Peter Marks, CBER (MDA USA via Twitter)

Pe­ter Marks on Covid-19 vac­cine ef­fi­ca­cy, EUAs and chal­lenge tri­als

A week af­ter the FDA is­sued guid­ance on vac­cines to pre­vent Covid-19, Pe­ter Marks, di­rec­tor of the Cen­ter for Bi­o­log­ics Eval­u­a­tion and Re­search, shed light on the rea­son­ing be­hind the agency’s 50% ef­fi­ca­cy thresh­old and where the agency stands on chal­lenge tri­als and emer­gency use au­tho­riza­tions.

Ef­fi­ca­cy and ap­proval

In its guid­ance, FDA said it ex­pect­ed spon­sors to demon­strate a vac­cine is at least 50% ef­fec­tive in a place­bo-con­trolled tri­al, with an ad­just­ed low­er bound of >30%.

Dur­ing a tele­con­fer­ence with the Al­liance for a Stronger FDA on Wednes­day, Marks ex­plained that the 50% fig­ure is based on what the agency could tol­er­ate for ef­fi­ca­cy. “Can we show you some cal­cu­la­tion of how we got there? No,” he said, not­ing that the agency does not typ­i­cal­ly set spe­cif­ic ef­fi­ca­cy tar­gets in its vac­cine guid­ance.

“If you go much low­er than 50% then the low­er bounds of things start to get to a place where vac­cines may have very lit­tle ef­fi­ca­cy,” Marks added. “On the oth­er hand, if we held that num­ber at 70% to 80% … we may not have a vac­cine un­til there’s herd im­mu­ni­ty that’s oc­curred nat­u­ral­ly.”

How­ev­er, Marks said that erad­i­cat­ing the virus will like­ly re­quire a more ef­fec­tive vac­cine. “We’re go­ing to need a vac­cine that’s prob­a­bly in the or­der of 70% ef­fec­tive and 70%, at least, of the pop­u­la­tion is go­ing to need to take it,” he said.

Based on those pa­ra­me­ters, Marks said that piv­otal tri­als for Covid-19 vac­cines will need to be large. “Large means tens of thou­sands of peo­ple, prob­a­bly … some­where be­tween ten to fif­teen thou­sand in­di­vid­u­als in each arm of a ran­dom­ized tri­al to get to the kind of pow­er that you need here.”

Marks could not com­ment on how quick­ly vac­cine could be avail­able but said, “We’re not go­ing to have one in ear­ly fall, it’s go­ing to take months.”

As stat­ed in the agency’s guid­ance, Marks stressed that ac­cel­er­at­ed ap­proval is not ap­pro­pri­ate un­til there are com­pelling sur­ro­gate end­points.

“Giv­en the cur­rent lack of da­ta that we have in­form­ing im­mune cor­re­lates of pro­tec­tion, we’re telling peo­ple that the clin­i­cal de­vel­op­ment pro­gram should pur­sue tra­di­tion­al ap­proval, based on di­rect ev­i­dence of vac­cine ef­fi­ca­cy,” Marks said. “Af­ter a few vac­cines come through the pipeline, we may un­der­stand what a good im­mune cor­re­late of pro­tec­tion is, but we don’t yet know that an­ti­bod­ies are the be-all-end-all of pro­tect­ing against COVID-19.”

Marks al­so ex­pand­ed on whether the agency would con­sid­er is­su­ing an emer­gency use au­tho­riza­tion for a Covid-19 vac­cine.

“We re­al­ly be­lieve that the most like­ly sit­u­a­tion in which an emer­gency use au­tho­riza­tion would be is­sued would be af­ter some in­ter­im analy­sis that shows vac­cine ef­fi­ca­cy and safe­ty, be­fore a for­mal sub­mis­sion is made to the FDA of a li­cen­sure ap­pli­ca­tion and FDA has had a chance to do its nor­mal re­view,” he said.

Chal­lenge tri­als

One of the more eye­brow-rais­ing as­pects of FDA’s guid­ance was a sec­tion dis­cussing the po­ten­tial for chal­lenge tri­als, or con­trol hu­man in­fec­tion mod­els, where­in vol­un­teers are in­ten­tion­al­ly ex­posed to a pathogen. In its guid­ance, FDA sug­gests that such tri­als could be en­ter­tained, “If it is no longer pos­si­ble to demon­strate vac­cine ef­fec­tive­ness by way of con­duct­ing clin­i­cal dis­ease end­point ef­fi­ca­cy stud­ies.”

“Why can’t we do that for COVID-19?” Marks asked. “Well, there are prob­a­bly a cou­ple rea­sons. One of which is that you don’t have some­thing that cures COVID-19 100% of the time or near 100% of the time.” Marks said there are oth­er is­sues that would need to be worked out be­fore such tri­als would be fea­si­ble, in­clud­ing im­prov­ing our un­der­stand­ing of the dis­ease and de­ter­min­ing which strain of the virus to use.

“This could be a way to­wards re­al­ly fa­cil­i­tat­ing get­ting an an­swer, if we had a res­cue treat­ment and if we knew more about the re­la­tion­ship be­tween car­riage and in­fec­tion, but right now it gives peo­ple some eth­i­cal heart­burn and sci­en­tif­i­cal­ly it’s com­pli­cat­ed,” Marks said.

That said, Marks said FDA would con­sid­er pro­pos­als for chal­lenge tri­als based on what was in the pro­to­col and the cir­cum­stances at the time. “It’s not a ‘no’, it’s a ‘we’ll see,’” he said.

Marks added that it might be more fea­si­ble to con­duct chal­lenge tri­als when there are more ef­fec­tive ther­a­peu­tics avail­able to treat the dis­ease. “If we have mon­o­clon­al an­ti­bod­ies that are re­al­ly good at shut­ting down the dis­ease, that could be a game chang­er.”

Safe­ty and qual­i­ty

Marks said that one of the things that “scares me more than any­thing else is that a third or half of Amer­i­cans are hes­i­tant about tak­ing a vac­cine [for COVID-19].” Marks stressed that part of FDA’s job is to as­sure that an even­tu­al vac­cine is safe and high qual­i­ty.

“For any of these vac­cines tar­get­ing SARS-CoV-2, im­por­tant things for us from the stand­point of our guid­ance… will be things like con­sis­ten­cy of man­u­fac­tur­ing, and the need for man­u­fac­tur­ing process­es and con­trols that have ap­pro­pri­ate steps in them, the need to have fa­cil­i­ties in­spect­ed to pro­duce vac­cines un­der good man­u­fac­tur­ing prac­tices, that’s im­por­tant be­cause we re­al­ly do need to make sure that these are go­ing to be high qual­i­ty prod­ucts that when we say they’re safe, they re­al­ly are,” Marks said.

For a look at all End­points News coro­n­avirus sto­ries, check out our spe­cial news chan­nel.


RAPS: 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.

2023 Spot­light on the Fu­ture of Drug De­vel­op­ment for Small and Mid-Sized Biotechs

In the context of today’s global economic environment, there is an increasing need to work smarter, faster and leaner across all facets of the life sciences industry.  This is particularly true for small and mid-sized biotech companies, many of which are facing declining valuations and competing for increasingly limited funding to propel their science forward.  It is important to recognize that within this framework, many of these smaller companies already find themselves resource-challenged to design and manage clinical studies themselves because they don’t have large teams or in-house experts in navigating the various aspects of the drug development journey. This can be particularly challenging for the most complex and difficult to treat diseases where no previous pathway exists and patients are urgently awaiting breakthroughs.

Dipal Doshi, Entrada Therapeutics CEO

Ver­tex just found the next big ‘trans­for­ma­tive’ thing for the pipeline — at a biotech just down the street

Back in the summer of 2019, when I was covering Vertex’s executive chairman Jeff Leiden’s plans for the pipeline, I picked up on a distinct focus on myotonic dystrophy Type I, or DM1 — one of what Leiden called “two diseases (with DMD) we’re interested in and we continue to look for those assets.”

Today, Leiden’s successor at the helm of Vertex, CEO Reshma Kewalramani, is plunking down $250 million in cash to go the extra mile on DM1. The lion’s share of that is for the upfront, with a small reserve for equity in a deal that lines Vertex up with a neighbor in Seaport that has been rather quietly going at both of Vertex’s early disease targets with preclinical assets.

Endpoints Premium

Premium subscription required

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

Ahead of ad­comm, FDA rais­es un­cer­tain­ties on ben­e­fit-risk pro­file of Cy­to­ki­net­ic­s' po­ten­tial heart drug

The FDA’s Cardiovascular and Renal Drugs Advisory Committee will meet next Tuesday to discuss whether Cytokinetics’ potential heart drug can safely reduce the risk of cardiovascular death and heart failure in patients with symptomatic chronic heart failure with reduced ejection fraction.

The drug, known as omecamtiv mecarbil and in development for more than 15 years, has seen mixed results, with a first Phase III readout from November 2020 hitting the primary endpoint of reducing the odds of hospitalization or other urgent care for heart failure by 8%. But it also missed a key secondary endpoint analysts had pegged as key to breaking into the market.

David Light, Valisure CEO

Val­isure in the hot seat: New Form 483 over a 2021 in­spec­tion as CEO fires back

The notorious drug testing company Valisure, which has made a name for itself by forcing FDA’s hand with some of its safety-related uncoverings, received a letter this week after the FDA uncovered violations at its Connecticut-based testing lab in 2021.

The letter, which was sent on Dec. 5, stated that the FDA is “concerned” that Valisure was not aware of  drug supply chain security requirements.

WIB22: Am­ber Salz­man had few op­tions when her son was di­ag­nosed with a rare ge­net­ic dis­ease. So she cre­at­ed a bet­ter one

This profile is part of Endpoints News’ 2022 special report about Women in Biopharma R&D. You can read the full report here.

Amber Salzman’s life changed on a cold, damp day in Paris over tiny plastic cups of lukewarm tea.

She was meeting with Patrick Aubourg, a French neurologist studying adrenoleukodystrophy, or ALD, a rare genetic condition that causes rapid neurological decline in young boys. It’s a sinister disease that often leads to disability or death within just a few years. Salzman’s nephew was diagnosed at just 6 or 7 years old, and died at the age of 12.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 154,300+ biopharma pros reading Endpoints daily — and it's free.

FDA re­view­ers head back to White Oak in 2023, with lead­er­ship look­ing to ap­pease a new Con­gress

Republicans have taken a stand against the pandemic era habit of lax work-from-home schedules. Now that they’ve wrestled control of the House majority, the FDA’s leadership is playing ball, sending many of the agency’s more than 18,000 employees back to their desks early next year.

Whether this exodus back to White Oak in Silver Spring, MD (many staff will still be allowed to work from home for multiple days per week) will mean more defections to industry and elsewhere remains to be seen.

Bags of shred­ded docs: In­di­an drug­mak­er Lupin hand­ed a Form 483 by FDA in­spec­tors

The generics manufacturer Lupin has been given another Form 483 from the FDA this year.

US regulators inspected Lupin’s pharmaceutical manufacturing site in the town of Mandideep, India from Nov. 14 through Nov. 23, with the 14-page report marking 16 observations.

The inspection report stated that the site did not have the appropriate controls over its computer systems to ensure that changes in “master production” or records are only done by authorized personnel, along with written procedures not being established to conduct annual reviews of records associated with drug batches.

Bro­ken promis­es? FDA needs more pow­er to re­move drugs from mar­ket­place, JA­MA analy­sis finds

The FDA is struggling to remove drugs from the marketplace that don’t show effectiveness in late stage trials, new JAMA analyses found, thanks to the persistent tension between speed and confidence in early clinical data.

Congress, regulated industry and patients have urged the FDA to shorten the amount of time that the market has to wait for drugs to become available that may help severe and prevalent diseases – and the FDA has listened, offering up a quick accelerated approval pathway that’s frequently used by new cancer drugs.

Ab­b­Vie slapped with age dis­crim­i­na­tion law­suit, fol­low­ing oth­er phar­mas

Add AbbVie to the list of pharma companies currently facing age discrimination allegations.

Pennsylvania resident Thomas Hesch filed suit against AbbVie on Wednesday, accusing the company of passing him over for promotions in favor of younger candidates.

Despite 30 years of pharma experience, “Hesch has consistently seen younger, less qualified employees promoted over him,” the complaint states.