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.

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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.

Justin Klee (L) and Joshua Cohen, Amylyx co-CEOs (Cody O'Loughlin/The New York Times; courtesy Amylyx)

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In an investor call Friday morning, Amylyx revealed that it would charge about $158,000 per year, a price point that immediately drew backlash from ALS advocates and some outside observers. The cost reveal had been highly anticipated in the immediate hours after Thursday evening’s approval, though Amylyx only teased Relyvrio would cost less than previously approved drugs.

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Land­mark Amy­lyx OK spurs de­bate; Some... pos­i­tive? Alzheimer's da­ta; Can­cer tri­al bot­tle­neck; Sanofi's CRISPR bet; 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.

After brief stops in Paris and Boston, John Carroll and the Endpoints crew are staying on the road in October with their return for a live/streaming EUBIO22 in London. The hybrid event fireside chats and panels on mRNA, oncology and the crazy public market. We hope you can join him there.

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

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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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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.

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#AAO22: J&J’s first look at com­mon eye dis­ease port­fo­lio pads the case for PhII of gene ther­a­py

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In­dus­try groups call to block WTO IP waiv­er ex­pan­sion to Covid-19 ther­a­peu­tics

The WTO’s TRIPS Council in mid-October is expected to debate whether to extend the IP waiver for Covid-19 vaccines to therapeutics and diagnostics too.

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Intercept Pharmaceuticals has run into another big setback in its yearslong quest to win an approval for OCA in NASH. The biotech put out word Friday morning that its Phase III REVERSE study failed the primary endpoint for the liver disease, sending its share price into a tailspin.

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