PMDA Eyes More Japan-First Approvals In Access Push
Executive Summary
Highlighting progress it has made over the past few years, Japan’s regulatory agency says it wants to raise even further the number of “Japan-first” approvals, as part of its stated mission to get safe and effective new drugs to patients more quickly.
Despite what it sees as improvements across multiple regulatory fronts over the past few years, Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) says “there still exists room for improvement” to increase the number of new drug approvals it issues ahead of any other country.
In a new activity update, chief executive Yasuhiro Fujiwara points out that the number of such clearances has already been increasing slightly over the past few years, but stresses that the regulator is committed to continued advances.
The next stage will be “to further promote patient access with more Japan-first approvals by nurturing a cooperative and efficient environment for product development, working with all stakeholders,” he declares.
Less Lag, Japan First
Figures from the agency show 80 (20%) of the 400 new pharmaceutical products (drugs with new active substances) approved in Japan between 2008-19 were first-in-world approvals, with oncology the leading category overall.
While 45 of these remained as Japan-only approvals by the end of the period, around 10% (35) of the 355 other new drugs approved both in Japan and other regions over the period were approved first in Japan. This suggests multiple cases in which the country issued world-first marketing authorizations for products that were being developed on a global basis across major markets.
Although the PMDA does not allude to this, many multinationals have for years now been routinely including Japan in their international parallel development programs for major new products, with simultaneous filings in the country, along with the US and EU, now not unusual.
By way of comparison, the US Food and Drug Administration’s review of 2019 approvals noted that 33 (69%) of the 48 novel drugs it approved that year were done so ahead of any other country.
Some Japan-first examples this year have included two oral hypoxia-inducible factor prolyl hydroxylase inhibitors, GlaxoSmithKline plc’s Duvroq (daprodustat) and Mitsubishi Tanabe Pharma Corporation’s Vafseo (vadadustat; licensed from Akebia Therapeutics, Inc.), for renal anemia due to chronic kidney disease in both dialysis-dependent and non-dialysis-dependent adults. Both were approved in June. (Also see "Japan Nods Include Global Firsts For Duvroq, Vafseo And First Local Biosimilar Humira" - Pink Sheet, 29 Jun, 2020.)
The Japan-first approach being pursued by the PMDA did not appear to come with any compromises on safety for the relevant products, judging by the frequency of post-marketing safety warnings or product discontinuations. “PMDA’s review for new drugs firstly approved in Japan was shown to be at the same level of excellence as those firstly approved outside of Japan,” Fujiwara states.
The unstated corollary here would seem to be that the prospect of speedy approval for safe new drugs in Japan may attract the industry to bring such products to the country early on in the development process, in turn feeding into the PMDA’s early access goals.
Drug Lag ‘Resolved’
“Drug lag” – the delay in Japanese approval of a specific drug versus other major markets – was a major worry and lobbying point for the research-based industry back in the 1990s and early 2000s. But Fujiwara says the PMDA has “now resolved this issue with measures such as the implementation of new systems.”
The data bear out the improvements. In the 2016-19 period, the median lag between approval of a specific new drug in Japan compared with its first-in-world approval was found to have decreased by more than 2.5 years compared to 2008-11.
A new retrospective analysis by PMDA staffers, published in the American Society for Clinical Pharmacology & Therapeutics journal online in October, found the median lags for the 400 new drugs and 355 new drugs with global approvals in the 2008-19 period were 4.3 and 4.7 years in the first tertile (2008–11), respectively.
These fell to 1.5 and 2.6 in the second tertile (2012–15) and further reduced again to 1.3 and 2.2 in the third tertile (2016–19).
Despite the big improvements, the authors, led by Mototsugu Tanaka of the PMDA’s new drug office, do concede “substantial drug lag remains in neurology, psychiatry, and therapeutic areas where the number of new drug approvals was relatively small.”
Multiple Initiatives
These and other improvements at the agency have come in steps over the course of more than a decade, chief executive Fujiwara notes, pointing to infrastructure improvements – particularly the strengthening of review staffing - as the most significant contributors.
The number of PMDA staff now engaged in product reviews is around 560, up from just 154 at the time of the agency’s establishment in 2004.
Other moves have included the adoption of accelerated approval pathways such as the “sakigake” (pioneering therapy) designation available for novel therapies being developed in Japan first or in parallel with other countries, and a conditional early approval system that allows rolling data submission, backed up by strengthened post-approval monitoring.
The latter scheme, implemented around three years ago, enables conditional approval of therapies for serious, life-threatening or irreversible disorders with limited treatment options, based on limited clinical data, and requires comprehensive post-marketing surveillance (including real-world evidence) to ensure proper product use in practice.
Several approvals have now been granted under the conditional early approval system, notably for Daiichi Sankyo Co., Ltd.’s HER2-directed antibody drug conjugate Enhertu (trastuzumab deruxtecan) this March, for HER2-positive unresectable or recurrent metastatic breast cancer after prior chemotherapy. (Also see "Japan Enhertu Nod Another Boost For Daiichi's Oncology Hopes" - Scrip, 26 Mar, 2020.)
With formalized legislation around these approval pathways passed last year, “further utilization of these processes is highly expected,” Fujiwara states. “Overall, these results show that the PMDA has made a big step forward for achieving earlier patient access to new pharmaceutical products in Japan.”
The pharma industry itself has also been generally positive on the changes that have taken place at the PMDA and in Japan’s approval processes over the past few years, and the American Chamber of Commerce in Japan recently awarded Fujiwara’s predecessor at the agency, Tatsuya Kondo, its Outstanding Achievement Award in recognition of these.
The research-based sector’s remaining concerns in the policy and regulation arena in Japan now focus more on reimbursement pricing and cost-effectiveness assessment processes, along with the need to more broadly involve all stakeholders – including patient groups – in discussions on healthcare reforms. (Also see "EFPIA Wants Continued And More Inclusive Japan Policy Dialog " - Pink Sheet, 27 Sep, 2019.)
Along these lines, Fujiwara notes in his update that, to achieve “access first” - one of his four priorities along with patient, safety and Asia “firsts” - facilitating patient and public involvement in the product development process will be key.
To this end, a Patient Centricity Working Group was set up at the PMDA in May 2019 and a guidance document to promote such engagement is under development.