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.

5AM Ven­tures: Fu­el­ing the Next Gen­er­a­tion of In­no­va­tors

By RBC Capital Markets
With Andy Schwab, Co-Founder and Managing Partner at 5AM Ventures

Key Points

Prescription Digital Therapeutics, cell therapy technologies, and in silico medicines will be a vital part of future treatment modalities.
Unlocking the potential of the microbiome could be the missing link to better disease diagnosis.
Growing links between academia, industry, and venture capital are spinning out more innovative biotech companies.
Biotech is now seen by investors as a growth space as well as a safe haven, fuelling the recent IPO boom.

Hal Barron, GSK via YouTube

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Janet Woodcock (AP Images)

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Charlie Fuchs, Roche and Genentech global head of product development for oncology and hematology (Yale Cancer Center)

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Jonathan Weissman (MIT)

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Michelle McMurry-Heath, BIO CEO (BIO via YouTube)

BIO looks to re­struc­ture, lay­ing off staff amid chal­lenge to the trade org's nor­mal face-to-face style

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Janet Woodcock and Joshua Sharfstein (AP, Images)

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