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.

Robert Bradway (Photographer: Scott Eisen/Bloomberg via Getty Images)

UP­DAT­ED: Am­gen snaps up can­cer drug play­er Five Prime, adding PhI­II-ready FGFR2b drug in $2B M&A play

Amgen is making a long-awaited move on the M&A side, buying South San Francisco-based Five Prime $FPRX for close to $2 billion and adding a slate of new cancer drugs to the pipeline.

Amgen is paying $38 a share, putting the deal value at $1.9 billion. The stock closed at $21.26 last night, giving investors a 78% premium.

The jewel in the crown of this deal is bemarituzumab, which Amgen describes as a first-in-class, Phase III-ready anti-FGFR2b antibody. Amgen was drawn to the bargaining table by Five Prime’s mid-stage data on gastric cancer, satisfied by PFS and OS data helping to validate FGFR2b as a target. Amgen researchers will now expand on the R&D program in other epithelial cancers, including lung, breast, ovarian and other cancers.

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David Liu (Casey Atkins Photography courtesy Broad Institute)

David Liu has a new big idea: pro­teome edit­ing. It could one day shred tau, RAS and some of the worst dis­ease-caus­ing pro­teins

Before David Liu became famous for inventing new forms of gene editing, he was known around academia in part for a more obscure innovation: a Rube Goldberg-esque system that uses bacteria-infecting viruses to take one protein and turn it into another.

Since 2011, Liu’s lab has used the system, called PACE, to dream up fantastical new proteins: DNA base editors far more powerful than the original; more versatile forms of the gene editor Cas9; insecticides that kill insecticide-resistant bugs; enzymes that slide synthetic amino acids into living organisms. But they struggled throughout to master one of the most common and powerful proteins in the biological world: proteases, a set of Swiss army knife enzymes that cut, cleave or shred other proteins in everything from viruses to humans.

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The 2021 top 100 bio­phar­ma in­vestors: As the pan­dem­ic hit and IPOs boomed, VCs swung in­to ac­tion like nev­er be­fore

The global pandemic may have roiled economies, killed hundreds of thousands and throttled entire industries, but the only effect it had on biopharma venture investing was to help turbocharge the field to giddy new heights.

Below you’ll find the new top 100 venture investors in the industry, ranked by the number of deals they were publicly involved in, as tracked by DealForma chief Chris Dokomajilar. The numbers master then calculated the estimated amount of money they put into each deal — divvying up the cash by the number of players — to indicate how they managed their syndicates.

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UP­DAT­ED: Mer­ck pulls Keytru­da in SCLC af­ter ac­cel­er­at­ed nod. Is the FDA get­ting tough on drug­mak­ers that don't hit their marks?

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Merck has withdrawn its marketing approval for PD-(L)1 inhibitor Keytruda in metastatic small cell lung cancer as part of what it describes as an “industry-wide evaluation” by the FDA of drugs that do not meet the post-marketing checkpoints on which their accelerated nods were based, the company said Monday.

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Pfiz­er's Xalko­ri fol­low-up, which smoked the old­er drug in 1st-line pa­tients, scores dou­ble win at the FDA

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It’s clear by now that biopharma experienced a massive boom in 2020, but a new report out Thursday says the Massachusetts hub was particularly successful.

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Amid back of­fice con­sol­i­da­tion, Gilead ax­es 179 jobs in Cal­i­for­nia

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Up to half of the roles would shift to Research Triangle Park, where the company is setting up a new business services and information technology center, the San Francisco Chronicle reported. The precise number will depend on how many employees choose to relocate.

Per a WARN notice filed with the state, the layoffs are expected to be effective May 30.