FDA should re­assess post­mar­ket tri­als for can­cer drugs ap­proved via ac­cel­er­at­ed path­way, re­searchers say

The FDA may need to re­assess how con­fir­ma­to­ry tri­als are con­duct­ed af­ter just one-fifth of such tri­als for can­cer drug in­di­ca­tions ap­proved via the FDA’s ac­cel­er­at­ed ap­proval path­way have demon­strat­ed im­prove­ments in over­all sur­vival (OS), re­searchers re­port­ed Tues­day in JA­MA In­ter­nal Med­i­cine re­search.

The re­searchers looked at 93 can­cer drug in­di­ca­tions grant­ed ac­cel­er­at­ed ap­proval by the FDA from 1992 through May 2017, find­ing con­fir­ma­to­ry tri­als re­port­ed that 20% had im­prove­ment in over­all sur­vival, 21% had im­prove­ment in a dif­fer­ent sur­ro­gate mea­sure and 20% had im­prove­ment in the same sur­ro­gate mea­sure used in con­fir­ma­to­ry tri­als and preap­proval tri­als.

“Ap­pro­pri­ate use of sur­ro­gates for ac­cel­er­at­ed ap­proval re­quires an ap­pre­ci­a­tion for how the va­lid­i­ty of a sur­ro­gate can vary from one in­di­ca­tion to an­oth­er. One strat­e­gy for cap­tur­ing this vari­abil­i­ty would be to have a con­tin­u­al­ly up­dat­ed data­base of strengths of sur­ro­gate val­i­da­tion across tu­mor types as re­sults from new­er tri­als be­come avail­able,” the re­searchers from the Pro­gram on Reg­u­la­tion, Ther­a­peu­tics, and Law (POR­TAL), Di­vi­sion of Phar­ma­coepi­demi­ol­o­gy and Phar­ma­coeco­nom­ics at Brigham and Women’s Hos­pi­tal and Har­vard Med­ical School said.

They al­so called to adapt the FDA’s re­cent­ly pub­lished list of sur­ro­gate mea­sures to in­clude the strengths of sur­ro­ga­cy val­i­da­tion. “Con­firm­ing the clin­i­cal ben­e­fit of a can­cer drug us­ing the same sur­ro­gate mea­sure as the one used in its preap­proval tri­al should be re­served for when the sur­ro­gate mea­sure for a giv­en in­di­ca­tion has been val­i­dat­ed,” they added.

In ad­di­tion, the re­searchers ad­dressed po­ten­tial crit­ics who may dis­agree that it is im­por­tant to demon­strate an OS ben­e­fit to ver­i­fy a clin­i­cal ben­e­fit. They use the ex­am­ple of ima­tinib for chron­ic myeloid leukemia (CML), which was ap­proved with­out the need to re­port OS ben­e­fit in tri­als.

“How­ev­er, ima­tinib for CML is an atyp­i­cal ex­am­ple of a drug with such huge ben­e­fits that it is con­sid­ered life­sav­ing rather than life pro­long­ing,” they wrote. “Most ap­proved can­cer drugs fall in­to the lat­ter cat­e­go­ry, and as a re­sult, even im­pres­sive ef­fects on sur­ro­gate mea­sures may not trans­late to ex­tend­ed sur­vival ben­e­fits. Thus, al­though im­prove­ment in sur­ro­gate mea­sures alone may be ac­cept­able for ac­cel­er­at­ed ap­proval, the con­fir­ma­to­ry tri­als should ver­i­fy the clin­i­cal ben­e­fit in terms of ben­e­fits in OS, qual­i­ty of life, or a valid sur­ro­gate of ei­ther.

“Re­assess­ment of the re­quire­ments for con­fir­ma­to­ry tri­als may be nec­es­sary to ob­tain more clin­i­cal­ly mean­ing­ful in­for­ma­tion,” they added. “FDA should adopt a con­sis­tent ap­proach re­gard­ing the re­sults of con­fir­ma­to­ry tri­als to help physi­cians and pa­tients bet­ter un­der­stand what con­sti­tutes ver­i­fi­ca­tion of ben­e­fit.”

Com­men­taries

In a com­men­tary ac­com­pa­ny­ing the study and a sec­ond study on can­cer drugs ap­proved based on re­sponse rates, pro­fes­sors from the Perel­man School of Med­i­cine at the Uni­ver­si­ty of Penn­syl­va­nia crit­i­cize the FDA for call­ing the ac­cel­er­at­ed ap­proval process a suc­cess be­cause on­ly 5% of con­fir­ma­to­ry tri­als failed.

“FDA is con­grat­u­lat­ing it­self, us­ing its own ‘sur­ro­gate’ end points, which it can al­ter to demon­strate that its poli­cies are suc­ceed­ing. This low rate of with­drawals is not a valid mea­sure of suc­cess. There is no good rea­son for the FDA to re­ly so heav­i­ly on ac­cel­er­at­ed ap­proval us­ing re­sponse rates or oth­er un­re­li­able sur­ro­gate end­points,” they write.

They al­so point to three nec­es­sary pol­i­cy changes: “First, the end­point for con­fir­ma­to­ry tri­als should nev­er be the same sur­ro­gate end­point used in the orig­i­nal study, and a new sur­ro­gate end­point should be used on­ly if there is a proven cor­re­la­tion be­tween that end­point and over­all sur­vival or im­proved qual­i­ty of life. Most con­fir­ma­to­ry tri­als should use over­all sur­vival and/or qual­i­ty-of-life end­points.

“Sec­ond, ap­proval of drugs should be rapid­ly with­drawn when con­fir­ma­to­ry tri­als re­port se­ri­ous tox­ic ef­fects or do not re­port mean­ing­ful clin­i­cal im­prove­ments. Fi­nal­ly, the con­fir­ma­to­ry tri­als must be con­duct­ed prompt­ly, with cred­i­ble threats of re­versed ap­proval. Hav­ing more than a quar­ter of tri­als in­com­plete years af­ter ac­cel­er­at­ed ap­proval is un­ac­cept­able,” they add.

An­oth­er com­men­tary from a pro­fes­sor at Yale School of Med­i­cine and a pro­fes­sor at the Uni­ver­si­ty of Birm­ing­ham in the UK ex­plain how the find­ings from the two stud­ies “build on a grow­ing body of work, which in ag­gre­gate, demon­strate a post­mar­ket­ing eval­u­a­tion process that is serv­ing nei­ther pa­tients nor so­ci­ety well.”

As­sess­ment of the Clin­i­cal Ben­e­fit of Can­cer Drugs Re­ceiv­ing Ac­cel­er­at­ed Ap­proval

An Overview of Can­cer Drugs Ap­proved by the US Food and Drug Ad­min­is­tra­tion Based on the Sur­ro­gate End Point of Re­sponse Rate

Ac­cel­er­at­ed Ap­proval of Can­cer Drugs—Right­ing the Ship of the US Food and Drug Ad­min­is­tra­tion

An In­ter­na­tion­al Per­spec­tive on Drugs for Can­cer


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.

Im­age: Jacque­lyn Mar­tin AP

Author

Zachary Brennan

managing editor, RAPS

De­vel­op­ment of the Next Gen­er­a­tion NKG2D CAR T-cell Man­u­fac­tur­ing Process

Celyad’s view on developing and delivering a CAR T-cell therapy with multi-tumor specificity combined with cell manufacturing success
Overview
Transitioning potential therapeutic assets from academia into the commercial environment is an exercise that is largely underappreciated by stakeholders, except for drug developers themselves. The promise of preclinical or early clinical results drives enthusiasm, but the pragmatic delivery of a therapy outside of small, local testing is most often a major challenge for drug developers especially, including among other things, the manufacturing challenges that surround the production of just-in-time and personalized autologous cell therapy products.

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 67,300+ biopharma pros reading Endpoints daily — and it's free.

Roger Perlmutter, Merck

#ASH19: Here’s why Mer­ck is pay­ing $2.7B to­day to grab Ar­Qule and its next-gen BTK drug, lin­ing up Eli Lil­ly ri­val­ry

Just a few months after making a splash at the European Hematology Association scientific confab with an early snapshot of positive data for their BTK inhibitor ARQ 531, ArQule has won a $2.7 billion buyout deal from Merck.

Merck is scooping up a next-gen BTK drug — which is making a splash at ASH today — from ArQule in an M&A pact set at $20 a share $ARQL. That’s more than twice Friday’s $9.66 close. And Merck R&D chief Roger Perlmutter heralded a deal that nets “multiple clinical-stage oral kinase inhibitors.”

This is the second biotech buyout pact today, marking a brisk tempo of M&A deals in the lead-up to the big JP Morgan gathering in mid-January. It’s no surprise the acquisitions are both for cancer drugs, where Sanofi will try to make its mark while Merck beefs up a stellar oncology franchise. And bolt-ons are all the rage at the major pharma players, which you could also see in Novartis’ recent $9.7 billion MedCo buyout.

ArQule — which comes out on top after their original lead drug foundered in Phase III — highlighted early data on ‘531 at EHA from a group of 6 chronic lymphocytic leukemia patients who got the 65 mg dose. Four of them experienced a partial response — a big advance for a company that failed with earlier attempts.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 67,300+ biopharma pros reading Endpoints daily — and it's free.

Paul Hudson, Sanofi

Paul Hud­son promis­es a bright new fu­ture at Sanofi, kick­ing loose me-too drugs and fo­cus­ing on land­mark ad­vances. But can he de­liv­er?

Paul Hudson was on a mission Tuesday morning as he stood up to address Sanofi’s new R&D and business strategy.

Still fresh into the job, the new CEO set out to convince his audience — including the legions of nervous staffers inevitably devoting much of their day to listening in — that the pharma giant is shedding the layers of bureaucracy that had held them back from making progress in the past, dropping the duds in the pipeline and reprioritizing a more narrow set of experimental drugs that were promised as first-in-class or best-in-class.  The company, he added, is now positioned to “go after other opportunities” that could offer a transformational approach to treating its core diseases.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 67,300+ biopharma pros reading Endpoints daily — and it's free.

Am­gen puts its foot down in shiny new South San Fran­cis­co hub as it re­or­ga­nizes R&D ops

Amgen has signed up to be AbbVie’s neighbor in South San Francisco as it moves into a nine-story R&D facility in the booming biotech hub.

The arrangement gives Amgen 240,000 square feet of space on the Gateway of Pacific Campus, just a few minutes drive from its current digs at Oyster Point. The new hub will open in 2022 and house the big biotech’s Bay Area employees working on cardiometabolic, inflammation and oncology research.

Left top to right: Mark Timney, Alex Denner, Vas Narasimhan. (The Medicines Company, Getty, AP/Endpoints News)

In a play-by-play of the $9.7B Med­Co buy­out, No­var­tis ad­mits it over­paid while of­fer­ing a huge wind­fall to ex­ecs

A month into his tenure at The Medicines Company, new CEO Mark Timney reached out to then-Novartis pharma chief Paul Hudson: Any interest in a partnership?

No, Hudson told him. Not now, at least.

Ten months later, Hudson had left to run Sanofi and Novartis CEO Vas Narasimhan was paying $9.7 billion for the one-drug biotech – the largest in the string of acquisitions Narasimhan has signed since his 2017 appointment.

The deal was the product of an activist investor and his controversial partner working through nearly a year of cat-and-mouse negotiations to secure a deal with Big Pharma’s most expansionist executive. It represented a huge bet in a cardiovascular field that already saw two major busts in recent years and brought massive returns for two of the industry’s most eye-raising names.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 67,300+ biopharma pros reading Endpoints daily — and it's free.

Paul Hudson. Sanofi

New Sanofi CEO Hud­son adds next-gen can­cer drug tech to the R&D quest, buy­ing Syn­thorx for $2.5B

When Paul Hudson lays out his R&D vision for Sanofi tomorrow, he will have a new slate of interleukin therapies and a synthetic biology platform to boast about.

The French pharma giant announced early Monday that it is snagging San Diego biotech Synthorx in a $2.5 billion deal. That marks an affordable bolt-on for Sanofi but a considerable return for Synthorx backers, including Avalon, RA Capital and OrbiMed: At $68 per share, the price represents a 172% premium to Friday’s closing.

Synthorx’s take on alternative IL-2 drugs for both cancer and autoimmune disorders — enabled by a synthetic DNA base pair pioneered by Scripps professor Floyd Romesberg — “fits perfectly” with the kind of innovation that he wants at Sanofi, Hudson said.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 67,300+ biopharma pros reading Endpoints daily — and it's free.

Ab­b­Vie, Scripps ex­pand part­ner­ship, for­ti­fy fo­cus on can­cer drugs

Scripps and AbbVie go way back. Research conducted in the lab of Scripps scientist Richard Lerner led to the discovery of Humira. The antibody, approved by the FDA in 2002 and sold by AbbVie, went on to become the world’s bestselling treatment. In 2018, the drugmaker and the non-profit organization signed a pact focused on developing cancer treatments — and now, the scope of that partnership has broadened to encompass a range of diseases, including immunological and neurological conditions.

South Ko­rea jails 3 Sam­sung ex­ecs for de­stroy­ing ev­i­dence in Bi­o­Log­ics probe

Three Samsung executives in Korea are going to jail.

The convictions came in what prosecutors had billed as “biggest crime of evidence destruction in the history of South Korea”: a case of alleged corporate intrigue that was thrown open when investigators found what was hidden beneath the floor of a Samsung BioLogics plant. Eight employees in total were found guilty of evidence tampering and the three executives were each sentenced to up to two years in prison.