EMA coun­ters the aca­d­e­mics who crit­i­cized the can­cer drug ap­proval process

As more can­cer drugs are ap­proved and prices con­tin­ue to rise, ques­tions have cir­cu­lat­ed on whether these drugs are ex­tend­ing pa­tient sur­vival or im­prov­ing qual­i­ty of life. A re­search ar­ti­cle pub­lished in the BMJ last week re­viewed the ap­proval of drugs by the EMA from 2009 to 2013 and not­ed that most drugs en­tered the mar­ket with­out ev­i­dence of sur­vival ben­e­fits or QoL. But rather than re­fute the BMJ ar­ti­cle’s find­ings in a re­sponse pub­lished Thurs­day, Francesco Pig­nat­ti, head of on­col­o­gy, hema­tol­ogy and di­ag­nos­tics at the EMA, wrote that the ar­ti­cle’s find­ings “are not sur­pris­ing to any­one fa­mil­iar with can­cer drug de­vel­op­ment.”

Vinay Prasad

The BMJ re­search is part of a large and grow­ing num­ber of ques­tions cir­cu­lat­ing on gains made with re­cent can­cer drug ap­provals. “When there were sur­vival gains over ex­ist­ing treat­ment op­tions or place­bo, they were of­ten mar­gin­al,” the UK and Lat­vian pro­fes­sors who con­duct­ed the re­search not­ed in its con­clu­sion.

Vinay Prasad, as­sis­tant pro­fes­sor of med­i­cine at Ore­gon Health and Sci­ence Uni­ver­si­ty, has been a vo­cal crit­ic of the wave of re­cent ap­provals and wrote the ac­com­pa­ny­ing ed­i­to­r­i­al to the BMJ ar­ti­cle, in which he called the reg­u­la­to­ry sys­tem “bro­ken.” He’s pre­vi­ous­ly writ­ten in Fo­cus on how most can­cer drugs “cost too much and give us too lit­tle” in re­sponse to an op-ed in Fo­cus on a JA­MA study he co-au­thored.

Back in June, Richard Paz­dur, FDA’s di­rec­tor of the On­col­o­gy Cen­ter of Ex­cel­lence, al­so dis­cussed in a blog post how to mea­sure pa­tient ben­e­fit with can­cer treat­ment.

EMA Re­sponse

Francesco Pig­nat­ti

Pig­nat­ti of­fered four rea­sons why in many sit­u­a­tions “demon­strat­ing a clear ef­fect on sur­vival or QoL is not fea­si­ble and a ben­e­fit can be shown on the ba­sis of oth­er end­points”:

  1. Over­all sur­vival may be dif­fi­cult to de­tect be­cause con­trol-group pa­tients in a ran­dom­ized clin­i­cal tri­al “switch to the ex­per­i­men­tal treat­ment af­ter pro­gres­sion, or mul­ti­ple sub­se­quent lines of ef­fec­tive treat­ments ‘di­lute’ the ef­fect of a drug used in ear­li­er lines.” In such cas­es, EMA says, pro­gres­sion-free sur­vival (de­fined as “the time dur­ing which treat­ment can in­duce and main­tain a re­sponse or at least de­lay the growth of can­cer”) has been the ef­fi­ca­cy out­come used for ap­proval.
  2. When tu­mor shrink­age and re­sponse du­ra­tion are ob­served on the ba­sis of a sin­gle-arm tri­al in a well-de­fined pop­u­la­tion with high un­met need, RCTs can be con­sid­ered un­eth­i­cal or in­fea­si­ble, and ear­ly ap­proval mech­a­nisms are used. Though he cau­tions that this “ap­plies to a mi­nor­i­ty of cas­es and re­quires that the course of the dis­ease is high­ly pre­dictable, that there are no good ther­a­peu­tic al­ter­na­tives and that there are suf­fi­cient sup­port­ive clin­i­cal and non-clin­i­cal da­ta to show a pos­i­tive ben­e­fit-risk bal­ance.”
  3. In terms of QoL, he notes that this “is rarely used as the pri­ma­ry ef­fi­ca­cy end­point in can­cer clin­i­cal tri­als and con­vinc­ing clin­i­cal ben­e­fits in terms of QoL are on­ly rarely shown. This, how­ev­er, does not mean that EMA does not val­ue such stud­ies, which are en­cour­aged even if of­ten they do not lead to ro­bust con­clu­sions.”
  4. And fi­nal­ly, he notes that “gi­ant leaps” in ben­e­fits are “rel­a­tive­ly rare” and the Eu­ro­pean So­ci­ety for Med­ical On­col­o­gy Mag­ni­tude of Clin­i­cal Ben­e­fit Scale used by the re­searchers in the BMJ ar­ti­cle “was nev­er de­signed for the pur­pose of clin­i­cal de­ci­sion-mak­ing and was main­ly con­struct­ed on the ba­sis of on­col­o­gists’ views rather than a sys­tem­at­ic eval­u­a­tion of pa­tient pref­er­ences.”

Pig­nat­ti adds that con­duct­ing tri­als “ac­cord­ing to the most rig­or­ous method­ol­o­gy is strong­ly en­cour­aged” but is not “a pre-req­ui­site for ap­proval pro­vid­ed that ex­ist­ing un­cer­tain­ties can be ad­dressed on the ba­sis of the to­tal­i­ty of the da­ta, in­clud­ing fu­ture stud­ies, where ap­pro­pri­ate … re­strict­ing ap­provals of can­cer drugs on­ly to sit­u­a­tions where there is in­dis­putable ev­i­dence of im­prove­ment in sur­vival or QoL will not im­prove the lives of can­cer pa­tients.”


First pub­lished here. Reg­u­la­to­ry Fo­cus is the flag­ship on­line pub­li­ca­tion of the Reg­u­la­to­ry Af­fairs Pro­fes­sion­als So­ci­ety (RAPS), the largest glob­al or­ga­ni­za­tion of and for those in­volved with the reg­u­la­tion of health­care and re­lat­ed prod­ucts, in­clud­ing med­ical de­vices, phar­ma­ceu­ti­cals, bi­o­log­ics and nu­tri­tion­al prod­ucts. Email news@raps.org for more in­for­ma­tion.

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Thomas Schall, ChemoCentryx CEO (file photo)

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