Reinventing the Regulation of Human Tissue
President Bill Clinton
Vice President Al Gore
National Performance Review
February 1997
EXECUTIVE SUMMARY
The Food and Drug Administration's sixth "Reinventing Government" report, produced in conjunction with the Vice President's National Performance Review1, focuses on the increasing use of human cellular and tissue-based products, and proposes a new approach to their regulation.
Tissues have long been transplanted in medicine for widespread uses--such as skin replacement after severe burns, tendons and ligaments to repair injuries, heart valves to replace defective heart valves, corneas to restore eyesight, and the use of human semen and implantation of eggs to help infertile couples start a family. In recent years, scientists have developed new techniques, many derived from biotechnology, that enhance and expand the use of human cells and tissues as therapeutic products. These new techniques hold the promise of providing therapies for cancer, AIDS, Parkinson's Disease, hemophilia, anemia, diabetes, and other serious conditions.
Although these products are often the result of the newest technologies, the concepts and procedures under which they are regulated were developed many years ago, and sometimes are ill-suited for their purpose. To remedy this shortcoming, FDA -- after consultation with the involved industries -- has designed a new regulatory framework for cells and tissues that would protect the public health without imposing unnecessary government oversight.
[This new framework would provide a tiered approach to cell and tissue regulation. Regulation would focus on three general areas: 1) preventing unwitting use of contaminated tissues with the potential for transmitting infectious diseases such as AIDS and hepatitis; 2) preventing improper handling or processing that might contaminate or damage tissues; 3) ensuring that clinical safety and effectiveness is demonstrated for tissues that are highly processed, are used for non-natural purposes, are combined with non-tissue components, or are used for metabolic purposes.
The agency would require infectious disease screening and testing be done for cells and tissues transplanted from one person to another. The agency would also require that cells and tissues be handled according to procedures designed to prevent contamination and to preserve tissue function and integrity. The agency would recommend, but not require, that screening and testing procedures be followed when reproductive tissues are used between sexually intimate partners, and when tissues are transplanted back into the person from whom they were obtained. In general, there would be no agency submissions required regarding infectious disease controls and handling requirements. Thus, most conventional and reproductive tissues would not be subject to premarket approval requirements. (The agency would impose no requirements on cells and tissues transplanted within a patient's body in a single surgical procedure.)
Cells and tissues that were manipulated extensively, combined with non-tissue components, or were to be used for other than their normal functions would be regulated as biologics or devices requiring premarket approval by FDA. Metabolic cells and tissues, unless minimally manipulated and used for their natural function in close relatives of the person from whom they were obtained, also would be regulated as biologics requiring premarket approval by FDA.
The agency would require that all tissue processing facilities register with the agency, and list their products, via a simple electronic system. And the agency would require that all labeling and promotion be clear, accurate, balanced, and non-misleading.
This new system would provide a rational, comprehensive and comprehensible framework under which tissue processors could develop and market their products. It would ensure that innovation and product development in this rapidly growing medical field could proceed unhindered by unnecessary regulation. At the same time, it would provide physicians and patients with the assurance of safety that the public has come to expect from drugs, biologics, medical devices and other medical products overseen by the FDA.]
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[This new framework would provide a tiered approach to tissue regulation. Regulation would focus on three general areas: 1) preventing unwitting use of contaminated tissues with the potential for transmitting infectious diseases such as AIDS and hepatitis; 2) preventing improper handling or processing that might contaminate or damage tissues; 3) ensuring that clinical safety and effectiveness is demonstrated for tissues that are highly processed, are used for non-natural purposes, are combined with non-tissue components, or are used for metabolic purposes. Additionally, the agency would require that tissue processing facilities register with the agency, and list their products, via a simple electronic system. And the agency would require that all labeling and promotion be clear, accurate, balanced, and non-misleading.
1 ) Communicable disease controls. The agency would set screening and testing requirements and recommendations, but in most cases would not require individuals to file information with the agency regarding those requirements and recommendations.
All uses of tissues (except removing and reimplanting tissue in the same patient in a single surgical procedure) would be subject to some infectious disease controls. Screening and testing would generally be required before use of tissues removed from one person and transplanted into another. Screening and testing would be recommended, but not required, before use of stored or processed tissue that had been removed from and transplanted back into the same person, and before use of reproductive tissue (such as semen or ova) between sexually intimate partners. Labeling and/or record keeping would be required to describe whether the recommended tests were performed, and what if any results were obtained. However, the agency would not be involved in the decision as to whether to use potentially contaminated tissues within a family, or between sexually intimate partners.
2 ) Handling and processing. All uses of tissues (except removing and reimplanting tissue in the same patient in a single surgical procedure) would be subject to handling and processing controls to prevent contamination and to preserve function. In general, there would not be agency submissions required to document adherence to such "good tissue practices."
3) Clinical safety and effectiveness. Tissues that are manipulated such that their biological characteristics or relevant functions are altered, that are used for purposes other than those they normally perform, that are combined with non-tissue components, or that are used for a metabolic purpose generally would be subject to more comprehensive regulatory requirements than other tissues. Such products would be regulated as biologics or devices subject to premarket approval. Sponsors of such products would have to provide submissions to the agency documenting use of processing controls aimed at ensuring clinical safety and effectiveness, and submissions of clinical trial data demonstrating safety and effectiveness.
In general, normal use of conventional tissues (such as skin, bones, ligaments, veins, corneas, dura mater and heart valves) and reproductive tissues would only be subject to infectious disease controls and good tissue practices, and would not entail agency submissions other than registration, listing, and reporting of adverse events. Use of tissue for a metabolic purpose in the person from whom it was obtained or in a close family member of the donor (if the tissue is only minimally manipulated, without non-tissue components and is used for its normal function, e.g., stem cells used to reconstitute blood after a patient's own stem cells were destroyed by chemotherapy), also would only be subject to infectious disease controls and good tissue practices, and would not entail agency submissions other than registration, listing, and reporting of adverse events.
This new system would provide a rational, comprehensive and comprehensible framework under which tissue processors could develop and market their products. It would ensure that innovation and product development in this rapidly growing medical field could proceed unhindered by unnecessary regulation. At the same time, it would provide physicians and patients with the assurance of safety that the public has come to expect from drugs, biologics, medical devices and other medical products overseen by the FDA.]
REINVENTING THE REGULATION OF CELLULAR AND TISSUE-BASED PRODUCTS
BACKGROUND
The term "tissues" covers a wide range of products used for many medical purposes. In the past, most human tissue used in medicine was comprised of such body components as skin, bone, corneas, and heart valves that were transplanted for replacement purposes, and semen and ova implanted for reproductive purposes. Three years ago, FDA started requiring that conventional non-reproductive tissues be tested for HIV and hepatitis, and that their donors be screened for risk of infection. FDA did not impose any requirements on reproductive tissues at that time.
In recent years, scientists have developed innovative methods of manipulating and using human cells and tissues for therapeutic purposes. For example, in somatic cell therapy, scientists are studying how to manipulate and use human cells to treat viral infections, Parkinson's Disease, diabetes, HIV infection (AIDS), and other diseases and conditions. Other tissue research includes the treatment of diseases and medical conditions by using blood from the placental/umbilical cord, and by using processed structural cells and tissues.
In general, these forms of cellular and tissue therapy are, and under the new proposal would continue to be, regulated by FDA as "biologics" or "devices" with premarketing approval requirements, in accordance with the Public Health Service Act and the Food, Drug, and Cosmetic Act. (NOTE: some uses of cord blood have not been actively regulated in the past, and when within a family some uses would not now be regulated).
A NEW REGULATORY FRAMEWORK
The FDA has formulated a comprehensive approach to the regulation of human cellular and tissue-based products2, . This approach, which could be put in place with new regulations but without change to existing law, would provide a more appropriate oversight for the wide spectrum of cellular and tissue-based products that are now marketed or envisioned for the future. It would maintain or improve protection of the public and increase public confidence in these new technologies, while permitting significant innovation to go forward unfettered by unnecessary regulatory requirements.
Cellular and tissue-based products and their potential uses are too diverse to be appropriately covered by a single set of regulatory requirements. In an effort to develop a comprehensive scheme that would treat like products alike -- but that would establish regulatory distinctions among cellular and tissue-based products when necessary -- the agency identified the principal public health concerns and attendant regulatory issues associated with the use of these products. Stated as questions, these five overarching public health and regulatory concerns are:
- How can the transmission of communicable disease be prevented?
- What processing controls are necessary to prevent contamination of cells and tissues and to preserve their integrity and function so that they can be safely and effectively used.
- How can clinical safety and effectiveness be assured?
- What labeling is necessary, and what kind of promotion is permissible, for proper use of the product?
- Should manufacturers notify FDA when they process and market tissue products?
PROPOSAL
With these concerns in mind, the FDA categorized cells and tissues and their uses by their risk relative to each concern, so as to enable the agency to provide only that level of oversight relevant to each of the individual areas of concern. Thus, under the plan, tissues would be regulated with a tiered approach based on risk and the necessity for FDA review. For example:
- Cells and tissues that are removed from and transplanted into the same person in a single surgical procedure would not be subject to FDA regulation.
- Tissues used for conventional purposes, such as to repair injuries, replace damaged or defective tissues, or overcome infertility, would be subject to very limited oversight as long as they were only minimally processed and were used for their normal functions. The oversight would be aimed at ensuring that the tissues were handled properly and were not infectious. Other than facility registration, product listing, and reporting of any adverse events, there would be no required submissions to FDA for most conventional and reproductive tissues used for their normal functions.
- All tissues (except that used in the patient from whom it was obtained in a single surgical procedure) would have to be handled according to according to "good tissue practices" aimed at preventing contamination and preserving integrity and function. Additionally, the agency would prescribe procedures for testing the tissue for infectious agents and for questioning (screening) the donor about potential exposure to disease agents.
- For tissue to be used in the same person from whom it was obtained, or in a sexually intimate partner of a reproductive-tissue donor, the agency would recommend, but not require, that such screening and testing procedures be followed. While the agency would not get involved in the decision as to whether the tissue should be used or not, the agency would require that the prospective recipient be informed as to whether the recommended procedures were or were not performed, and of any results obtained. Additionally, the agency would require that tissues be labeled according to whether they posed a potential biohazard or not, for the protection of health care workers.
- For tissue transplanted from one person to another (other than reproductive tissues between sexually intimate partners) the agency would require infectious disease screening and testing, as well as biohazard labeling.
- Tissues and cells processed such that their biological or functional characteristics may have been altered (or were intentionally altered), used to perform other than their normal functions, used for metabolic purposes (except when used between close blood relatives) or combined with devices, drugs or other biologics, would require FDA review for safety and effectiveness. These products would have to receive an Investigational New Drug (IND) exemption or Investigational Device Exemption (IDE) prior to human testing, and they would have to be approved by FDA prior to marketing.
Marketing approval would signify that the product is a safe and effective therapy that has been produced under appropriate processing controls. Technologies such as somatic cell therapy and gene therapy would fall into this category, as would stem cell therapy in patients not closely related to the cell donor
IMPACT OF REFORMS
This regulatory plan would establish a sensible, efficient, and comprehensive mechanism for classifying and regulating human cell and tissue products according to the potential risk they pose to human health. This plan would prevent pitfalls inherent in addressing each type of product separately under existing rules.
Under the plan, all facilities working with human cells or tissues would be required to register with the agency, and list their products, but only after the agency had in place a simple electronic system for such registration and listing. Thus, this new requirement would be of minimal burden to those affected. Additionally, the agency would minimize submissions by not requiring individuals or companies to provide information concerning communicable disease screening and testing, except in specified circumstances.
As a result, sponsors of lower-risk tissues (e.g., minimally processed conventional tissues for replacement purposes and minimally processed reproductive tissues) would not need to submit reports to FDA except for cases of adverse effect on a tissue recipient. The same minimal requirements would also apply to minimally processed tissues used for their normal metabolic purposes in close relatives of the tissue donor. Sponsors of higher-risk tissues would have to submit information to the agency to receive premarket approval.
Thus, some products, such as dura mater, would be subject to lesser regulatory requirements than apply currently. The agency would be also able to reduce the regulatory burden for other products. For example, the agency would regulate heart valves as tissues, with no premarket approval requirements, rather than as devices with evaluation and approval requirements. For stem cells intended to reconstitute blood in a patient whose own ability to do so has been destroyed, the agency expects to be able to develop class-wide standards based on clinical data to be submitted by stem cell researchers. The new standards would obviate the need for detailed submissions in support of requests to investigate or market such products in patients not closely related to the cell donor.
In sum, the proposed approach would enhance both public health and public confidence in the safety and utility of cells and tissues, while imposing minimum burden on researchers and tissue facilities. Innovative new technologies that utilize cells and tissues for therapies would be regulated only to the extent appropriate to protect public health. The promulgation of consistent and rational rules also would enable product developers to anticipate regulatory requirements, and would thereby greatly facilitate their work.
THE REGULATORY FRAMEWORK IN DETAIL
As noted above, cells or tissues that are removed from a patient and transplanted back into that same patient during a single surgical procedure would not be regulated. For all other cellular and tissue-based products encompassed in the plan, the regulatory obligations would be determined by an analysis of the five public health and regulatory areas, as described below and as summarized in Table 1.
Transmission of communicable disease. Cells and tissues can transmit infectious diseases, which makes infectious disease controls critical. The agency would require that certain donor screening and donor or tissue testing procedures be followed when the cells or tissue will be used in someone other than the donor him/herself, or, for reproductive tissue, in a person not sexually intimate with the donor. The screening and testing requirements would depend on the communicable disease risks presented by the different types of cells or tissue. However, there would be no required submissions to the agency regarding the testing and screening.
For cells and tissues to be used in the person from whom they were obtained, or in sexually intimate partners of reproductive-tissue donors, the agency would only recommend that screening and testing procedures be followed. The agency would require that record keeping and labeling reflect the performance or omission of the recommended tests and the results, and that the use of material from infected or high risk donors, or from untested or unscreened donors, be contingent on informed consent. However, the agency would not interfere with the choices made by the family and physician.
Handling and processing. All uses of cells and tissues other than in a single surgical procedure would be subject to either good tissue practices (GTPs) or good manufacturing practices (GMPs). Both GTPs and GMPs would encompass handling procedures aimed at preventing contamination and preserving cellular and tissue function and integrity, however GMPs would encompass additional processing controls as needed to ensure clinical safety and effectiveness. GTPs would apply to products whose characteristics and uses do not raise clinical safety and effectiveness issues that call for marketing approval requirements. GMPs would apply to products that do raise such concerns and for which the agency would require marketing approval. To the extent that the GTPs and GMPs would cover the same areas of concern (i.e., handling and minimal processing), however, there would be no duplication of requirements.
Products subject to premarketing approval also generally would be subject to premarket submission requirements demonstrating that their products are manufactured according to validated controls and meet product specifications.
Clinical safety and effectiveness. Not all cellular and tissue-based products would be required to undergo clinical safety and effectiveness testing under regulatory controls. Products would be subject to premarketing clinical safety and effectiveness study and approval requirements only if they are more-than-minimally manipulated such that their biological or functional characteristics may have been altered; are used for a function other than that which they normally perform, or for structural tissues, used in a location where such structural function is not normally performed; are combined with noncell or nontissue components; or are used for a metabolic function. (However, as mentioned previously, the agency would not impose these regulatory requirements on the use of minimally manipulated cells or tissue for their normal metabolic purpose in a patient closely related to the donor.) Any of these factors raise issues of clinical safety and effectiveness in addition to the communicable disease concerns discussed above.
In cases where the FDA had not stated whether a particular kind of processing was more-than-minimal manipulation or a particular use was not for normal function, the agency would expect innovators to make that determination themselves based on general information provided by the FDA. However, the FDA would encourage individuals to seek the agency's guidance when they have questions about the appropriate regulatory procedures. To respond to such inquiries, the agency is establishing a Tissue Reference Group consisting of three employees each of the Center for Biologics and Center for Devices. Sponsors may also make use of the agency's Office of the Ombudsman and Chief Mediator to address such matters.
The use of cells or tissue in a combination product with drugs, biologics, or mechanical or synthetic devices raises clinical safety issues that are associated with those noncellular and nontissue products. Such combination products would continue to be regulated according to their primary mode of action (that is, depending on how they act, as a device, drug, or biologic).
Metabolic products raise potentially serious systemic safety and effectiveness issues. For example, the use of nonfunctional (and therefore ineffective) stem cells to reconstitute the cellular elements of the blood of a patient whose own stem cells have been destroyed by chemotherapy may lead to the death of that patient. Because of the higher level of concerns associated with metabolic products, they would receive close study and scrutiny.
However, while important medical issues exist for metabolic tissue used in the patient from whom it was obtained or in a close blood relative, the agency would not interfere with a family decision on the use of such tissue. FDA therefore would not require premarketing approval for family use of such tissue when it is minimally manipulated, used for its normal function, and without noncell/nontissue components.
The agency intends to adjust its approval requirements, in particular for the clinical data on safety and effectiveness, in accordance with the types of tissues and cells, and their uses. Thus, structural tissues requiring premarket approval would generally be reviewed in accordance with requirements for clinical safety and effectiveness data that apply to devices, while tissues used for metabolic or reproductive functions would be subject to the kinds of requirements that apply to licensed biologics.
Additionally, the agency would call on industry and academia to submit manufacturing and product standards designed to ensure safety and effectiveness of specific product-use classes for which supporting clinical data exists or may soon exist in the public domain. At present, the agency believes that such standards can be developed over the next two years for stem cells intended for hematopoietic reconstitution. The agency would phase in the licensure requirements as the standards were formulated. For products for which such standards were developed and adopted by the agency, applicants could certify that they met the standards, and would not have to submit individual applications containing clinical data to receive licensure.
Promotional claims and labeling. Promotional claims and labeling would be required to be clear, accurate, balanced, and non-misleading. For products subject to premarket approval, the current labeling requirements applicable to biological drugs and devices would apply; in all other cases, the sponsor would be obliged to label the products clearly and accurately, but no submissions to the FDA would be required.
The agency would require labeling and/or record keeping as to what required or recommended testing and screening procedures were carried out, and the results of such procedures. The agency would allow labeling as to whether additional tests or procedures, such as retesting after quarantine, were carried out.
For products not subject to premarket approval, promotional claims would be limited to those for normal uses of the cells or tissue. Thus, stem cells for hematopoietic reconstitution, or for hematopoietic reconstitution in the case of chemotherapy-induced stem cell ablation or Fanconi's anemia, would be allowed. Claims for non-normal use (e.g., stem cells to treat melanoma) would trigger a requirement that the sponsor demonstrate safety and effectiveness for such claims and obtain premarket approval.
Baseline knowledge of industry (registration and listing). The agency has been criticized by government oversight bodies for not knowing "who is doing what" regarding cellular and tissue-based products. The agency is developing a simple electronic registration and listing system under which all establishments procuring, processing, shipping, banking, or distributing cellular or tissue-based products would be required to register with the agency and list their products. The agency would use this system for monitoring purposes and to distribute new information regarding guidances, policies, or requirements.
In sum, the agency has tried to develop a regulatory approach for cellular and tissue-based products that would treat like products alike, that would be flexible and allow innovators to develop new therapies with a minimum regulatory burden, and that would establish standards to protect the public health. The agency has distinguished between the kinds of human experimentation that required only minimal regulatory oversight, and the kinds of human experimentation that warrant greater surveillance.
The approach would put much of the burden of compliance on the industry, and would require a minimum of regulatory submissions to the agency. Roll out is envisioned as:
- making available a detailed document describing the proposed regulatory approach;
- a public meeting to discuss and refine the approach;
- notice and comment rule-making for new rules, such as for registration and listing, screening and testing requirements, GTPs, and labeling.
New requirements, as well as the application of existing requirements to new product classes, would be phased in over the next two or possibly three years.
1Previous reports include: "Reinventing the Regulation of Drugs and Medical Devices" (issued April 1995); "Reinventing the Regulation of Drugs Made from Biotechnology" (issued in November 1995); "Reinventing the Regulation of Food" (issued January 1996); "Reinventing the Regulation of Cancer Drugs" (issued March 1996); and "Reinventing the Regulation of Animal Drugs" (issued May 1996).
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2The approach does not encompass whole organs or minimally-manipulated bone marrow (both of which are regulated by the Health Resources and Services Administration), or transfusable blood products (e.g., whole blood, red blood cells, platelets, and plasma), which FDA already comprehensively regulates. The approach also does not encompass other FDA-regulated tissue-related products, such as tissues derived from animals, products used in the propagation of cells or tissues, or products that are secreted by or extracted from cells or tissues (such as human milk, collagen, or growth factors).
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