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

Bris­tol My­ers is clean­ing up the post-Cel­gene merg­er pipeline, and they’re sweep­ing out an ex­per­i­men­tal check­point in the process

Back during the lead up to the $74 billion buyout of Celgene, the big biotech’s leadership did a little housecleaning with a major pact it had forged with Jounce. Out went the $2.6 billion deal and a collaboration on ICOS and PD-1.

Celgene, though, also added a $530 million deal — $50 million up front — to get the worldwide rights to JTX-8064, a drug that targets the LILRB2 receptor on macrophages.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 83,100+ biopharma pros reading Endpoints daily — and it's free.

Fangliang Zhang, AP Images

UP­DAT­ED: Leg­end fetch­es $424 mil­lion, emerges as biggest win­ner yet in pan­dem­ic IPO boom as shares soar

Amid a flurry of splashy pandemic IPOs, a J&J-partnered Chinese biotech has emerged with one of the largest public raises in biotech history.

Legend Biotech, the Nanjing-based CAR-T developer, has raised $424 million on NASDAQ. The biotech had originally filed for a still-hefty $350 million, based on a range of $18-$20, but managed to fetch $23 per share, allowing them to well-eclipse the massive raises from companies like Allogene, Juno, Galapagos, though they’ll still fall a few dollars short of Moderna’s record-setting $600 million raise from 2018.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 83,100+ biopharma pros reading Endpoints daily — and it's free.

As it hap­pened: A bid­ding war for an an­tibi­ot­ic mak­er in a mar­ket that has rav­aged its peers

In a bewildering twist to the long-suffering market for antibiotics — there has actually been a bidding war for an antibiotic company: Tetraphase.

It all started back in March, when the maker of Xerava (an FDA approved therapy for complicated intra-abdominal infections) said it had received an offer from AcelRx for an all-stock deal valued at $14.4 million.

The offer was well-timed. Xerava was approved in 2018, four years after Tetraphase posted its first batch of pivotal trial data, and sales were nowhere near where they needed to be in order for the company to keep its head above water.

Drug man­u­fac­tur­ing gi­ant Lon­za taps Roche/phar­ma ‘rein­ven­tion’ vet as its new CEO

Lonza chairman Albert Baehny took his time headhunting a new CEO for the company, making it absolutely clear he wanted a Big Pharma or biotech CEO with a good long track record in the business for the top spot. In the end, he went with the gold standard, turning to Roche’s ranks to recruit Pierre-Alain Ruffieux for the job.

Ruffieux, a member of the pharma leadership team at Roche, spent close to 5 years at the company. But like a small army of manufacturing execs, he gained much of his experience at the other Big Pharma in Basel, remaining at Novartis for 12 years before expanding his horizons.

Is a pow­er­house Mer­ck team prepar­ing to leap past Roche — and leave Gilead and Bris­tol My­ers be­hind — in the race to TIG­IT dom­i­na­tion?

Roche caused quite a stir at ASCO with its first look at some positive — but not so impressive — data for their combination of Tecentriq with their anti-TIGIT drug tiragolumab. But some analysts believe that Merck is positioned to make a bid — soon — for the lead in the race to a second-wave combo immuno-oncology approach with its own ambitious early-stage program tied to a dominant Keytruda.

Endpoints Premium

Premium subscription required

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

Covid-19 roundup: Ab­b­Vie jumps in­to Covid-19 an­ti­body hunt; As­traZeneca shoots for 2B dos­es of Ox­ford vac­cine — with $750M from CEPI, Gavi

Another Big Pharma is entering the Covid-19 antibody hunt.

AbbVie has announced a collaboration with the Netherlands’ Utrecht University and Erasmus Medical Center and the Chinese-Dutch biotech Harbour Biomed to develop a neutralizing antibody that can treat Covid-19. The antibody, called 47D11, was discovered by AbbVie’s three partners, and AbbVie will support early preclinical work, while preparing for later preclinical and clinical development. Researchers described the antibody in Nature Communications last month.

Leen Kawas, Athira CEO (Athira)

Can a small biotech suc­cess­ful­ly tack­le an Ever­est climb like Alzheimer’s? Athi­ra has $85M and some in­flu­en­tial back­ers ready to give it a shot

There haven’t been a lot of big venture rounds for biotech companies looking to run a Phase II study in Alzheimer’s.

The field has been a disaster over the past decade. Amyloid didn’t pan out as a target — going down in a litany of Phase III failures — and is now making its last stand at Biogen. Tau is a comer, but when you look around and all you see is destruction, the idea of backing a startup trying to find complex cocktails to swing the course of this devilishly complicated memory-wasting disease would daunt the pluckiest investors.

GSK presents case to ex­pand use of its lu­pus drug in pa­tients with kid­ney dis­ease, but the field is evolv­ing. How long will the mo­nop­oly last?

In 2011, GlaxoSmithKline’s Benlysta became the first biologic to win approval for lupus patients. Nine years on, the British drugmaker has unveiled detailed positive results from a study testing the drug in lupus patients with associated kidney disease — a post-marketing requirement from the initial FDA approval.

Lupus is a drug developer’s nightmare. In the last six decades, there has been just one FDA approval (Benlysta), with the field resembling a graveyard in recent years with a string of failures including UCB and Biogen’s late-stage flop, as well as defeats in Xencor and Sanofi’s programs. One of the main reasons the success has eluded researchers is because lupus, akin to cancer, is not just one disease — it really is a disease of many diseases, noted Al Roy, executive director of Lupus Clinical Investigators Network, an initiative of New York-based Lupus Research Alliance that claims it is the world’s leading private funder of lupus research, in an interview.

Pfiz­er’s Doug Gior­dano has $500M — and some ad­vice — to of­fer a cer­tain breed of 'break­through' biotech

So let’s say you’re running a cutting-edge, clinical-stage biotech, probably public, but not necessarily so, which could see some big advantages teaming up with some marquee researchers, picking up say $50 million to $75 million dollars in a non-threatening minority equity investment that could take you to the next level.

Doug Giordano might have some thoughts on how that could work out.

The SVP of business development at the pharma giant has helped forge a new fund called the Pfizer Breakthrough Growth Initiative. And he has $500 million of Pfizer’s money to put behind 7 to 10 — or so — biotech stocks that fit that general description.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 83,100+ biopharma pros reading Endpoints daily — and it's free.