**4. Conclusions**

**3. Non-U.S. regulatory systems**

210 Regenerative Medicine and Tissue Engineering

product is safe, effective and of high quality.

ing[17].

regulatory systems for the use of post-natal human HCT/Ps.

The European Union, Australia and Canada and other countries have established similar

The European Medicines Agency (EMEA) is the regulating body with authorization and supervision of cell therapy products and other "advanced therapy medicinal products" [15]. As of January 2011, the EMA's Committee for Advanced Therapies (CAT) recognized the potential of stem cell therapies and released a reflection paper to work in conjunction with the *Guideline on Human Cell-based Medicinal Products* (EMEA/CHMP/410869/2006) for the Market‐ ing Authorization Application (MA). Both the reflection paper and the guidance detail the quality and manufacturing, non-clinical, and clinical aspects required for MA approval. The quality and manufacturing considerations include starting and raw materials, manufacturing process, quality control, validation of the manufacturing process, development pharmaceutics, traceability and biovigilance, and comparability. Pharmacology and toxicology are the nonclinical development aspects to be considered. From a clinical development standpoint, general aspects, pharmacodynamics, pharmacokinetics, dose finding studies, clinical efficacy, clinical safety,pharmacovigilance, and risk management plans are necessary for approval.

In Australia, HCT/Ps or products (biologicals) are regulated by the Therapeutic Goods Administration (TGA) which is the Australian equivalent to the FDA. Similar to the FDA approach, the TGA's regulatory framework for biological imposes varying levels of regulation on the therapy or product depending on risk, extent of manipulation, and whether the intended use of the biological is its *usual biological function[16].* In order to gain approval a treatment that used a biological, and the biologicals intended use was not its normal function, a hospital or company would be required to submit substantial evidence that the particular therapy or

In order for a stem cell therapy to be approved by Health Canada it must meet the regulations as stated in the Safety of Human Cells, Tissues and Organs for Transplantation Regulations (CTO Regulations[17]). The CTO Regulations detail requirements to ensure safety in process‐ ing; storage; record keeping; distribution; importation; error, accident and adverse reaction investigation and reporting. Requirements for donor screening, testing, and suitability assessment are described in the processing regulations as well as the testing and measurements performed on the products after retrieval or in preparation for use, preservation, or packag‐

Health Canada, the FDA equivalent in Canada, is the first approving body in the world to approve a manufactured stem cell based drug intended to treat a systemic disease -acute Graft versus Host Disease (aGvHD) [18]. Osiris Therapeutics of Columbia, Maryland developed Prochymal [remestemcel-L, adult human mesenchymal stem cells (hMSCs) for intravenous infusion], a liquid cell suspension of ex vivo cultured adult MSCs derived from the bone marrow of healthy adult donors. Prochymal is the first stem cell therapy approved for clinical use in patients, specifically pediatric patients. Health Canada required Osiris to continue a Risk Management Plan to demonstrate that the benefits of Prochymal continue to outweigh

This report examines the different processes involved in HCT/Ps manufacturing and high‐ lights the guidelines that must be followed to obtain FDA or other country specific regulatory approval. Ex vivo expansion, cell selection or gene modification will likely be necessary for most advanced cell and tissue therapies. These modifications increase the risk associated with the treatment and render the product to be regulated under a higher risk category of morethan-minimally-manipulated product. Key to biomanufacturing is the implementation of a QA/QC program including a quality control system and GMP principles which apply to all phases of manufacturing.

**Figure 1.** Regulatory Pathway Assessment If an HCT/Ps product is minimally manipulated it is regulated as a "361 HCT/Ps", and it is not subject to any premarket review requirements. However, if the HCT/Ps is more-than-minimally manipulated, and does not qualify for exemptions under 21 CFR 1271.15, it will be regulated as drug, device and/or biologic product under 351 of the PHS Act.

Many counties actively regulate the use of stem cell products, however, there are still a number of areas around the world that have little regulations and unregulated treatments pose risk to patients and the careful development of the field. The current challenge to deliv‐ er safe cell and tissue therapies and curb unregulated treatments may soon apply to gene therapy and other innovative technologies. Early government regulation and active educa‐ tion by a number of professional organizations should reduce the spread of medical tourism and aid in the development of safe and effective treatments in the field of regenerative med‐ icine.
