Con­gres­sion­al watch­dog ad­vis­es HHS to im­ple­ment 'post-mar­ket­ing' in­cen­tives to ad­dress dwin­dling an­tibi­ot­ic de­vel­op­ment ef­forts

With the Covid-19 cri­sis ex­pect­ed to shore up an­tibi­ot­ic use with op­por­tunis­tic sec­ondary bac­te­r­i­al in­fec­tions — and po­ten­tial­ly ex­ac­er­bate the rate an­tibi­ot­ic re­sis­tance — a con­gres­sion­al watch­dog has put to­geth­er a list of rec­om­men­da­tions to sort out the chal­lenges af­fect­ing an­tibi­ot­ic stew­ard­ship, track rates of drug re­sis­tance, and fix the ‘bro­ken’ mar­ket for an­tibi­otics.

While bac­te­r­i­al pathogens mu­tate and grow re­sis­tant to the ex­ist­ing crop of an­tibi­otics, dri­ven by un­bri­dled use in hu­mans and live­stock — the in­dus­try play­ers con­tribut­ing to the ar­se­nal of an­timi­cro­bials are fast dwin­dling, and the pipeline for new an­tibi­otics is em­bar­rass­ing­ly sparse, the WHO has warned.

The US Gov­ern­ment Ac­count­abil­i­ty Of­fice, on Wednes­day, is­sued a re­port en­com­pass­ing da­ta from doc­u­ments and in­ter­views with agency of­fi­cials and ex­perts, find­ing that there are var­i­ous chal­lenges in im­ple­ment­ing ap­pro­pri­ate an­tibi­ot­ic use in the Unit­ed States, for in­stance, fed­er­al re­quire­ments for an­tibi­ot­ic stew­ard­ship pro­grams ap­ply to on­ly cer­tain health care fa­cil­i­ties, and in­cen­tives for doc­tors to adopt an­tibi­ot­ic stew­ard­ship ac­tiv­i­ties are op­tion­al.

Source: GAO, 2020

Click on the im­age to see the full-sized ver­sion

The re­port rec­og­nized that al­though there is a raft of in­cen­tives in place to push drug­mak­ers to de­vel­op an­tibi­otics, such as fund­ing sup­port through the Bio­med­ical Ad­vanced Re­search and De­vel­op­ment Au­thor­i­ty (BAR­DA) and reg­u­la­to­ry re­forms such as the Lim­it­ed Pop­u­la­tion Path­way for An­tibac­te­r­i­al and An­ti­fun­gal Drugs (LPAD) —  there is a des­per­ate need for the pas­sage of “pull in­cen­tives,” or pol­i­cy mea­sures to in­crease the val­ue of a mar­ket­ed an­tibi­ot­ic by re­ward­ing drug­mak­ers on­ly af­ter their an­tibi­ot­ic is ap­proved.

Ex­ist­ing in­cen­tives, “while well-in­ten­tioned…ap­pear to have been in­suf­fi­cient, as they fo­cused ex­clu­sive­ly on bol­ster­ing the de­vel­op­ment pipeline with­out re­mov­ing the block­age cre­at­ed by is­sues with pay­ment,” CMS ad­min­is­tra­tor Seema Ver­ma con­ced­ed last Au­gust.

There has been a slew of bank­rupt­cies in the an­tibi­ot­ic sec­tor, as com­pa­nies see their val­ue go up in smoke as fee­ble sales frus­trat­ed growth. The long, ar­du­ous and ex­pen­sive path to an­tibi­ot­ic ap­proval — com­pli­cat­ed by is­sues of clin­i­cal tri­al en­roll­ment (there are no rapid di­ag­nos­tic tests to iden­ti­fy in­fec­tions,  and it is hard to re­cruit pa­tients in clin­i­cal tri­als to test an­tibi­otics that tar­get re­sis­tant bac­te­ria) of­fers lit­tle fi­nan­cial gain as treat­ments are typ­i­cal­ly priced cheap­ly. The me­di­an an­nu­al sales for brand name an­tibi­otics be­tween 2011 and 2015 ranged from $24 mil­lion to $75 mil­lion, where­as an­nu­al sales for most new, brand-name on­col­o­gy drugs were more than $500 mil­lion dur­ing the same pe­ri­od, the GAO re­port said.

For one of the biggest threats to glob­al health, the li­on’s share of an­tibi­ot­ic de­vel­op­ment is now tak­ing place in a hand­ful of labs of small bio­phar­ma com­pa­nies as a ma­jor­i­ty of their larg­er coun­ter­parts fo­cus on more lu­cra­tive en­deav­ors such as on­col­o­gy. Big Phar­ma has large­ly re­treat­ed from an­tibi­otics, and on­ly a hand­ful re­main in the space — in­clud­ing Mer­ck, Roche and GSK — down from more than 20 in the 1980s.

For­mer FDA com­mis­sion­er Scott Got­tlieb, in 2018, sug­gest­ed a “li­cens­ing mod­el” in which acute care in­sti­tu­tions that pre­scribe an­timi­cro­bial med­i­cines pay a fixed li­cens­ing fee for ac­cess to these drugs, grant­i­ng them the right to use a cer­tain num­ber of an­nu­al dos­es. Last year, the CMS un­veiled a pro­pos­al to re­struc­ture the pay­ment ap­pa­ra­tus to res­cue ex­ist­ing an­tibi­ot­ic man­u­fac­tur­ers, by clas­si­fy­ing drug re­sis­tance in a way that would com­pel high­er pay­ments to hos­pi­tals treat­ing pa­tients with an­timi­cro­bial re­sis­tance, and craft­ing a path­way for doc­tors to pre­scribe ap­pro­pri­ate new an­tibi­otics with­out dis­rupt­ing hos­pi­tal bud­gets. Un­der the cur­rent sys­tem, hos­pi­tals bun­dle to­geth­er the costs of all the ser­vices for a giv­en di­ag­no­sis, which tends to in­cen­tivize hos­pi­tals to pre­scribe cheap­er, gener­ic an­tibi­otics that are not en­gi­neered to tack­le drug-re­sis­tant in­fec­tions.

The GAO made 8 rec­om­men­da­tions fix the myr­i­ad of prob­lems, in­clud­ing that the CDC should de­vel­op a plan for con­sol­i­dat­ed re­ports of an­tibi­ot­ic re­sis­tance in pri­or­i­ty pathogens at reg­u­lar in­ter­vals; the HHS should iden­ti­fy lead­er­ship and clar­i­fy roles and re­spon­si­bil­i­ties among HHS agen­cies to as­sess the clin­i­cal out­comes of di­ag­nos­tic test­ing for iden­ti­fy­ing an­tibi­ot­ic-re­sis­tant bac­te­ria; and im­por­tant­ly that the HHS should come up with a strate­gic frame­work to fur­ther in­cen­tivize an­tibi­otics for drug-re­sis­tant in­fec­tions, in­clud­ing through the use of post­mar­ket fi­nan­cial in­cen­tives.

Each rec­om­men­da­tion apart from the post­mar­ket fi­nan­cial in­cen­tives was ac­cept­ed by the var­i­ous agen­cies. “HHS not­ed that, while it agrees that ad­di­tion­al in­cen­tives are need­ed to ad­dress the lim­it­ed pipeline for nov­el and in­no­v­a­tive treat­ments to com­bat an­tibi­ot­ic re­sis­tance, it is still con­duct­ing analy­ses to un­der­stand whether post­mar­ket in­cen­tives should be in­clud­ed as a com­po­nent of its forth­com­ing strate­gic frame­work to fur­ther in­cen­tivize the de­vel­op­ment of new treat­ments. How­ev­er, HHS did not spec­i­fy when its frame­work would be re­leased,” the GAO re­port said.

The au­thors, how­ev­er, stood by their call: “We be­lieve our rec­om­men­da­tion is still war­rant­ed.”

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