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.

Pi­o­neer­ing Click Chem­istry in Hu­mans

Reimagining cancer treatments

Cancer is a leading cause of death worldwide, accounting for nearly 10 million deaths in 2020, which is nearly one in six deaths. Recently, we have seen incredible advances in novel cancer therapies such as immune checkpoint inhibitors, cell therapies, and antibody-drug conjugates that have revamped cancer care and improved survival rates for patients.

Despite this significant progress in therapeutic targeting, why are we still seeing such a high mortality rate? The reason is that promising therapies are often limited by their therapeutic index, which is a measure of the effective dose of a drug, relative to its safety. If we could broaden the therapeutic indices of currently available medicines, it would revolutionize cancer treatments. We are still on the quest to find the ultimate cancer medicine – highly effective in several cancer types, safe, and precisely targeted to the tumor site.

Joshua Cohen (L) and Justin Klee, Amylyx co-CEOs

BREAK­ING: Af­ter long and wind­ing road, FDA ap­proves Amy­lyx's ALS drug in vic­to­ry for pa­tients and ad­vo­ca­cy groups

For just the third time in its 116-year history, the FDA has approved a new treatment for Lou Gehrig’s disease, or ALS.

US regulators gave the thumbs-up to the drug, known as Relyvrio, in a massive win for patients and their families. The approval, given to Boston-area biotech Amylyx Pharmaceuticals, comes after two years of long and contentious debates over the drug’s effectiveness between advocacy groups and FDA scientists, following the readout of a mid-stage clinical trial in September 2020.

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Ivan Cheung, Eisai US chairman and CEO

Bio­gen, Ei­sai re­fresh amy­loid hy­poth­e­sis with PhI­II show­ing Alzheimer's med slows cog­ni­tive de­cline

In the first look at Phase III data for lecanemab, Eisai and Biogen’s follow-up Alzheimer’s drug to the embattled Aduhelm launch, results show the drug passed with flying colors on a test looking at memory, problem solving and other dementia metrics.

One of the most-watched Alzheimer’s therapies in the clinic, lecanemab met the study’s primary goal on the CDR-SB — Clinical Dementia Rating-Sum of Boxes — giving the biotech the confidence to ask for full approval in the US, EU and Japan by next March 31. The experimental drug reduced clinical decline on the scale by 27% compared to placebo at 18 months, the companies said Tuesday night Eastern time and Wednesday morning in Japan.

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Nooman Haque, head of life sciences and healthcare at Silicon Valley Bank, and John Carroll

I’m head­ed to Lon­don soon for #EU­BIO22. Care to join me?

It was great getting back to a live ESMO conference/webinar in Paris followed by a live pop-up event for the Endpoints 11 in Boston. We’re staying on the road in October with our return for a live/streaming EUBIO22 in London.

Silicon Valley Bank’s Nooman Haque and I are once again jumping back into the thick of it with a slate of virtual and live events on October 12. I’ll get the ball rolling with a virtual fireside chat with Novo Nordisk R&D chief Marcus Schindler, covering their pipeline plans and BD work.

CMS spent more than $18B in four years on ac­cel­er­at­ed ap­provals with in­com­plete con­fir­ma­to­ry tri­als, in­spec­tor gen­er­al finds

The battle over whether and how to reform the FDA’s accelerated approval pathway is heating up again, just as the Senate punted any talks until the lame duck session just before the end of the year.

On Thursday, HHS’ inspector general released a new report reiterating concerns, also noted recently by the FDA’s Oncology Center of Excellence, about delayed or slowed confirmatory trials that are necessary to prove that the accelerated approvals were worth their salt in the first place.

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Some­one old, some­one new: Mod­er­na pro­motes CTO, raids No­var­tis for re­place­ment amid pipeline push

Moderna CEO Stéphane Bancel made clear on the last quarterly call that “now is not the time to slow down.” On Thursday, he made a bit more room in the cockpit.

The company unveiled a new executive role on Thursday, promoting former chief technical operations and quality officer Juan Andres to president of strategic partnerships and enterprise expansion, and poaching a former Novartis exec to take his place.

Sens. Rand Paul (R-KY) and Cory Booker (D-NJ) (Olivier Douliery/Sipa USA (Sipa via AP Images)

Sen­ate pass­es bill to re­work an­i­mal test­ing re­quire­ments for drug de­vel­op­ers

The US Senate passed via unanimous consent on Thursday afternoon a bipartisan bill that would alter a federal mandate for animal testing on new drugs, but stops short of removing animal testing entirely.

Touted as a much-needed modernization of FDA’s rules, co-sponsor Sens. Rand Paul (R-KY) and Cory Booker (D-NJ) have said the bill will stop lots of needless suffering of animals.

Cell and gene ther­a­pies from acad­e­mia: EMA to help 5 projects go­ing af­ter un­met clin­i­cal needs

The European Medicines Agency said Thursday that it’s launching a new pilot program to help academic and other nonprofit researchers developing advanced therapy medicinal products, which includes cell and gene therapies.

Academics have proven to be enormously useful in feeding new products, like chimeric antigen receptor (CAR)-T cell therapies first developed by Memorial Sloan Kettering, and ushered to the market by biopharma companies. Jean Bennett, formerly with the University of Pennsylvania, also saw her research lead to the approval of gene therapy Luxturna, which Roche now owns.

Gilead names 'k­ing­pin­s' in coun­ter­feit HIV med law­suit

Gilead is mounting its counterfeit drug lawsuit, naming two “kingpins” and a complex network of conspirators who allegedly sold imitation bottles of its HIV meds, some of which ended up in US pharmacies.

The pharma giant on Wednesday provided an update on what it called a “large-scale, sophisticated counterfeiting conspiracy,” accusing two new defendants of “leading and orchestrating” a scheme to sell hundreds of millions of dollars in illegitimate drugs posing as meds such as Biktarvy and Descovy.