- Email: [email protected]
Japan Strengthens Regenerative Medicine Oversight
Cell Stem Cell
Forum Japan Strengthens Regenerative Medicine Oversight Douglas Sipp1,2,3,4 and Hideyuki Okano1,2,* 1Keio
University School of Medicine, Department of Physiology, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan University Global Research Institute, 2-15-45 Mita, Minato-ku, Tokyo 108-8345, Japan 3RIKEN Center for Developmental Biology, 2-2-3 Minatojima Minamimachi, Chuo-ku, Kobe 650-0047, Japan 4RIKEN Center for Advanced Intelligence Project, Nihonbashi 1-chome Mitsui Building, 15th floor, 1-4-1 Nihonbashi, Chuo-ku, Tokyo 103-0027, Japan *Correspondence: [email protected] https://doi.org/10.1016/j.stem.2018.01.001 2Keio
The Japanese government initiated sweeping reforms targeting regenerative medicine in 2014, accompanied by substantial investment into stem cell research and development. We survey the impact of these developments and discuss how the government is working to accelerate regenerative medicine while ensuring safety and efficacy. Introduction In September 2014, the Japanese Diet, or legislature, enacted a suite of laws and amendments specifically designed to rationalize and streamline the regulation of regenerative medicine, including many interventions involving the use of stem cells (Konomi et al., 2015; Azuma and Yamanaka, 2016). These reforms were inspired in part by the 2012 ‘‘Yokohama Declaration’’ issued by the Japanese Society for Regenerative Medicine (JSRM), which expressed concerns that the existing drug regulatory system was poorly suited to the timely and efficient premarket review and approval of cell-based therapeutics. The previous year, the JSRM had also issued a statement voicing concerns that the lack of effective practice standards governing the use of cell-based interventions by private clinics had turned Japan into a ‘‘therapeutic haven’’ for businesses marketing unproven stem cellbased interventions to foreign patients. The death of a Korean patient who had received an injection of stem cells at a Kyoto-based clinic attracted international attention to the broad discretion in the use of cell-based procedures afforded to Japanese physicians at the time (Cyranoski, 2010). These new reforms thus represent the government’s attempts to both rapidly deliver regenerative medicine to patients while ensuring its safety and efficacy during implementation. The 2014 regulatory package included a number of notable reforms that were designed to promote safety while expediting the regulatory review process. These reforms include the establishment of a new category of medical product
(‘‘regenerative medicine products’’) and the amendment of the previous Pharmaceutical Affairs Law (PAL) to become the Pharmaceuticals, Medical Devices, and Other Therapeutic Products Act (PMDA). The new PMDA includes a conditional, and thus expedited, approval pathway specifically for regenerative medicine products. Around the same time, the government passed the Act on the Safety of Regenerative Medicine (ASRM), which established a review system for the use of regenerative medicine in private medical practices operating outside the national health insurance system in an effort to increase oversight and safety. While some early efforts to enforce ASRM have been made to maintain the safety of regenerative medicine, the governance framework for private practices offering regenerative procedures remains leaky. This highly permissive oversight system for cell-based procedures in the private system through ASRM represents a challenge for the parallel industry seeking to gain market authorization for regenerative medicine products under PMDA. Companies that need to invest significant amounts of time, money, and effort into developing cell-based medical products within the PMDA market authorization pathway may find it difficult to recruit patients into clinical trials if nominally similar interventions are available in the weakly regulated ASRM sector. Even those companies that do receive approval from Japan’s drug regulatory agency (the Pharmaceuticals and Medical Devices Agency) and reimbursement form the national health insurance system for these new regenerative medicine products may
face challenges in competing with private practices subject to much weaker oversight of promotional claims and pricing under ASRM. Finding an appropriate balance between encouraging innovation and reining in exploitative business practices will be crucially important for Japan, which has pledged to invest 110 billion yen ($980 million) on stem cell research and regenerative medicine development in the 10-year period beginning in 2014 (as noted in the Nihon Keizai Shimbun). The 16.8 billion yen allocated to regenerative medicine research in the 2017 fiscal year budget (as noted by the Cabinet Secretariat) represents more than 10% of all biomedical research spending managed by the Japan Agency for Medical Research and Development (AMED) for the year. ASRM Enforced In August 2017, the Japan Times reported that police in Tokyo and several other prefectures arrested six individuals under suspicion of selling unproven stem cell interventions outside the scope of the ASRM. Under this law, providers are required to seek external review from special subcommittees for regenerative medicine procedures. The suspects reportedly injected patients with derivatives of cord blood or other perinatal tissue obtained from a private cord blood bank that had gone bankrupt in 2009. As many as 30% of the patients came from abroad, paying 3–4 million yen ($26,700– $35,600) per treatment. This enforcement of the ASRM is particularly important given the ambiguous governmental
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Forum Table 1. Regenerative Medicine Protocols Submitted to MHLW Classification
Cell Types Included
Use
Number of Registered Plans
Class I
pluripotent/ genetically modified/ xenogeneic cells
therapy
0
research
17
Class II Class III
autologous stem cells autologous differentiated cells
regulation of the private sector (Takeuchi et al., 2016), which includes human cell biobanks in Japan. The distribution of banked human cellular biomaterials is governed by guidelines and ministerial directives, which strictly speaking are not legally binding. These arrests mark the first law enforcement action under the ASRM, and they send an important signal of the government’s resolve to maintain control over the sector. But as we will subsequently describe, the market for ‘‘regenerative’’ procedures has expanded rapidly since the law’s implementation, and its growth may be attributable in part to how it has defined regenerative medicine in extremely broad terms. This more stringent approach to the regulation of the domestic market in Japan may reflect heightened international concern about the irresponsible marketing of stem cell interventions. For example, in late 2017, the Therapeutic Goods Administration in Australia announced stricter oversight of autologous cell products, the India Council for Medical Research tightened its guidelines on clinical uses of stem cells, and the US Food and Drug Administration published finalized draft guidance documents that put significant limitations on regulatory loopholes that had been exploited by clinics in the USA. What Makes a Medicine ‘‘Regenerative?’’ In the ASRM, regenerative medicine procedures are defined (as noted in the Ministry of Health, Labour and Welfare’s Act on the Safety of Regenerative Medicine) as those involving human cells processed for use in (1) the reconstruction, formation, or repair of human bodily structures or functions, or (2) the treatment or pre154 Cell Stem Cell 22, February 1, 2018
therapy
105
research
54
therapy
3,486
research
55
total therapy
3,591
total research
126
vention of human diseases. The second of these clauses suggests that nearly any medical use of human cells is encompassed under the ASRM, and as indicated in Table 1, the scope of the law is not limited to stem/progenitor cells, but appears to extend to human cellular materials in general, including uses not ordinarily considered ‘‘regenerative’’ in nature (e.g., cytotoxic T cells used against tumor cells). This has significant implications for Japan, where non-regenerative cell-based interventions, such as socalled ‘‘cellular immunotherapies’’ have been offered by private clinics since the late 1990s (Egawa, 2004), although no cell-based immunotherapy product has been approved by the PMDA to date. The lax independent oversight of cellbased modalities means that patients with serious diseases, including cancer, continue to be exposed to aggressive promotion of unsubstantiated therapeutic claims. Under ASRM, any medical institution that plans to offer regenerative medicine must undergo review by a Certified Committee for Regenerative Medicine (CCRM) or Certified Special Committee for Regenerative Medicine (CSCRM) for class III and class I/II regenerative medicine techniques, respectively. For class I procedures, the institution next submits their protocol to the Ministry of Health, Labour and Welfare (MHLW) to seek its approval. However, for class II interventions, prior authorization from the Ministry is not required. A table published by the MHLW on August 31, 2017 lists all class I–III regenerative medicine protocols reviewed to date for either research plans or intended clinical uses. These protocols are distinct from investigational regenerative medi-
cine product applications submitted to be reviewed for market authorization by PMDA. Submissions in the high-risk class I group have uniformly (17 of 17) been for clinical research studies, whereas in class II therapeutic protocols outnumber research protocols nearly 2-fold (105 versus 54), and in class III, therapeutic protocols are overwhelmingly predominant (3,486 versus 55). The overwhelming bias toward registration of putatively ‘‘therapeutic’’ uses of class III regenerative medicines is indicative of a rush into clinical application of procedures that have not been shown to be safe and efficacious in well-designed studies. While these numbers reflect individual research and therapy plans reviewed by a CCRM/CSCRM, they do not necessarily represent discrete organizations, as a single entity may file multiple regenerative medicine protocols. The extremely large number of registered class III therapeutic plans, however, suggests dynamic activity in the sector. A 2016 study by Fujita et al. identified 74 clinics offering stem cell interventions (Fujita et al., 2016). The thousands of class III therapies that have passed CCRM review to date strongly indicate expansion of the domestic industry in Japan. The Ministry does not list details of the individual protocols; however, it does maintain a separate record of CCRMs and CSCRMs. Of the 103 CCRMs registered with MHLW, the largest number (41) are affiliated with medical or dental schools, publicly funded research centers, professional societies, or local government agencies. An additional five are independent bodies specializing in the review of regenerative medicine protocols under ASRM. Nearly all of the remainder are directly affiliated with private clinics specializing in areas of medicine such as cosmetic surgery, dentistry, or neurology. Surprisingly, however, the most common area of medicine among the private clinics is oncology; 22 private cancer clinics have registered CCRMs. These businesses advertise diverse interventions involving the use of dendritic cells, natural killer cells, and activated lymphocytes with putative anti-tumor activity. The appropriateness of recognizing immune-cell based regimens in the lowest-risk tier of ‘‘regenerative’’ medicine should be reviewed by the Ministry, particularly in light
Cell Stem Cell
Forum of the apparently uneven implementation of the review-by-committee system (Lysaght and Sugii, 2016). More worrisome still is the registration of CSCRMs, which are empowered to review class I and II regenerative medicine protocols, by private businesses. While the 16 of the 49 registered CSCRMs are registered by institutions with academic (.ac.jp) or government (.go.jp) domains, the remaining 33 either list a private email (including gmail.com and yahoo.co.jp addresses) or no contact email at all. Several CSCRMs have been registered by private clinics marketing stem cell injections for applications such as cosmetic surgery, hair restoration, and anti-aging, many of which advertise not only in Japanese, but in other Asian languages such as Chinese and Vietnamese. Thus, not only has the ASRM empowered private CSCRMs to review plans for potentially risky procedures involving pluripotent or genetically modified cells (which goes against the International Society for Stem Cell Research’s Guidelines for Stem Cell Research and Clinical Translation), it has evidently failed to silence the ‘‘therapeutic haven’’ alarm raised by JSRM in 2011. Health Ministry Response The porosity of the ASRM has not gone unnoticed by regulators. In October 2017, the MHLW announced plans to publish more detailed information on private entities practicing regenerative medicine techniques. Under the new system, institutions performing therapeutic (but not research) uses of class II and III regenerative medicine techniques will be required to publish the name of the institution, a descriptive name for each procedure, contact information (address, telephone, and email), the name of the CCRM or CSCRM that reviewed the relevant protocol, and a link to the detailed protocol on the MHLW website. Institutions engaged in either research or private-practice regenerative therapeutic uses of class I technologies will be required to list these same details. By making such information public, the Ministry will dramatically increase the transparency of Japan’s domestic regenerative medicine industry at a time when the direct-to-consumer marketing of unproven stem cell interventions has expanded on a global scale (Berger et al., 2016).
Appropriate regulation of private-practice regenerative medicine clinics will also be crucial in providing a level playing field for PMDA-approved regenerative medicine products, which also benefited from the introduction of a conditional approval system in 2014. Unlike in the case of the ASRM, however, this relaxed pathway to the market has seen only moderate use; only a single regenerative medicine product has received conditional approval since the amended law went into effect (McCabe and Sipp, 2016). The costs of developing a reimbursable stem cell-based medical product are extraordinarily high, and many such products are intended for small patient populations, which will necessitate high prices that are unlikely to be competitive with those offered by private clinics advertising putatively similar regenerative medicine techniques. While reimbursement of approved products and the imprimatur of PMDA approval will go some way to redressing the competitive advantage of the underregulated sector, the weaker pre-market evidentiary requirement thresholds that private clinics currently enjoy may enable them to attract patients away from participation in clinical trials, a particularly worrisome prospect for rare diseases with small patient populations. Moreover, the lower evidence bar under ASRM may enable the continued expansion of the private-practice regenerative medicine industry, with concomitant increases in diversity of clinical offerings, price competition, and political lobbying power. In order to make the most of its great investment into stem cell clinical translation, the government of Japan should continue to refine the ways it defines and regulates regenerative medicine. The MHLW should place stricter limits on the discretionary use of class III regenerative medicine techniques by private businesses, and medical professional organizations, such as the Japan Medical Association and the JSRM, should step up their monitoring of and disciplinary activity against practitioners who take undue advantage of the current regulatory looseness in ways that jeopardize individual patients, the public health system, and the stakeholder community. The Japanese experience, in both its successes and its missteps, may be
instructive for other nations seeking to support the development and growth of the regenerative medicine sector. Strong public funding is clearly a key driver of both scientific advancement and commercial translation, and Japan provides an example of how support at the highest levels of government can benefit a research field. Appropriate regulation is another ingredient for success, but one for which the benefits are sometimes not as well appreciated. Japan’s first efforts at regulatory reform may have opened the door to the market a bit too widely, both in reducing the evidence requirements for regenerative medicine products licensed through the drug approval pathway, and in formalizing weak supervised use of many human cell-based procedures in private practice. The reforms we have outlined above indicate that the Japanese government continues to learn and revise its oversight mechanisms with an eye to enabling scientific progress in the regenerative medicine field and reducing the harms of a rush to the clinic. Other countries, such as India, Australia, and the United States have also recently undertaken steps to rein in irresponsible marketing of unproven stem cell treatments, which are welcome developments in the face of the explosive growth of this problematic industry. ACKNOWLEDGMENTS The present study was partly supported by a grant ‘‘Project to Build Foundation for Promoting Clinical Research of Regenerative Medicine’’ from AMED (Grant No. 17bk0204001s0102). AUTHOR CONTRIBUTIONS D.S. and H.O. both contributed to the research, analysis, and writing of this manuscript. DECLARATIONS OF INTEREST D.S. is a research specialist at RIKEN Center for Developmental Biology and a project professor at Keio University School of Medicine; both institutions have received MHLW and AMED funding for clinical translation of induced pluripotent stem cells. H.O. is Dean of Keio University Graduate School of Medicine, a Board of Director at JSRM, and a founding scientist of SanBio Co. Ltd. and K Pharma Inc. WEB RESOURCES
Cabinet Secretariat (Heisei 29 nendo iryou bun’ya no kenkyuu kaihatu kanren yosan no gaiyou youkyuu no pointo; Main points in
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Forum medical research and development-related budget for Fiscal Year 2017), http://www. kantei.go.jp/jp/singi/kenkouiryou/suisin/suisin_ dai15/siryou2.pdf International Society for Stem Cell Research (Guidelines for Stem Cell Research and Clinical Translation), http://www.isscr.org/docs/ default-source/all-isscr-guidelines/guidelines2016/isscr-guidelines-for-stem-cell-researchand-clinical-translation.pdf?sfvrsn=4 Japan Society for Regenerative Medicine (Nihon saisei iryou gakkai seimei; statement by Japanese Society for Regenerative Medicine), https://www.jsrm.jp/news/%E6%97% A5%E6%9C%AC%E5%86%8D%E7%94% 9F%E5%8C%BB%E7%99%82%E5%AD% A6%E4%BC%9A%E5%A3%B0%E6%98% 8E%EF%BC%882011-1%EF%BC%89/ Japan Society for Regenerative Medicine (Yokohama sengen; Yokohama Declaration), https://www.jsrm.jp/news/yokohama%E5% AE%A3%E8%A8%80/ Japan Times (Six arrested in connection with unauthorized blood treatments), https://www.japantimes.co.jp/news/2017/ 08/27/national/crime-legal/six-arrested-con nection-unauthorized-cord-blood-treatments/ Japan Times (Medical tours linked to cord blood arrests), https://www.japantimes. co.jp/news/2017/08/28/national/crime-legal/ medical-tours-linked-cord-blood-arrests/ Ministry of Health, Labour and Welfare (Saisei iryou tou no anzensei no kakuho tou ni kan suru houritsu; Act on the Safety of Regenerative Medicine), http://www.mhlw.go.jp/ file/06-Seisakujouhou-10800000-Iseikyoku/ 0000030847.pdf
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Ministry of Health, Labour and Welfare (2017a). Saisei iryou tou anzensei kakuho-hou no jikkou joukyou ni tsuite (Regarding current status of implementation of the Act on the Safety of Regenerative Medicine). http://www.mhlw.go.jp/file/06-Seisakujouhou10800000-Iseikyoku/0000150612.pdf Ministry of Health, Labour and Welfare (2017b). Saisei iryou tou anzensei kakuho-hou dai-26 jou 4 kou no kitei ni yori nintei sareta nintei saisei iryou tou iinkai no ichiran – daisanshu saisei iryou tou teikyou keikaku nomi ni kakawaru shinsa tou gyoumu wo jisshi suru iinkai (List of Certified Committees for Regenerative Medicine certified pursuant to Article 26, Section 4 of the Act on the Safety of Regenerative Medicine; committees involved in reviewing only plans for the provision of Class III regenerative medicine). http://www.mhlw.go.jp/file/06-Seisakujouhou10800000-Iseikyoku/0000150616.pdf Ministry of Health, Labour and Welfare (2017c). Saisei iryou tou anzensei kakuho-hou dai-26 jou 4 kou no kitei ni yori nintei sareta nintei saisei iryou tou iinkai no ichiran – tokutei nintei saisei iryou tou iinkai (List of Certified Committees for Regenerative Medicine certified pursuant to Article 26, Section 4 of the Act on the Safety of Regenerative Medicine; Certified Special Committees for Regenerative Medicine). http://www.mhlw.go.jp/ file/06-Seisakujouhou-10800000-Iseikyoku/ 0000150613.pdf Nihon Keizai Shimbun (Saisei iryou kenkyuu ni 1100 oku en, iPS chuushin ni monkasou hyoumei; MHLW announces 110 billion yen regenerative medicine research
budget, focused on iPSCs), https:// www.nikkei.com/article/DGXNASDG1003Z_ Q3A110C1CR8000/
REFERENCES Azuma, K., and Yamanaka, S. (2016). Recent policies that support clinical application of induced pluripotent stem cell-based regenerative therapies. Regenerative Therapy 4, 36–47. Berger, I., Ahmad, A., Bansal, A., Kapoor, T., Sipp, D., and Rasko, J.E.J. (2016). Global Distribution of Businesses Marketing Stem Cell-Based Interventions. Cell Stem Cell 19, 158–162. Cyranoski, D. (2010). Korean deaths spark inquiry. Nature 468, 485. Egawa, K. (2004). Immuno-cell therapy of cancer in Japan. Anticancer Res. 24 (5C), 3321–3326. Fujita, M., Hatta, T., Ozeki, R., and Akabayashi, A. (2016). The current status of clinics providing private practice cell therapy in Japan. Regen. Med. 11, 23–32. Konomi, K., Tobita, M., Kimura, K., and Sato, D. (2015). New Japanese initiatives on stem cell therapies. Cell Stem Cell 16, 350–352. Lysaght, T., and Sugii, S. (2016). Uncertain Oversight of Regenerative Medicines in Japan under the ASRM. Cell Stem Cell 18, 438–439. McCabe, C., and Sipp, D. (2016). Undertested and Overpriced: Japan Issues First Conditional Approval of Stem Cell Product. Cell Stem Cell 18, 436–437. Takeuchi, T., Noguchi, M., Kawakami, Y., and Ohkochi, N. (2016). Human tissue biobank: Current and Future Trends. Organ Biology 23, 21–28.
Forum Japan Strengthens Regenerative Medicine Oversight Douglas Sipp1,2,3,4 and Hideyuki Okano1,2,* 1Keio
University School of Medicine, Department of Physiology, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan University Global Research Institute, 2-15-45 Mita, Minato-ku, Tokyo 108-8345, Japan 3RIKEN Center for Developmental Biology, 2-2-3 Minatojima Minamimachi, Chuo-ku, Kobe 650-0047, Japan 4RIKEN Center for Advanced Intelligence Project, Nihonbashi 1-chome Mitsui Building, 15th floor, 1-4-1 Nihonbashi, Chuo-ku, Tokyo 103-0027, Japan *Correspondence: [email protected] https://doi.org/10.1016/j.stem.2018.01.001 2Keio
The Japanese government initiated sweeping reforms targeting regenerative medicine in 2014, accompanied by substantial investment into stem cell research and development. We survey the impact of these developments and discuss how the government is working to accelerate regenerative medicine while ensuring safety and efficacy. Introduction In September 2014, the Japanese Diet, or legislature, enacted a suite of laws and amendments specifically designed to rationalize and streamline the regulation of regenerative medicine, including many interventions involving the use of stem cells (Konomi et al., 2015; Azuma and Yamanaka, 2016). These reforms were inspired in part by the 2012 ‘‘Yokohama Declaration’’ issued by the Japanese Society for Regenerative Medicine (JSRM), which expressed concerns that the existing drug regulatory system was poorly suited to the timely and efficient premarket review and approval of cell-based therapeutics. The previous year, the JSRM had also issued a statement voicing concerns that the lack of effective practice standards governing the use of cell-based interventions by private clinics had turned Japan into a ‘‘therapeutic haven’’ for businesses marketing unproven stem cellbased interventions to foreign patients. The death of a Korean patient who had received an injection of stem cells at a Kyoto-based clinic attracted international attention to the broad discretion in the use of cell-based procedures afforded to Japanese physicians at the time (Cyranoski, 2010). These new reforms thus represent the government’s attempts to both rapidly deliver regenerative medicine to patients while ensuring its safety and efficacy during implementation. The 2014 regulatory package included a number of notable reforms that were designed to promote safety while expediting the regulatory review process. These reforms include the establishment of a new category of medical product
(‘‘regenerative medicine products’’) and the amendment of the previous Pharmaceutical Affairs Law (PAL) to become the Pharmaceuticals, Medical Devices, and Other Therapeutic Products Act (PMDA). The new PMDA includes a conditional, and thus expedited, approval pathway specifically for regenerative medicine products. Around the same time, the government passed the Act on the Safety of Regenerative Medicine (ASRM), which established a review system for the use of regenerative medicine in private medical practices operating outside the national health insurance system in an effort to increase oversight and safety. While some early efforts to enforce ASRM have been made to maintain the safety of regenerative medicine, the governance framework for private practices offering regenerative procedures remains leaky. This highly permissive oversight system for cell-based procedures in the private system through ASRM represents a challenge for the parallel industry seeking to gain market authorization for regenerative medicine products under PMDA. Companies that need to invest significant amounts of time, money, and effort into developing cell-based medical products within the PMDA market authorization pathway may find it difficult to recruit patients into clinical trials if nominally similar interventions are available in the weakly regulated ASRM sector. Even those companies that do receive approval from Japan’s drug regulatory agency (the Pharmaceuticals and Medical Devices Agency) and reimbursement form the national health insurance system for these new regenerative medicine products may
face challenges in competing with private practices subject to much weaker oversight of promotional claims and pricing under ASRM. Finding an appropriate balance between encouraging innovation and reining in exploitative business practices will be crucially important for Japan, which has pledged to invest 110 billion yen ($980 million) on stem cell research and regenerative medicine development in the 10-year period beginning in 2014 (as noted in the Nihon Keizai Shimbun). The 16.8 billion yen allocated to regenerative medicine research in the 2017 fiscal year budget (as noted by the Cabinet Secretariat) represents more than 10% of all biomedical research spending managed by the Japan Agency for Medical Research and Development (AMED) for the year. ASRM Enforced In August 2017, the Japan Times reported that police in Tokyo and several other prefectures arrested six individuals under suspicion of selling unproven stem cell interventions outside the scope of the ASRM. Under this law, providers are required to seek external review from special subcommittees for regenerative medicine procedures. The suspects reportedly injected patients with derivatives of cord blood or other perinatal tissue obtained from a private cord blood bank that had gone bankrupt in 2009. As many as 30% of the patients came from abroad, paying 3–4 million yen ($26,700– $35,600) per treatment. This enforcement of the ASRM is particularly important given the ambiguous governmental
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Forum Table 1. Regenerative Medicine Protocols Submitted to MHLW Classification
Cell Types Included
Use
Number of Registered Plans
Class I
pluripotent/ genetically modified/ xenogeneic cells
therapy
0
research
17
Class II Class III
autologous stem cells autologous differentiated cells
regulation of the private sector (Takeuchi et al., 2016), which includes human cell biobanks in Japan. The distribution of banked human cellular biomaterials is governed by guidelines and ministerial directives, which strictly speaking are not legally binding. These arrests mark the first law enforcement action under the ASRM, and they send an important signal of the government’s resolve to maintain control over the sector. But as we will subsequently describe, the market for ‘‘regenerative’’ procedures has expanded rapidly since the law’s implementation, and its growth may be attributable in part to how it has defined regenerative medicine in extremely broad terms. This more stringent approach to the regulation of the domestic market in Japan may reflect heightened international concern about the irresponsible marketing of stem cell interventions. For example, in late 2017, the Therapeutic Goods Administration in Australia announced stricter oversight of autologous cell products, the India Council for Medical Research tightened its guidelines on clinical uses of stem cells, and the US Food and Drug Administration published finalized draft guidance documents that put significant limitations on regulatory loopholes that had been exploited by clinics in the USA. What Makes a Medicine ‘‘Regenerative?’’ In the ASRM, regenerative medicine procedures are defined (as noted in the Ministry of Health, Labour and Welfare’s Act on the Safety of Regenerative Medicine) as those involving human cells processed for use in (1) the reconstruction, formation, or repair of human bodily structures or functions, or (2) the treatment or pre154 Cell Stem Cell 22, February 1, 2018
therapy
105
research
54
therapy
3,486
research
55
total therapy
3,591
total research
126
vention of human diseases. The second of these clauses suggests that nearly any medical use of human cells is encompassed under the ASRM, and as indicated in Table 1, the scope of the law is not limited to stem/progenitor cells, but appears to extend to human cellular materials in general, including uses not ordinarily considered ‘‘regenerative’’ in nature (e.g., cytotoxic T cells used against tumor cells). This has significant implications for Japan, where non-regenerative cell-based interventions, such as socalled ‘‘cellular immunotherapies’’ have been offered by private clinics since the late 1990s (Egawa, 2004), although no cell-based immunotherapy product has been approved by the PMDA to date. The lax independent oversight of cellbased modalities means that patients with serious diseases, including cancer, continue to be exposed to aggressive promotion of unsubstantiated therapeutic claims. Under ASRM, any medical institution that plans to offer regenerative medicine must undergo review by a Certified Committee for Regenerative Medicine (CCRM) or Certified Special Committee for Regenerative Medicine (CSCRM) for class III and class I/II regenerative medicine techniques, respectively. For class I procedures, the institution next submits their protocol to the Ministry of Health, Labour and Welfare (MHLW) to seek its approval. However, for class II interventions, prior authorization from the Ministry is not required. A table published by the MHLW on August 31, 2017 lists all class I–III regenerative medicine protocols reviewed to date for either research plans or intended clinical uses. These protocols are distinct from investigational regenerative medi-
cine product applications submitted to be reviewed for market authorization by PMDA. Submissions in the high-risk class I group have uniformly (17 of 17) been for clinical research studies, whereas in class II therapeutic protocols outnumber research protocols nearly 2-fold (105 versus 54), and in class III, therapeutic protocols are overwhelmingly predominant (3,486 versus 55). The overwhelming bias toward registration of putatively ‘‘therapeutic’’ uses of class III regenerative medicines is indicative of a rush into clinical application of procedures that have not been shown to be safe and efficacious in well-designed studies. While these numbers reflect individual research and therapy plans reviewed by a CCRM/CSCRM, they do not necessarily represent discrete organizations, as a single entity may file multiple regenerative medicine protocols. The extremely large number of registered class III therapeutic plans, however, suggests dynamic activity in the sector. A 2016 study by Fujita et al. identified 74 clinics offering stem cell interventions (Fujita et al., 2016). The thousands of class III therapies that have passed CCRM review to date strongly indicate expansion of the domestic industry in Japan. The Ministry does not list details of the individual protocols; however, it does maintain a separate record of CCRMs and CSCRMs. Of the 103 CCRMs registered with MHLW, the largest number (41) are affiliated with medical or dental schools, publicly funded research centers, professional societies, or local government agencies. An additional five are independent bodies specializing in the review of regenerative medicine protocols under ASRM. Nearly all of the remainder are directly affiliated with private clinics specializing in areas of medicine such as cosmetic surgery, dentistry, or neurology. Surprisingly, however, the most common area of medicine among the private clinics is oncology; 22 private cancer clinics have registered CCRMs. These businesses advertise diverse interventions involving the use of dendritic cells, natural killer cells, and activated lymphocytes with putative anti-tumor activity. The appropriateness of recognizing immune-cell based regimens in the lowest-risk tier of ‘‘regenerative’’ medicine should be reviewed by the Ministry, particularly in light
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Forum of the apparently uneven implementation of the review-by-committee system (Lysaght and Sugii, 2016). More worrisome still is the registration of CSCRMs, which are empowered to review class I and II regenerative medicine protocols, by private businesses. While the 16 of the 49 registered CSCRMs are registered by institutions with academic (.ac.jp) or government (.go.jp) domains, the remaining 33 either list a private email (including gmail.com and yahoo.co.jp addresses) or no contact email at all. Several CSCRMs have been registered by private clinics marketing stem cell injections for applications such as cosmetic surgery, hair restoration, and anti-aging, many of which advertise not only in Japanese, but in other Asian languages such as Chinese and Vietnamese. Thus, not only has the ASRM empowered private CSCRMs to review plans for potentially risky procedures involving pluripotent or genetically modified cells (which goes against the International Society for Stem Cell Research’s Guidelines for Stem Cell Research and Clinical Translation), it has evidently failed to silence the ‘‘therapeutic haven’’ alarm raised by JSRM in 2011. Health Ministry Response The porosity of the ASRM has not gone unnoticed by regulators. In October 2017, the MHLW announced plans to publish more detailed information on private entities practicing regenerative medicine techniques. Under the new system, institutions performing therapeutic (but not research) uses of class II and III regenerative medicine techniques will be required to publish the name of the institution, a descriptive name for each procedure, contact information (address, telephone, and email), the name of the CCRM or CSCRM that reviewed the relevant protocol, and a link to the detailed protocol on the MHLW website. Institutions engaged in either research or private-practice regenerative therapeutic uses of class I technologies will be required to list these same details. By making such information public, the Ministry will dramatically increase the transparency of Japan’s domestic regenerative medicine industry at a time when the direct-to-consumer marketing of unproven stem cell interventions has expanded on a global scale (Berger et al., 2016).
Appropriate regulation of private-practice regenerative medicine clinics will also be crucial in providing a level playing field for PMDA-approved regenerative medicine products, which also benefited from the introduction of a conditional approval system in 2014. Unlike in the case of the ASRM, however, this relaxed pathway to the market has seen only moderate use; only a single regenerative medicine product has received conditional approval since the amended law went into effect (McCabe and Sipp, 2016). The costs of developing a reimbursable stem cell-based medical product are extraordinarily high, and many such products are intended for small patient populations, which will necessitate high prices that are unlikely to be competitive with those offered by private clinics advertising putatively similar regenerative medicine techniques. While reimbursement of approved products and the imprimatur of PMDA approval will go some way to redressing the competitive advantage of the underregulated sector, the weaker pre-market evidentiary requirement thresholds that private clinics currently enjoy may enable them to attract patients away from participation in clinical trials, a particularly worrisome prospect for rare diseases with small patient populations. Moreover, the lower evidence bar under ASRM may enable the continued expansion of the private-practice regenerative medicine industry, with concomitant increases in diversity of clinical offerings, price competition, and political lobbying power. In order to make the most of its great investment into stem cell clinical translation, the government of Japan should continue to refine the ways it defines and regulates regenerative medicine. The MHLW should place stricter limits on the discretionary use of class III regenerative medicine techniques by private businesses, and medical professional organizations, such as the Japan Medical Association and the JSRM, should step up their monitoring of and disciplinary activity against practitioners who take undue advantage of the current regulatory looseness in ways that jeopardize individual patients, the public health system, and the stakeholder community. The Japanese experience, in both its successes and its missteps, may be
instructive for other nations seeking to support the development and growth of the regenerative medicine sector. Strong public funding is clearly a key driver of both scientific advancement and commercial translation, and Japan provides an example of how support at the highest levels of government can benefit a research field. Appropriate regulation is another ingredient for success, but one for which the benefits are sometimes not as well appreciated. Japan’s first efforts at regulatory reform may have opened the door to the market a bit too widely, both in reducing the evidence requirements for regenerative medicine products licensed through the drug approval pathway, and in formalizing weak supervised use of many human cell-based procedures in private practice. The reforms we have outlined above indicate that the Japanese government continues to learn and revise its oversight mechanisms with an eye to enabling scientific progress in the regenerative medicine field and reducing the harms of a rush to the clinic. Other countries, such as India, Australia, and the United States have also recently undertaken steps to rein in irresponsible marketing of unproven stem cell treatments, which are welcome developments in the face of the explosive growth of this problematic industry. ACKNOWLEDGMENTS The present study was partly supported by a grant ‘‘Project to Build Foundation for Promoting Clinical Research of Regenerative Medicine’’ from AMED (Grant No. 17bk0204001s0102). AUTHOR CONTRIBUTIONS D.S. and H.O. both contributed to the research, analysis, and writing of this manuscript. DECLARATIONS OF INTEREST D.S. is a research specialist at RIKEN Center for Developmental Biology and a project professor at Keio University School of Medicine; both institutions have received MHLW and AMED funding for clinical translation of induced pluripotent stem cells. H.O. is Dean of Keio University Graduate School of Medicine, a Board of Director at JSRM, and a founding scientist of SanBio Co. Ltd. and K Pharma Inc. WEB RESOURCES
Cabinet Secretariat (Heisei 29 nendo iryou bun’ya no kenkyuu kaihatu kanren yosan no gaiyou youkyuu no pointo; Main points in
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Forum medical research and development-related budget for Fiscal Year 2017), http://www. kantei.go.jp/jp/singi/kenkouiryou/suisin/suisin_ dai15/siryou2.pdf International Society for Stem Cell Research (Guidelines for Stem Cell Research and Clinical Translation), http://www.isscr.org/docs/ default-source/all-isscr-guidelines/guidelines2016/isscr-guidelines-for-stem-cell-researchand-clinical-translation.pdf?sfvrsn=4 Japan Society for Regenerative Medicine (Nihon saisei iryou gakkai seimei; statement by Japanese Society for Regenerative Medicine), https://www.jsrm.jp/news/%E6%97% A5%E6%9C%AC%E5%86%8D%E7%94% 9F%E5%8C%BB%E7%99%82%E5%AD% A6%E4%BC%9A%E5%A3%B0%E6%98% 8E%EF%BC%882011-1%EF%BC%89/ Japan Society for Regenerative Medicine (Yokohama sengen; Yokohama Declaration), https://www.jsrm.jp/news/yokohama%E5% AE%A3%E8%A8%80/ Japan Times (Six arrested in connection with unauthorized blood treatments), https://www.japantimes.co.jp/news/2017/ 08/27/national/crime-legal/six-arrested-con nection-unauthorized-cord-blood-treatments/ Japan Times (Medical tours linked to cord blood arrests), https://www.japantimes. co.jp/news/2017/08/28/national/crime-legal/ medical-tours-linked-cord-blood-arrests/ Ministry of Health, Labour and Welfare (Saisei iryou tou no anzensei no kakuho tou ni kan suru houritsu; Act on the Safety of Regenerative Medicine), http://www.mhlw.go.jp/ file/06-Seisakujouhou-10800000-Iseikyoku/ 0000030847.pdf
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Ministry of Health, Labour and Welfare (2017a). Saisei iryou tou anzensei kakuho-hou no jikkou joukyou ni tsuite (Regarding current status of implementation of the Act on the Safety of Regenerative Medicine). http://www.mhlw.go.jp/file/06-Seisakujouhou10800000-Iseikyoku/0000150612.pdf Ministry of Health, Labour and Welfare (2017b). Saisei iryou tou anzensei kakuho-hou dai-26 jou 4 kou no kitei ni yori nintei sareta nintei saisei iryou tou iinkai no ichiran – daisanshu saisei iryou tou teikyou keikaku nomi ni kakawaru shinsa tou gyoumu wo jisshi suru iinkai (List of Certified Committees for Regenerative Medicine certified pursuant to Article 26, Section 4 of the Act on the Safety of Regenerative Medicine; committees involved in reviewing only plans for the provision of Class III regenerative medicine). http://www.mhlw.go.jp/file/06-Seisakujouhou10800000-Iseikyoku/0000150616.pdf Ministry of Health, Labour and Welfare (2017c). Saisei iryou tou anzensei kakuho-hou dai-26 jou 4 kou no kitei ni yori nintei sareta nintei saisei iryou tou iinkai no ichiran – tokutei nintei saisei iryou tou iinkai (List of Certified Committees for Regenerative Medicine certified pursuant to Article 26, Section 4 of the Act on the Safety of Regenerative Medicine; Certified Special Committees for Regenerative Medicine). http://www.mhlw.go.jp/ file/06-Seisakujouhou-10800000-Iseikyoku/ 0000150613.pdf Nihon Keizai Shimbun (Saisei iryou kenkyuu ni 1100 oku en, iPS chuushin ni monkasou hyoumei; MHLW announces 110 billion yen regenerative medicine research
budget, focused on iPSCs), https:// www.nikkei.com/article/DGXNASDG1003Z_ Q3A110C1CR8000/
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