FDA up­dates Covid-19 clin­i­cal tri­als guid­ance to ad­dress se­ri­ous ad­verse events

The FDA last week up­dat­ed its guid­ance on con­duct­ing clin­i­cal tri­als amid the coro­n­avirus dis­ease pan­dem­ic to ad­dress how and when spon­sors and ap­pli­ca­tion hold­ers should re­port se­ri­ous ad­verse events (SAE).

The lat­est up­date to the guid­ance comes just days af­ter FDA added new ques­tions and an­swers to the doc­u­ment ad­dress­ing the use of al­ter­nate lab­o­ra­to­ry or imag­ing cen­ters, video con­fer­enc­ing and post­mar­ket­ing stud­ies.

Se­ri­ous ad­verse events

The up­dat­ed guid­ance in­cludes two new ques­tions and an­swers on se­ri­ous ad­verse event re­port­ing re­quire­ments in dif­fer­ent cir­cum­stances.

The first ques­tion ad­dress­es sit­u­a­tions where a com­pa­ny study­ing an al­ready ap­proved drug to treat COVID-19 un­der an in­ves­ti­ga­tion­al new drug ap­pli­ca­tion (IND) re­ceives a spon­ta­neous re­port of a se­ri­ous ad­verse event stem­ming from the prod­uct’s off-la­bel use in clin­i­cal prac­tice to treat Covid-19.

FDA ex­plains that se­ri­ous ad­verse events that oc­cur in clin­i­cal prac­tice “must be re­port­ed in ac­cor­dance with the ap­plic­a­ble post-mar­ket­ing re­port­ing re­quire­ments,” whether or not the ad­verse event is in­clud­ed in la­bel­ing to the ap­pro­pri­ate FDA data­base, the Vac­cine Ad­verse Event Re­port­ing Sys­tem (VAERS) for vac­cines and the FDA Ad­verse Event Re­port­ing Sys­tem (FAERS) for drugs and bi­o­log­ics.

When the se­ri­ous ad­verse event oc­curs dur­ing a clin­i­cal tri­al, FDA says the event “must be re­port­ed as an IND safe­ty re­port … if they are un­ex­pect­ed and the spon­sor de­ter­mines that there is a rea­son­able pos­si­bil­i­ty that the drug caused the SAE.”

“Re­gard­less of whether an SAE oc­curs in the course of clin­i­cal prac­tice or dur­ing a clin­i­cal tri­al, and re­gard­less of where it is first re­port­ed, [a new drug ap­pli­ca­tion or bi­o­log­ics li­cense ap­pli­ca­tion] hold­er who is al­so the spon­sor of an IND in­ves­ti­gat­ing the same drug for COVID-19 is re­spon­si­ble for mon­i­tor­ing the safe­ty of its drug and eval­u­at­ing all ac­cu­mu­lat­ing safe­ty da­ta,” FDA writes, adding that if that da­ta in­di­cat­ed there may be a new se­ri­ous risk as­so­ci­at­ed with the drug that an IND safe­ty re­port must be filed.

In the sec­ond ques­tion, FDA ex­plains how spon­sors study­ing drugs for non-Covid-19 in­di­ca­tions should han­dle re­port­ing se­ri­ous ad­verse events as­so­ci­at­ed with Covid-19 dur­ing the tri­al.

FDA again ex­plains that spon­sors are re­quired to re­port any se­ri­ous ad­verse events that are un­ex­pect­ed and could rea­son­ably have been caused by the drug.

As such, FDA says that spon­sors must de­ter­mine whether the in­ves­ti­ga­tion­al drug “might be causal­ly re­lat­ed to a SAE as­so­ci­at­ed with COVID-19,” though the agency ac­knowl­edges that do­ing so “like­ly re­quires more than sin­gle or even a few cas­es.”

For ran­dom­ized con­trolled tri­als, FDA says spon­sors should com­pare the rate of ob­served se­ri­ous ad­verse events in par­tic­i­pants with Covid-19 in the in­ves­ti­ga­tion­al to those in the con­trol arm of the study. Be­cause such as­sess­ments would in­volve un­blind­ed da­ta, FDA says they should on­ly be done by a da­ta mon­i­tor­ing com­mit­tee or a “fire­walled” and in­de­pen­dent spe­cial­ly con­sti­tut­ed safe­ty com­mit­tee.

For non­ran­dom­ized stud­ies, FDA says spon­sors should com­pare the rate of se­ri­ous ad­verse events and mor­tal­i­ty for tri­al par­tic­i­pants di­ag­nosed with Covid-19 to a sim­i­lar ex­ter­nal pop­u­la­tion.

“If the dif­fer­ence in SAEs across treat­ment arms or com­pared to an ex­ter­nal pop­u­la­tion sug­gests a causal re­la­tion­ship be­tween the in­ves­ti­ga­tion­al prod­uct and the SAEs in sub­jects di­ag­nosed with COVID-19, this find­ing must be sub­mit­ted to FDA as an IND safe­ty re­port,” FDA writes.


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