How Mul­ti-Stake­hold­er Strate­gies for Ex­ter­nal Con­trol Arms Can Over­come Ap­proval and Ac­cess Bar­ri­ers

Leanne Lar­son, Se­nior Vice Pres­i­dent & Head of Re­al-World Ev­i­dence and Ac­cess
Amy Mc­K­ee, Head of Reg­u­la­to­ry On­col­o­gy
Sangee­ta Bud­hia, Glob­al HTA Strat­e­gy Lead & Vice Pres­i­dent, Pric­ing & Mar­ket Ac­cess

The COVID-19 pan­dem­ic cast a spot­light on the ex­pand­ing role of re­al-world ev­i­dence (RWE) and the win­dow it pro­vides in­to a more thor­ough un­der­stand­ing of the pa­tient jour­ney. De­vel­op­ers are find­ing that the cap­ture of all rel­e­vant da­ta—from ran­dom­ized clin­i­cal tri­als and re­al-world ev­i­dence—can safe­ly ex­pe­dite new ther­a­pies for pa­tients with high un­met needs.

Ex­ter­nal con­trol arms, which use pa­tient-lev­el da­ta sourced from wear­able tech­nol­o­gy, ret­ro­spec­tive stud­ies, elec­tron­ic health records (EHRs), ex­ist­ing datasets, and oth­er tri­al con­trol pop­u­la­tions, are pro­vid­ing im­por­tant re­al-world con­text and clar­i­ty dur­ing clin­i­cal de­vel­op­ment and eval­u­a­tion. With in­creas­ing­ly flu­id clin­i­cal study de­signs, de­vel­op­ers, reg­u­la­tors, and pay­ers are adopt­ing new ways of think­ing about vast sources of da­ta amassed from con­trolled tri­als and re­al-world sources—and how that da­ta can be fit-for-pur­pose to meet drug ap­proval and ac­cess stan­dards.

Flex­i­ble con­trols and clin­i­cal het­ero­gene­ity

Many stake­hold­ers see strong po­ten­tial with in­te­grat­ed datasets that com­ple­ment and con­tex­tu­al­ize pa­tient care and out­comes. For ex­am­ple, ex­ter­nal con­trols can iden­ti­fy pa­tient pop­u­la­tion sig­nals that may be un­de­tect­ed in ran­dom­ized tri­als and ap­ply those study re­sults to broad­er pa­tient pop­u­la­tions. Ex­ter­nal con­trol arms can al­so be used to mim­ic ran­dom­ized datasets and pro­vide much-need­ed flex­i­bil­i­ty for pub­lic health crises like COVID-19 and in rare dis­ease mar­kets with small­er pa­tient pop­u­la­tions.

In ad­di­tion to pro­vid­ing a dy­nam­ic, re­al-time win­dow in­to the pa­tient ex­pe­ri­ence, ex­ter­nal con­trols hold great promise in ad­dress­ing the long-stand­ing chal­lenge of ho­mo­ge­neous clin­i­cal tri­als. With strict in­clu­sion and ex­clu­sion cri­te­ria, it is es­ti­mat­ed that on­ly three per­cent of the on­col­o­gy pa­tient pop­u­la­tion is rep­re­sent­ed in con­trolled tri­als.

De­tailed method­olo­gies for reg­u­la­to­ry con­fi­dence

The U.S. FDA has ap­proved dozens of drug prod­ucts pre­sent­ed with com­pelling, com­ple­men­tary ev­i­dence from in­te­grat­ed datasets. Though reg­u­la­tors do con­sid­er ex­ter­nal con­trol arm da­ta, their fo­cus has large­ly been on rare dis­ease and on­col­o­gy drug can­di­dates. Cog­nizant of the ex­pand­ing role of ex­ter­nal con­trol arms, many glob­al agen­cies are prepar­ing for­mal guid­ance for de­vel­op­ers to ex­pand its ap­pli­ca­tion across oth­er ar­eas of med­i­cine.

In the mean­time, de­vel­op­ers are en­cour­aged to en­gage reg­u­la­tors ear­ly in the process with de­tailed method­olo­gies for the cap­ture and analy­sis of ex­ter­nal da­ta. Do­ing so will help reg­u­la­to­ry agen­cies bet­ter un­der­stand what the da­ta will cap­ture and bet­ter an­tic­i­pate the pa­tient out­comes.

While there is no sin­gu­lar source of da­ta ro­bust enough to an­swer every ques­tion, a hy­brid of ret­ro­spec­tive da­ta gleaned from EHRs and prospec­tive da­ta gath­ered from ac­tive in­ves­ti­ga­tion­al arms can pro­vide a more com­pre­hen­sive view for reg­u­la­tors. How­ev­er, de­vel­op­ers must be mind­ful to de­sign da­ta method­olo­gies that align with the spe­cif­ic dis­ease con­text and its ex­ist­ing stan­dard of care. For in­stance, ret­ro­spec­tive re­al-world da­ta may no longer be rel­e­vant in some dis­ease ar­eas with rapid treat­ment ad­vances, but it may prove in­valu­able in an emerg­ing pub­lic health cri­sis like COVID-19 that de­mands re­al-time pa­tient in­sight.

Map­ping the pa­tient jour­ney for pay­ers

Health tech­nol­o­gy as­sess­ment (HTA) au­thor­i­ties are pri­mar­i­ly fo­cused on whether da­ta—re­gard­less of the study de­sign in which it was col­lect­ed—re­flects the re­al-world pa­tient pop­u­la­tion. Where­as reg­u­la­tors eval­u­ate ex­ter­nal con­trol stud­ies us­ing qual­i­ty, safe­ty, and ef­fi­ca­cy stan­dards, HTA agen­cies screen against oth­er ar­eas of com­par­a­tive ben­e­fit and cost risk.

Clin­i­cal stud­ies with ex­ter­nal con­trols can pro­vide pay­ers with valu­able in­sight to de­ter­mine a drug’s com­par­a­tive clin­i­cal ben­e­fits to ex­ist­ing prod­ucts, as well as its in­cre­men­tal cost-ef­fec­tive­ness in treat­ing the greater pa­tient pop­u­la­tion. How­ev­er, it is in­cum­bent on de­vel­op­ers to pro­vide HTA au­thor­i­ties with the prop­er method­olo­gies to map re­al-world da­ta to con­trolled tri­al da­ta. If ex­ter­nal con­trols are clear­ly de­fined, they can help pay­er au­thor­i­ties un­der­stand the course of a dis­ease and how pa­tients progress through each stage of the dis­ease and its treat­ment un­der rou­tine, stan­dard-of-care treat­ment. A de­fined method­ol­o­gy is par­tic­u­lar­ly im­por­tant when de­vel­op­ers seek to ex­pand a prod­uct in­to a new mar­ket, as they must en­sure the com­par­a­tive re­al-world da­ta re­flects the dif­fer­ent pa­tient pop­u­la­tion in their health­care sys­tem.

Much like reg­u­la­to­ry bod­ies, HTA agen­cies ad­vise de­vel­op­ers to com­mu­ni­cate ear­ly and of­ten with the de­tails of planned da­ta col­lec­tion and analy­sis to elim­i­nate guess­work and re­duce risk.

Fu­ture ex­plo­ration

While the long-term im­pact of in­te­grat­ed clin­i­cal da­ta sys­tems re­mains to be seen, some ex­perts fore­see the evo­lu­tion of re­al-world end­points retro-en­gi­neered by mul­ti­ple stake­hold­ers. Oth­ers ad­vise that keep­ing the pa­tient voice at the fore­front of every stage of de­vel­op­ment will nat­u­ral­ly lead to more suc­cess­ful ap­proval and ac­cess out­comes.

As stake­hold­ers con­tin­ue to learn, em­brace, and ap­ply learn­ings from the com­plete pa­tient ex­pe­ri­ence, the in­dus­try will progress with in­no­v­a­tive ther­a­pies for all pa­tients in need.

For fur­ther RWE in­sights and more, down­load our eBook “The new im­per­a­tives: Adapt­ing on­col­o­gy drug de­vel­op­ment to a post-COVID world.”