FDA of­fers sta­tis­ti­cal guid­ance for tri­als im­pact­ed by Covid-19

The FDA on Wednes­day is­sued im­me­di­ate­ly ef­fec­tive guid­ance of­fer­ing sta­tis­ti­cal ad­vice to clin­i­cal tri­al spon­sors with the aim of main­tain­ing tri­al in­tegri­ty and mit­i­gat­ing the ef­fects of Covid-19 pub­lic health emer­gency on clin­i­cal tri­als.

The new doc­u­ment fol­lows the agency’s guid­ance on the con­duct of clin­i­cal tri­als amid the pan­dem­ic, which has been up­dat­ed sev­er­al times to in­clude ad­di­tion­al ques­tions and an­swers since be­ing is­sued in March.


While the agency’s clin­i­cal tri­al con­duct guid­ance has fo­cused on ways to pro­tect pa­tients and mit­i­gate the ef­fects of Covid-19, the new sta­tis­ti­cal con­sid­er­a­tions guid­ance is meant to help spon­sors with sta­tis­ti­cal con­sid­er­a­tions for changes to a tri­al.

“To help en­sure that the tri­al will pro­vide in­ter­pretable find­ings with cor­rect sta­tis­ti­cal quan­tifi­ca­tion of un­cer­tain­ty, this guid­ance ad­dress­es sta­tis­ti­cal con­sid­er­a­tions for pro­posed changes to tri­al con­duct due to the COVID-19 pan­dem­ic that may im­pact the analy­sis and in­ter­pre­ta­tion of the pri­ma­ry or key sec­ondary end­points in the tri­al,” FDA writes, adding that spon­sors should dis­cuss any pro­posed pro­to­col changes and changes to their sta­tis­ti­cal analy­sis plan with the rel­e­vant re­view di­vi­sion.

To en­sure tri­al in­tegri­ty, FDA says spon­sors should “proac­tive­ly plan to ad­dress the im­pact of Covid-19 on the abil­i­ty to meet the tri­al ob­jec­tives.”

Changes that would im­pact the as­cer­tain­ment of pri­ma­ry or key sec­ondary end­points should be sub­mit­ted in a pro­to­col amend­ment or an in­ves­ti­ga­tion­al de­vice ex­emp­tion (IDE) sup­ple­ment, while mod­i­fi­ca­tions to pri­ma­ry or key sec­ondary end­point analy­ses “should be re­flect­ed in an up­dat­ed sta­tis­ti­cal analy­sis plan be­fore lock­ing the data­base and be­fore any mod­i­fi­ca­tion to un­blind­ed in­ter­im analy­ses.”

FDA al­so says that spon­sors should avoid any mod­i­fi­ca­tions to the tri­al that may in­tro­duce bias in­to the in­ter­pre­ta­tion of the re­sults of the study.

“Gen­er­al­ly, for a blind­ed tri­al, mod­i­fi­ca­tions based on in­for­ma­tion that re­veals the mag­ni­tude of the treat­ment ef­fect or in­for­ma­tion pre­sent­ed by treat­ment arm have the po­ten­tial to in­tro­duce bias,” FDA writes.

The guid­ance pro­vides a list of da­ta to con­sid­er when mak­ing mod­i­fi­ca­tions to a tri­al to ad­dress Covid-19, in­clud­ing sum­maries pooled over treat­ment arms, par­tic­i­pant treat­ment dis­con­tin­u­a­tion or in­ter­rup­tions, par­tic­i­pant tri­al with­draw­al and end­points. Site clo­sures and sup­ply dis­rup­tions may al­so be ap­pro­pri­ate to con­sid­er.

Ad­di­tion­al­ly, the guid­ance pro­vides sev­er­al de­sign and analy­sis strate­gies for eval­u­at­ing pri­ma­ry and key sec­ondary end­points in tri­als af­fect­ed by Covid-19.

“As dis­cussed in the Con­duct Guid­ance, it is im­por­tant to cap­ture spe­cif­ic in­for­ma­tion at the par­tic­i­pant lev­el, de­scrib­ing the con­text and/or rea­sons for post-base­line events as they re­late to COVID-19, such as dis­con­tin­u­a­tion of treat­ment, with­draw­al from the tri­al, use of al­ter­na­tive or res­cue treat­ments, missed end­point as­cer­tain­ment, and the use of al­ter­na­tive end­point as­cer­tain­ment meth­ods,” FDA writes, not­ing that such in­for­ma­tion may be use­ful to ad­dress po­ten­tial bi­as­es or for sen­si­tiv­i­ty analy­ses.

Oth­er strate­gies in­clude how to han­dle loss of sta­tis­ti­cal pow­er due to small­er sam­ple sizes or short­er fol­low-up du­ra­tions; how to ap­proach sta­tis­ti­cal analy­ses in tri­als stopped ear­ly or the ad­di­tion of in­ter­im analy­ses to tri­als; con­sid­er­a­tions for in­creas­ing en­roll­ment af­ter the pan­dem­ic or ex­tend­ing fol­low-up; how to han­dle miss­ing end­point as­cer­tain­ment or in­ves­ti­ga­tion­al prod­uct sup­ply dis­rup­tions; and where mod­i­fi­ca­tions to the de­f­i­n­i­tion and as­cer­tain­ment of end­points might be war­rant­ed.

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.

Regeneron CEO Leonard Schleifer speaks at a meeting with President Donald Trump, members of the Coronavirus Task Force, and pharmaceutical executives in the Cabinet Room of the White House (AP Photo/Andrew Harnik)

OWS shifts spot­light to drugs to fight Covid-19, hand­ing Re­gen­eron $450M to be­gin large scale man­u­fac­tur­ing in the US

The US government is on a spending spree. And after committing billions to vaccines defense operations are now doling out more of the big bucks through Operation Warp Speed to back a rapid flip of a drug into the market to stop Covid-19 from ravaging patients — possibly inside of 2 months.

The beneficiary this morning is Regeneron, the big biotech engaged in a frenzied race to develop an antibody cocktail called REGN-COV2 that just started a late-stage program to prove its worth in fighting the virus. BARDA and the Department of Defense are awarding Regeneron a $450 million contract to cover bulk delivery of the cocktail starting as early as late summer, with money added for fill/finish and storage activities.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 84,800+ biopharma pros reading Endpoints daily — and it's free.

UP­DAT­ED: Bio­gen shares spike as ex­ecs com­plete a de­layed pitch for their con­tro­ver­sial Alzheimer's drug — the next move be­longs to the FDA

Biogen is stepping out onto the high wire today, reporting that the team working on the controversial Alzheimer’s drug aducanumab has now completed their submission to the FDA. And they want the agency to bless it with a priority review that would cut the agency’s decision-making time to a mere 6 months.

The news drove a 10% spike in Biogen’s stock $BIIB ahead of the bell.

Part of that spike can be attributed to a relief rally. Biogen execs rattled backers and a host of analysts earlier in the year when they unexpectedly delayed their filing to the third quarter. That delay provoked all manner of speculation after CEO Michel Vounatsos and R&D chief Al Sandrock failed to persuade influential observers that the pandemic and other factors had slowed the timeline for filing. Actually making the pitch at least satisfies skeptics that the FDA was not likely pushing back as Biogen was pushing in. From the start, Biogen execs claimed that they were doing everything in cooperation with the FDA, saying that regulators had signaled their interest in reviewing the submission.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 84,800+ biopharma pros reading Endpoints daily — and it's free.

FDA bars the door — for now — against Mer­ck’s star can­cer drug af­ter Roche beat them to the punch

Merck has been handed a rare setback at the FDA.

After filing for the accelerated approval of a combination of their star PD-1 drug Keytruda with Eisai’s Lenvima as a first-line treatment for unresectable hepatocellular carcinoma, the FDA nixed the move, handing out a CRL because Roche beat them to the punch on the same indication by a matter of weeks.

According to Merck:

Ahead of the Prescription Drug User Fee Act action dates of Merck’s and Eisai’s applications, another combination therapy was approved based on a randomized, controlled trial that demonstrated overall survival. Consequently, the CRL stated that Merck’s and Eisai’s applications do not provide evidence that Keytruda in combination with Lenvima represents a meaningful advantage over available therapies for the treatment of unresectable or metastatic HCC with no prior systemic therapy for advanced disease. Since the applications for KEYNOTE-524/Study 116 no longer meet the criteria for accelerated approval, both companies plan to work with the FDA to take appropriate next steps, which include conducting a well-controlled clinical trial that demonstrates substantial evidence of effectiveness and the clinical benefit of the combination.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 84,800+ biopharma pros reading Endpoints daily — and it's free.

Covid-19 roundup: Mod­er­na sticks to Ju­ly for its Phase III as ru­mors swirl; Fol­low­ing US lead, EU buys up Covid-19 treat­ments

The Phase III might be delayed from its original early July goal, but Moderna says it will still kick off the pivotal study for what could ultimately be the first Covid-19 vaccine before the end of the month.

A day after Reuters reported that squabbling between the Cambridge biotech and government regulators had held up the trial by about two weeks, Moderna released a statement saying that they had completed enrollment of their 650-person Phase II trial and were on track to begin Phase III by the end of the month. The protocol for that study, which is meant to prove whether or not the vaccine can prevent people from becoming sick, has been finalized, they said.

Stephen Hahn, AP

Trump and Navar­ro press again for hy­drox­y­chloro­quine. Can the FDA stay in­de­pen­dent?

Tuesday morning, economist and Trump advisor Peter Navarro walked onto the White House driveway and promptly brought a political cloud back onto the FDA.

Speaking to a White House pool reporter, Navarro said that four Detroit doctors were, based on a single disputed study, filing for the FDA to again issue an emergency authorization for hydroxychloroquine, the anti-malarial pill that President Trump hyped for months as a Covid-19 treatment over the objections of his own scientists. Then, while avoiding directly calling for the FDA to OK the drug, blasted the agency. He said its decision to pull an earlier authorization “was based on bad science” and “had a tremendously negative effect” on doctors and patients.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 84,800+ biopharma pros reading Endpoints daily — and it's free.

Roger Tung, Concert Pharmaceuticals CEO (Concert)

Con­cert gets BTD for alope­cia drug, set­ting up a late-stage show­down with gi­ant ri­val Pfiz­er

Concert Pharmaceuticals’ path to developing a drug that treats alopecia areata has been bumpy, but the pharma company scored a win Wednesday.

The FDA granted Concert a Breakthrough Therapy Designation (BTD) for its oral Janus kinase inhibitor, named CTP-543, paving the way for a Phase III study of the drug to begin in the fourth quarter of 2020. The news follows positive Phase II results from last September, which saw the drug meet its primary endpoint in both 8 mg and 12 mg twice-daily doses.

Donald and Melania Trump watch the smoke of fireworks from the South Lawn of the White House on July 4, 2020 (via Getty)

Which drug de­vel­op­ers of­fer Trump a quick, game-chang­ing ‘so­lu­tion’ as the pan­dem­ic roars back? Eli Lil­ly and Ab­Cellera look to break out of the pack

We are unleashing our nation’s scientific brilliance and will likely have a therapeutic and/or vaccine solution long before the end of the year.

— Donald Trump, July 4

Next week administration officials plan to promote a new study they say shows promising results on therapeutics, the officials said. They wouldn’t describe the study in any further detail because, they said, its disclosure would be “market-moving.”

— NBC News, July 3

Something’s cooking. And it’s not just July 4 leftovers involving stale buns and uneaten hot dogs.

Over the long weekend observers picked up signs that the focus in the Trump administration may swiftly shift from the bright spotlight on vaccines being promised this fall, around the time of the election, to include drugs that could possibly keep patients out of the hospital and take the political sting out of the soaring Covid-19 numbers causing embarrassment in states that swiftly reopened — as Trump cheered along.

So far, Gilead has been the chief beneficiary of the drive on drugs, swiftly offering enough early data to get remdesivir an emergency authorization and into the hands of the US government. But their drug, while helpful in cutting stays, is known for a limited, modest effect. And that won’t tamp down on the hurricane of criticism that’s been tearing at the White House, and buffeting the president’s most stalwart core defenders as the economy suffers.

We’ve had positive early-stage vaccine data, most recently from Pfizer and BioNTech, playing catchup on an mRNA race led by Moderna — where every little sign of potential trouble is magnified into a lethal threat, just as every advance excites a frenzy of support. But that race still has months to play out, with more Phase I data due ahead of the mid-stage numbers looming ahead. A vaccine may not be available in large enough quantities until well into 2021, which is still wildly ambitious.

So what about a drug solution?

Trump’s initial support for a panacea focused on hydroxychloroquine. But that fizzled in the face of data underscoring its ineffectiveness — killing trials that aren’t likely to be restarted because of a recent population-based study offering some support. And there are a number of existing drugs being repurposed to see how they help hospitalized patients.

Endpoints Premium

Premium subscription required

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

Covid-19 roundup: Squab­bles with gov­ern­ment de­lay Mod­er­na’s PhI­II — re­ports; No­vavax se­cures largest Warp Speed deal yet: $1.6B

A much-anticipated Phase III trial for Moderna’s Covid-19 vaccine is being held up as the company delayed submitting trial protocols and sparred with government scientists on how to run the study and even what the benchmark for success should be, Reuters reported.

Moderna, the first US company to put their vaccine into human testing, was supposed to enter a 30,000-person study this month in partnership with the NIH to determine whether it can prevent infection. STAT reported last week that the trial was facing delays over the protocol, but that a July start was still possible. Neither the NIH nor Moderna ever disclosed a specific date the trial should start, but Reuters reported that the agency had hoped to begin on July 10.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 84,800+ biopharma pros reading Endpoints daily — and it's free.

Cel­lec­tis slammed af­ter pa­tient dies and FDA slaps a hold on their tri­al for an off-the-shelf CAR-T for mul­ti­ple myelo­ma

Cellectis was slammed after the market close on Monday as the biotech reported that the FDA demanded it hit the brakes on their MELANI-01 trial for their off-the-shelf cell therapy UCARTCS1A after one of the patients in the study died of treatment-related cardiac arrest.

The multiple myeloma patient had previously been treated unsuccessfully with various therapies, noted the biotech, and had been given dose level two (DL2) of their allogeneic CAR-T.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 84,800+ biopharma pros reading Endpoints daily — and it's free.