Al­most half of all new drug ap­provals in 2018 re­lied on one clin­i­cal tri­al

Back in the 1970s and 1980s, the FDA made clear that at least two ad­e­quate and well-con­trolled stud­ies were nec­es­sary to es­tab­lish a new drug’s ef­fec­tive­ness, ex­cept in on­ly the rarest of cir­cum­stances.

Then in 1997, the Food and Drug Ad­min­is­tra­tion Mod­ern­iza­tion Act was passed, and Con­gress clar­i­fied that the FDA may con­sid­er “da­ta from one ad­e­quate and well-con­trolled clin­i­cal in­ves­ti­ga­tion and con­fir­ma­to­ry ev­i­dence” to ap­prove a new drug.

But in guid­ance from 1998, the FDA says that its re­liance on on­ly a sin­gle study “will gen­er­al­ly be lim­it­ed to sit­u­a­tions in which a tri­al has demon­strat­ed a clin­i­cal­ly mean­ing­ful ef­fect on mor­tal­i­ty, ir­re­versible mor­bid­i­ty, or pre­ven­tion of a dis­ease with po­ten­tial­ly se­ri­ous out­come and con­fir­ma­tion of the re­sult in a sec­ond tri­al would be prac­ti­cal­ly or eth­i­cal­ly im­pos­si­ble.”

The agency al­so ex­plains the per­sua­sive­ness of us­ing two stud­ies ver­sus one.

“Whether to re­ly on a sin­gle ad­e­quate and well-con­trolled study is in­evitably a mat­ter of judg­ment. A con­clu­sion based on two per­sua­sive stud­ies will al­ways be more se­cure than a con­clu­sion based on a sin­gle, com­pa­ra­bly per­sua­sive study,” the guid­ance notes.

Aaron Kessel­heim, pro­fes­sor of med­i­cine at Har­vard Med­ical School, told Fo­cus: “His­tor­i­cal­ly, the FDA guid­ance seemed to in­di­cate a pref­er­ence for two ad­e­quate and well-con­trolled tri­als since any sin­gle tri­al may be sub­ject to unan­tic­i­pat­ed or un­de­tect­ed sys­tem­at­ic bi­as­es. Of course, in some cas­es, the clin­i­cal need is high enough or the drug’s ef­fi­ca­cy is pow­er­ful enough that a sin­gle tri­al should be suf­fi­cient at least for ini­tial FDA ap­proval.

“But re­liance on a sin­gle tri­al—par­tic­u­lar­ly if that tri­al is sin­gle-arm, un­blind­ed, or eval­u­ates un­val­i­dat­ed sur­ro­gate mea­sures as the end­point—in­creas­es the risk to pa­tients that the drug may not work as well as ex­pect­ed (or, sep­a­rate­ly, may have safe­ty is­sues that out­weigh its ben­e­fits).  It would be use­ful to clear­ly in­form pa­tients when a new drug is ap­proved on the ba­sis of a sin­gle piv­otal tri­al and fol­low those drugs more close­ly af­ter ap­proval, with the idea of for­mal­ly re­vis­it­ing their ben­e­fit-risk bal­ance in the fu­ture. But stud­ies un­for­tu­nate­ly show that post­mar­ket re­quire­ments are of­ten not fol­lowed up com­plete­ly or in a time­ly fash­ion,” Kessel­heim added.

Ap­provals Based on a Sin­gle Tri­al

Ac­cord­ing to a 2014 JA­MA study, be­tween 2005 and 2012, the FDA ap­proved 188 nov­el ther­a­peu­tic agents for 206 in­di­ca­tions, and 74 in­di­ca­tions (36.8%) were ap­proved on the ba­sis of a sin­gle piv­otal tri­al.

Most re­cent­ly, IQVIA re­leased a re­port find­ing that 25 of 59 (42%) nov­el drugs ap­proved in 2018 were ap­proved on the ba­sis of on­ly one tri­al. And one out of eight ap­provals re­lied on­ly on Phase 1 or 2 tri­als, with no Phase 3 tri­als. But as in pre­vi­ous years, a large por­tion of the drugs re­ly­ing on on­ly one tri­al were new or­phan and can­cer drugs.

For in­stance, As­traZeneca’s or­phan drug Lu­mox­i­ti (mox­e­tu­momab pa­su­do­tox-td­fk) was ap­proved in Sep­tem­ber 2018 based on one tri­al of less than 100 pa­tients with a rare, slow-grow­ing blood can­cer. Stem­line Ther­a­peu­tics al­so won ap­proval in De­cem­ber 2018 for El­zon­ris (tagrax­o­fusp-erzx) to treat a rare, rapid­ly pro­gress­ing can­cer of the bone mar­row and blood af­ter con­duct­ing one tri­al of 94 pa­tients in the US.

Oth­er can­cer drugs, mean­while, won ap­proval af­ter larg­er sin­gle tri­als.

Pfiz­er’s Viz­im­pro (da­comi­tinib), for ex­am­ple, was ap­proved in Sep­tem­ber 2018 on the ba­sis of one clin­i­cal tri­al of 452 pa­tients with ad­vanced non-small cell lung can­cer in Asia. Ar­ray Bio­phar­ma’s Braftovi (en­co­rafenib) was ap­proved in June 2018 on ev­i­dence from one clin­i­cal tri­al of 383 pa­tients with BRAF V600 mu­ta­tion-pos­i­tive melanoma that was ad­vanced or could not be re­moved by surgery. The tri­al was con­duct­ed at 162 sites in Eu­rope, North Amer­i­ca and else­where.

And Ad­vanced Ac­cel­er­a­tor Ap­pli­ca­tions’ Lu­tathera (lutetium 177 dotate) was ap­proved based on one tri­al of 229 pa­tients with a spe­cif­ic type of rare tu­mor at 41 sites in Bel­gium, France, Ger­many, Italy, Por­tu­gal, Spain, UK and the US.

But not all the new drugs ap­proved in 2018 based on one clin­i­cal tri­al were can­cer treat­ments. For in­stance, Achao­gen’s Zem­dri (pla­zomicin) was ap­proved in June 2018 as a com­pli­cat­ed uri­nary tract in­fec­tion treat­ment based on one tri­al of 604 pa­tients in Eu­rope, the US and Mex­i­co.

Paratek Phar­ma­ceu­ti­cals al­so won ap­proval for its an­tibac­te­r­i­al med­i­cine Nuzyra (omada­cy­cline) in Oc­to­ber 2018 on the ba­sis of a sin­gle tri­al of 774 pa­tients with com­mu­ni­ty ac­quired bac­te­r­i­al pneu­mo­nia at 86 sites in Asia, Eu­rope, Is­rael, Latin Amer­i­ca, South Africa and the US.

But Kessel­heim said he does not think this is a re­cent shift to the use of one piv­otal tri­al, and he did not know if the 42% fig­ure from 2018 “is a sign that the num­ber is creep­ing high­er or just nor­mal year to year fluc­tu­a­tion.”

The IQVIA re­port al­so re­ports a slight uptick in the num­ber of piv­otal tri­als in 2018 be­ing ran­dom­ized con­trolled tri­als com­pared to pre­vi­ous years and that ac­tive con­trol arms were more com­mon in 2018 than re­cent past years.

The Chang­ing Land­scape of Re­search and De­vel­op­ment


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.

Author

Zachary Brennan

managing editor, RAPS

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Christos Kyratsous (via LinkedIn)

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Kristen Pascal (Regeneron)

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