March 15, 2005 (Vol. 25, No. 6)

Completing the Regulatory Framework for Human Cells, Tissues, and Cellular and Tissue-Based Products

May 25 will mark the end of the beginning for FDA regulation of human cells, tissues, and cellular and tissue-based products (HCT/Ps). The last and, in some respects, most important of its panoply of regulations to govern the collection of antecedent donor materials and the processing and distribution of resulting products will be made effective from that date forward.

This final piece of the regulatory framework, first announced by the Agency in early 1997, was published in the Federal Register on November 24, 2004, as the Current Good Tissue Practice for Human Cell, Tissue and Cellular and Tissue-based Product Establishments; Inspection and Enforcement; Final Rule (referred to in this article as the CGTP Rule).

Two earlier Final Rules, one providing for establishment registration (the Registration Rule) and the other establishing processes for donor screening (the Donor Screening Rule), had already set out significant portions of this framework.

The Registration Rule was made effective as of January 21, 2004; the regulations set forth in the Donor Screening Rule come into effect on the same day as the CGTP Rule.

A conference, FDA and the New Paradigm for Tissue Regulation, held in Dallas on February 1, allowed for a dialogue between FDA and industry participants on the eve of the implementation of the completed regulatory plan for HCT/Ps.

The conference, sponsored by associations of the impacted industry, including the American Association of Tissue Banks, Eye Bank Association of America, and American Society for Reproductive Medicine, among others, covered the rules requirements for these products and for establishments or individuals engaged in different areas of the industry, from donor testing and screening, cell and tissue recovery, to processing, storage, and distribution of the final product.

Culmination of Efforts

The CGTP Rule represents the culmination of FDAs efforts over several years to establish a comprehensive system for regulating human cell, tissue, and cellular and tissue-based products.

Defined as articles containing or consisting of human cells or tissues that are intended for implantation, transplantation, infusion, or transfer into a human recipient, HCT/Ps include skin, musculoskeletal tissue (notably, bone and ligaments), ocular tissue (especially corneas), heart valve allografts, dura mater, hematopoietic stem and progenitor cells derived from peripheral and cord blood, reproductive tissue, cellular therapies, and combination products consisting of tissue with a device and/or drug (such as cells on a natural or synthetic matrix).

The initial version of the CGTP Rule (issued as a proposed rule on January 8, 2001) had distinguished between tissues intended for transplantation, and human cellular and tissue-based products; the CGTP Rule absorbs the former category into the all-encompassing class of HCT/Ps for donor materials collected after May 25, 2005.

In the late 1980s and early 1990s, the Agency recognized the need for regulatory oversight of these products. First, documented evidence of communicable-disease transmission to recipients from infected donor tissue (such as Creutzfeldt-Jakob disease) through dura mater and eye tissue; HIV and hepatitis virus, through organ and tissue transplantation; as well as bacterial and fungal infections, presented a primary public-health concern.

Second, the rapid growth of the industry, with the development of new applications and technologies for processing human cells and tissues, coupled with increased demand and international commerce, presented different issues.

Finally, voluntary standards established by certain organizations had not been uniformly followed, as they are not legally enforceable.

All these factors, among others, together with public demand for safe products, compelled the Agency to affect appropriate solutions.

Since many of the products were not easily categorized into a regulatory niche, FDA undertook a new risk-based approach to provide the background for the appropriate oversight.

Novel Approach

The approach, announced in February 1997 through two documents, Reinventing the Regulation of Human Tissue and Proposed Approach to the Regulation of Cellular and Tissue-based Products (the Proposed Approach), indicated that the level and type of regulatory oversight would be based on the risk(s) posed by a product’s characteristics and the commensurate degree of oversight needed to protect the public health.

This framework was expected to complement, but not replace, existing regulations governing traditional medical products subject to pre-market review and post-market compliance requirements.

The primary concerns addressed through the Proposed Approach were: prevention of communicable-disease transmission; assurance of safe processing and handling; claims of safety and effectiveness; monitoring the industry; and promotional claims.

The Proposed Approach identified two regulatory tiers: products meeting certain criteria would be regulated solely under provisions of Section 361 of the U.S. Public Health Service Act (so-called 361 Tissues in the Proposed Approach, but more accurately, 361 Products going forward) and would not be required to undergo pre-market review.

All others to be subject to this framework would be regulated under existing drug, device, and biological-product regulations, in addition to new regulations addressing the incorporation of living biological materials into the finished product.

The Public Health Service Act provides the legal authority for FDA to develop and enforce regulations necessary to prevent the introduction, transmission, or spread of communicable diseases through the distribution of medical products.

Under the Proposed Approach and subsequent rulemaking to implement the framework for regulating HCT/Ps, 361 Products are identified by: minimal manipulation of the source tissue through the processing stage; homologous use (i.e., the HCT/P performs the same function(s) in the recipient as does the source tissue performed in the donor); freedom from combination with another article; absence of intended systemic effect; and absence of dependence upon the metabolic activity of living cells (except in cases of autologous use, use in first- or second-degree blood relatives, or reproductive use).

HCT/Ps not meeting these criteria would be regulated under the U.S. Food, Drug and Cosmetic Act (the Act) as devices, drugs, or biological products.

The Registration and Donor Screening Rules were subsequently published to implement aspects of the Proposed Approach. The Registration Rule has created a unified system for registering HCT/P establishments and listing their products.

Unified System

The Donor Screening Rule, published on May 25, 2004, requires most cell and tissue donors to be tested and screened for relevant communicable diseases, with the type of testing and screening dependent on the type of tissue, once the regulations promulgated under the Rule become effective on May 25. Testing and screening are not required for tissues obtained for autologous applications.

FDA’s framework for establishing adherence to Current Good Tissue Practice (CGTP) was initiated approximately three years ago, with a proposed rule published on January 8, 2001. Significantly, the CGTP proposed rule stated that the Agency would require cells and tissues to be handled according to procedures designed to prevent contamination and to preserve tissue function and integrity.

The CGTPs incorporated in the proposed rule, included, among others, proper handling, processing, labeling, and recordkeeping procedures. The development and maintenance of a quality program by each establishment would be required to ensure compliance with CGTP.

In drafting the CGTP Rule, FDA reevaluated each requirement of the proposed rule and considered the approximately 197 comments to the public docket, feedback from the industry and others through public meetings, and consultations with a number of different entities, to ensure that the requirements either directly prevent introduction, transmission, or spread of communicable disease, or support such a requirement.

The Rule established certain core CGTP requirements. As a result, these requirements are viewed as the necessary minimum for assuring a safe manufacturing process and a safe product.

Important Changes

The CGTP Rule incorporates a number of important changes and additions to the requirements initially outlined in the proposed rule. Bowing to confusion and concern expressed in a number of public comments, the Agency struck from the CGTP Rule any reference to preservation of function and integrity as measures of CGTP compliance.

The provisions of the CGTP Rule providing for inspection and enforcement authority, and extension of requirements to imports, are additions to the proposed rule.

The CGTP core requirements, effective as of May 25, govern methods used in HCT/Ps as well as facilities and controls used for the manufacture of HCT/Ps. As such, they are fundamental components of the risk-based approach to regulating 361 Products, intended to assure that sufficient regulatory controls are in place to protect the public health.

But those HCT/Ps regulated as devices, drugs, or biological products must also be manufactured in accordance with existing requirements of current good manufacturing practices (CGMP) and quality-system regulations (QSR), to the extent applicable to these products.

Summing It All Up

In summary, CGTP requirements cover all aspects of production, including: cell/tissue recovery; donor screening and testing; donor-eligibility determinations; processing and process controls; supplies and reagents; equipment; facilities; environmental and labeling controls; storage conditions; product receipt, predistribution shipment and distribution; advertisement/deviation reporting; and tracking from donor to product consignee.

As indicated, each individual establishment must develop and maintain a quality program covering all these requirements.

The final rule affects several types of entities involved in HCT/P manufacture, including conventional tissue banks and those processing hematopoietic stem and progenitor cells, and eye banks.

Assisted-reproductive–technology establishments and semen banks are subject only to the inspection and enforcement procedures as they apply to donor-eligibility requirements and will be minimally affected by the rule. Information published with the rule demonstrates the size of this large and diverse industry.

For example, there are approximately 166 establishments for conventional tissue, 134 for eye tissue, 425 for hematopoietic stem/progenitor cells, and 510 for reproductive tissue. Each establishment is required to comply only with those requirements that apply to the specific activities in which it is engaged, and the Agency is working with industry and others to develop guidance specific to different types of HCT/Ps.

However, as noted by the diversity of HCT/Ps covered in the rule, requirements have been extended to products that were not considered earlier.

In general, public comments supported the rule, acknowledging that the development of the entire regulatory framework was an enormous undertaking of great importance.

Publication of the CGTP Rule completes the set of regulations, proposed in 1997 and issued in proposed or interim form since 2001, to implement FDA’s framework for the regulation of HCT/Ps.

As will be readily recognized, there are many advantages to a unified comprehensive regulatory framework for these products. The risk-based approach is tiered, i.e., stratified, to provide the appropriate type and level of regulation based on a product’s characteristics, with a platform of minimal requirements for all cells and tissues, and additional requirements where necessary for product safety and effectiveness.

Clear, enforceable requirements will protect the industry as well as the products and help assure the continued availability of products deemed medically necessary. Predictable regulatory requirements support innovation in technology and the industry and minimize elements of uncertainty in the product-development process.

Finally, reducing the risks of communicable-disease transmission through HCT/Ps will result in improved product safety, improved outcomes for patients, and reduction in health-care costs associated with treating complications from use of contaminated products, all helping to maintain the public confidence.

However, certain challenges still lie ahead, as articulated at the February 1 Dallas Conference by the staff of the Office of Cellular, Tissue, and Gene Therapies in FDA’s Center for Biologics Evaluation and Research.

Among others, reliance on existing statutory authority limits the Agency’s ability to address tissue quality and functionality, and efficient oversight of hospital-based treatments is a continuing problem. In addition, the Agency has not yet finalized its proposed rules regarding reproductive tissue.

Next steps and priorities in moving forward, as viewed by FDA, include, among others: measures to rapidly detect, analyze, and respond to adverse reactions relating to communicable-disease transmission; providing outreach, training, and guidance on implementation of the rule; defining licensure criteria for hematopoietic stem cells; and collaboration with the international community to enhance the safety of these products.

Future guidance documents can be anticipated to help the industry apply the HCT/P regulations to specific product classes or applications.

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