Five strate­gies for mit­i­gat­ing the im­pact of COVID-19 on clin­i­cal tri­als

By Jen­ny Gi­d­ley, Vice Pres­i­dent, Glob­al Clin­i­cal Op­er­a­tions, Al­ber­to Grig­no­lo, Cor­po­rate Vice Pres­i­dent, Brid­get Hee­lan, Vice Pres­i­dent, Reg­u­la­to­ry and Ac­cess Con­sult­ing Group, and Amy Mc­K­ee, Vice Pres­i­dent, Reg­u­la­to­ry Con­sult­ing Ser­vices — Parex­el In­ter­na­tion­al

COVID-19 has brought with it a num­ber of chal­lenges in man­ag­ing on­go­ing clin­i­cal tri­als for chron­ic, life-threat­en­ing, and rare dis­eases. En­roll­ment is slow­ing or even stop­ping in some cas­es to pri­or­i­tize pa­tient safe­ty; trav­el re­stric­tions are pre­vent­ing in-per­son pa­tient site vis­its and CRA mon­i­tor­ing vis­its; reg­u­la­tors and in­dus­try staff who once trav­eled wide­ly are work­ing from home; some IRBs are de­fer­ring pro­to­col re­view meet­ings, and in­ves­ti­ga­tor sites and hos­pi­tals are jus­ti­fi­ably pri­or­i­tiz­ing care over clin­i­cal re­search ac­tiv­i­ties.

How­ev­er, to en­sure that pa­tients – es­pe­cial­ly those where clin­i­cal re­search is re­al­ly their on­ly care op­tion
– are sup­port­ed as much as pos­si­ble, com­pa­nies can nav­i­gate this cri­sis suc­cess­ful­ly by re-ex­am­in­ing and adapt­ing their clin­i­cal re­search op­er­a­tions to en­sure pa­tient safe­ty, in­crease com­mu­ni­ca­tions with reg­u­la­tors, as­sess risks, pre­serve da­ta in­tegri­ty, and com­ply with fast-chang­ing reg­u­la­tions.

Reg­u­la­tors are re­spond­ing with flex­i­bil­i­ty and prag­ma­tism

Reg­u­la­tors world­wide have mo­bi­lized to stream­line re­quire­ments for de­vel­op­ing di­ag­nos­tics and prod­ucts to treat COVID-19. For ex­am­ple, the FDA’s new Coro­n­avirus Treat­ment Ac­cel­er­a­tion Pro­gram (CTAP) (launched March 31) is re­view­ing COVID-19 study pro­to­cols with­in 24 hours, ap­prov­ing sin­gle- pa­tient ex­pand­ed ac­cess re­quests in three hours, and an­a­lyz­ing the use of re­al-world da­ta (RWD) for ill­ness pat­terns and treat­ment out­comes.

But what about non-COVID-19 tri­als? Agen­cies have is­sued guid­ance doc­u­ments for com­pa­nies on how to con­duct tri­als dur­ing the coro­n­avirus pan­dem­ic (see Ta­ble 1), but we are in un­chart­ed ter­ri­to­ry.

Spon­sors face com­plex choic­es, among them ex­tend­ing the du­ra­tion of tri­als, halt­ing or post­pon­ing tri­als or clos­ing tri­al sites, trans­fer­ring pa­tients from sites hit hard by COVID-19, con­duct­ing pro­ce­dures at new lo­ca­tions, sus­pend­ing the en­roll­ment of new pa­tients, and mod­i­fy­ing tri­al pro­to­cols.

Dis­rup­tions could lead to a new nor­mal

New tech­nolo­gies, such as risk-based mon­i­tor­ing, eCon­sent, wear­ables, telemed­i­cine pa­tient vis­its, and re­mote source doc­u­ment ver­i­fi­ca­tion, are be­ing de­ployed and pres­sure-test­ed in a clin­i­cal re­search en­vi­ron­ment unimag­in­able just a few months ago.

Al­though study time­lines will change, en­roll­ment may quick­ly re­bound once sites re­open. For ex­am­ple, Parex­el is al­ready see­ing some re­cov­ery in Asia-Pa­cif­ic coun­tries like Chi­na, where ac­tiv­i­ties are re­sum­ing, as are our on-site mon­i­tor­ing vis­its. How time­lines will ul­ti­mate­ly be af­fect­ed will de­pend on how long stay-at-home or­ders per­sist in many dif­fer­ent places.

New best prac­tices adopt­ed now to adapt to and mit­i­gate the dis­rup­tions of the cur­rent cri­sis will like­ly have a shelf life be­yond it. The speed, ef­fi­cien­cy and cost sav­ings of vir­tu­al tri­als (that lever­age dig­i­tal health tech­nolo­gies and al­low pa­tients to par­tic­i­pate from home), and hy­brid tri­als (that com­bine ran­dom­iza­tion and blind­ing with re­al- world da­ta col­lec­tion), could al­ter the clin­i­cal tri­al land­scape per­ma­nent­ly.

To that end, spon­sors, CROs, in­ves­ti­ga­tors, sites, reg­u­la­tors, and pa­tients should fo­cus on de­vel­op­ing and re­fin­ing prac­tices that will al­low clin­i­cal tri­als to con­tin­ue, and that will im­prove the ef­fi­cien­cy and out­comes of clin­i­cal re­search in the fu­ture.

Five strate­gies to help nav­i­gate the cur­rent cri­sis while im­prov­ing fu­ture clin­i­cal tri­als:

1. En­sur­ing pa­tient safe­ty with re­mote mon­i­tor­ing

The pri­or­i­ty of drug de­vel­op­ment has al­ways been pa­tient safe­ty. As a re­sult, the in­dus­try has quick­ly piv­ot­ed to­wards re­mote so­lu­tions for the safe­ty chal­lenges to clin­i­cal tri­als posed by COVID-19 so­cial dis­tanc­ing and stay-at-home or­ders.

In the cur­rent en­vi­ron­ment, spon­sors will not be able to mon­i­tor stud­ies in the tra­di­tion­al way. In most in­stances, clin­i­cal re­search as­so­ciates (CRAs) or tri­al mon­i­tors will not be able to trav­el to sites to re­view, ver­i­fy, and dis­cuss study da­ta. The in­formed con­sent process, ad­verse event re­port­ing and re­view, in­ves­ti­ga­tion­al prod­uct han­dling, and da­ta mon­i­tor­ing – tasks that are nor­mal­ly done on-site in a con­ven­tion­al tri­al – will now have to be ac­com­plished re­mote­ly, via tele­phone or elec­tron­ic com­mu­ni­ca­tion, in a struc­tured man­ner. This rep­re­sents a sea change, and a sig­nif­i­cant chal­lenge, for spon­sors and reg­u­la­tors.

At Parex­el, we have been able to im­ple­ment pro­ce­dures for re­mote mon­i­tor­ing vis­its by lever­ag­ing our ex­pe­ri­ence in late-phase stud­ies and ap­ply­ing it to ear­li­er Phase II and III stud­ies. We are ex­plor­ing new meth­ods to ac­cess source doc­u­ments re­mote­ly, and in­ves­ti­ga­tors are find­ing ways to in­ter­act with pa­tients via phone or video (of­ten re­ferred to as tele­health or telemed­i­cine). We are send­ing clin­i­cal tri­al ma­te­ri­als – in­clud­ing the study drug when pos­si­ble – di­rect­ly to pa­tients if those pa­tients are not able to come to the site.

Of course, if an in­ves­ti­ga­tor or spon­sor can­not run a study in com­pli­ance with the pro­to­col, or mon­i­tor pa­tient safe­ty vir­tu­al­ly with com­plete con­fi­dence, they will need to pause a study, halt en­roll­ment, or dis­con­tin­ue a par­tic­i­pant. For ex­am­ple, on March 22, due to safe­ty con­cerns re­gard­ing im­munomod­u­la­to­ry agents, Gala­pa­gos NV paused en­roll­ment in the Phase II and III tri­als of its JAK1 in­hibitor fil­go­tinib in Crohn’s dis­ease, pso­ri­at­ic arthri­tis, in­flam­ma­to­ry bow­el dis­ease, uveitis, and oth­er in­flam­ma­to­ry con­di­tions. Paus­ing en­roll­ment al­lows sites to fo­cus on the safe­ty of those pa­tients al­ready en­rolled in stud­ies, and main­tain con­ti­nu­ity of treat­ment.

The safe­ty of pa­tients can be pro­tect­ed re­mote­ly. How­ev­er, so­lu­tions will need to be cus­tomized to a tri­al’s pa­tient pop­u­la­tion, pro­to­col, and ge­og­ra­phy, among oth­er fac­tors.

2. Tak­ing a new ap­proach to risk as­sess­ment in a time of new risks

Every­one is strug­gling with the risk as­sess­ment as­pect of mod­i­fy­ing the pro­to­cols of on­go­ing clin­i­cal tri­als. How will pro­to­col changes im­pact pa­tient safe­ty, da­ta in­tegri­ty, and in­ter­pre­ta­tion of re­sults?

Risk as­sess­ment is a high­ly gran­u­lar process. Each is­sue must be as­sessed for each pa­tient in each tri­al in each coun­try. That de­mands at­ten­tion to de­tail and deep ex­per­tise. It al­so adds ex­pense. There are few gener­ic an­swers to the new risk as­sess­ment prob­lems that have arisen in the time of COVID-19, but we have found there are workarounds that are ef­fec­tive in a ma­jor­i­ty of clin­i­cal tri­als, even some with com­plex de­signs.

Spon­sors must as­sess both the risk of COVID-19 po­ten­tial­ly af­fect­ing study par­tic­i­pants di­rect­ly (for ex­am­ple, if they fall ill with the dis­ease), and whether COVID-19 re­lat­ed mea­sures (such as so­cial dis­tanc­ing) will af­fect tri­al con­duct.

The re­cent EU guid­ance on COVID-19 (see Ta­ble 1) re­quires the spon­sor of each tri­al to per­form a COVID-19-dri­ven ben­e­fit-risk eval­u­a­tion with risk mit­i­ga­tion mea­sures, ide­al­ly as an amend­ment to the ben­e­fit-risk sec­tion in the pro­to­col. This ben­e­fit-risk as­sess­ment should in­clude:

• Ac­count­ing for the ad­di­tion­al risks posed to par­tic­i­pants by the COVID-19 pan­dem­ic, along with risk mit­i­ga­tion mea­sures tak­en;
• How the risks of in­volve­ment in the tri­al (fac­tor­ing in COVID-19) are weighed against an­tic­i­pat­ed ben­e­fits for the par­tic­i­pant and so­ci­ety. In case these two con­flict, sub­ject safe­ty al­ways pre­vails;
• The rel­e­vant par­ties’ in­put (for ex­am­ple, the med­ical mon­i­tor’s), doc­u­ment­ed on an on­go­ing ba­sis, pri­or­i­tiz­ing crit­i­cal tasks in the clin­i­cal tri­al and how those are best ex­e­cut­ed.

Build­ing out the ex­per­tise and find­ing the band­width to con­duct com­pre­hen­sive risk as­sess­ments for on­go­ing clin­i­cal tri­als should be an even greater pri­or­i­ty for spon­sors to­day.

3. Com­mu­ni­cat­ing in new ways with reg­u­la­tors who are lis­ten­ing

Once risk mit­i­ga­tion strate­gies and risk as­sess­ments of clin­i­cal tri­al changes are un­der­way, spon­sors must in­form reg­u­la­tors through any means pos­si­ble, even by email or tele­phone, and be open with them about po­ten­tial prob­lems they have iden­ti­fied.

To­day, de­vel­op­ing COVID-19 vac­cines and treat­ments is a glob­al pri­or­i­ty. The FDA is pri­or­i­tiz­ing sub­mis­sions for COVID-19-re­lat­ed prod­ucts. To achieve that, they are re­de­ploy­ing staff from less busy ar­eas, or those who have pri­or ex­pe­ri­ence reg­u­lat­ing a prod­uct that has been re­pur­posed for treat­ment of COVID-19. Al­though the re­de­ploy­ment has not cre­at­ed de­lays in re­view ac­tiv­i­ties to date, de­lays re­main a re­al pos­si­bil­i­ty.

In the EU, face-to-face meet­ings and sci­en­tif­ic ad­vice in per­son are no longer com­mon. It is thus in­creas­ing­ly im­por­tant to in­ter­act with and so­lic­it in­put from reg­u­la­tors by phone and email. But poli­cies on new ways to col­lect da­ta vary by coun­try. For ex­am­ple, some mem­ber states are al­low­ing cen­tral­ized mon­i­tor­ing of clin­i­cal tri­als and source da­ta ver­i­fi­ca­tion as long as pa­tient con­fi­den­tial­i­ty is main­tained. How­ev­er, the elec­tron­ic trans­fer of da­ta is not broad­ly ac­cept­ed: it is pos­si­ble in some Eu­ro­pean coun­tries and not in oth­ers. The key is dis­cussing it with reg­u­la­tors pri­or to do­ing it.

The FDA is show­ing re­mark­able flex­i­bil­i­ty on a range of is­sues, from how a spon­sor may doc­u­ment in­formed con­sent, to con­duct­ing clin­i­cal tri­als vir­tu­al­ly (see Ta­ble 1), to us­ing re­al-world ev­i­dence in a mar­ket­ing sub­mis­sion. This gives the in­dus­try per­mis­sion to test the bound­aries. If an un­prece­dent­ed so­lu­tion can meet reg­u­la­to­ry re­quire­ments, as well as the needs of pa­tients and spon­sors, reg­u­la­tors may be more open to it to­day than in the past.

Al­though reg­u­la­tors will nev­er com­pro­mise on pa­tient safe­ty, or on the need to show ef­fi­ca­cy with GCP-com­pli­ant da­ta, there is now flex­i­bil­i­ty on how and when da­ta are col­lect­ed (for ex­am­ple, end­points can be de­layed), how study mon­i­tor­ing can be done, and how in­ves­ti­ga­tion­al drugs may be de­liv­ered to pa­tients, to name just a few. Reg­u­la­tors need to be in­formed about any so­lu­tions spon­sors may want to try, and com­pa­nies can pro­tect their drug de­vel­op­ment pro­grams by com­mu­ni­cat­ing them ef­fec­tive­ly.

4. Pre­serv­ing da­ta in­tegri­ty un­der ex­tra­or­di­nary con­di­tions

Where spon­sors have to mod­i­fy study pro­to­cols in re­sponse to the Coro­n­avirus pan­dem­ic, reg­u­la­to­ry agen­cies ex­pect metic­u­lous records of de­vi­a­tions in or­der to pre­serve the in­tegri­ty and in­ter­pretabil­i­ty of tri­al da­ta.

Reg­u­la­tors around the world have in­di­cat­ed they will be more flex­i­ble than in the past. For ex­am­ple, new FDA guid­ance (Ta­ble 1) spec­i­fies that changes to a pro­to­col or in­ves­ti­ga­tion­al plan meant “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 IND/IDE amend­ment—but are re­quired
to be re­port­ed af­ter­wards.”

Ac­knowl­edg­ing that the dis­rup­tions caused by the pan­dem­ic may re­sult in an in­crease in miss­ing da­ta, the FDA is re­quir­ing that missed vis­its, pa­tient dis­con­tin­u­a­tions, and sim­i­lar changes in pro­to­col- spec­i­fied pro­ce­dures must be tracked in case re­port forms and must in­clude spe­cif­ic in­for­ma­tion ex­plain­ing how the miss­ing da­ta re­late to the COVID-19 pan­dem­ic (see Ta­ble 1).

The EMA has en­cour­aged spon­sors to “pre-plan” how pro­to­col de­vi­a­tions re­lat­ed to COVID-19 are record­ed and how rea­sons for miss­ing da­ta are cap­tured, in or­der to dis­tin­guish be­tween “af­fect­ed” and “un­af­fect­ed” da­ta when in­ter­pret­ing tri­al re­sults. While the EMA have re­leased an over­all guid­ance for the EU, the Na­tion­al Reg­u­la­to­ry Au­thor­i­ties of EU mem­ber states are di­rect­ly re­spon­si­ble for the tri­als. Ac­cord­ing­ly, spon­sors need to check coun­try- spe­cif­ic guid­ance doc­u­ments (see Ta­ble 1).

5. Stay­ing alert to chang­ing reg­u­la­tions; stay­ing en­gaged

Spon­sors will need to track the ever-chang­ing COVID-19 guide­lines is­sued by health au­thor­i­ties and reg­u­la­tors in every lo­cal­i­ty where they are con­duct­ing clin­i­cal tri­als. Re­gions vary in terms of the strin­gency of their trav­el re­stric­tions, their re­quire­ments for so­cial dis­tanc­ing, lock­down and quar­an­tine rules, and those for test­ing and con­tact trac­ing.

A large num­ber of clin­i­cal tri­als (though not all) will in­evitably be paused un­til the coro­n­avirus pan­dem­ic sub­sides, but spon­sors should stay en­gaged. For ex­am­ple, Parex­el is cur­rent­ly in­volved in a high vol­ume of reg­u­la­to­ry work for clients who are get­ting every­thing in line for when their paused tri­als re­sume. If the prepara­to­ry work is done now, stud­ies can restart more ef­fi­cient­ly. This cri­sis will not last for­ev­er.

Track­ing reg­u­la­to­ry guid­ances and as­sess­ing how flex­i­ble dif­fer­ent agen­cies may be will be key to sur­viv­ing in this tem­porar­i­ly dis­rupt­ed drug de­vel­op­ment en­vi­ron­ment.

Change is a mat­ter of sur­vival

This pub­lic health emer­gency will change clin­i­cal tri­als for­ev­er but many of those changes will be for the bet­ter. Both in­dus­try and reg­u­la­tors are be­ing pushed to ex­plore new ways to con­duct clin­i­cal tri­als, dis­cov­er­ing the ben­e­fits and lim­its of a more vir­tu­al, de­cen­tral­ized ap­proach. This ex­per­i­ment forced up­on us will teach us cru­cial lessons about what works and what doesn’t.

If new path­ways and pro­ce­dures are proven ef­fec­tive dur­ing this pan­dem­ic, reg­u­la­to­ry au­thor­i­ties will like­ly con­tin­ue to ac­cept them in the fu­ture. Af­ter all, the ex­pe­dit­ed ap­proval path­ways and reg­u­la­tions that so many com­pa­nies use to­day were writ­ten in re­sponse to the HIV cri­sis, when pa­tients need­ed ac­cess to new ther­a­pies quick­ly. Change was a mat­ter of sur­vival then, and it is a mat­ter of sur­vival now.

The lega­cy of our cur­rent pub­lic health cri­sis could be that vir­tu­al tri­als and hy­brid tri­als will be­come much more wide­ly ac­cept­ed and that these and oth­er pa­tient-cen­tric study de­signs will be work­ing to ben­e­fit pa­tients and spon­sors when the nov­el Coro­n­avirus has be­come a mat­ter for his­to­ri­ans, and ceased to be one for re­searchers.

FDA Guid­ance on Con­duct of Clin­i­cal Tri­als of Med­i­c­i­nal Prod­ucts dur­ing the COVID-19 Pan­dem­ic (non­bind­ing rec­om­men­da­tions)
18 March 2020 / 2 April 2020
Unit­ed States, FDA

• 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 IND/IDE amend­ment—but are re­quired to be re­port­ed af­ter­wards
• Changes in pro­to­col-spec­i­fied pro­ce­dures that lead to miss­ing da­ta (e.g., missed vis­its, pa­tient dis­con­tin­u­a­tions) must be tracked in case re­port forms and must in­clude spe­cif­ic in­for­ma­tion ex­plain­ing the ba­sis of miss­ing da­ta and how it re­lates to COVID-19