The United States and European Union Tighten Regulations

Robert Brady, Linda Horton, and Ellen Chung

Not many people think of the human body as a source for components of medical products used to treat diseases and conditions. Yet increasingly, medicines and medical devices are being developed from blood, cells, skin, bone marrow, and other more complex human tissues.

In May of this year, the U.S. Food and Drug Administration (FDA) implemented a comprehensive regulatory program for a wide range of tissues and cells—from basic human tissues, such as bone and skin, to more complex cells and cell components, such as umbilical cord blood cells, pancreatic islets, and leukocytes. The regulations also capture novel therapeutic uses made possible by rapid advances in technology, such as using engineered cells to treat cancer, Parkinson's disease, and Alzheimer's disease.

Now that the FDA has finalized mechanisms to regulate these products, and the European Union has announced a key step in its analogous regulatory framework, the world's leading regulators are beginning to catch up with the leading biotechnology companies, which are close to product commercialization. However, important issues remain unanswered as the FDA and its counterparts implement tissue regulations. How can the research community and industry develop products that save lives and reduce suffering, and at the same time, how can regulators protect public health and ensure ethical practices? Can a balance be struck without regulatory overkill? How will tissue regulations be harmonized between countries?

US regulation of human tissue
Until recently, the US regulatory scheme for human cell, tissue, and cellular and tissue-based products (HCT/Ps) largely was limited to human blood and basic tissues (including bone, skin, ligaments, tendons, and corneas) intended for homologous use—referring to their normal functions in the body. Examples include using bone fragments to treat orthopedic injuries or transplanting corneas to restore sight (1).

The FDA strictly regulated blood and blood products for decades, and have allowed the transplanting of tissue since the 1990s. However, what was lacking was an overall regulatory framework for commercial tissue products. Without uniform FDA regulation, some marketed tissue products were approved case-by-case. But in 1997, the Clinton administration announced a risk-based framework for tissues.

Eight years later, this process nears fruition. Effective 25 May 2005, the FDA finalized the last components of its comprehensive regulatory framework for HCT/Ps intended for implantation (2). Three sets of tissue standards were established: registration of establishments that remove, process, store, label, package, or distribute HCT/Ps, or that screen donors or donor samples for communicable diseases; standards for donor screening and sample testing; and good tissue practices ensuring the proper handling and manufacturing of HCT/Ps.

Although FDA continues to regulate basic tissues for basic functions, the scope of the new regulations is much broader. The framework now addresses highly engineered tissues intended for purposes other than their normal functions. To accommodate these various HCT/Ps and therapeutic uses, the FDA created a tiered regulatory structure in which the degree of communicable disease risk determines the degree of regulation.

Where risk of communicable disease transmission is minimal, HCT/Ps are exempt from regulation. On the other hand, tissues that pose more than a minimal risk of communicable disease and are "minimally manipulated" belong to an intermediate-risk category. Although compliance with tissue standards is required, these HCT/Ps can be marketed without premarket approval from the FDA. Examples of minimally manipulated HCT/Ps include stem cells removed and then reimplanted into their donor or a close relative of that donor.

The most stringent regulatory requirements are reserved for HCT/Ps that are more than minimally manipulated, combined with a drug or medical device, and/or implanted into unrelated patients. For such products, FDA not only requires compliance with tissue standards, but also requires that the product receive premarket approval as a drug, biological product, or medical device. Generally, such approval is granted when safety and efficacy are demonstrated through human clinical studies.

Thus, as you move along the spectrum of HCT/Ps—from basic tissue for homologous use to sophisticated and engineered cells intended for novel therapies—the FDA increases the level of regulation.

FDA'S substantial new authority
This extensive federal control is based on the FDA's creative use of an old authority under the Public Health Service Act, aimed at preventing communicable disease transmission. It is not the first time the FDA relied on that provision to regulate items moving through commerce.

However, with the increase of viral infection transmission (e.g., HIV/AIDs and hepatitis C), the tissue regulations gave the agency the chance to use a very general grant of authority (preventing communicable disease transmission) to implement very specific and substantial new enforcement and inspection powers.

For instance, all establishments handling HCT/Ps must track their movement from the donor to the person responsible for implanting the tissue. This could involve multiple players: hospitals, testing facilities, processing labs, and manufacturers.

The FDA also granted itself broad authority to inspect locations that remove, process, store, label, package, test, or distribute HCT/Ps; require notification to the agency of certain imported HCT/Ps; and order entities to recall, retain, destroy, or stop the manufacture or distribution of HCT/ Ps that the FDA believes may pose a communicable disease risk.

As a result, the FDA gave itself significantly more detailed enforcement provisions than were previously implemented. How and to what extent they will be implemented in practice is still to be determined.

Proposed EU Regulation
By April 2006, all EU member countries must enact laws implementing a 2004 directive on donation, procurement, testing, processing, preservation, storage, and distribution of human tissues and cells. In May 2005 the European Commission proposed a regulation to establish a uniform regulatory framework for "advanced therapies"—gene therapy, somatic cell therapy, and human tissue-engineered products (hTEPs)—along with a proposed framework for future requirements for hTEPs (3).

This proposal would give the European Medicines Agency (EMEA) jurisdiction over hTEPs as medicinal products (pharmaceuticals, drugs, biologics). It would create "a single, integrated and tailored framework" for all advanced therapies. Using the EMEA—which relies on committees of member state representatives—sends a clear signal that EU authorities regard hTEPs as products that need centralized handling and stringent regulation. Flexibility is promised, but few details are provided.

The assignment of hTEPs to the EMEA was disappointing to the medical device industry, which hoped for a regulatory approach like the EU medical device system. EU medical device assessments are carried out not by regulators but by various accredited conformity assessment bodies, generally in the private sector. There is no EU medical devices agency.

The Commission says that treating hTEPs as medicines creates legal certainty, bridges a regulatory gap, and thus fosters innovation by clarifying the regulatory rules. The EMEA already evaluates 70% of new medicines entering the EU marketplace and has gained respect for sound decisions through a centralized system that relies on member states' pooled expert resources. Also, intellectual property unique to pharmaceuticals would be available to tissue product innovators—regulatory exclusivity periods, for example.

Manufacturers of therapies such as wound-healing tissue-based products that entered the EU market as medical devices would have three years to obtain EMEA authorizations. One piece of good news is that such products would be exempt from EMEA user fees. Manufacturers that have already jumped through the medical device hoop have a good case for an exemption or at least more time for an EMEA approval.

Harmonization
With the globalization of the biotechnology industry, harmonization of regulatory requirements encourages the development of innovative medical therapies. The US and EU regulators could provide global leadership to achieve a harmonized approach to regulation of human tissue products. But first they must bilaterally harmonize their approaches.

In both the United States and the European Union, HCT/Ps that are removed and then implanted into the same person during the same surgical procedure are treated as low-risk and exempted from regulation. At the opposite end of the spectrum, US and EU regulators agree that products posing a high risk of communicable disease transmission must comply with tissue safety standards as well as undergo costly and time-consuming testing and approval requirements.

In the middle are products subject to tissue standards that, in the United States, will not be subjected to approvals as drugs, biologics, or medical devices. For these products, convergence between the US and EU approaches is important.

The EU hTEP proposal, which has no corresponding middle category, apparently would require the submission of individual premarket applications for nonexempt products. EU lawmakers should give the European Commission or EMEA clear authority to regulate products in this category through stringent class regulations but without individual product applications, in a manner similar to that of the FDA. Such a category would represent a sensible, risk-based approach that prevents overregulation and advances harmonization.

International collaboration and harmonization of regulatory frameworks will be needed precisely because bioengineered tissue products do not fit squarely within existing regulatory frameworks. For instance, can data from animal tissue predict the safety of human tissue products? What analytical testing methods are suited for tissue products? What does effectiveness mean for autologous therapies, in which patient-specific tissues and cells are used rather a common formulation for all patients?

Those are some of the issues that biotechnology companies and regulators will face, and complementary regulations would help ensure uniform and timely commercialization of beneficial tissue therapies.

In sum, human tissue therapies offer tremendous potential to save lives, but they present a host of regulatory issues. Regulators need to fine-tune their requirements based on risk, seek harmonization, and avoid excessive requirements.

This article is adapted and reprinted with permission from the 20 June 2005 issue of Legal Times, © 2005ALM Properties, Inc.

References

1 See, e.g., Food and Drug Administration. Proposed Approach to Regulation of Cellular and Tissue-Based Products (28 February 1997); Web site (external) .

2 Eligibility Determination for Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products. Fed. Regist. 69(101) 2004: 29786–29834; Current Good Tissue Practice for Human Cell, Tissue, and Cellular and Tissue-Based Product Establishment. Fed. Regist. 69(226) 2004: 68612–68688; Human Cells, Tissues, and Cellular and Tissue-Based Products: Donor Screening and Testing, and Related Labeling, Fed. Regist. 70(100) 2005: 29949–29952; Web site (external) .

3 The European Commission, Enterprise and Industry Directorate-General. Consultation Paper on Human Tissue Engineering and Beyond: Proposal for a Community Regulatory Framework on Advanced Therapies. 4 May 2005; Web site (external) (case-sensitive).

Robert Brady is a partner in the Washington D.C. office of Hogan & Hartson, LLP, where he specializes in pharmaceutical, biological/biotechnology product law. Linda Horton is a partner in Hogan & Hartson's Brussels office, where she specializes in pharmaceutical, medical device, animal health, food, and cosmetic product laws in the United States and Europe. Ellen Chung is an associate in the firm's Washington D.C. office.