Abstract
Background
A significant hurdle identified consistently in previous publications has been a lack of clarity or inconsistencies between regulatory agencies on how TE/RM products are regulated. From an international perspective, this regulatory imperative can be considered via at least three general themes:
Regulatory Framework—Principles and requirements governing assessment of TE/RM products, that is, review and marketing approval
Globalization—Challenges for regulatory authorities due to the global R&D effort in TE/RM outside their purview, that is, outside the US and EU
Regulatory Harmonization—Development of a common dialogue and approach among regulatory authorities leading to congruence of national practices and consensus on regulatory requirements, that is, a unified regulatory strategy
Although differences in the interpretation of the regulatory framework and consequent guidelines exist (e.g., Hospital Exemption Rule) and regulatory barriers to TE/RM commercialization have been raised,1,3 a direct comparison of the regulatory principles and guidelines in Europe (European Medicines Agency [EMA]) and the United States (Food and Drug Administration [FDA]) have not been conducted. Toward establishing a basis for discussing these three general themes, TERMIS-America (AM) and TERMIS-Europe (EU) developed a joint symposium to initiate the process of understanding what, if any, differences might exist between EMA and FDA practices and guidelines that may represent barriers to commercialization of TE/RM products.
To initiate this process, the joint TERMIS Industrial Committee invited Lucia D'Apote, PhD; EMA and Celia Witten, MD, PhD; FDA to address a series of questions through a review of the regulatory framework guidelines for TE/RM product development and commercialization with a panel of industrial representatives, including Maria Pascual-Martinez, PhD (TiGenix); Alison Wilson (Cell Data Services); Leslie Wolfe, PhD (Genzyme); Kiki Hellman, PhD (The Hellman Group, LLC); and Tim Bertram, DVM, PhD (Tengion).
Questions
1. With the recognition that product development, including clinical studies, in tissue engineering and regenerative medicine is a global enterprise, what chemistry manufacturing controls, clinical, and pharmacology/toxicology aspects of international studies may or may not be acceptable? What criteria will form the basis for decision-making re’ product approval and, how can best practices be developed and adopted to accommodate reciprocity across national boundaries?
The FDA and EMA have different legislated product approval pathways at their disposal, permitting expedited product approval, for example, for orphan drugs and humanitarian-use devices in FDA. Are any other means of rapid product approval for TE/RM products being considered as long as patient safety is demonstrated? What criteria would form the basis for accelerated/expedited product review?
What priorities do the FDA and EMA foresee for industry in developing best practices for TE/RM products, for example, manufacturing, release criteria (functionality, fitness for use), and other issues specific to their products? What mechanisms are the most effective in establishing a cooperative and collegial dialogue with FDA and EMA re’ such issues?
Each of the two agency's representatives presented detailed responses to these questions in a comprehensive slide presentation. 11 Although clear differences exist in certain areas (e.g., Hospital Exemption and CE-Mark) between the FDA and EMA, and EMA developed working parties with scientific arms of TERMIS (i.e., TERMIS-EU) to address key development questions, the overall regulatory principles and general guidelines for TE/RM product development are quite similar. Since specific comments from each speaker can be reviewed in their slides, only a general summary is provided below.
Summary
The international TE/RM product pipeline is broad and deep presenting unique challenges for regulatory authorities such as the EMA Committee on Advanced Therapies (CAT) and FDA CBER. Presubmission meetings permit sponsors to obtain specific guidance on their respective technology at an early stage of development. Product submissions are presented to the agencies for regulatory review and approval for marketing from academic institutions and companies ranging in size from small start-up and biotechnology companies to large, well-established pharmaceutical, and device companies. Each of these entities comes with varying levels of expertise and understanding of current regulatory guidelines and practices.
TE/RM products are complex in composition and vary widely in the active biological ingredient, matrix, and delivery method. Additionally, these products may present unique manufacturing, pre-/nonclinical and clinical challenges for regulatory consideration, such as experimental reagents and undefined product specifications, among others.
The FDA and EMA have recognized the regulatory challenges presented by TE/RM products, raw materials, preclinical testing, and clinical assessment. Both agencies have developed specific pathways for these products, and each agency has a mechanism for evaluating the safety and efficacy of these novel breakthrough products.
Similar regulatory approaches are taken by EMA and FDA. In that, both
1. adopt risk-based/tiered approaches to evaluate the specific risks unique to each TE/RM product submission;
2. have identified specific pathways that can be utilized for TE/RM therapies to reach the market expeditiously provided they are safe and effective for the intended patient population;
3. promote long-term follow-up on safety, efficacy, and durability of TE/RM products and the clinical outcomes;
4. have entered into agreements for parallel advice and collaborations with industrial organizations on regulation of TE/RM product development and conduct of joint reviews;
5. encourage sponsors to meet, so agencies can offer specific guidance to sponsors in key technological areas of concern, such as nonclinical challenges and clinical trial design and evaluation;
6. accept international studies for marketing applications if they meet specific requirements for data validity, good clinical practices, and appropriate supporting information.
The TE/RM industry is emerging with many years of growth yet to come. A clear path forward for developers of TE/RM products will include the following:
1. Raising awareness of unique safety challenges and efficacy opportunities.
2. Learning from each submission as these new technologies advance through the development process to commercialization and become standards of care with long-term follow-up.
3. Promoting industrial-regulatory dialogue to advance the development and commercialization of safe and effective TE/RM products for unmet medical needs.
4. Identifying the regulatory pathway that the product being developed is going to follow as part of the development process. This will define the questions that need to be addressed before clinical translation.
Next Steps
The regulation of TE/RM products represents an ever-changing environment that requires close alignment between sponsors and regulatory agencies, so that advanced therapies can be brought forward to address unmet medical needs. By exploring the regulatory principles governing assessment of TE/RM products thought joint symposia, a logical and rational basis for decision-making and a framework for governing regulatory decisions can be further developed for products to benefit patients, and advance health care.
Initiatives in TE/RM as well as other research areas now represent a global R&D effort with an increasing number of clinical studies performed outside their purview (outside the United States and EU) presenting certain challenges for regulatory entities. As scientific and technological discoveries in TE/RM provide products leading to improved patient outcomes and reduced healthcare costs, a robust partnership between the regulatory agencies and product developers is required. Ongoing efforts exist in the regulatory agencies to develop a common dialogue and approach leading to congruence among national practices toward subsequent consensus on harmonization of regulatory requirements for TE/RM products.
A common goal for both the TE/RM industry and regulatory agencies is to ensure that a robust scientific foundation exists for evaluating each product candidate progressing through the development process. Such a goal can only be achieved with a regular and frequent dialogue between representatives of each entity. However, broad perspectives especially as related to standards, evaluation of break-through technologies and understanding of current scientific methods for risk-based evaluation are independent of specific product input. Such scientific dialogue surpasses any one sponsor and is dependent on societies and trade organizations to provide the foundation for open discussion, and a forum for rigorous debate focused on the best approaches to evaluate product safety and efficacy for advanced therapeutics provided by TE/RM.
The TERMIS Industry Committees stand ready to engage in a productive dialogue with regulatory authorities regarding the scientific methods/approaches and elucidation of technological advances afforded by this emerging industry. The Industrial Committees will continue to serve TERMIS organizations worldwide and reach out to other industrial organizations to engage with regulatory agencies through a scientifically based forum to reduce barriers and advance the development of TE/RM products.
Footnotes
Disclosure Statement
No competing financial interests exist.