Japan­ese phar­ma­ceu­ti­cal reg­u­la­tions un­der re­view to re­solve drug short­ages and en­sure sta­ble sup­ply

A com­mit­tee es­tab­lished last Ju­ly by Japan’s Min­istry of Health, Labour and Wel­fare has been re­view­ing phar­ma­ceu­ti­cal reg­u­la­tions in Japan, look­ing at re­vi­sions to the re­quire­ments for or­phan drugs, pro­mot­ing the de­vel­op­ment of pe­di­atric med­i­cines and the ne­ces­si­ty of da­ta from Japan­ese par­tic­i­pants, and al­so the is­sue of drug short­ages.

Since hold­ing its first meet­ing on Ju­ly 10, 2023, dis­cus­sions by the re­view com­mit­tee have tak­en place about once a month, and a draft re­port was pre­sent­ed at the ninth and fi­nal meet­ing on March 21.

The com­mit­tee was es­tab­lished in part to re­view what’s known as the “drug lag/drug loss” is­sue, where new drugs ap­proved in Eu­rope and the US are not in­tro­duced in Japan, as well as the prob­lem of short­ages in the sup­ply of gener­ic drugs. It has been is­su­ing no­ti­fi­ca­tions call­ing for re­vised reg­u­la­tions as soon as dis­cus­sions on cer­tain top­ics are com­plet­ed.

For ex­am­ple, in De­cem­ber 2023, the MHLW is­sued a no­ti­fi­ca­tion ti­tled “Ba­sic prin­ci­ples for con­duct­ing phase 1 stud­ies in Japan­ese pri­or to ini­ti­at­ing mul­ti-re­gion­al clin­i­cal tri­als in­clud­ing Japan for drugs in which ear­ly clin­i­cal de­vel­op­ment is pre­ced­ing out­side Japan.” In Jan­u­ary 2024, four no­ti­fi­ca­tions were is­sued re­gard­ing the des­ig­na­tion of or­phan drugs and the pro­mo­tion of pe­di­atric drug de­vel­op­ment.

“I’m im­pressed by such speedy re­spons­es,” says Yu­ji Kashi­waya, chair­per­son of the Phar­ma­ceu­ti­cal Af­fairs Com­mit­tee of the Japan Phar­ma­ceu­ti­cal Man­u­fac­tur­ers As­so­ci­a­tion (JP­MA) and a mem­ber of the com­mit­tee. “I’m grate­ful for the op­por­tu­ni­ty to present the opin­ions of the phar­ma­ceu­ti­cal in­dus­try in the com­mit­tee. Not all of the in­dus­try’s opin­ions have been adopt­ed, but I think our pro­pos­als have been ac­cept­ed to a con­sid­er­able ex­tent.”

Among the dis­cus­sions at the com­mit­tee, rep­re­sen­ta­tives from phar­ma­ceu­ti­cal com­pa­nies were par­tic­u­lar­ly in­ter­est­ed in the mat­ter con­cern­ing the ne­ces­si­ty of Phase 1 clin­i­cal tri­als in Japan­ese par­tic­i­pants.

Phase 3 clin­i­cal tri­als, which are the fi­nal stage of drug de­vel­op­ment, are typ­i­cal­ly con­duct­ed as large-scale in­ter­na­tion­al joint tri­als. If Japan par­tic­i­pates in these in­ter­na­tion­al joint tri­als, ap­proval and mar­ket­ing can take place al­most si­mul­ta­ne­ous­ly in Japan, the US and Eu­rope. How­ev­er, if Japan does not par­tic­i­pate, it leads to drug lag or drug loss.

A no­ti­fi­ca­tion is­sued in 2007 ti­tled “Ba­sic prin­ci­ples on Glob­al Clin­i­cal Tri­als” stat­ed that, in prin­ci­ple, Phase 1 tri­als in­volv­ing Japan­ese par­tic­i­pants were nec­es­sary. How­ev­er, there has been an in­crease in cas­es where start­up com­pa­nies con­duct Phase 1 and Phase 2 clin­i­cal tri­als in­volv­ing on­ly non-Japan­ese sub­jects over­seas, ob­tain proof of con­cept (PoC), and then have the de­vel­op­ment tak­en over by ma­jor phar­ma­ceu­ti­cal com­pa­nies through li­cens­ing. In such cas­es, if a Phase 1 tri­al in­volv­ing Japan­ese sub­jects is re­quired be­fore the in­ter­na­tion­al joint tri­al, it would de­lay the start of the in­ter­na­tion­al joint tri­al, and there could even be a de­ci­sion to ex­clude Japan from the tri­al.

The re­view of this reg­u­la­tion was dis­cussed in the com­mit­tee, and the no­ti­fi­ca­tion is­sued in De­cem­ber 2023 stat­ed that, “In gen­er­al, it is not manda­to­ry to con­duct a phase 1 study in each race/eth­nic­i­ty or coun­try/re­gion be­fore ini­ti­at­ing an mul­ti-re­gion­al clin­i­cal tri­als.”

How­ev­er, some have point­ed out that “the re­quire­ment for Phase 1 tri­als in­volv­ing Japan­ese sub­jects was not nec­es­sar­i­ly de­mand­ed pre­vi­ous­ly, so es­sen­tial­ly noth­ing has changed.” Nev­er­the­less, Kashi­waya of JP­MA said, “If safe­ty can be en­sured based on over­seas da­ta, there is no need to de­lib­er­ate­ly col­lect da­ta from Japan­ese sub­jects. This is a sig­nif­i­cant step for­ward in terms of be­ing able to pro­vide drugs to pa­tients more quick­ly.”

Fur­ther­more, Kashi­waya added, “Pre­vi­ous­ly, even if we thought a Phase 1 tri­al in­volv­ing Japan­ese sub­jects was un­nec­es­sary, we need­ed to ob­tain ap­proval through face-to-face con­sul­ta­tions with the Phar­ma­ceu­ti­cals and Med­ical De­vices Agency (PM­DA). Go­ing for­ward, we can elim­i­nate such un­nec­es­sary time. How­ev­er, when sub­mit­ting a clin­i­cal tri­al ap­pli­ca­tion, if we are un­able to pro­vide a co­gent ra­tio­nale as to why we be­lieve the safe­ty of Japan­ese par­tic­i­pants can be en­sured, we are like­ly to be asked to con­duct a Phase 1 tri­al.”

Ad­di­tion­al­ly, the com­mit­tee dis­cussed biosim­i­lars, and it was de­ter­mined that Japan­ese da­ta are not re­quired if eth­nic fac­tors of the sub­jects are not ex­pect­ed to af­fect the tri­al re­sults.

The com­mit­tee al­so dis­cussed the ne­ces­si­ty of Japan­ese da­ta in piv­otal tri­als. This is be­cause there have been cas­es where Japan­ese pa­tients’ ac­cess to drugs was de­layed or de­vel­op­ment in Japan was aban­doned due to the need to con­duct clin­i­cal tri­als in Japan when de­vel­op­ment was al­ready hap­pen­ing over­seas. The draft re­port pro­vid­ed sev­er­al ex­am­ples of sit­u­a­tions where new drug ap­pli­ca­tions could be made with­out Japan­ese da­ta, as shown in the draft re­port. It was al­so stat­ed that, in prin­ci­ple, the con­di­tion­al ap­proval sys­tem should be uti­lized in cas­es where the sub­mis­sion of re­sults from clin­i­cal tri­als in­volv­ing Japan­ese sub­jects is re­quired af­ter ap­proval.

In re­sponse to com­pli­ance is­sues at some gener­ic drug com­pa­nies, when com­pa­nies con­duct­ed self-in­spec­tions to ver­i­fy the con­sis­ten­cy be­tween their man­u­fac­tur­ing and mar­ket­ing ap­provals and their ac­tu­al man­u­fac­tur­ing prac­tices, many have iden­ti­fied cas­es in which they must com­ply with phar­ma­ceu­ti­cal reg­u­la­tions.

The com­mit­tee dis­cussed the pro­ce­dures for man­ag­ing changes to man­u­fac­tur­ing meth­ods. Japan will in­tro­duce a cat­e­go­ry of “mod­er­ate changes,” adding to what pre­vi­ous­ly were two cat­e­gories: “par­tial change ap­proval ap­pli­ca­tion,” which re­quired pri­or ap­pli­ca­tion be­fore mak­ing changes, and “mi­nor change no­ti­fi­ca­tion,” where no­ti­fi­ca­tion had to be sub­mit­ted with­in 30 days af­ter the change.

Sec­ond, since there is a sys­tem in oth­er coun­tries to sub­mit mi­nor change items in an an­nu­al re­port once a year, a sim­i­lar sys­tem will be con­sid­ered in Japan. And the man­ner of de­scrib­ing items in ap­proval doc­u­ments, which have been crit­i­cized as be­ing “too de­tailed,” will al­so be re­viewed to en­sure in­ter­na­tion­al con­sis­ten­cy. The spe­cif­ic de­tails will con­tin­ue to be dis­cussed be­tween the phar­ma­ceu­ti­cal in­dus­try and the MHLW.

Ad­di­tion­al­ly, a pol­i­cy to re­view the phar­ma­ceu­ti­cal af­fairs mon­i­tor­ing sys­tem, in­clud­ing GMP com­pli­ance in­spec­tions, was al­so called for. In par­tic­u­lar, since there have been sig­nif­i­cant vari­a­tions in the ex­pe­ri­ence and abil­i­ties of in­spec­tors among pre­fec­tures, ef­forts will be made to raise the lev­el through col­lab­o­ra­tion with the PM­DA go­ing for­ward.

Com­pared to the US and Eu­rope, Japan has sig­nif­i­cant­ly few­er or­phan drug des­ig­na­tions, which has been point­ed out as a con­tribut­ing fac­tor to drug lag and drug loss. Af­ter dis­cus­sions in the com­mit­tee, re­vi­sions were made to al­low more can­di­date prod­ucts to be des­ig­nat­ed as or­phan drugs. How­ev­er, with an in­crease in prod­ucts sub­ject to pri­or­i­ty re­view, con­cerns were raised about the PM­DA’s lack of re­view re­sources. Con­se­quent­ly, it was stat­ed in (4) that “while strength­en­ing the PM­DA’s struc­ture will be con­sid­ered in par­al­lel, un­til this is re­al­ized, the scope of prod­ucts sub­ject to pri­or­i­ty re­view will be lim­it­ed to those meet­ing the con­ven­tion­al re­quire­ments.”

Re­gard­ing this, Kashi­waya of the JP­MA said, “It was un­ex­pect­ed that the num­ber of prod­ucts sub­ject to pri­or­i­ty re­view would not be in­creased due to the PM­DA’s lack of re­sources. On the oth­er hand, many peo­ple al­so move from the PM­DA to phar­ma­ceu­ti­cal com­pa­nies, so staff short­ages are some­what un­avoid­able. As the phar­ma­ceu­ti­cal in­dus­try, we would like to pro­pose ar­eas where we can co­op­er­ate with the PM­DA. Oth­er­wise, there are con­cerns that Japan’s re­view process may be­come stag­nant.”

The is­sues of en­sur­ing sta­ble sup­ply and re­solv­ing drug loss, which mo­ti­vat­ed the es­tab­lish­ment of the com­mit­tee, are un­like­ly to be solved sole­ly by re­view­ing the phar­ma­ceu­ti­cal reg­u­la­tions. Be­hind the short­age of gener­ic drug sup­ply lie is­sues with in­dus­tri­al struc­tures and dis­tri­b­u­tion prac­tices, while drug loss is caused by a com­plex in­ter­play of fac­tors such as Japan’s clin­i­cal tri­al en­vi­ron­ment and the de­clin­ing at­trac­tive­ness of the Japan­ese phar­ma­ceu­ti­cal mar­ket. Ef­forts to ad­dress each of these is­sues one by one are es­sen­tial.

Ad­di­tion­al­ly, as sci­ence and tech­nol­o­gy progress with the emer­gence of new modal­i­ties, the state of phar­ma­ceu­ti­cal reg­u­la­tions will re­quire con­stant re­view. While some top­ics are ex­pect­ed to con­tin­ue be­ing dis­cussed af­ter the com­pi­la­tion of the com­mit­tee’s re­port, it is hoped that dis­cus­sions will al­so con­tin­ue on broad­er sys­temic re­vi­sions.

Ed­i­tor’s note: This sto­ry has been up­date to clar­i­fy a trans­lat­ed quote.