Robert Califf, FDA commissioner nominee (Graeme Sloan/Sipa USA/Sipa via AP Images)

Califf on ac­cel­er­at­ed ap­provals: Com­pa­nies need to do more work be­fore FDA says OK

As he awaits a tight Sen­ate vote, Rob Califf, Pres­i­dent Joe Biden’s nom­i­nee to be the next FDA com­mis­sion­er, is sig­nal­ing where the agency may move on ac­cel­er­at­ed ap­provals if he takes over at FDA.

Build­ing off com­ments from his Sen­ate con­fir­ma­tion hear­ing, in which Califf said that he’s “a fan of ac­cel­er­at­ed ap­proval” but the US needs a bet­ter sys­tem to eval­u­ate these drugs once they’re on the mar­ket, the nom­i­nee raised ques­tions about how well the cur­rent struc­ture serves pa­tients.

There’s been “fail­ure to pro­duce con­fir­ma­to­ry ev­i­dence quick­ly and in a way that re­al­ly gives us the in­for­ma­tion we need as pa­tients and clin­i­cians to de­cide which treat­ments are most ef­fec­tive and in which or­der,” he said at the CER­SI Sum­mit last week.

Com­par­ing the ac­cel­er­at­ed ap­proval path­way to a re­lay race — po­ten­tial­ly pok­ing at the con­tro­ver­sial sit­u­a­tion where the FDA grant­ed an ac­cel­er­at­ed ap­proval to Bio­gen’s Alzheimer’s drug but CMS is re­quir­ing an ad­di­tion­al ran­dom­ized clin­i­cal tri­al — Califf ar­gued the “FDA runs the first lap, gets to the end, drops the ba­ton down on the ground, and some­one else like CMS has to fig­ure out where the ba­ton is, pick it up and start all over.”

“I think one of the most im­por­tant things I learned from my time [as FDA com­mis­sion­er un­der the Oba­ma ad­min­is­tra­tion] is the pow­er of fed­er­al agen­cies work­ing to­geth­er with com­mon pur­pose,” Califf said. “In a re­lay race, you have a num­ber of yards where the sec­ond run­ner is run­ning along­side the first, and we just don’t have that.”

He al­so lament­ed the fact that the US is “los­ing life ex­pectan­cy in the US and rel­a­tive­ly faster than the rest of the world. We’re in­no­vat­ing in the US in a way that’s help­ing the en­tire world, but there’s some­thing we’re not do­ing right in im­ple­ment­ing those in­no­va­tions. That’s the way I see it.”

Ju­lia Beaver

Ju­lia Beaver, chief of med­ical on­col­o­gy at the FDA’s On­col­o­gy Cen­ter of Ex­cel­lence, al­so spoke on the CER­SI pan­el with Califf, not­ing that over­all, OCE’s work in ac­cel­er­at­ed ap­provals has been “a suc­cess” by pro­vid­ing years of ear­ly ac­cess to “trans­for­ma­tive, life-pro­long­ing ther­a­pies.”

She not­ed that half of all ac­cel­er­at­ed ap­proval in­di­ca­tions have con­firmed ben­e­fit in a me­di­an of 3 years, and the re­main­der of those that have not yet con­firmed ben­e­fit have been those grant­ed AA in the last few years. Less than 10% of these in­di­ca­tions have been with­drawn ei­ther due to failed tri­als or be­cause the tri­als weren’t con­duct­ed, she said.

“The sit­u­a­tion and frame­work we’re in now is that al­though we can’t re­quire this, we are stress­ing the need for the con­fir­ma­to­ry tri­al to be well un­der­way, if not ful­ly en­rolled, at the time of the ac­cel­er­at­ed ap­proval ac­tion to avoid these de­lays and get the ev­i­dence,” Beaver said. “But in terms of our con­fi­dence in get­ting that con­fir­ma­to­ry ev­i­dence, that does now play in­to our over­all risk/ben­e­fit de­ci­sion. So if we have con­fi­dence or ear­ly agree­ment on ev­i­dence need­ed for con­fir­ma­to­ry tri­al, that’s the ide­al.”

Such ear­li­er agree­ments be­tween FDA and com­pa­nies seek­ing ac­cel­er­at­ed ap­provals, “po­ten­tial­ly even on con­fir­ma­to­ry met­rics,” Beaver not­ed, would al­low for greater con­fi­dence in the ap­proval path­way.

Hal Bar­ron, who re­cent­ly made the leap from CSO at Glax­o­SmithK­line to CEO of start­up Al­tos Labs, al­so not­ed on the pan­el that there a num­ber of sur­ro­gates where the ben­e­fit of an ac­cel­er­at­ed ap­proval is a “smart risk to take.” But “in terms of where it’s failed,” he stressed that there needs to be more rig­or in de­sign­ing the con­fir­ma­to­ry tri­als, “so you be­lieve” the re­sults when they’re pos­i­tive or neg­a­tive.

Hal Bar­ron

Some of these tri­als are tak­ing an “enor­mous­ly long time to con­vert” to full ap­proval, Bar­ron not­ed, and he said there’s been a lot of talk about us­ing RWE to sat­is­fy con­fir­ma­to­ry tri­al re­sults. “But I’m not as con­vinced that that will help as much as ran­dom­ized tri­als,” he said.

Califf, a long­time fan of us­ing RWE when ran­dom­ized, stressed, “Noth­ing about RWE ex­cludes ran­dom­iza­tion, which is one of the most pow­er­ful tools we have.” He point­ed to the UK-based Re­cov­ery tri­al, which quick­ly test­ed a num­ber of dif­fer­ent Covid-19 ther­a­peu­tics, and which “beat the socks off” the US tri­als.

“If the tri­als are most­ly en­rolled be­fore the [ac­cel­er­at­ed] ap­proval comes, you’re go­ing to get the an­swer,” Califf said.

Bar­ron, mean­while, not­ed the push to­ward do­ing more ob­ser­va­tion­al stud­ies and us­ing those to con­clude a drug works when com­pared to un­treat­ed pa­tients: “You can use all these so­phis­ti­cat­ed tech­niques, but I’m just not con­fi­dent. Giv­en that these drugs are go­ing to be used for a long, long time, we’ve got to get it right and not skimp­ing on the ran­dom­iza­tion, and un­der­stand­ing ef­fi­ca­cy and ef­fec­tive­ness is crit­i­cal.”

Bar­ron al­so stressed that for a small­er com­pa­ny, it can be a big risk to ini­ti­ate a con­fir­ma­to­ry tri­al be­fore an ap­proval is grant­ed or be­fore the sur­vey tri­als are un­blind­ed. He al­so called for more com­pa­nies to work in a pre-com­pet­i­tive way to de­fine the util­i­ty around the sur­ro­gates on which the ac­cel­er­at­ed ap­provals are based.

“What­ev­er leg­isla­tive frame­work is in­sert­ed, think hard about how every group has skin in the game. In­cen­tivize ap­provals to get to pa­tients faster but in­cen­tivize to quick­ly fig­ure out if you made a smart de­ci­sion that was wrong or a smart de­ci­sion that was right,” he added when asked how Con­gress could im­prove the ac­cel­er­at­ed path­way.

The Big Phar­ma dis­card pile; Lay­offs all around while some biotechs bid farewell; New Roche CEO as­sem­bles top team; and more

Welcome back to Endpoints Weekly, your review of the week’s top biopharma headlines. Want this in your inbox every Saturday morning? Current Endpoints readers can visit their reader profile to add Endpoints Weekly. New to Endpoints? Sign up here.

With earnings seasons in full swing, we’ve listened in on all the calls so you don’t have to. But news is popping up from all corners, so make sure you check out our other updates, too.

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Sen. Ron Wyden (D-OR) (Francis Chung/E&E News/Politico via AP Images)

In­fla­tion re­bates in­com­ing: Wyden calls on CMS to move quick­ly as No­var­tis CEO pledges re­ver­sal

Senate Finance Chair Ron Wyden (D-OR) this week sent a letter to the head of the Centers for Medicare & Medicaid Services seeking an update on how and when new inflation-linked rebates will take effect for drugs that see major price spikes.

The newly signed Inflation Reduction Act requires manufacturers to pay a rebate to Medicare when they increase drug prices faster than the rate of inflation.

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Trodelvy notch­es a win in most com­mon form of breast can­cer

Following a promise last year to go “big and fast in breast cancer,” Gilead has secured a win for Trodelvy in the most common form.

The drug was approved to treat HR-positive, HER2-negative breast cancer patients who’ve already received endocrine-based therapy and at least two other systemic therapies for metastatic cancer, Gilead announced on Friday.

Trodelvy won its first indication in metastatic triple-negative breast cancer back in 2020, and has since added urothelial cancer to the list. HR-positive HER2-negative breast cancer accounts for roughly 70% of new breast cancer cases worldwide per year, according to senior VP of oncology clinical development Bill Grossman, and many patients develop resistance to endocrine-based therapies or worsen on chemotherapy.

David Kirn, 4D Molecular Therapeutics CEO (via website)

FDA places hold on 4D Mol­e­c­u­lar’s Fab­ry gene ther­a­py

4D Molecular Therapeutics quietly tucked an FDA clinical hold on its Fabry gene therapy into an SEC filing.

Meanwhile, the biotech issued a press release the same day after the closing bell on Thursday touting an IND for another asset, in diabetic macular edema.

The California biotech had paused enrollment of patients in its two trials of the Fabry gene therapy (4D-310) last month after three patients experienced kidney issues, all of which were resolved within four weeks. At the time, 4DMT said it would wait until the second half of this year to look at 12-month clinical data on six patients in the Phase I/II trials, one in the US and one in Taiwan and Australia.

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Raymond Stevens, Structure Therapeutics CEO

Be­hind Fri­day's $161M IPO: A star sci­en­tist, GPCR drug dis­cov­ery and a plan to chal­lenge phar­ma in di­a­betes

What does it take to pull off a $161 million biotech IPO these days?

In Structure Therapeutics’ case, it means having a star scientist co-founder paired with the computational drug discovery company Schrödinger, $198 million in private funding from blue-chip investors, almost six years of research work on G protein-coupled receptors and a slate of oral, small-molecule drugs, with an eye on the huge and growing diabetes and weight-loss market.

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Af­ter 13 years, Ramy Mah­moud steps in­to CEO seat at Opti­nose; Ru­pert Vessey set to ex­it Bris­tol My­ers in Ju­ly

After 13 years as president and COO at Optinose, Ramy Mahmoud has stepped into a new role as its CEO. He is taking the place of Peter Miller, who stepped down earlier this week, though Miller is still staying with the company as a consultant.

In 2010, the two business partners joined Optinose to take it in a new direction, transforming it from a delivery platform to product company. They previously worked together at Johnson & Johnson, when Miller was president at Janssen and Mahmoud headed medical affairs. Miller said after he learned about Optinose, “I did what I always do, which is find people smarter than me to talk with about the idea. And the first person I called was Ramy … and I said, ‘Hey, Ramy, what do you think of this technology?’”

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FDA ap­proves GSK's ane­mia drug with safe­ty warn­ing — af­ter bat­ting back sim­i­lar drugs

GSK has secured the first of four US approvals it’s hoping for this year, as the FDA greenlit daprodustat as a treatment for anemia due to chronic kidney disease.

But the FDA limited the use of the drug, to be marketed as Jesduvroq, to patients who have been receiving dialysis for at least four months and stopped short of approving it for patients not dependent on dialysis — in line with the recommendations of the advisory committee it consulted.

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Photo: Julia Weeks/AP Images

FDA ax­es re­quire­ment for pos­i­tive Covid test be­fore Paxlovid use

FDA announced today that doctors and pharmacists can now prescribe Paxlovid to patients without a positive test for Covid-19.

CDER Director Patrizia Cavazzoni reissued Paxlovid’s authorization letter Wednesday, saying it has revised the authorization to “no longer require positive results of direct SARS-CoV-2 viral testing.” The EUA now requires instead that adults and kids 12 years of age and older have a “current diagnosis of mild-to-moderate COVID-19.”

Te­va drops out of in­dus­try trade group PhRMA

Following in AbbVie’s footsteps, Teva confirmed on Friday that it’s dropping out of the industry trade group Pharmaceutical Research and Manufacturers of America (PhRMA).

Teva didn’t give a reason for its decision to leave, saying only in a statement to Endpoints News that it annually reviews “effectiveness and value of engagements, consultants and memberships to ensure our investments are properly seated.”

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