US Food and Drug Administration international collaborations for cellular therapy product regulation

Cellular therapy products are an emerging medical product class undergoing rapid scientific and clinical innovation worldwide. These products pose unique regulatory challenges both for countries with existing regulatory frameworks and for countries where regulatory frameworks for cellular therapy products are under development. The United States Food and Drug Administration (US FDA) has a history of productive working relationships with international regulatory authorities, and seeks to extend this to the cellular therapy field. The US FDA and its global regulatory counterparts are engaged in collaborations focused on the convergence of scientific and regulatory approaches, and the education of scientists, clinicians, regulators, and the public at large on the development of cellular therapies.


Introduction
Th e fi eld of cellular therapies is undergoing rapid scientifi c and clinical innovation, and product development and clinical investigations are frequently conducted internationally. Regulatory authorities must confront the scientifi c and medical complexities of these products in order to protect the public health and promote eff ective product development. Regulatory frameworks for cellular therapies are in diff erent states of maturity internationally; some are only now being established, and others are in a more mature state. Th e development of cellular therapies would benefi t from a maturation and evolution of regulatory frameworks. Th is may be aided, in part, by information exchange between international regulatory authorities. Information and experiences shared by regulatory authorities with established regulatory frameworks for cellular therapy products can be considered and potentially incorporated by countries that have yet to fully design and implement their regulations and policies for cellular therapies. US FDA welcomes interactions with international regulatory authorities to work towards prospective regulatory harmonization and convergence.
Th e term 'harmonization' is typically interpreted as the production of consensus guidelines, such as the guidelines produced by the International Conference on Harmoni sation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). 'Harmonization' can also refer to a convergence of regulatory perspectives that informs the independent development of national guidelines and regulations. For the purposes of this document, we will use 'regulatory convergence' to describe interactions that generate a shared regulatory perspective but do not have the explicit goal of production of a consensus guideline.
Th e purpose of this article is to provide an overview of US FDA's participation in regulatory convergence activities with international regulatory authorities on regulation of cellular therapies, including stem cells. In the US, cellular therapy products are regulated by the US FDA, Center for Biologics Evaluation and Research (CBER, Offi ce of Cellular, Tissue, and Gene Th erapies (OCTGT); the FDA Offi ce of International Programs co ordinates activities between the US FDA and inter national regulatory authorities). For information on the regulatory process for cell therapy products and bio logics, please see the US FDA website [1][2][3].

US FDA's global strategy for regulatory harmonization and convergence
US FDA has a history of productive working relationships with regulatory authorities around the globe, as well as international organizations such as the World Health Organization (WHO). Activities have included infor mational exchanges, support for establishment of international standards, and harmonization of regulatory requirements.
Regulatory convergence and leveraging of regulatory eff ort have emerged as shared goals of the global regulatory community [4]. Like other regulatory authorities, US FDA's global eff orts aim to pool regulators' resources for public health protection and facilitate the marketing of safe and eff ective treatments to consumers and patients. Regulatory convergence can contribute to these goals by supporting best regulatory practices, assuring that the global regulatory community is wellinformed of current scientifi c and regulatory issues, and establishing regulatory pathways for industry that are predictable and that share a foundation of common, internationally recognized requirements. And while such collaborative activities can benefi t global public health in general, they also hold direct benefi t for US FDA and the US public health by helping to ensure that medical products imported into the US are subject to more eff ective regulatory oversight to assure their quality, safety, and eff ectiveness.

Regulatory convergence for cellular therapy products
Cellular therapy is an emerging product class that poses unique regulatory challenges. Only a few cell-based medical products have been authorized for marketing in one or more countries; therefore, most regulatory bodies have minimal experience with cellular products in the marketplace. Th e lack of regulatory oversight in some nations is a widely recognized risk to public health. To address the limited experience and the recognized risks, it is important for regulatory authorities to share information and experiences and to develop common regulatory approaches for these products.
At the Regulators Forum (RF) held in November 2010 (Fukuoka, Japan) in association with the ICH, US FDA proposed that the RF consider undertaking a preliminary assessment of potential topics of regulatory importance for cellular therapy products. Th e intent of these eff orts is to provide a forum for discussions among international regulatory authorities on the convergence of regulatory perspectives.
Th e goal of US FDA's global eff orts in the cell therapy product area is to support the independent development of national/regional guidelines and regulations that refl ect a shared regulatory experience. Information exchanges regarding regulations, policy, and experience between US FDA and our international counterparts are essential for achieving these goals. US FDA participates in various activities that support this eff ort. For example, regulatory staff from US FDA and representatives from other international regulatory authorities have participated in an exchange program whereby staff members visit their counterpart organization to observe regulatory practices. Other activities include the Regulators Forum Cellular Th erapy Group mentioned above; standing interactions with the European Medicines Agency (EMA) Committee for Advanced Th erapies (CAT) and Health Canada; and ad hoc interactions with EMA, Japan Ministry of Health, Labour and Welfare (MHLW) and Pharmaceutical and Medical Device Agency (PMDA), Health Canada, Singapore Health Sciences Authority, and others. US FDA actively engages with international organizations, including the Pan-American Health Organization (PAHO), WHO, ICH, and Asia-Pacifi c Economic Cooperation (APEC). It is important to note that the information exchanged during US FDA's engagements with international regu la tory counterparts may be limited by whether or not Confi dentiality Commitments and Memorandums of Understanding are in eff ect. Th ese arrangements allow for the discussion of non-public regulatory information, and protect against the disclosure of such information. In the absence of such arrangements with regulatory counterparts, US FDA's activities are limited to information that is in the public domain.
Below is a description of some of US FDA's regulatory convergence activities in the cellular therapy area.

US FDA-EMA-Health Canada Advanced Therapy Medicinal Products Cluster
In 2008, US FDA and EMA established the Advanced Th erapy Medicinal Products (ATMP) Cluster. ATMPs are medicines for human use that are based on gene therapy, somatic cell therapy, or tissue engineering [5]. Th e purpose of the ATMP cluster is to provide a forum for US FDA and EMA to share thinking on regulatory approaches, both in general and on specifi c issues, to share information on draft documents, and to discuss participation in workshops, advisory committees, and working parties. Th e ATMP cluster teleconferences take place fi ve to six times per year. Health Canada joined the ATMP cluster in June 2012.

EMA-US FDA Parallel Scientifi c Advice
In 2004, EMA and US FDA began a program known as Parallel Scientifi c Advice (PSA), in which US FDA and the EMA Scientifi c Advice Working Party (SAWP) exchange views on scientifi c issues during the development phase of a medical product. For the US FDA, this program most closely aligns with pre-investigational new drug application or end-of-phase 2 meetings. PSA meetings are voluntary and usually occur at the request of the sponsor. Th e goal of a PSA procedure is to increase dialogue between the agencies (US FDA and EMA) and the sponsor and to avoid duplication of eff orts in the evaluation and conduct of a proposed clinical trial. During the PSA procedure, each agency provides independent advice to the sponsor on the questions presented. Th e expectation is that the PSA procedure will result in a sponsor having a greater understanding of the respective requirements of the US FDA and EMA. It is important to note, however, that the US FDA and EMA may provide diff erent advice or have diff erent regulatory requirements.

Cellular Therapy Convergence Eff orts by the Regulators Forum (ICH)
Th e Regulators Forum is composed of: ICH members (US FDA, EMA, and Japan PMDA/MHLW); ICH ob servers (Canada, European Free Trade Association (EFTA), WHO); regional harmonization initiatives (APEC, Association of the Southeast Asian Nations (ASEAN), Southern African Development Community (SADC), Gulf Cooperation Council (GCC), Pan-American Network for Drug Regulatory Harmonization (PANDRH)); individual drug regulatory authorities from Australia, Brazil, China, Chinese Taipei, India, Republic of Korea, Russia, and Singapore.
Th e purpose of the RF is to provide an environment in which regulatory and scientifi c expertise can be shared among regulatory authorities in order to enhance the availability of safe and eff ective products in the global market. Meetings of the RF are held in association with ICH biannual meetings.

Regulators Forum Cell Therapy Group
In March 2011, members of the RF formed a brain storming group with the goal of identifying potential areas for convergence in the regulation of cellular therapy products. Th is Cell Th erapy Group agreed that an understanding of the similarities and diff erences in the global regulations and policies applicable to cellular therapy products would be essential to identify common ground for future regulatory convergence activities. Th erefore, this Cell Th erapy Group initially focused on understanding the regulatory landscapes in diff erent regions. Th is included identifying existing regulations and guidelines/guidance documents, and identifying the types of cell-based products that are under clinical investigation and those that have received marketing authorization. Taking the responses of this initial landscaping exercise into consideration, the group decided to next focus on terminology for cellular therapy products, in order to facilitate mutual understanding during our discussions. Th is terminology project is ongoing. Th e RF is considering potential mechanisms to publicly disseminate the information we have gathered and exchanged.

Asia-Pacifi c Economic Cooperation (APEC)
APEC was established in 1989 to promote and facilitate trade among the Asian Pacifi c countries and beyond. APEC members include Australia, Brunei, Darussalam, Canada, Chile, China, Chinese Taipei, Indonesia, Japan, Republic of Korea, Malaysia, Mexico, New Zealand, Papua New Guinea, Peru, Philippines, Russia, Singapore, Th ailand, United States, and Vietnam. In 2002, APEC established the Life Sciences Innovation Forum (LSIF), a tripartite forum of government, industry, and academia whose purpose is to create a policy environment for life sciences innovation. LSIF operates under the guiding principles of transparency and meaningful dialogue with stakeholders and due process for successful imple mentation of policies. Eff orts by APEC LSIF are supported by the APEC LSIF Regulatory Harmonization Steering Committee (RHSC). Th e primary objectives of RHSC are to identify international standards and guidelines to propose to APEC economies and to facilitate implementation of standards and guidelines through education and workshop support.

APEC LSIF RHSC recently accepted a new Priority Work
Area to 'promote regulatory convergence for the regulation of cell and tissue-based therapies' . Th e short-term goals of this Priority Work Area are to establish a harmonized understanding of cell and tissue-based therapies and to establish training programs. Th e long-term goal is to stimulate prospective convergence of technical requirements. Th e next step will be the development of a strategic roadmap by a team of interested regulators with Singapore Health Sciences Authority (HSA) as the project lead. Th e roadmap will outline the project scope, roles and responsibilities, and expected milestones and deliverables.

APEC Workshop on Stem Cell Product QA/QC
In July 2011, the APEC LSIF Workshop on Stem Cell Product QA/QC (Quality Assurance/Quality Control) took place in Bangkok, Th ailand, hosted by the Th ai Ministry of Health. Participants in this workshop included representatives from 13 countries or regions, including Australia, Canada, China (Hong Kong), Chinese Taipei the European Union, Indonesia, Japan, Pan American Health Organization (PAHO) representing the WHO, Saudi Arabia, Singapore, Republic of Korea, Switzerland, Th ailand, and the United States. Th e US was represented by FDA/CBER/OCTGT. Th e goal of the workshop was to discuss QA/QC aspects for stem cell therapy products. Th e workshop also provided an ideal opportunity to gather information on the regulatory landscape for cellular therapy products.
Workshop sessions consisted of presentations on stem cell banking, perspectives on the promise of stem cell therapies in Th ailand, presentations of international regu latory frameworks or proposed frameworks for cellular therapy products by national authorities, a session on considerations for manufacturing QA/QC, pre-clinical studies, and pre-marketing clinical trials. Th e workshop concluded with a roundtable discussion on regulatory issues for cellular therapy products. Th e workshop is summarized below.
Presentations of international regulatory frameworks or proposed frameworks for cellular therapy products were provided by US FDA, EMA, Health Canada, Japan MHLW, Swissmedic, Th ai FDA, Republic of Korea FDA (KFDA), Singapore HSA, Saudi Arabia FDA (SFDA), Chinese Taipei (Taiwan FDA), and Australia Th erapeutic Goods Administration (TGA). It was noted that there are no specifi c legislative distinctions between stem cell products and other cellular therapy products. Common considerations for the determination of the regulatory pathway for cellular therapy products included the amount of manipulation and the clinical use.
Presentations on considerations for manufacturing QA/QC, pre-clinical studies, and pre-marketing clinical trials for cell-derived products were presented by US FDA, EMA, Japan PMDA, KFDA, Th ai FDA, and HSA. Th e presentations highlighted unique safety concerns posed by cellular therapy products, including stem cells. Considerations for QA/QC focused on identity, purity (including testing for undiff erentiated cell populations and for cells that are lineage-committed), tumorigenicity (especially for human embryonic stem cells and inducedpluripotent stem cells), and potency testing. A major challenge in assuring the safety of a stem cell product is the development of assays that can detect cells with undesired characteristics and identify characteristics that are predictive for safety and clinical eff ectiveness. Th e presenters recommended in vitro assays for karyotyping, proliferation capacity, and senescence assays. IPS cells may present risks associated with the method of reprogramming, such as insertional mutagenesis from a viral vector, or genetic instability. EMA pointed to their 'Guideline on Human Cell-Based Medicinal Products' [6], 'Refl ection Paper on Stem Cell-Based Medicinal Products' [7], and 'Draft Guideline on the Risk-Based Approach defi ned in Annex 1, Part IV of Directive 2011/83/EC applied to Advanced Th erapy Medicinal Products (ATMP)' [8]. Th e key recommendations from the US FDA 'Guidance for Industry: Potency Tests for Cellular and Gene Th erapy Products' (January, 2011) [9] were also highlighted.
Pre-clinical testing for stem cell products is challenging in that non-clinical fi ndings are diffi cult to extrapolate to the human population. Th e pre-clinical data needed to support a clinical trial and subsequent licensing depend on the nature of the stem cell product. For clinical trials with stem cells, a specifi c surveillance plan for the assessment of long-term safety was recommended. It was also suggested that post-authorization safety and effi cacy follow-up should be required for high-risk stem cell products.
During the roundtable discussions, a preliminary eff ort was made to identify technical requirements for stem cell products for clinical use. Th e group acknowledged that the level of regulatory oversight depends on the type of stem cell product. Substantially manipulated cells are considered to be higher risk than minimally manipulated cells, and therefore more extensive QA/QC testing is expected for substantially manipulated cells. Some participants suggested that development of a minimum set of quality/manufacturing requirements for minimally manipulated stem cell therapy products is important, and could be used as a guide in regions where regulatory oversight is limited.
Major outcomes of this workshop included the identifi cation of regulatory gaps for cell therapy products among international regulatory authorities, and recognition that QA/QC requirements for stem cells depend on the type of stem cell product. Th e group also concluded that in order to provide safe and eff ective stem cell products to patients, it is important to educate patients on the current limitations of stem cell therapy, as well as to educate physicians and scientists on the conduct of appropriate clinical trials for such products. Th e fi nal report of the workshop will be presented to APEC, ICH, and the RF.

Conclusion
Th e US FDA is committed to active participation in international regulatory convergence eff orts for cellular therapy products, as part of our mission to facilitate the development of safe and eff ective medical products in the US and worldwide. Th ese eff orts are currently in early stages, with an initial focus on development of a common understanding of the similarities and diff erences in regulations and policies for cellular therapy products in diff erent countries/regions.