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.

Guid­ance

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.

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