An­tibac­te­rial ap­provals lag

New law of­fers in­cen­tives to de­velop an­tibi­otics

Modern Healthcare - - FRONT PAGE - Jaimy Lee

Apa­tient balks at paying $50 for a dose of an­tibi­otics. How­ever, that same pa­tient has no is­sue paying $50,000 for an on­col­ogy drug that may ex­tend life for a few weeks. This ex­am­ple, in one form or an­other, is re­counted by drug man­u­fac­tur­ers, physi­cians and pa­tient groups that are ad­vo­cat­ing for changes in how an­tibac­te­rial drugs are devel­oped, ap­proved, priced and mon­i­tored.

Few in­cen­tives ex­ist for drug­mak­ers de­vel­op­ing an­tibi­otics. The sci­ence is dif­fi­cult, the reg­u­la­tory process has chal­leng­ing clin­i­cal re­quire­ments, and the prices of drugs on the mar­ket are low.

“Those three things com­bined put us into the an­tibi­otic mar­ket fail­ure that we have now,” said Dr. Brad Spell­berg, as­so­ciate pro­fes­sor of medicine at the Los An­ge­les Bio­med­i­cal Re­search In­sti­tute at Har­bor-UCLA Med­i­cal Cen­ter in Tor­rance, Calif.

Even as the ex­cess health­care costs for an­tibi­otic-re­sis­tant in­fec­tions have grown to $20 bil­lion, drug devel­op­ment in this sec­tor has de­clined.

A new law that pro­vides fi­nan­cial in­cen- tives to man­u­fac­tur­ers de­vel­op­ing an­tibi­otics and re­quires the Food and Drug Ad­min­is­tra­tion to is­sue new guid­ance on how cer­tain an­tibi­otics are ap­proved has set the stage for a new reg­u­la­tory path­way that may be sim­i­lar to the suc­cess­ful or­phan-drug devel­op­ment pro­gram.

The mar­ket for or­phan drugs, which tar­get rare dis­eases af­fect­ing fewer than 200,000 pa­tients in the U.S., is boom­ing. Nine of the 35 new drugs ap­proved by the FDA dur­ing fis­cal 2012 were or­phan drugs, many of which cost $10,000 or more a month.

“It’s not iden­ti­cal to or­phan drugs, but many of the prin­ci­ples that de­fine why we have or­phan drug leg­is­la­tion do ap­ply to ar­eas of un­met need of an­tibac­te­rial ther­apy,” Spell­berg said.

The law, which passed in 2012 as a pro­vi­sion in the Food and Drug Ad­min­is­tra­tion Safety and In­no­va­tion Act, seeks to stream­line devel­op­ment of cer­tain an­tibac­te­rial drugs. It also pro­vides pri­or­ity re­view, fast-track el­i­gi­bil­ity and ex­tended ex­clu­siv­ity pe­ri­ods to man­u­fac­tur­ers with drugs that are des­ig­nated “qual­i­fied in­fec­tious disease prod­ucts.”

Two drugs devel­oped by Cu­bist Phar­ma­ceu­ti­cals, a Lex­ing­ton, Mass.-based bio­phar­ma­ceu­ti­cal com­pany, re­ceived those des­ig­na­tions in De­cem­ber. Both drugs are

in phase 3 clin­i­cal tri­als.

“Although th­ese in­fec­tions are get­ting more and more com­mon, and more and more wor­ri­some, they’re still not yet at the level of epi­demic where in­dus­try can eas­ily do a large phase 3 trial on that highly re­sis­tant group of or­gan­isms,” said Dr. Barry Eisen­stein, se­nior vice pres­i­dent of sci­en­tific af­fairs for Cu­bist Phar­ma­ceu­ti­cals. “The nor­mal path­ways to get ap­provals for new drugs, par­tic­u­larly new an­tibi­otics, are not avail­able” for drug-re­sis­tant in­fec­tions.

Eisen­stein and ex­ec­u­tives at six other drug com­pa­nies pro­posed a new reg­u­la­tory frame­work that they say will im­prove devel­op­ment of new an­tibac­te­rial treat­ments for un­met needs, in part by al­low­ing smaller pop­u­la­tions in clin­i­cal tri­als.

The frame­work has four tiers, which would al­low for vary­ing indi­ca­tions, la­bels and ef­fi­cacy re­quire­ments. Only one of the tiers would re­quire two ran­dom­ized, con­trolled clin­i­cal tri­als, the stan­dard re­quire­ment for new drug ap­provals in the U.S.

“Although his­tor­i­cally an­tibi­otics have not qual­i­fied for or­phan drug-based reg­is­tra­tion, we pro­pose the ap­pli­ca­tion of suc­cess­ful ideas from reg­is­tra­tion of or­phan drug prod­ucts and other ex­ist­ing suc­cess­ful reg­u­la­tory frame­works to ad­dress the chal­lenges of an­tibi­otic drug devel­op­ment,” the ex­ec­u­tives wrote in the Jan­uary is­sue of the Lancet.

Price is an­other is­sue that may align the or­phan drug and an­tibi­otic mar­kets. The prices of an­tibi­otics ap­proved to treat a nar­row sub­set of pa­tients will in­crease markedly, Robert Gui­dos, vice pres­i­dent of pub­lic pol­icy and government re­la­tions for the In­fec­tious Dis­eases So­ci­ety of Amer­ica, said dur­ing a meet­ing con­vened last week by the Pew Char­i­ta­ble Trusts.

“Cre­at­ing sce­nar­ios in which there is a pric­ing pre­mium placed on an­tibac­te­ri­als is prob­a­bly the sin­gle big­gest fi­nan­cial in­cen­tive that one could cre­ate,” Spell­berg said. “That would have a tremen­dous im­pact.”

The FDA plans to hold a hear­ing this week to gather in­for­ma­tion on de­vel­op­ing a new ap­proval path­way for drugs tar­get­ing se­ri­ous or life-threat­en­ing con­di­tions that ad­dress an un­met med­i­cal need, in­clud­ing an­tibi­otics.

Even as the FDA eval­u­ates a new path­way for an­tibi­otics, a step that is likely to im­prove a weak pipe­line of new drugs, other ques­tions per­sist about post­mar­ket mon­i­tor­ing, off-la­bel pre­scrib­ing and the agency’s role in stem­ming fur­ther an­timi­cro­bial re­sis­tance.

“The chal­lenge for pub­lic pol­icy is how you in­cen­tivize new drugs but in a way that you don’t recre­ate the prob­lem of re­sis­tance all over again,” said Ra­manan Laxmi­narayan, di­rec­tor of the Cen­ter for Disease Dy­nam­ics, Eco­nom­ics & Pol­icy, a Washington-based not-for­profit that seeks to im­prove de­ci­sion­mak­ing in health pol­icy. “The FDA is now se­ri­ously start­ing to look at how we can man­age drug ef­fec­tive­ness while at the same time try­ing to get some new drugs in the pipe­line.”

Physi­cians have the dis­cre­tion to pre­scribe off-la­bel uses for drugs. High prices and bet­ter ed­u­ca­tion of physi­cians and health­care providers could de­ter some off-la­bel use of drugs ap­proved un­der a new path­way, drug ex­ec­u­tives said dur­ing the Pew meet­ing. How­ever, hospi­tal of­fi­cials said physi­cians are of­ten un­aware of a drug’s in­di­ca­tion or have not read its la­bel.

Dr. Pranita Tamma, di­rec­tor of pe­di­atric an­timi­cro­bial ste­ward­ship at Johns Hop­kins Hospi­tal in Baltimore, said dur­ing the Pew meet­ing that spe­cial la­bel­ing and high prices are “not enough to en­sure drugs are used ju­di­ciously.”


Test tubes are filled with a so­lu­tion at a re­search fa­cil­ity for Cu­bist Phar­ma­ceu­ti­cals, which makes one of five an­tibac­te­rial agents the FDA ap­proved from 2003-07.

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