FDA un­veils guid­ance for Covid-19 tri­als

The FDA on Wednes­day is­sued new fi­nal guid­ance to help spon­sors as­sure the safe­ty of tri­al par­tic­i­pants, main­tain com­pli­ance with good clin­i­cal prac­tice (GCP) and min­i­mize the risks to tri­al in­tegri­ty dur­ing the Covid-19 pan­dem­ic.

The guid­ance comes as the Na­tion­al In­sti­tutes of Health last week ini­ti­at­ed the first Covid-19 vac­cine Phase 1 tri­al in Seat­tle. Sanofi and Re­gen­eron Phar­ma­ceu­ti­cals al­so an­nounced on Mon­day they have start­ed a Phase 2/3 tri­al at med­ical cen­ters in New York eval­u­at­ing the IL-6 tar­get­ed Kevzara (sar­ilum­ab) in pa­tients hos­pi­tal­ized with se­vere Covid-19.

In ad­di­tion, Gilead has ini­ti­at­ed two Phase 3 stud­ies at sites across Asia to eval­u­ate the safe­ty and ef­fi­ca­cy of the an­tivi­ral remde­sivir in adults di­ag­nosed with Covid-19, as well as in Ne­bras­ka, while Eu­sa Phar­ma said Wednes­day that it ini­ti­at­ed a study at a hos­pi­tal in Berg­amo, Italy for sil­tux­imab, an­oth­er IL-6 tar­get­ed mon­o­clon­al an­ti­body, for the treat­ment of pa­tients with Covid-19 who have de­vel­oped se­ri­ous res­pi­ra­to­ry com­pli­ca­tions.

FDA Guid­ance De­tails

While rec­og­niz­ing that pro­to­col mod­i­fi­ca­tions may be re­quired, and that there may be un­avoid­able pro­to­col de­vi­a­tions due to Covid-19 ill­ness and/or Covid-19 con­trol mea­sures, FDA urges spon­sors and clin­i­cal in­ves­ti­ga­tors to en­gage with In­sti­tu­tion­al Re­view Boards (IRBs)/In­de­pen­dent Ethics Com­mit­tees (IECs) “as ear­ly as pos­si­ble when ur­gent or emer­gent changes to the pro­to­col or in­formed con­sent are an­tic­i­pat­ed as a re­sult of COVID-19.”

But FDA al­so says that such changes to the pro­to­col or in­ves­ti­ga­tion­al plan to min­i­mize or elim­i­nate im­me­di­ate haz­ards or to pro­tect the life and well-be­ing of re­search par­tic­i­pants (e.g., to lim­it ex­po­sure to Covid-19) “may be im­ple­ment­ed with­out IRB ap­proval or be­fore fil­ing an amend­ment to the IND or IDE, but are re­quired to be re­port­ed af­ter­wards.”

David Bo­rasky, VP of IRB Com­pli­ance at WCG, said in a we­bi­nar on Covid-19 tri­als on Wednes­day that IRBs want to know about changes as soon as pos­si­ble and hope that they’ll be re­port­ed with­in five days, but they un­der­stand the cir­cum­stances.

He added that IRBs should not be a road­block to mak­ing changes that are es­sen­tial to main­tain­ing re­search that is eth­i­cal­ly ap­pro­pri­ate, max­i­mizes the safe­ty of study par­tic­i­pants and re­search teams, sci­en­tif­i­cal­ly valid and com­pli­ant with the reg­u­la­tions.

As far as ef­fi­ca­cy as­sess­ments, FDA’s guid­ance “rec­om­mends con­sul­ta­tion with the ap­pro­pri­ate re­view di­vi­sion re­gard­ing pro­to­col mod­i­fi­ca­tions for the col­lec­tion of ef­fi­ca­cy end­points, such as use of vir­tu­al as­sess­ments, de­lays in as­sess­ments, and al­ter­na­tive col­lec­tion of re­search-spe­cif­ic spec­i­mens, if fea­si­ble. For in­di­vid­ual in­stances where ef­fi­ca­cy end­points are not col­lect­ed, the rea­sons for fail­ing to ob­tain the ef­fi­ca­cy as­sess­ment should be doc­u­ment­ed (e.g., iden­ti­fy­ing the spe­cif­ic lim­i­ta­tion im­posed by COVID-19 lead­ing to the in­abil­i­ty to per­form the pro­to­col-spec­i­fied as­sess­ment).”

And pri­or to lock­ing the data­base, the 9-page guid­ance says spon­sors should use its sta­tis­ti­cal analy­sis plan to ad­dress how pro­to­col de­vi­a­tions re­lat­ed to Covid-19 will be han­dled for the pre­spec­i­fied analy­ses.

In ad­di­tion, the guid­ance adds that spon­sors and clin­i­cal in­ves­ti­ga­tors should doc­u­ment how Covid-19-re­lat­ed re­stric­tions led to changes in study con­duct and the du­ra­tion of those changes, as well as in­di­cat­ing which tri­al par­tic­i­pants were im­pact­ed and how those tri­al par­tic­i­pants were im­pact­ed.

“Spon­sors, in con­sul­ta­tion with clin­i­cal in­ves­ti­ga­tors and, may de­ter­mine that the pro­tec­tion of a par­tic­i­pant’s safe­ty, wel­fare, and rights is best served by con­tin­u­ing a study par­tic­i­pant in the tri­al as per the pro­to­col or by dis­con­tin­u­ing the ad­min­is­tra­tion or use of the in­ves­ti­ga­tion­al prod­uct or even par­tic­i­pa­tion in the tri­al. Such de­ci­sions will de­pend on spe­cif­ic cir­cum­stances, in­clud­ing the na­ture of the in­ves­ti­ga­tion­al prod­uct, the abil­i­ty to con­duct ap­pro­pri­ate safe­ty mon­i­tor­ing, the po­ten­tial im­pact on the in­ves­ti­ga­tion­al prod­uct sup­ply chain, and the na­ture of the dis­ease un­der study in the tri­al,” the guid­ance adds.

Dif­fi­cul­ties in get­ting prospec­tive pa­tients to tri­al sites al­so mean that spon­sors should eval­u­ate whether al­ter­na­tive meth­ods for safe­ty as­sess­ments (e.g., phone con­tact, vir­tu­al vis­it, al­ter­na­tive lo­ca­tion for as­sess­ment, in­clud­ing lo­cal labs or imag­ing cen­ters) could be im­ple­ment­ed when nec­es­sary and fea­si­ble, and would be suf­fi­cient to as­sure the safe­ty of tri­al par­tic­i­pants, FDA says.

“COVID-19 screen­ing pro­ce­dures that may be man­dat­ed by the health care sys­tem in which a clin­i­cal tri­al is be­ing con­duct­ed do not need to be re­port­ed as an amend­ment to the pro­to­col even if done dur­ing clin­i­cal study vis­its un­less the spon­sor is in­cor­po­rat­ing the da­ta col­lect­ed as part of a new re­search ob­jec­tive,” the guid­ance adds.

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