Table 1. . Access to new regenerative medicine/stem cell treatments: key regulations and access pathways in the USA, UK and Japan.

Country	Regulatory bodies	Key regulations	Scope	Effect
USA	US FDA	Code of Federal Regulations (21 CFR 1271) PHSA 1944, s351 and 361	HCTPs	HCTPs that are ‘minimally manipulated’; ‘intended for homologous use only’ and not combined with ‘another article’ are regulated under s361 of the PHSA (21 CFR 1271.10). They are considered part of the practice of medicine and out with the FDA's jurisdiction. HCTPs that do not meet these criteria are more strictly regulated, under s351 of the PHSA, as biological drugs requiring premarket evaluation. There is an exception to this for HCTPs that are removed and reimplanted into the same patient during the ‘same surgical procedure’ (21 CFR 1271.15)
		Draft guidance issued 2014–2015 (same surgical procedure exception; minimal manipulation; adipose tissue-derived cells; homologous use)	–	In an attempt to clarify the regulation of HCTPs and whether premarket FDA approval is required, the FDA published draft guidance on these provisions and sought comment on these, including a series of public hearings, in September 2016. Many of the clinics currently providing cell-based treatments rely on the ‘same surgical procedure’ exception and the definition of ‘minimal manipulation’ to avoid the FDA having jurisdiction over their activities
		Early access regulations [55]	Products regulated by the FDA	There are various pathways established by regulation for allowing early access to treatments regulated by the FDA, notably the accelerated access pathway for treatments that are not fully validated but are thought likely to provide a significant benefit. Approvals issued in this pathway are intended to be subject to postmarket evaluation of efficacy
		21st Century Cures Act 2017, s3033	Defines a class of ‘RMATs’	RMATs are “defined as a cell therapy, therapeutic tissue engineering product, human cell and tissue product, or any combination product using such therapies or products”, aimed at ‘serious or life-threatening’ diseases or conditions, with “the potential to address unmet medical needs”. Products falling under s361 of the PHSA are excepted. Designated RMATs may be eligible for expedited review. In order to obtain a designation, an IND application is needed, in turn requiring an evidence base of scientific data
UK	EMA MHRA	Tissue Framework Directive (2004/23/EC) Advanced Therapy Medicinal Products Regulation (EC No 1394/2007) Advanced Therapy Medicinal Products Directive (2001/83/EC)	‘Advanced therapy medicinal products’: gene therapy; somatic cell therapy; engineered tissues	Current UK regulation of cell-based therapies includes compliance with the EC regulatory framework, which requires approval from the EMA based on review of safety and efficacy data. The MHRA is the UK regulatory body for medicinal products including ATMPs, and applies the standards and procedures established by the EC framework and the EMA. Under the ATMP specifications, ‘somatic cell therapy’ refers to products that are ‘substantially manipulated’, meaning that minimally manipulated products are not covered by ATMP regulations; the Tissue Framework Directive also has an exemption for autologous uses as part of the same surgical procedure [56]
		Early access regulations [55,57]	–	The EMA regulatory framework also includes accelerated access pathways, including a 1-year conditional marketing authorization for products that address unmet medical need in relation to ‘seriously debilitating or life-threatening conditions’
Japan	MHLW	Regenerative Medicine Promotion Law (2013)	Regenerative medicine therapies	Establishes “the responsibility of government to provide people with opportunities to receive treatment with regenerative medicines based on the latest scientific knowledge. In addition, the law requires the government to develop basic policy regarding promotion of timely and safe research and to establish suitable legislative, budget, and taxation measures for this purpose” [49]. The ASRM and new PMDA were enacted in consequence of this
		Act on the Safety of Regenerative Medicine 2013	Regenerative medicine	The ASRM applies to both clinical trials and medically innovative uses of regenerative therapies, and applies to technologies aimed at “reconstruction, repair or formation of structures or functions of the human body” [49], or cell-based therapies. It classifies these therapies into three levels of risk, and specifies the procedure to be followed in each. Lower-risk treatments (Classes II and III) require the treatment protocol to be submitted to the MHLW without further evaluation; in the case of Class I treatments, the highest risk category, the MHLW must also approve or require changes to the proposed plan
		Pharmaceuticals, Medical Devices and Other Therapeutic Products Act 2013	Regenerative medicine products (new class defined by PMDA)	The most salient effect of the PMDA with respect to stem cell therapies is to establish the conditional approval pathway, by which regenerative medical products may obtain marketing authorization after early clinical studies that establish some degree of safety and a likelihood of efficacy, rather than after full clinical trials. The authorization is valid for 7 years, during which time postmarket evaluation of safety and efficacy is expected

ASRM: Act on the Safety of Regenerative Medicine; ATMP: Advanced Therapy Medicinal Products; EC: European Commission; HCTP: Human cell or tissue-based product; IND: Investigational new drug; MHLW: Ministry of Health, Labour and Welfare; MHRA: Medicines and healthcare products regulatory agency; PHSA: Public Health Services Act; PMDA: Pharmaceuticals, Medical Devices and other Therapeutic Products Act; RMAT: Regenerative medicine advanced therapy.