FDA should re­assess post­mar­ket tri­als for can­cer drugs ap­proved via ac­cel­er­at­ed path­way, re­searchers say

The FDA may need to re­assess how con­fir­ma­to­ry tri­als are con­duct­ed af­ter just one-fifth of such tri­als for can­cer drug in­di­ca­tions ap­proved via the FDA’s ac­cel­er­at­ed ap­proval path­way have demon­strat­ed im­prove­ments in over­all sur­vival (OS), re­searchers re­port­ed Tues­day in JA­MA In­ter­nal Med­i­cine re­search.

The re­searchers looked at 93 can­cer drug in­di­ca­tions grant­ed ac­cel­er­at­ed ap­proval by the FDA from 1992 through May 2017, find­ing con­fir­ma­to­ry tri­als re­port­ed that 20% had im­prove­ment in over­all sur­vival, 21% had im­prove­ment in a dif­fer­ent sur­ro­gate mea­sure and 20% had im­prove­ment in the same sur­ro­gate mea­sure used in con­fir­ma­to­ry tri­als and preap­proval tri­als.

“Ap­pro­pri­ate use of sur­ro­gates for ac­cel­er­at­ed ap­proval re­quires an ap­pre­ci­a­tion for how the va­lid­i­ty of a sur­ro­gate can vary from one in­di­ca­tion to an­oth­er. One strat­e­gy for cap­tur­ing this vari­abil­i­ty would be to have a con­tin­u­al­ly up­dat­ed data­base of strengths of sur­ro­gate val­i­da­tion across tu­mor types as re­sults from new­er tri­als be­come avail­able,” the re­searchers from the Pro­gram on Reg­u­la­tion, Ther­a­peu­tics, and Law (POR­TAL), Di­vi­sion of Phar­ma­coepi­demi­ol­o­gy and Phar­ma­coeco­nom­ics at Brigham and Women’s Hos­pi­tal and Har­vard Med­ical School said.

They al­so called to adapt the FDA’s re­cent­ly pub­lished list of sur­ro­gate mea­sures to in­clude the strengths of sur­ro­ga­cy val­i­da­tion. “Con­firm­ing the clin­i­cal ben­e­fit of a can­cer drug us­ing the same sur­ro­gate mea­sure as the one used in its preap­proval tri­al should be re­served for when the sur­ro­gate mea­sure for a giv­en in­di­ca­tion has been val­i­dat­ed,” they added.

In ad­di­tion, the re­searchers ad­dressed po­ten­tial crit­ics who may dis­agree that it is im­por­tant to demon­strate an OS ben­e­fit to ver­i­fy a clin­i­cal ben­e­fit. They use the ex­am­ple of ima­tinib for chron­ic myeloid leukemia (CML), which was ap­proved with­out the need to re­port OS ben­e­fit in tri­als.

“How­ev­er, ima­tinib for CML is an atyp­i­cal ex­am­ple of a drug with such huge ben­e­fits that it is con­sid­ered life­sav­ing rather than life pro­long­ing,” they wrote. “Most ap­proved can­cer drugs fall in­to the lat­ter cat­e­go­ry, and as a re­sult, even im­pres­sive ef­fects on sur­ro­gate mea­sures may not trans­late to ex­tend­ed sur­vival ben­e­fits. Thus, al­though im­prove­ment in sur­ro­gate mea­sures alone may be ac­cept­able for ac­cel­er­at­ed ap­proval, the con­fir­ma­to­ry tri­als should ver­i­fy the clin­i­cal ben­e­fit in terms of ben­e­fits in OS, qual­i­ty of life, or a valid sur­ro­gate of ei­ther.

“Re­assess­ment of the re­quire­ments for con­fir­ma­to­ry tri­als may be nec­es­sary to ob­tain more clin­i­cal­ly mean­ing­ful in­for­ma­tion,” they added. “FDA should adopt a con­sis­tent ap­proach re­gard­ing the re­sults of con­fir­ma­to­ry tri­als to help physi­cians and pa­tients bet­ter un­der­stand what con­sti­tutes ver­i­fi­ca­tion of ben­e­fit.”

Com­men­taries

In a com­men­tary ac­com­pa­ny­ing the study and a sec­ond study on can­cer drugs ap­proved based on re­sponse rates, pro­fes­sors from the Perel­man School of Med­i­cine at the Uni­ver­si­ty of Penn­syl­va­nia crit­i­cize the FDA for call­ing the ac­cel­er­at­ed ap­proval process a suc­cess be­cause on­ly 5% of con­fir­ma­to­ry tri­als failed.

“FDA is con­grat­u­lat­ing it­self, us­ing its own ‘sur­ro­gate’ end points, which it can al­ter to demon­strate that its poli­cies are suc­ceed­ing. This low rate of with­drawals is not a valid mea­sure of suc­cess. There is no good rea­son for the FDA to re­ly so heav­i­ly on ac­cel­er­at­ed ap­proval us­ing re­sponse rates or oth­er un­re­li­able sur­ro­gate end­points,” they write.

They al­so point to three nec­es­sary pol­i­cy changes: “First, the end­point for con­fir­ma­to­ry tri­als should nev­er be the same sur­ro­gate end­point used in the orig­i­nal study, and a new sur­ro­gate end­point should be used on­ly if there is a proven cor­re­la­tion be­tween that end­point and over­all sur­vival or im­proved qual­i­ty of life. Most con­fir­ma­to­ry tri­als should use over­all sur­vival and/or qual­i­ty-of-life end­points.

“Sec­ond, ap­proval of drugs should be rapid­ly with­drawn when con­fir­ma­to­ry tri­als re­port se­ri­ous tox­ic ef­fects or do not re­port mean­ing­ful clin­i­cal im­prove­ments. Fi­nal­ly, the con­fir­ma­to­ry tri­als must be con­duct­ed prompt­ly, with cred­i­ble threats of re­versed ap­proval. Hav­ing more than a quar­ter of tri­als in­com­plete years af­ter ac­cel­er­at­ed ap­proval is un­ac­cept­able,” they add.

An­oth­er com­men­tary from a pro­fes­sor at Yale School of Med­i­cine and a pro­fes­sor at the Uni­ver­si­ty of Birm­ing­ham in the UK ex­plain how the find­ings from the two stud­ies “build on a grow­ing body of work, which in ag­gre­gate, demon­strate a post­mar­ket­ing eval­u­a­tion process that is serv­ing nei­ther pa­tients nor so­ci­ety well.”

As­sess­ment of the Clin­i­cal Ben­e­fit of Can­cer Drugs Re­ceiv­ing Ac­cel­er­at­ed Ap­proval

An Overview of Can­cer Drugs Ap­proved by the US Food and Drug Ad­min­is­tra­tion Based on the Sur­ro­gate End Point of Re­sponse Rate

Ac­cel­er­at­ed Ap­proval of Can­cer Drugs—Right­ing the Ship of the US Food and Drug Ad­min­is­tra­tion

An In­ter­na­tion­al Per­spec­tive on Drugs for Can­cer


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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