Since early 2004, several scientific and legal developments have significantly changed the regulatory landscape pertaining to tissue banking for research and transplantation purposes. More legal twists and turns are expected later this year (perhaps as early as this summer) when the U.S. Food and Drug Administration announces the final two rules, in a set of three, that will form a more comprehensive regulatory regime with respect to tissue banking. However, even before these new final regulations are issued, significant changes have already occurred of which health care providers and the health care industry should be aware and to which they should be prepared to comply.
Stem Cell Research
On February 13, 2004, South Korean scientists announced, in an article published in the journal Science, that they had successfully cloned the first human stem cells. This announcement was noteworthy for two reasons. First, the initial cloning of human stem cells represents a step forward in the opportunity to begin the longer journey towards potentially curing countless debilitating illnesses and increases the possibility of new opportunities for cure and treatment by selectively targeting genetic causes. Second, the success of non-U.S. scientists in human cloning and the corresponding lack of substantial progress made by U.S. investigators has lead some commentators to be more vocal in their criticisms of President Bush’s August 2001 Executive Order limiting stem cell research to existing stem cell lines. The Executive Order requires federally funded researchers engaged in stem cell research to conduct research using one of only a few (some of which are fragile and unproductive) stem cell lines in existence at the time of the Executive Order. Critics worry that American researchers will lose their scientific advantage to scientists abroad who are unfettered by such restrictions, and that the federal government is losing an opportunity to regulate stem cell research. This is particularly so since at least one nongovernmental research center has already created its own stem cell lines without federal dollars. Health care providers should be aware of potential opportunities in the private sector to engage in this important research.
More generally, tissue banking, which includes banking stem cells, is also receiving increased industry interest. In 1998, the FDA decided that tissue banks-- private banks and entities often associated with health care providers (such as hospitals)-- which "manufactured" human tissue were not sufficiently regulated.1 Though the initial source of concern derived from situations involving contaminated tissue samples, the FDA’s response was to undertake rulemaking for a more comprehensive regulatory regime governing all aspects of human tissue manufacture, including Registration,2 Good Tissue Practices (GTPs),3 and Donor Suitability4 (the "FDA Tissue System").
Currently, there are six potential sources of regulation of an entity engaged in human tissue banking: first, federal Common Rule human research protections (if the tissue banking is done for research purposes by an institution subject to regulation by the Office of Human Research Protections (OHRP) through an Federal Wide Assurance or other assurance); second, FDA human research protections (if the tissue banking is done for research purposes by an institution subject to the FDA because the entity intends to make submissions to the FDA or is conducting research using an FDA-regulated article); third, federal privacy protections under HIPAA and the privacy regulations promulgated thereunder (if "protected health information" is disclosed by a covered entity); fourth, the FDA Tissue System (once the three-part regulatory scheme goes into effect); fifth, the National Organ Transplantation Act (NOTA) that prohibits the buying and selling of tissue but may permit other commercial exchanges involving tissue; and sixth, state law (for example, buying and selling tissues, state privacy regulations, and non-preempted state regulation of stem cells).
Despite these six overlapping regulatory frameworks, important questions remain. First, not all tissue banks may, in fact, be regulated. Private tissue banks may not be engaged in research or transplantation (and, therefore, outside OHRP and FDA research rules), but may only store the tissues and transport them to other health care facilities at investigator or physician request. Such tissue banks must determine whether they fall within the broad definition of a "manufacturer" of human tissue under the FDA Tissue System. In addition, a hospital that banks tissues solely for use at its own facility may also fall outside the ambit of the regulations. However, despite falling beyond the regulations, entities may come to see some aspects of the regulations as "best practices" even if not required.
Second, though FDA and OHRP human subject protections and federal and state privacy regulations speak to principles not unique to human tissue, the harvesting and banking of human tissue often involves new actors and institutions, raising thorny questions of IRB and privacy issue jurisdiction and oversight, the context of "informed" consent for tissue donors, licensing and intellectual property issues, and state and federal prohibitions on the buying and selling of tissue. Institutions, as part of their overall compliance plans, should revisit their IRB policies and SOPs to ensure that they are equipped to address the particular issues associated with tissue banking.
Third, almost all tissue banking relates to "future unspecified research"-- within the meaning of HIPAA-- raising issues with respect to the adequacy of HIPAA authorizations, which require specific protections in the event of authorizations for such open-ended disclosures. Institutions wishing to create databanks or donate to databanks should reexamine their existing authorizations to see if they are adequate for the purpose. While this process may involve a set of complex discussions and procedures, it can be implemented successfully with proper advance planning. Failure to examine these procedures consistently with regulatory standards, patient expectation, and industry practice may jeopardize research conducted on tissue donated to that tissue bank.
Fourth, given the OIG’s strong statement in Spring 2003 relating to financial relationships between health care providers and industry, health care institutions and private tissue banks (and related intermediaries) should closely examine their relationships and thoroughly document them consistent with applicable legal and regulatory guidance such as the OIG’s Compliance Program Guidance for Pharmaceutical Manufacturers issued in April 2003.
Lastly, the FDA Tissue System is not yet complete. Because of a series of delays in the finalization of rules for the last two rules (GTPs and Donor Suitability), there is understandable confusion about Registration, GTP and Suitability obligations. Initially, in January 2001, the FDA announced its Registration Final Rule for establishments that manufacture human tissue (referred to in the regulation as HCT/P)5, but included two distinct effective dates. For HCT/P articles then regulated by the FDA pursuant to Section 361 of the PHS (essentially, biologics), the effective date for the Registration final rule, the first and only finalized rule of the FDA Tissue System, was April 2001. However, for all other establishments manufacturing HCT/Ps, the effective date was January 2003, intended to coincide with the announcement of the Final Rules for GTPs and Suitability. When the two Final Rules were deferred until January 2004, registration for remaining HCT/P establishments was also deferred. In January 2004, however, the FDA announced that it was not quite finished with the GTP and Suitability rules. Rather than delay registration any longer for HCT/P entities, however, it announced that it would require all remaining HCT/P establishments to register by March 29, 2004. It granted this additional time because it understood that HCT/P establishments may have been expecting the Registration rule effective date to once again tag-along with the outstanding Final Rules. Thus, as of March 29, 2004, all HCT/P establishments had to register and list their HCT/Ps with the FDA. Establishments "manufacturing" articles falling within the definition of HCT/Ps should be sure that they have complied with the registration and listing requirements. In addition, the two remaining Final Rules are expected in the coming months.
As science focuses more intensely on the genetic roots of many illnesses, and as medicine is increasingly equipped to deal with the unwanted risk factors associated with tissue transplantation (such as rejection, contamination, shortages, etc.), tissue banking will be ever more important. Though tissue and organ banks have existed for years, the regulatory framework in which they operate is undergoing fundamental change, and new types of health care institutions are playing a role in the harvesting, processing, storage, transport and ultimate disposition of human tissue. Virtually every player in the health care community must be prepared not only for human tissue to occupy an increasing space in treatment and research, but also to comply with the complex array of regulations and regulators who control these transactions.
1 The definition of manufacture does not carry its customary meaning for the purposes of the FDA regulations. An entity manufactures human tissue and is, therefore, subject to the FDA’s comprehensive scheme, if it participates in "any or all steps in the recovery, processing, storage, labeling, packaging, distribution, of any human cell or tissue, and the screening or testing of the cell or tissue donor." 21 CFR § 1271.3(e).
2 The proposed rule was issued in 1998, 63 FR 26744 (1998), and was finalized in 2001. 66 FR 5447 (2001). However, not all HCT/P banks are currently required to register. The FDA required certain entities, those already regulated by the FDA pursuant to Section 351 of PHS, to register after the rule was finalized in 2001 (such entities were required to register by April 4, 2001). The remaining HCT/P banks that fall within the ambit of the FDA Tissue System (but were not then already regulated by the FDA pursuant to Section 351 of PHS) were to register when the second two rules became final (see, fn. three and four).
3 The proposed rule was issued in 2000. 66 FR 1508 (2000). The initial effective date was January 2001 and then January 2003, but it had been postponed until January 2004. 68 FR 2689 (2003). The final rule was not announced in January 2004, but the FDA declined to formally extend the effective date. Instead, the FDA indicated that it expected to announce the Final Rule shortly.
4 The proposed rule was issued in 1999. 64 FR 52696 (1999). The initial effective date was January 2001 and then January 2003, but it had been postponed until January 2004. 68 FR 2689 (2003). The final rule was not announced in January 2004, but the FDA declined to formally extend the effective date. Instead, the FDA indicated that it expected to announce the Final Rule shortly.
5 HCT/P’s refers to "human cells, tissues, and cellular and tissue-based products." 21 CFR 1271.1(a).