Clin­i­cal Stud­ies In Japan To­day: An­oth­er Look At The World’s Sec­ond-Largest Pre­scrip­tion Drug Mar­ket In A Post-Pan­dem­ic World

The phar­ma in­dus­try has com­pelling rea­sons to in­clude Japan in clin­i­cal tri­als and the coun­try’s re­spons­es to the COVID-19 pan­dem­ic have on­ly fur­thered the coun­try’s ap­peal to the rest of the phar­ma in­dus­try. Japan’s large pa­tient pop­u­la­tion, ma­ture lo­cal mar­ket and flex­i­ble da­ta reg­u­la­tions for clin­i­cal tri­als are just a few rea­sons to in­volve Japan in glob­al stud­ies. To be­come more at­trac­tive to glob­al spon­sors, Japan has un­der­gone sweep­ing changes to cre­ate a cli­mate con­ducive to clin­i­cal de­vel­op­ment pro­grams by align­ing drug ap­proval time­lines with those of the US and Eu­rope.

As with most coun­tries, Japan’s in­dus­try had to adapt to the cur­rent en­vi­ron­ment, thus cre­at­ing a sys­tem open to de­cen­tral­ized clin­i­cal tri­als (DCTs). As in­cred­i­bly im­por­tant as Japan is, there were and still are mul­ti­ple chal­lenges phar­ma­ceu­ti­cal com­pa­nies tack­le while look­ing to ex­pand their glob­al reach in­to Japan. Spon­sors are faced with chal­lenges such as pa­tient re­cruit­ment, site man­age­ment, and chang­ing lo­cal reg­u­la­tions.

One of Japan’s reg­u­la­tions is that over­seas spon­sors must use in-coun­try clin­i­cal care­tak­ers (IC­CCs) to spon­sor tri­als on over­seas com­pa­nies’ be­half if they do not have an en­ti­ty lo­cat­ed in Japan. At a fun­da­men­tal lev­el, IC­CCs man­age both safe­ty re­port­ing and reg­u­la­to­ry in­ter­ac­tions such as reg­is­ter­ing the tri­al.  IC­CCs may al­so be con­tract re­search or­ga­ni­za­tions (CROs), which plan and su­per­vise the clin­i­cal tri­al’s de­vel­op­ment from plan­ning to ex­e­cu­tion. In ad­di­tion to the CROs, Site man­age­ment or­ga­ni­za­tions (SMOs) are ex­treme­ly im­por­tant in Japan as they bridge the gaps be­tween the spon­sor phar­ma­ceu­ti­cal com­pa­ny, CROs and Japan­ese med­ical in­sti­tu­tions. They pro­vide to­tal ad­min­is­tra­tive and prac­ti­cal sup­port to med­ical in­sti­tu­tions and pa­tients dur­ing clin­i­cal tri­als.

Be­cause of the ad­di­tion­al sup­port SMOs pro­vide, many large Japan­ese phar­ma­ceu­ti­cal com­pa­nies al­so use them for clin­i­cal tri­als in ad­di­tion to CROs. SMO sup­port can be the key to con­duct­ing suc­cess­ful, high-qual­i­ty clin­i­cal tri­als. SMOs pro­vide sup­port to tri­als via clin­i­cal re­search co­or­di­na­tors (CRCs) and Site man­age­ment as­so­ciates (SMAs). CRCs im­prove the qual­i­ty of clin­i­cal tri­als in by man­ag­ing key ar­eas such as pa­tient el­i­gi­bil­i­ty, in­formed con­sent sup­port, hos­pi­tal vis­its, test­ing sched­ules and oth­er clin­i­cal tri­al ma­te­ri­als such as prepar­ing case re­port forms (CRFs). To fa­cil­i­tate smooth clin­i­cal tri­als, they pro­vide ad­di­tion­al sup­port to clin­i­cal re­search as­so­ciates and as­sist med­ical in­sti­tu­tions with au­dits/reg­u­la­to­ry in­spec­tions.

SMAs rou­tine­ly per­form ad­min­is­tra­tive tasks such as in­voic­es, doc­u­men­ta­tion, sup­port­ing IRB sub­mis­sion and re­views, prepar­ing sites for clin­i­cal tri­als, and sup­port­ing both au­dit and reg­u­la­to­ry in­spec­tions. SMO sup­port is so vi­tal that larg­er CROs, such as the CMIC Group, have de­vel­oped and added in-house SMOs in­to their of­fer­ings.

Re­duc­ing Reg­u­la­to­ry Is­sues

Ef­forts have been made to im­prove reg­u­la­to­ry chal­lenges in Japan dur­ing the past decade, which have re­sult­ed in an en­vi­ron­ment that is sig­nif­i­cant­ly friend­lier to clin­i­cal tri­als. This is not to say that start­ing a clin­i­cal tri­al in Japan is with­out chal­lenges.

Since the Min­istry of Health, La­bor and Wel­fare (MHLW) reg­u­lates clin­i­cal tri­als in Japan, spon­sors must ad­here to MHLW’s stan­dards all the way from spon­sor­ing to clin­i­cal tri­al ex­e­cu­tion and drug ap­proval. Over­seas and lo­cal spon­sors find that they must ad­here to the Good Clin­i­cal Prac­tices (GCP) set forth by the Phar­ma­ceu­ti­cals and Med­ical De­vices Agency (PM­DA) as well as lo­cal reg­u­la­tions, such as the Phar­ma­ceu­ti­cal and Med­ical De­vice Act and Clin­i­cal Tri­als Act.

While CROs mon­i­tor clin­i­cal tri­als to make sure they run smooth­ly and ad­here to all laws and reg­u­la­tions, SMOs are im­per­a­tive to stream­line the process in the med­ical in­sti­tu­tions. SMOs col­lab­o­rate with CROs as they man­age the reg­u­la­to­ry frame­work to ver­i­fy that the tri­als ad­here to all laws and reg­u­la­tions.  As CROs ver­i­fy com­pli­ance, and the spon­sor to in­ves­ti­ga­tors and in­sti­tu­tion­al re­view board (IRB) com­mit­tees, SMOs co­or­di­nate with them through­out the process to pro­vide prac­ti­cal and ad­min­is­tra­tive sup­port which stream­lines process­es and val­i­dates that the clin­i­cal tri­als are ad­her­ing to all reg­u­la­tions.

Sim­pli­fy­ing Pa­tient and Site Man­age­ment

One of the ma­jor chal­lenges in Japan, sim­i­lar to oth­er re­gions, re­lates to pa­tient re­cruit­ment and en­gage­ment. Japan­ese pa­tients are part of the coun­try’s na­tion­al health in­sur­ance sys­tem. This can be prob­lem­at­ic be­cause pa­tients may not be mo­tived to par­tic­i­pate in clin­i­cal stud­ies.  Ad­di­tion­al­ly, com­mon prac­tices and meth­ods uti­lized heav­i­ly in oth­er re­gions to im­prove pa­tient en­gage­ment, such as telemed­i­cine and home nurs­ing, are not yet wide­ly used in Japan. This is a re­sult of the coun­try hav­ing rel­a­tive­ly more med­ical in­sti­tu­tions than any oth­er coun­try, which al­so may be close to home for many pa­tients than any oth­er coun­try.iii Thus, telemed­i­cine has not been nec­es­sary be­fore COVID-19 and is still go­ing through a time of ad­just­ment.

SMOs use their ex­ten­sive knowl­edge to guide clin­i­cal tri­al spon­sors to high-po­ten­tial can­di­date sites. Busi­ness De­vel­op­ment Dept., Di­rec­tor at CMIC Group’s SMO Busi­ness, Mr. Masanobu Mi­namino, ex­plained to Cite­line that SMOs es­sen­tial­ly man­age med­ical in­sti­tu­tion sites for each clin­i­cal tri­al. Be­fore a tri­al is even sched­uled to take place, an SMO con­ducts fea­si­bil­i­ty stud­ies to ver­i­fy that it will be suc­cess­ful in the med­ical in­sti­tu­tion set­ting.

Rec­og­niz­ing the chal­lenges of con­tin­u­ous pa­tient en­gage­ment, es­pe­cial­ly while fac­ing cur­rent en­vi­ron­men­tal fac­tors, SMOs pro­vide each study with clin­i­cal re­search co­or­di­na­tors (CRCs) to serve as the li­aisons be­tween doc­tors and pa­tients. Pa­tients and CRCs com­mu­ni­cate dai­ly re­gard­ing med­ical ques­tions or ad­verse events, and this con­tin­u­ous en­gage­ment and care means pa­tients are less like­ly to drop out of a study. This type of pa­tient and doc­tor in­ter­ac­tion is cru­cial for the suc­cess of clin­i­cal tri­als, es­pe­cial­ly DCT tri­als, where pa­tient en­gage­ment needs to be care­ful­ly cul­ti­vat­ed and mon­i­tored.

Since both glob­al and lo­cal phar­ma­ceu­ti­cal com­pa­nies use SMOs, they are ac­cus­tomed to sup­port­ing both types of clients.  While there are few dif­fer­ences be­tween sup­port­ing both clients, there are a few im­por­tant dif­fer­ences. CMIC Group SMO Busi­ness, Man­ag­ing Ex­ec­u­tive Of­fi­cer, Mr. Ko­hei Sakaza­ki, dis­cussed the main dif­fer­ences be­tween glob­al and lo­cal clients for SMOs. “Japan­ese guide­lines might be dif­fer­ent from the glob­al guide­lines. So based up­on glob­al clients’ re­quire­ments, we just look for the med­ical in­sti­tu­tion that can re­spond to our re­quire­ments. The same ap­plies to dif­fer­ences be­tween larg­er and small­er clin­i­cal sites. The pri­ma­ry vari­ance is gen­er­al­ly work­loads be­tween the sites, which in­cludes ad­min­is­tra­tive tasks such as in­sti­tu­tion­al re­view board sub­mis­sion. Larg­er sites take more steps and more time to com­plete, mak­ing SMOs crit­i­cal for CROs and spon­sors.”

Cus­tomiz­ing Japan­ese De­cen­tral­ized Clin­i­cal Tri­als

Pri­or to the pan­dem­ic, many cor­po­ra­tions were ex­plor­ing DCTs but had not start­ed im­ple­men­ta­tion. While pa­tients tra­di­tion­al­ly went to med­ical in­sti­tu­tions due to the easy ac­ces­si­bil­i­ty pre­vi­ous­ly men­tioned, pa­tients avoid­ed hos­pi­tals dur­ing the first pan­dem­ic wave. As a re­sponse to the pan­dem­ic, some new clin­i­cal tri­al meth­ods were in­tro­duced with guid­ance from reg­u­la­to­ry agen­cies.

The MHLW is­sued the Time­ly/Ex­cep­tion­al Han­dling of Con­sul­ta­tions Us­ing Tele­phones and Oth­er Telecom­mu­ni­ca­tion Equip­ment Due to the Spread of Nov­el Coro­n­avirus In­fec­tions guid­ance on April 10, 2020, which be­came per­ma­nent in Oc­to­ber 2020. As a re­sult, new clin­i­cal tri­al meth­ods that do not de­pend on live pa­tient vis­its to med­ical in­sti­tu­tions, such as tri­als us­ing DCTs or vir­tu­al clin­i­cal tri­als (VCTs), are now be­com­ing more avail­able in Japan.

Nei­ther med­ical in­sti­tu­tions nor pa­tients were ac­cus­tomed to DCTs, mean­ing adop­tion was slow. How­ev­er, these mod­els have be­come in­creas­ing­ly nec­es­sary as Japan, along with the rest of the world, ex­pe­ri­ences ad­di­tion­al pan­dem­ic waves. Since the cost ef­fec­tive­ness of DCTs is still be­ing as­sessed, spon­sors/CROs must adapt cur­rent DCT/VCT mod­els to Japan with sup­port from SMOs, to min­i­mize costs and in­crease both pa­tient and med­ical in­sti­tu­tion com­fort. As these mod­els are adopt­ed, com­pa­nies with both CRO and SMO func­tions be­come even more im­por­tant due to lan­guage and reg­u­la­to­ry bar­ri­ers for spon­sors.

CMIC Group’s CRO Busi­ness, Fu­ture De­sign De­part­ment Di­rec­tor, Mr. Shu­ji Oza­wa, re­cent­ly ad­dressed how they cus­tomize DCT/VCT mod­els to ad­dress lan­guage and reg­u­la­tion ob­sta­cles. CMIC Group’s clin­i­cal tri­al plat­form is like many DCT mod­els, but since the chal­lenges and sit­u­a­tions are dif­fer­ent for each DCT/VCT, they cus­tomize it for Japan by “an­a­lyz­ing the reg­u­la­tion gaps, con­sult­ing with PM­DA, an­a­lyz­ing the ven­dor set­tings and cre­at­ing pro­ce­dures” to en­sure that the tri­al is free from any po­ten­tial hur­dles. CMIC al­so high­lights the need for CROs/SMOs to col­lab­o­rate with dig­i­tal part­ners to en­sure that tri­als pro­ceed flaw­less­ly, from sys­tem or de­vice in­tro­duc­tion to pro­duc­tiv­i­ty. This in­cludes as­sist­ing with the sys­tem in­tro­duc­tion to site staff, pa­tients, and in­ves­ti­ga­tors. Their cur­rent CRO and SMO struc­ture works seam­less­ly to pro­vide tri­al man­age­ment and health­care ser­vices to pa­tients us­ing dig­i­tal tech­nolo­gies.

As Japan con­tin­ues to be in­clud­ed in glob­al clin­i­cal tri­als, there is a strong need to in­crease DCT ca­pa­bil­i­ties go­ing for­ward. One po­ten­tial chal­lenge fac­ing Japan right now is the in­vest­ment in tech­nolo­gies used for DCTs/VCTs in oth­er coun­tries. Ms. Mari Kawa­mu­ra, CMIC Group’s SMO Busi­ness, Team Leader of Busi­ness Plan­ning, notes that “ven­ture com­pa­nies are not so preva­lent in Japan com­pared with the Unit­ed States be­cause of the reg­u­la­tions as well as our busi­ness, en­vi­ron­ment and cul­ture. How­ev­er, hav­ing said that, if you look at re­cent years and the ven­ture com­pa­nies en­gag­ing in DCTs, the num­ber is in­creas­ing.” SMOs have field knowl­edge at the lo­cal lev­el, which in­cludes med­ical in­sti­tu­tions, and com­mu­ni­ties. As DCTs/VCTs con­tin­ue to be­come more wide­ly ac­cept­ed, SMOs are es­sen­tial for suc­cess­ful im­ple­men­ta­tion in all as­pects.

Look­ing At a Hy­brid Fu­ture

Al­though its reg­u­la­to­ry bod­ies are ac­tive­ly pro­duc­ing guide­lines to make clin­i­cal tri­als eas­i­er in Japan, the process is still full of com­pli­ca­tions that can de­lay such stud­ies. Japan’s re­sponse to COVID-19 has been pa­tient-cen­tric, al­low­ing for pa­tients to par­tic­i­pate in both vir­tu­al and de­cen­tral­ized tri­als. It is clear that these tri­als, in ad­di­tion to live sites, are es­sen­tial to the fu­ture.

An ex­pe­ri­enced SMO with knowl­edge of the reg­u­la­to­ry is­sues, doc­u­men­ta­tion, lo­cal cul­ture and con­nec­tions with the lo­cal med­ical in­sti­tu­tions s es­sen­tial for the suc­cess of clin­i­cal tri­als. As Japan moves to­wards adopt­ing DCTs/VCTs, it is wise to se­lect a part­ner with both CRO and SMO ca­pa­bil­i­ties so that they are able to seam­less­ly im­ple­ment dig­i­tal tech­nol­o­gy.  While the CRO as­pect of the com­pa­ny cre­ates the study and pro­to­col de­signs to in­cor­po­rate dig­i­tal so­lu­tions, hence work­ing with dig­i­tal part­ners, the SMO will co­or­di­nate with med­ical in­sti­tu­tions, pa­tients and in­ves­ti­ga­tors to as­sist them with the use of the tech­nol­o­gy. As we move for­ward to a dig­i­tal word, a SMO/CRO part­ner is es­sen­tial to the growth and suc­cess of clin­i­cal tri­als.