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

Amarin CEO John Thero discussing the company's plans for Vascepa, August 2019 — via Bloomberg

Amarin wins a block­buster ap­proval from the FDA. Now every­one can shift fo­cus to the patent

For all those people who could never quite believe that Amarin $AMRN would get an expanded label with blockbuster implications, the stress and anxiety on display right up to the last minute on Twitter can now end. But new, pressing questions will immediately surface now that the OK has come through.

On Friday afternoon, the FDA stamped its landmark approval on the industrial strength fish oil for reducing cardio risks for a large and well defined population of patients. The approval doesn’t give Amarin everything it wants in expanding its use, losing out on the primary prevention group, but it goes a long way to doing what the company needed to make a major splash. The approval was cited for patients with “elevated triglyceride levels (a type of fat in the blood) of 150 milligrams per deciliter or higher. Patients must also have either established cardiovascular disease or diabetes and two or more additional risk factors for cardiovascular disease.”

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 67,600+ biopharma pros reading Endpoints daily — and it's free.

Sarep­ta was stunned by the re­jec­tion of Vyondys 53. Now it's stun­ning every­one with a sur­prise ac­cel­er­at­ed ap­proval

Sarepta has a friend in the FDA after all. Four months after the agency determined that it would be wrong to give Sarepta an accelerated approval for their Duchenne MD drug golodirsen, regulators have executed a stunning about face and offered the biotech a quick green light in any case.

It was the agency that first put out the news late Thursday, announcing that Duchenne MD patients with a mutation amenable to exon 53 skipping will now have their first targeted treatment: Vyondys 53, or golodirsen. Having secured the OK via a dispute resolution mechanism, the biotech said the new drug has been priced on par with their only other marketed drug, Exondys 51 — which for an average patient costs about $300,000 per year, but since pricing is based on weight, that sticker price can even cross $1 million.

Sarepta shares $SRPT surged 23% after-market to $124.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 67,600+ biopharma pros reading Endpoints daily — and it's free.

Paul Hudson, Getty Images

UP­DAT­ED: Sanofi CEO Hud­son lays out new R&D fo­cus — chop­ping di­a­betes, car­dio and slash­ing $2B-plus costs in sur­gi­cal dis­sec­tion

Earlier on Monday, new Sanofi CEO Paul Hudson baited the hook on his upcoming strategy presentation Tuesday with a tell-tale deal to buy Synthorx for $2.5 billion. That fits squarely with hints that he’s pointing the company to a bigger future in oncology, which also squares with a major industry tilt.

In a big reveal later in the day, though, Hudson offered a slate of stunners on his plans to surgically dissect and reassemble the portfoloio, saying that the company is dropping cardio and diabetes research — which covers two of its biggest franchise arenas. Sanofi missed the boat on developing new diabetes drugs, and now it’s pulling out entirely. As part of the pullback, it’s dropping efpeglenatide, their once-weekly GLP-1 injection for diabetes.

“To be out of cardiovascular and diabetes is not easy for a company like ours with an incredibly proud history,” Hudson said on a call with reporters, according to the Wall Street Journal. “As tough a choice as that is, we’re making that choice.”

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 67,600+ biopharma pros reading Endpoints daily — and it's free.

Paul Biondi (File photo)

Paul Biondi's track record at Bris­tol-My­ers cov­ered bil­lions in deals of every shape and size. Here's the com­plete break­down

Paul Biondi was never afraid to bet big during his stint as business development chief at Bristol-Myers Squibb. And while the gambles didn’t all pay out, by any means, his roster of pacts illustrates the broad ambitions the pharma giant has had over the last 5 years — capped by the $74 billion Celgene buyout.

On Thursday, we learned that Biondi had exited the company. And Chris Dokomajilar at DealForma came up with the complete breakdown on every buyout, licensing pact and product purchase Bristol-Myers forged during his tenure in charge of the BD team at one of the busiest companies in biopharma.

Endpoints Premium

Premium subscription required

Unlock this article along with other benefits by subscribing to one of our paid plans.

Arie Belldegrun (Photo: Jeff Rumans for Endpoints News)

Ju­ry finds Gilead li­able for $585M and big roy­al­ties in Kite CAR-T patent case

A Kite deal that’s already become a burden on Gilead’s back just got heavier as a California jury has ruled Gilead must pay Bristol-Myers Squibb and Sloan Kettering $585 million plus a 27.6% royalty for patent infringement committed by its subsidiary. The ruling is almost certain to be appealed.

Kite Pharma — founded by Arie Belldegrun, now focused on a next-gen CAR-T company — has been facing a lawsuit since the day its first CAR–T therapy won approval in October, 2017. Juno Therapeutics and Sloan Kettering filed a complaint saying Kite had copied its technology. Gilead acquired Kite in June of that year for $11.9 billion.  Juno was acquired the following year by Celgene for $9 billion, before Celgene was acquired by Bristol-Myers Squibb in 2019.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 67,600+ biopharma pros reading Endpoints daily — and it's free.

FDA ex­pert pan­el unan­i­mous­ly rec­om­mends ap­proval for Hori­zon Ther­a­peu­tics eye drug

An FDA advisory committee noted with concern a small safety database but unanimously endorsed a Horizon Therapeutics drug for a rare eye autoimmune disease that can blind patients: teprotumumab for thyroid eye disease (TED).

“It was a pretty easy vote,” said Erica Brittain, an NIH biostatistician and one of the 12 panelists on FDA’s Dermatologic and Ophthalmic Drugs Advisory Committee.

Paul Biondi (File photo)

Bris­tol-My­er­s' strat­e­gy, BD chief Paul Bion­di ex­it­ed the com­pa­ny — just ahead of the $74B Cel­gene deal close

Paul Biondi, who orchestrated billions of dollars in deals for Bristol-Myers Squibb over the 5 years he’s run their business development team, has exited the company. Biondi left last month, according to a company spokesperson, in pursuit of another — unspecified — external opportunity.

After 17 years with Bristol-Myers Squibb, Paul Biondi, Head of Strategy and Business Development, decided to leave the company to pursue an external opportunity. The company wishes him well in his new endeavors. Bristol-Myers Squibb  is actively searching for Paul’s successor, and will make an announcement, as appropriate.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 67,600+ biopharma pros reading Endpoints daily — and it's free.

Arie Belldegrun at UKBIO 2019. Shai Dolev for Endpoints News

Kite Phar­ma's ex-CEO con­tra­dicts founder as CAR-T patent tri­al heats up, with con­flict­ing val­u­a­tions

Two days after Kite Pharma founder Arie Belldegrun told a federal courtroom that a meeting he had with a Memorial Sloan Kettering executive wasn’t about licensing their immunotherapy patent, Kite’s ex-CEO Aya Jakobovits said it was.

The admission came Tuesday during cross-examination in a patent infringement case that features two of the biggest cancer biotechs and some of the most well-known names in American medicine.

Jakobovits initially said she was not in attendance, didn’t know it was going to happen and didn’t know what took place, according to Law360. But then the plaintiff’s lawyer handed her a document – whose contents were not publicly revealed – and asked again if she learned after-the-fact that the meeting involved a potential patent license.

“Yes,” Jakobovits eventually said.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 67,600+ biopharma pros reading Endpoints daily — and it's free.

On the heels of promis­ing MCL da­ta, Kite hus­tles its 2nd CAR-T to the FDA as the next big race in the field draws to the fin­ish line

Three days after Gilead’s Kite subsidiary showed off stellar data on their number 2 CAR-T KTE-X19 at ASH, the executive team has pivoted straight to the FDA with a BLA filing and a shot at a near-term approval.

In a small, 74-patient Phase II trial reported out at the beginning of the week, investigators tracked a 93% response rate with two out of three mantle cell lymphoma patients experiencing a complete response.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 67,600+ biopharma pros reading Endpoints daily — and it's free.