Risk Mit­i­ga­tion in Di­rect-to-Pa­tient Clin­i­cal Tri­als

The COVID-19 pan­dem­ic has made so­ci­ety very aware of the need to be flex­i­ble in the ap­proach to dai­ly life. Every part of “nor­mal” day-to-day life has been dis­rupt­ed. Clin­i­cal tri­als and the tra­di­tion­al way of con­duct­ing them has been no dif­fer­ent. Flex­i­bil­i­ty be­came an im­me­di­ate need for spon­sors, CROs, clin­i­cal sites, and pa­tients. Quick ad­just­ments had to be made, along with find­ing new ways to make sure that pa­tients had the ap­pro­pri­ate care, over­sight of the clin­i­cal sites con­tin­ued to be man­aged, and drug sup­ply and ac­count­abil­i­ty were main­tained. Many clin­i­cal sites found them­selves act­ing as a ship­ping de­part­ment, try­ing to make sure all of their pa­tients re­ceived their drug safe­ly and on time. CRAs per­formed re­mote over­sight vis­its, vir­tu­al site tours, and vir­tu­al ac­count­abil­i­ty au­dits. Spon­sors quick­ly be­gan to re­think their Di­rect-to-Pa­tient (DTP) ap­proach as pa­tients in­creas­ing­ly re­quest­ed that their study drugs be shipped to their homes.

Use and ac­cep­tance of DTP may have grown faster due to the pan­dem­ic, but the over­all trend to­ward the de­cen­tral­ized clin­i­cal tri­al (DCT)/DTP mod­el was on the rise pre-2020 and is pro­ject­ed to grow sig­nif­i­cant­ly over the next few years. As more and more DCTs come on board, it is im­por­tant to re­mem­ber that clear roles and re­spon­si­bil­i­ties and ex­pe­ri­enced man­age­ment are vi­tal to suc­cess. Spon­sors that can add flex­i­bil­i­ty in­to their pro­to­col de­signs, stan­dard op­er­at­ing pro­ce­dures and qual­i­ty over­sight process will be able to ef­fec­tive­ly ben­e­fit from uti­liz­ing the DTP mod­el. The DTP mod­el can help mit­i­gate risks in pa­tient en­roll­ment (in­clud­ing di­ver­si­ty), pa­tient re­ten­tion, and ad­her­ence to over­all study time­lines and bud­get. A well-planned DTP study can be ben­e­fi­cial to pa­tients and spon­sors, but this mod­el can prove to be more com­plex to get start­ed than the tra­di­tion­al mod­el. An ef­fi­cient ap­proach re­quires re­think­ing Stan­dard Op­er­at­ing Pro­ce­dures (SOPs) and just about every oth­er as­pect of how tri­als have been tra­di­tion­al­ly man­aged, in­clud­ing the pro­to­col de­sign and dos­ing win­dows. Form­ing a di­verse team knowl­edge­able in all as­pects of the study over­sight and sup­ply chain pri­or to fi­nal­iz­ing the pro­to­col should be con­sid­ered.

How to Mit­i­gate Risk in DTP Stud­ies

The de­cen­tral­ized mod­el, as well as the tra­di­tion­al site-based mod­el with a DTP com­po­nent, can open up spon­sors to new risks in ad­di­tion to those found in the con­ven­tion­al mod­el. Some con­cerns that are fair­ly straight­for­ward to re­solve in con­ven­tion­al stud­ies can cause prob­lems for un­pre­pared spon­sors of tri­als with a DTP com­po­nent. By iden­ti­fy­ing the risks as­so­ci­at­ed with a study up­front, spon­sors can mit­i­gate these risks and po­si­tion them­selves to bet­ter re­al­ize the ben­e­fits of DTP sup­ply for their clin­i­cal tri­al op­er­a­tions and pa­tients alike.

Suc­cess­ful stud­ies start with a clear un­der­stand­ing of the goals tied to the use of DTP and knowl­edge of re­gion­al re­quire­ments and pos­si­ble con­straints. There is con­sid­er­able coun­try-to-coun­try vari­a­tion in DTP reg­u­la­tions, mak­ing it crit­i­cal to work with lo­cal ex­perts to un­der­stand what is and is not pos­si­ble in a par­tic­u­lar re­gion, as well as how to ap­proach key tasks such as con­sent and clin­i­cal la­bel con­tent. A dif­fer­ent plan is strong­ly rec­om­mend­ed for each coun­try; there is no “one size fits all” ap­proach to de­ploy­ing DTP glob­al­ly. In­di­vid­ual coun­try plans al­low for eas­i­er ad­just­ment on a coun­try-by-coun­try ba­sis if nec­es­sary, with­out hav­ing to dis­rupt or de­lay the en­tire study.

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There are some el­e­ments, how­ev­er, that are the cor­ner­stones of all DTP de­ploy­ments. If us­ing a CRO, se­lect­ing one with a sol­id track record of run­ning de­cen­tral­ized stud­ies is im­por­tant. Equal­ly im­por­tant is hav­ing a strong clin­i­cal sup­ply part­ner with DTP ex­pe­ri­ence, as is a flex­i­ble In­ter­ac­tive Re­sponse Tech­nol­o­gy (IRT) ca­pa­ble of man­ag­ing the unique re­quire­ments of DTP, es­pe­cial­ly in a hy­brid mod­el con­sist­ing of site-to-pa­tient ship­ments, di­rect-to-pa­tient ship­ments from a de­pot, and clin­i­cal site dis­pens­ing vis­its.

All par­ties need to com­mu­ni­cate well and have a clear view of their roles and re­spon­si­bil­i­ties. Fail­ing to con­firm all the de­tails, no mat­ter how mi­nor they may seem at first glance, and oth­er­wise pre­pare for the study up­front can lead to the per­sis­tence of as­sump­tions and oth­er is­sues that can re­sult in sur­prise costs and de­lays down the line.

Spe­cif­ic points that teams need to con­sid­er in­clude han­dling of pa­tient in­for­ma­tion, how to pre­vent the study drug from be­ing giv­en to some­one oth­er than the par­tic­i­pant, tem­per­a­ture stor­age/dis­tri­b­u­tion re­quire­ments, re­turns/ac­count­abil­i­ty, and home health care in­volve­ment. Ven­dors with ac­cess to pa­tient in­for­ma­tion should be au­dit­ed to en­sure they are fol­low­ing all lo­cal pri­va­cy laws and that on­ly those who “need to know” the pa­tient in­for­ma­tion to car­ry out a spe­cif­ic task have ac­cess. Couri­ers can be in­struct­ed to on­ly de­liv­er to the named pa­tient or au­tho­rized rep­re­sen­ta­tive to mit­i­gate some of the risk, in­clud­ing the safe­ty prob­lems it could cre­ate if the drug were de­liv­ered to a mi­nor, for ex­am­ple. The han­dling of re­turns and CRA over­sight of ac­count­abil­i­ty will re­quire a dif­fer­ent ap­proach — a vir­tu­al au­dit of doc­u­ments and re­ports may be re­quired if the clin­i­cal site is not stor­ing the drug. In­volv­ing home health care can al­so help mit­i­gate some risk: they can en­sure that the pa­tient is tak­ing the drug ap­pro­pri­ate­ly, and they can al­so as­sist with pack­ing up re­turns and com­plet­ing rec­on­cil­i­a­tion pa­per­work.

Vir­tu­al “vis­its” on the day of drug de­liv­ery, cou­pled with quizzes and task re­minders in a mo­bile app can help mit­i­gate the risk of a pa­tient re­ceiv­ing and tak­ing the in­cor­rect drug, as well as en­sur­ing a full un­der­stand­ing of how and when to take their drug.

How DTP Stud­ies Mit­i­gate Op­er­a­tional Risks

Con­ven­tion­al clin­i­cal tri­als car­ry their own risks. The COVID-19 pan­dem­ic ex­posed some of the risks of the site-based mod­el, but it is far from the first event to dis­rupt the abil­i­ty for pa­tients to re­ceive study drug on time.

Risk mit­i­ga­tion is pos­si­ble when DTP is used as an en­abling com­po­nent in the de­cen­tral­iza­tion of clin­i­cal tri­als. By de­cen­tral­iz­ing tri­als, spon­sors can re­duce the risk of slow en­roll­ment and dropouts. DCTs elim­i­nate the need for sub­jects to be phys­i­cal­ly lo­cat­ed close to a clin­i­cal site in or­der to par­tic­i­pate, there­by ex­pand­ing the ge­o­graph­ic area and re­duc­ing the so­cio-eco­nom­ic and di­ver­si­ty bar­ri­ers that de­ter or pre­clude pa­tients from en­rolling or cause them to drop out if the bur­den be­comes too great.

De­cen­tral­iza­tion of stud­ies al­so sup­ports pa­tient com­pli­ance and ad­her­ence by pre­vent­ing missed vis­its and in­creas­es the di­ver­si­ty of the pool of po­ten­tial par­tic­i­pants. Col­lec­tive­ly, the ben­e­fits sup­port the swift en­roll­ment and strong re­ten­tion that im­prove ad­her­ence to over­all study time­lines and bud­gets.

Faster re­cruit­ment and in­creased re­ten­tion are just two of the ways that de­cen­tral­iza­tion and DTP from a cen­tral lo­ca­tion can dri­ve cost sav­ings. Spon­sors al­so ben­e­fit from hav­ing to pro­duce less drug over­age as there is no need to stock sites just in case a pa­tient en­rolls, there­by re­duc­ing the amount of study drug that is po­ten­tial­ly wast­ed over the course of the tri­al. Ad­di­tion­al­ly, spon­sors may see a re­duc­tion in clin­i­cal site fees for stor­age, vis­its, and han­dling. These sav­ings help off­set any up­front costs from us­ing DTP.

Putting DTP In­to Prac­tice

The ben­e­fits of DTP are now well-val­i­dat­ed, with the COVID-19 pan­dem­ic hav­ing ac­cel­er­at­ed the tran­si­tion to the mod­el and hav­ing shown all stake­hold­ers just how it can im­prove clin­i­cal tri­al op­er­a­tions and re­duce risk. As DTP be­comes an in­creas­ing­ly rou­tine part of drug de­vel­op­ment in the post-pan­dem­ic pe­ri­od, spon­sors and their ven­dor part­ners will need to stay abreast of the evolv­ing best prac­tices re­gard­ing use of this ap­proach and cog­nizant of op­por­tu­ni­ties to use DTP in or­der to help mit­i­gate op­er­a­tional risk and main­tain pa­tient cen­tric­i­ty.

Spon­sors are ris­ing to that chal­lenge in a fast-chang­ing sec­tor that is sub­ject to coun­try-to-coun­try vari­a­tions in reg­u­la­tions by part­ner­ing with ex­pe­ri­enced clin­i­cal sup­ply providers that have a track record of suc­cess and knowl­edge of the evolv­ing DTP space.