­tries, with In­dia and Chi­na be­ing home to about a third of for­eign drug es­tab­lish­ments.

GAO found that from March, when FDA halt­ed most for­eign in­spec­tions, to Sep­tem­ber, the agency con­duct­ed just three “mis­sion crit­i­cal” for­eign in­spec­tions: two for-cause in­spec­tions in­volv­ing a Cana­di­an hand san­i­tiz­er man­u­fac­tur­er and a Ger­man ac­tive phar­ma­ceu­ti­cal in­gre­di­ent (API) mak­er, and one pre-ap­proval in­spec­tion re­lat­ed to an In­di­an drug­mak­er’s ap­pli­ca­tion for chloro­quine phos­phate tablets. In FY2018 and FY 019, FDA car­ried out more than 600 for­eign in­spec­tions in the same span of time.

FDA al­so con­duct­ed just 52 do­mes­tic in­spec­tions from March to Sep­tem­ber, com­pared to about 400 in that time in each of the pri­or two years.

In FY2020, GAO found that FDA sub­sti­tut­ed in­spec­tion re­ports from Eu­ro­pean reg­u­la­tors for more than 160 in­spec­tion in Eu­rope and asked for 30 re­ports from Eu­ro­pean reg­u­la­tors or Phar­ma­ceu­ti­cal In­spec­tion Co-op­er­a­tion Scheme (PIC/S) mem­bers per­tain­ing to es­tab­lish­ments in Chi­na, In­dia, Ko­rea, Japan and else­where.

The ex­tent that FDA can re­ly on in­spec­tions car­ried out by oth­er reg­u­la­tors varies. “Ac­cord­ing to FDA of­fi­cials, as of No­vem­ber 2020, FDA deemed that in­spec­tions con­duct­ed out­side of Eu­rope from 19 of 28 Eu­ro­pean reg­u­la­tors can be sub­sti­tut­ed for an FDA in­spec­tion. How­ev­er, re­ports for in­spec­tions from the oth­er 9 Eu­ro­pean reg­u­la­tors con­duct­ed out­side of Eu­rope and by PIC/S mem­bers can on­ly be used to help ob­tain ‘sur­veil­lance-lev­el over­sight’ while in­spec­tions are paused and are not full sub­sti­tutes for an FDA in­spec­tion,” GAO writes.

The re­port points out that FDA’s abil­i­ty to re­ly on in­spec­tions car­ried out by its over­seas coun­ter­parts may be lim­it­ed go­ing for­ward, as oth­er reg­u­la­tors have al­so post­poned in­spec­tions dur­ing the pan­dem­ic.

For­eign reg­u­la­tors may not be able to fill in the gap for in­spec­tions in two of the largest phar­ma­ceu­ti­cal ex­port mar­kets, In­dia and Chi­na, where FDA typ­i­cal­ly con­ducts more for­eign in­spec­tions than oth­er reg­u­la­tors.

“Thus, there may not al­ways be a for­eign reg­u­la­tor re­port to re­ly on while FDA in­spec­tions are paused,” GAO states, adding that in FY2019, FDA con­duct­ed near­ly 1000 in­spec­tions in In­dia and Chi­na.

FDA has al­so re­lied on al­ter­na­tive tools to com­pen­sate for its in­abil­i­ty to con­duct most preap­proval in­spec­tions amid the pan­dem­ic. Ac­cord­ing to GAO, in FY2020 FDA made “over 130 re­quests for records and oth­er in­for­ma­tion to sup­port preap­proval ap­pli­ca­tions list­ing es­tab­lish­ments in at least 27 coun­tries.”

Sim­i­lar­ly, FDA made more than 310 re­quests for records and oth­er in­for­ma­tion in lieu of sur­veil­lance in­spec­tions for es­tab­lish­ments in 36 coun­tries.

Rec­om­men­da­tions and a new back­log

Based on its find­ings, GAO makes two rec­om­men­da­tions to FDA re­lat­ed to in­spec­tions dur­ing and be­yond the pan­dem­ic.

First, GAO calls on FDA to ful­ly as­sess its al­ter­na­tive in­spec­tion tools and “con­sid­er whether these tools or oth­ers could pro­vide the in­for­ma­tion need­ed to sup­ple­ment reg­u­lar in­spec­tion ac­tiv­i­ties or help meet its drug over­sight ob­jec­tives when in­spec­tions are not pos­si­ble in the fu­ture.”

Sec­ond, GAO frets that a loom­ing back­log of in­spec­tions could jeop­ar­dize the agency’s strate­gic goal of shift­ing more of its in­spec­tions to a risk-based mod­el and in­structs the agency to as­sess its in­spec­tion plans for the com­ing years.

Ac­cord­ing to GAO, FDA has not ful­ly as­sessed its al­ter­na­tive tools be­yond re­liance on Eu­ro­pean reg­u­la­tor in­spec­tion re­ports. “FDA has not as­sessed whether in­spec­tions con­duct­ed by PIC/S mem­bers are equiv­a­lent to FDA in­spec­tions. Thus, any es­tab­lish­ments for which FDA us­es PIC/S mem­ber re­ports for sur­veil­lance-lev­el over­sight dur­ing the COVID-19 in­spec­tion pause will still re­quire an FDA in­spec­tion in the near fu­ture.” But FDA of­fi­cials told GAO there are lim­its to what it can use such al­ter­na­tive tools for. “For ex­am­ple, FDA of­fi­cials told us that on­ly FDA in-per­son in­spec­tions and Eu­ro­pean reg­u­la­tor re­ports can sat­is­fy its statu­to­ry re­quire­ments for risk-based sur­veil­lance in­spec­tions.”

Such an as­sess­ment could al­so in­form whether any statu­to­ry changes “would al­low [FDA] to more ful­ly uti­lize al­ter­na­tive tools to meet its in­spec­tion re­spon­si­bil­i­ties [and] in­crease the re­silience of its drug man­u­fac­tur­ing over­sight go­ing for­ward.”

While FDA’s new and gener­ic drug ap­provals have con­tin­ued apace dur­ing the pan­dem­ic and the agency has been able to meet its user fee agree­ment per­for­mance goals, there have been in­stances where the agency’s in­abil­i­ty to con­duct an in­spec­tion has de­layed de­ci­sions on prod­ucts.

GAO and drug in­dus­try rep­re­sen­ta­tives in­ter­viewed for the re­port warn that a con­tin­ued pause in preap­proval in­spec­tions could lead to fu­ture de­lays in drug ap­provals.

GAO al­so ex­pressed con­cern that the post­pone­ments could cre­ate a back­log of in­spec­tions of fa­cil­i­ties that have nev­er been in­spect­ed or that have not been in­spect­ed with­in five years. FDA con­sid­ers such in­spec­tions to be manda­to­ry and pri­or­i­tizes the re­main­der of the in­spec­tions it car­ries out each year based on risk.

“The back­log of manda­to­ry in­spec­tions this will cre­ate if in­spec­tions con­tin­ue to be post­poned could both ex­tend the max­i­mum in­ter­val be­tween FDA in­spec­tions be­yond FDA’s 5-year pol­i­cy and re­duce the re­sources avail­able in fis­cal year 2022 for in­spect­ing the oth­er high­est pri­or­i­ty es­tab­lish­ments iden­ti­fied by its mod­el,” GAO writes, not­ing that the agency has not yet fi­nal­ized its sur­veil­lance in­spec­tion ap­proach for FY2022, giv­ing it an op­por­tu­ni­ty to as­sess its ap­proach.

Drug in­dus­try rep­re­sen­ta­tives sug­gest­ed to GAO that FDA could al­so add re­mote in­spec­tion ca­pa­bil­i­ties to its ar­se­nal of al­ter­na­tive in­spec­tion tools. FDA con­firmed to GAO that it is look­ing in­to the pos­si­bil­i­ty of us­ing “oth­er tools to serve as sup­ple­ments to FDA in­spec­tions, in­clud­ing us­ing re­mote video and oth­er re­mote and live in­ter­ac­tions with es­tab­lish­ment staff and records to eval­u­ate drug man­u­fac­tur­ing op­er­a­tions.”

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