Bio-Science Law Review

A.J. BAEYENS European Organisation for Research and Treatment of Cancer Data Center (EORTC), Brussels, Belgium

R. HAKIMIAN National Cancer Institute, Cancer Diagnosis Program, Bethesda, Maryland, USA*

R. AAMODT Chief, Resources Development Branch, Cancer Diagnosis Program, National Cancer Institute, Bethesda, Maryland, USA

A. SPATZ Department of Pathology, Institut Gustave-Roussy, Villejuif, France

The authors wrote this article in the context of a joint Working Group on Tissue Banks and Repositories from the National Cancer Institute, National Institutes of Health, and the EORTC

Introduction

Recent progress in the field of molecular biology, genetics, and pathology presents extraordinary research opportunities for the better understanding of diseases, and for subsequent prevention and treatment. Much of this progress would have been impossible without access to human biological specimens and associated patient data.

Addressing the ethical and legal issues related to use of human biological samples in research has become a vital element of a successful research project. During this period of scientific progress and promise, the rights of individuals to exercise autonomy and control in the informed consent process have been reinforced in many countries. The number of regional and national regulations, most notably in the area of privacy and confidentiality, has similarly multiplied.

Tissue research is currently regulated though by an amalgam of differing and occasionally conflicting laws and policies. In Europe, regional laws, national laws and local laws apply, and in the United States federal and state laws are in force. In Europe, public health and the conduct of medical research has traditionally been a matter for national and even local laws. Lately, however, there has been a clear trend towards broader attempts to regulate in this area, with regional and even international efforts. ¹ The debate surrounding these issues is influenced by cultural and religious sensitivities, reflected in jurisprudence, local laws and policy decisions. In the United States, federal law has traditionally governed the conduct of research, but state laws have proliferated in the last decade, with many specialised laws enacted in the areas of health information privacy and genetic testing.

Identifying the trends in the United States and Europe is important since progress in disease research depends on collaborative efforts. Scientific success may require international collaboration, sharing both expertise and research material.

Sources of Law

The United States

Federal law

In the United States, federal law for human subjects research applies to research using human biological materials. When federal law applies, the research must comply with the ‘Federal Policy for the Protection of Human Subjects (Basic Department of Health and Human Services Policy for Protection of Human Research Subjects)’, 45 CFR 46 Subpart A. This code section is also known as the ‘Common Rule’ as it was adopted commonly by 17 entities of the federal government. The federal law is based on the principles of the Belmont Report² that identified three main ethical principles for the conduct of research: respect for persons, beneficence, and justice.

To comply with the Common Rule, proposed research must undergo independent scientific and ethical review (the protocol must be reviewed by an Institutional Review Board, ‘IRB’). Informed consent from participants (tissue donors) must be obtained or waived, unless an exemption applies. Tissue that does not include identifying information, and also tissue that is stored, or previously archived, may be exempt from the requirements of IRB review and informed consent.

The Common Rule permits a waiver of the requirement to obtain informed consent for research when the risk to subjects is minimal, and other criteria are met. In addition, the Common Rule permits expedited review for some research where there is no more than minimal risk posed to subjects. IRBs often determined that tissue research presented no more than minimal risk to participants, and was thus eligible for waiver of the requirement of informed consent, or for expedited IRB review. ³

According to federal regulations, oversight of federal policy for human subject protection in research is delegated to the Office for Human Research Protections (OHRP) of the Department of Health and Human Services. The OHRP monitors compliance with federal regulations for research conducted or supported by the Department of Health and Human Services. The OHRP monitors the system of human subjects research through administration of Federal Wide Assurances indicating an institution’s commitment to comply with federal regulations.

The OHRP issued guidance on the topic of human tissue and repositories in 1997. ⁴ According to this guidance, IRBs are to set the conditions under which data and specimens may be shared, and the circumstances where written consent should be obtained. Informed consent is to be as specific as possiblewith regard to the nature and purposes of the research, and use of exculpatory language through which subjects are made to waive (or appear to waive) any legal rights is prohibited. The OHRP has indicated its intention to update these standards for tissue research. ⁵

For research on products regulated by the US federal Food and Drug Administration, ⁶ researchers conducting human subjects research (including tissue research) must comply with the FDA regulations found at 21CFR50 and 21CFR56 for informed consent and IRB review. In addition to differences in definitions and scope, FDA regulations do not include a mechanism to exempt research on certain types of tissue as permitted under the Common Rule. ⁷

Finally, broad new standards limiting uses and disclosures of certain types of personal health information have recently been enacted in the United States, with significant potential impact on research. The new federal privacy rule, drafted by the Department of Health and Human Services as part of the mandate created by the Health Insurance Portability and Accountability Act of 1996, addresses use of health information by healthcare providers and insurers, and others who transmit information electronically. The use of protected health information by researchers is also regulated, although the rule excludes from its direct purview regulation of human biological materials. Nevertheless, associated patient data, if not de-identified according to the stringent standards set forth in the regulation, is subject to limits on uses and releases. The rule creates a new type of consent, called an authorisation, for uses and releases of identified patient information. Valid authorisations must include proscribed elements, and must contemplate a specific use. ⁸ This new requirement is separate from the requirements of obtaining informed consent for research purposes. ⁹ While the new rule has not yet been implemented (the implementation date is 14 April 2003), the law is drafted broadly and is expected to cause significant impediments to the conduct of research.

State law

In the United States, research is regulated at the state level as well as the federal level. Therefore, tissue researchers must comply with the requirements of state law, in addition to the federal laws mentioned in the previous section.

Several states have laws requiring researchers to comply with the Common Rule, whether the research is funded by a private commercial sponsor or if federal funds are used. ¹⁰ These states extend the scope of the Common Rule to all human subjects research conducted within their borders, compelling IRB review and obtaining informed consent from participants.

Other states, California, for example, require that researchers obtain informed consent from human subjects under most circumstances and also for the use of tissue in research projects. ¹¹ Still other states have enacted laws creating a patients’ bill of rights, some of which include provisions requiring specific elements of informed consent for patients who participate in research studies.

Many states have enacted state privacy laws that pre-date the new federal privacy law. These laws on general privacy and health information privacy may affect releases of patient data associated with specimens. When states have defined health information in a way that includes specimens, additional protections apply.

While the informed consent form permits researchers to use a tissue specimen, the question of ownership of the sample and the associated data remains murky. The issue has been considered at the ethical, intellectual, and practical level, but few legal cases have been heard in most jurisdictions. In the single published case, Moore v University of California Board of Regents et al., ¹² the Supreme Court of California held that an individual did not have ownership rights in his excised cells. The court did uphold the right of individuals to be informed that they are participating in a research study, and that they are contributing tissue for research purposes, and the right to be given the opportunity to consent or to refuse participation in the research. This case is only binding in the state of California, and the issue of ownership remains in dispute by scholars, jurists, and public policy analysts. Some groups openly disagreed with the findings of the Moore court, and four states¹³ have laws ontheir books declaring genetic information to be the personal property of the individual.

Equally important for tissue researchers are the myriad state laws establishing certain permitted uses and procedures for the conduct of genetic tests and research. In recent years, some of the 50 states have enacted statutes restricting tissue testing and use, particularly when the tests involve genetic testing and genetic information.

Unlike the federal statute which does not protect genetic information specially, but rather addresses ‘medical information’, some states have focused on the nature of the information, and often on whether ‘genetic’ information is acquired and used. The concern of the states has been to protect individuals from ‘genetic discrimination’ in obtaining insurance and employment. Clearly, an understanding of these laws revolves around a careful examination of the definition of ‘genetic test’ or ‘genetic information’ as defined by statute. Many of these laws impose limits on the ability of third parties to retain genetic information, or impose duties that individuals be notified when their genetic information is used.

In the United States, new state laws and new federal privacy legislation are expected to increase the regulatory burden on researchers, and require new efforts at harmonisation, if health and medical research is to continue and succeed.

Europe

European law and regulations

In Europe, the use of tissue for research purposes was not explicitly addressed as a component of human subject protection for most of the last century. Legal protection for human subjects in research derives chiefly from the national clinical trials laws that must implement the European Union Directive on Clinical Trials by 1 May 2003 and should come in to force by 1 May 2004. ¹⁴

An important source of European law is the European regulation related to data protection. The use and transfer of patient data associated with tissue samples is covered by the EU Data Protection Directive, ¹⁵ which ensures the protection of individuals with regard to the processing of personal data¹⁶ (including sensitive data¹⁷) and the free movement of such data. According to the Data Protection Directive, Member States are obligated to protect the fundamental rights and freedoms of natural persons, and especially their right to privacy with respect to the processing of ‘personal data’ and ‘sensitive data’.

Data-processing systems are designed to contribute to economic and social progress, trade expansion and the protection of individuals. The aim of the Directive is therefore to facilitate collaboration between Member States by ensuring the free movement of personal data from one Member State to another, while guaranteeing the safeguard of fundamental rights of individuals.

On a broader level than the European Union, namely the Council of Europe, ¹⁸ which includes many members not currently part of the EU, reference must be made to the Convention on Human Rights and Biomedicine (the so-called Convention of Oviedo) reflecting the principle of individual rights and self-determination in the area of medical research, genetic research, and informed consent. Since 4 April 1997 this Convention had been open for signature and ratification by the 43 Member States. It entered into force on 1 December 1999, and is binding on those countries that ratified it. ¹⁹

One Article of the Convention considers the principle of individual rights and self-determination in the light of tissue research and mandates an appropriate information and consent procedure for the secondary use of tissue. With regard to this provision, a proposal for an instrument on the use of archived human biological materials in biomedical research was made available to the public for comments in autumn 2002. The guidelines were entitled ‘Draft instrument on the use of archived human biological materials in biomedical research’, proposed by the Council of Europe, Steering Committee on Bioethics. The main principles of this proposal are: the subject should give consent, approval of the research must be obtained from the competent authority (ethics committee or state authority), non-identifiable human biological materials are still subject to the provisions of the guidelines, and transfer to another country is only possible if the recipient country has a regulation offering a similar level of protection as the sending country.

In the area of protection of the rights and dignity of individuals, the Declaration of Helsinki champions broad principles for protection of human subjects of medical research, and the Preamble of the 2000 Revision makes reference to ‘identifiable human material or identifiable data’. However, it still is unclear how the principles of the Declaration of Helsinki apply to tissue research.

Besides the Declaration of Helsinki, other guidelines have been promulgated that are pertinent to medical research and tissue research. Many national organisations²⁰ in Europe have adopted the guidelines recommended by CIOMS²¹ and the World Health Organization to respond to the requests from groups demanding more stringent regulation of the use of tissue and other bodily materials.

Laws and regulations at a national level

At the moment, there are no specific regulations addressing all the relevant issues related to the use of tissue in research specifically. However, it must be mentioned that several countries are preparing future regulations. The Netherlands, France, and the United Kingdom are all in the process of drafting rules for use of tissue.

Besides the national data protection laws in force in almost all Member States as a result of the implementation of the EU Data Protection Directive, several countries do have some provisions in other laws that relate to some of the legal and ethical issues of tissue research.

Three different approaches can be distinguished. ²² In Denmark, the legal framework for tissue research and the ethical and legal issues related thereto is to be found in the data protection law. Patients must give their informed consent for the secondary use of their tissue. Further, each new research project requires an EC approval.

In other countries and regions, notably Sweden, the legal framework is found in laws and policies governing biobanks (human tissue and data repositories), where the use of tissue in research (especially for commercial purposes) is very restricted. Here too, informed consent and EC approval are required. In the case of secondary use of tissue, when samples are to be used for a purpose other than that for which it has been stored, a new consent will normally be required.²³. If the new purpose is research, the EC may agree to exceptions from the consent requirement. ²⁴

In other countries, the civil code contains some provisions related to the protection of human biological samples or parts of the human body as a matter of concern of informed consent, privacy and respect for the human dignity. Besides the provisions in Code Pénal, Code de la Santé Publique, the French Civil Code also contains some specific chapters with specific provisions aimed at protecting the human body and its parts (Articles 16, 16–1 to 16–9, ‘Chapter II Du respect du corps humain, Livre premier – Des personnes, Code Civil’; Articles 16–10 to 16–12, ‘Chapter III De l’étude génétique des caractéristiques d’une personne, Code Civil’). In The Netherlands, consent can be waived only if the human biological samples have been anonymised. Article 467 of the Dutch Civil Code states that anonymous cells and parts removed from the human body can be used for medical statistics or other research purposes in as far as the patient, from whom the human biological material is derived, has made no objection against this research and in as far as this research is performed with the utmost care. Research with anonymous cells and parts of the body must be understood as research whereby it is guaranteed that the cells and parts used in the research as well as its results are not retraceable to the individual concerned. France introduced a license system for institutions to maintain tissue banks, and an authorisation system to import and export tissues outside France. ²⁵

In general, in Europe there has been a backlash against the perceived tendency of modern medicine to reduce the human body to exploitable material²⁶

Besides the restriction of commercial aspects, some countries protect as a paramount value individual rights and autonomy. In France, for example, 1994 bio-ethics laws apply. ²⁷ France has been at the forefront of new legislation in the creation of statutes regulating use and control of the human body and its parts. An analysis of the French bio-ethics laws has revealed an attempt to guarantee the dignity of the person. ²⁸

A similar approach can be found in one of the provisions of the Charter of Fundamental Rights of the European Union prohibiting any profit from the human body or any of its parts as such. ²⁹

Not only legislators have been active in addressing some of the legal and ethical issues. Some professional organisations and consumer representatives have developed policies and recommendations, and various ethics guidelines have been adopted. ³⁰ While not legally binding, they have served as the basis on which many countries have established their national laws and policies.

Prior to the well-publicised scandals at the Alder Hey pathology unit, with allegations that organs and tissue were taken from cadavers for research uses without consent, the practice in the United Kingdom as reflected in the Human Tissue Act 1961 permitted ‘tacit consent’. According to the Act, individuals were given the opportunity to object to the use of their tissue after death; however, absent written objection, consent was presumed. ³¹ Although the pediatrician implicated in the scandal was exonerated from the most egregious allegations (namely, dishonesty and unprofessional behaviour), public criticism of the practices is expected to result in increased oversight and restrictions on the ability of researchers to obtain and utilise tissue for research purposes. The Medical Research Council in England has reviewed tissue practices in the United Kingdom following the serious allegations of misuse of tissue for research purposes in the infamous incidents summarised in the Redfern Report.

Discussion

A review of the various laws and customs in different countries in Europe reveals that despite adherence to broad general principles regarding use of the human body and its materials, national laws and customs still prevail. Researchers in the United States face a parallel predicament since the states have enacted a range of statutes that utilize different standards and mechanisms of protection.

Court decisions and new regulations covering tissue research must be framed in a larger, general context of society, and the particular concerns regarding religious precepts, social values, and commercialisation. The countries of Europe reflect a range of conduct based on fundamental cultural and social values. Nevertheless, the general trend is towards increasing the individual rights of citizens, and especially the right of privacy. These conflicting trends often present barriers and hindrances to the effective conduct of research that relies on timely collaboration, and the ability to transfer data and material.

Appropriate handling of the ethical and legal issues related to use of human biological samples in research has become a vital element to the successful completion of a research project.

In the last decade, the field of tissue research has received increased attention by European legislators and politicians, and in general, where national laws and policies have been implemented, use, transfer, and retention of tissue for research have been restricted, with new national standards imposed for obtaining informed consent. Thus, in the last several years, where regulation has occurred, it has been more restrictive than the laws in the United States. This reflects an interesting dynamic with certain implications for future research, particularly international collaborations.

Rules are becoming more stringent, however, with different standards and provisions from state to state. Thus, researchers wishing to obtain samples from various Member States and non-Member States encounter varying rules pertaining to informed consent, retention of samples, retention of data, cross-border transfers of samples and data, and so on. Only harmonisation of the rules at national level or European Union level will facilitate smooth collaboration within Europe and between Europe and the United States.

Conclusion

It is clear from the preceding sections that there is a desire to retain some element of local control over protection for human subjects in research and over their donated tissue. With the tremendous variation in law, it is equally clear that research will be hindered without harmonisation of some of the most important practices affecting tissue transfer and use.

Until the many conflicts between various jurisdictions are resolved, researchers should proceed cautiously.

Perhaps it would be useful to institute a system for the transfer of tissue comparable to the model of data protection used in the EU Data Protection Directive. Such a scheme should recognise the vital importance of tissue to research by enabling the flow of data and tissue, while concomitantly acknowledging the privacy rights of individuals and affording basic trans-national protections. Researchers have clear incentives to co-operate in this process, while regulators should be satisfied that human subjects are protected from the real risks of this type of research: loss of privacy and related harms.

In order to implement such a framework, specific issues, such as consent, transfer of data and tissue, commercialisation and rights of individuals, intellectual property rights and ethical and regulatory review need to be agreed upon and clearly defined. Such a framework is long overdue.

*Currently the Regulatory Counsel for the Association of American Medical Colleges (AAMC), Division of Biomedical and Health Sciences Research (Rhakimian@aamc.org).

1. H. Nys, ‘Patients’ rights in the context of internationalization of care and cross-border care’, 14th World Congress on Medical Law, 11–15 August 2002, Book of Proceedings I, at 10.

2. The Belmont Report, Office of the Secretary, Ethical Principles and Guidelines for the Protection of Human Subjects of Research, The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (18 April 1979).

3. §46.110 Expedited review procedures for certain kinds of research involving no more than minimal risk, and for minor changes in approved research. (A) Research activities that (1) present no more than minimal risk to human subjects, and (2) involve only procedures listed in one or more of the following categories, may be reviewed by the IRB through the expedited review procedure authorized by 45 CFR 46.110 and 21 CFR 56.110.

4. Issues to Consider in the Research Use of Stored Data or Tissues, 7 November 1997, Guidance Topic: Office for Protection from Research Risks, Department of Health and Human Services.

5. Significantly, the OHRP has articulated a new position for research using de-identified stem cells that should apply to research on tissue as well. The new OHRP guidance states that research on de-identified stem cells will not be considered human subjects research and hence, not subject to the Common Rule, if the identity of the donor cannot be ‘readily ascertained’. The OHRP has indicated that if the recipient investigator does not have access to the identifiable information, and the holder of the identifiable information offers written assurance that the information will not be conveyed to the researcher, then research on the de-identified information will not be considered human subjects research. Guidance for Investigators and Institutional Review Boards Regarding Research Involving Human Embryonic Stem Cells, Germ Cells and Stem Cell-Derived Test Articles, date: 19 March 2002. ‘(1) the investigator and research institution do not have access to identifiable private information related to the cell line; and (2) a written agreement is obtained from the holder of the identifiable private information related to the cell line providing that such information will not be released to the investigator under any circumstances. In this case, the research may be considered to not involve human subjects because the identity of the donor(s) could not be “readily ascertained” by the investigator or associated with the cell line. Under such circumstances, an institution or an IRB could determine that IRB review of the research using the cell line was not needed.’ While not explicitly confirmed, the OHRP is expected to apply this policy towards a broad range of human specimens.

6. These sections of the code of federal regulations include mandatory provisions for informed consent and IRB review. The scope of these sections is designed for IRBs that review clinical investigations regulated by the FDA under sections 505(i), 507(d), and 520(g) of the Act, as well as clinical investigations that support applications for research or marketing permits for products regulated by the FDA, including food and colour additives, drugs for human use, medical devices for human use, biological products for human use, and electronic products.

7. See 45 CFR 46.101 and 21 CFR 56.104 for comparison.

8. The new rule curtails uses of blanket authorisations in favour of authorisations that are both ‘specific’ and ‘meaningful’.

9. The federal privacy regulation also institutes new rules to track disclosures of information, limit releases to the ‘minimum necessary’, and otherwise utilise certain health information according to the new mandates.

10. New York, Maryland, Virginia.

11. Several states, like Washington, New Jersey, and Illinois, have additional requirements for informed consent in research or treatment.

12. 51 Cal. 3d 120; 793 P.2d 479 (1990).

13. Colorado, Florida, Georgia, Louisiana.

14. European Directive on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use, EC 2001/20, L 121, 01/05/2001 P. 0034–0044.

15. Directive 95/46/EC of the European Parliament and of the Council of 24 October 1995 on the protection of individuals with regard to the processing of personal data and on the free movement of such data, EC 95/46, L 281, 23/11/1995 P. 0031 – 0050.

16. In Article 2(a) of Directive 95/46 personal data is defined as ‘any information relating to an identified or identifiable natural; an identifiable person is one who can be identified, directly or indirectly, in particular by an identification number or to one or more factors specific to his physical, psychological, mental, economic, cultural or societal identity person’.

17. Data as referred to in Point 1 of Article 8 of Directive 95/46: personal data revealing racial or ethnic origin, political opinions, religious or philosophical beliefs, trade-union membership, and the processing of data concerning health or sex life.

18. The Council of Europe consists of 43 countries and resulted from The Hague Congress, May 1948, where a series of resolutions was adopted, calling, among other things, for the creation of an economic and political union to guarantee security, economic independence and social progress, the establishment of a consultative assembly elected by national parliaments, the drafting of a European charter of human rights, and the setting up of a court to enforce its decisions.

19. On 17 October 2002 the following countries had signed the Convention: Bulgaria, Croatia, Cyprus, the Czech Republic, Denmark, Estonia, Finland, France, Georgia, Greece, Hungary, Iceland, Italy, Latvia, Lithuania (entry into force on 1 February 2003), Luxembourg, Moldova (entry into force 1 March 2003), The Netherlands, Norway, Poland, Portugal, Romania, San Marino, Slovakia, Slovenia, Spain, Sweden, Switzerland, the former Yugoslav Republic of Macedonia, Turkey, Ukraine and the United Kingdom, of which 15 countries (in italics) have ratified it.

20. For a list of the national organisations that are members of CIOMS see the following website: http://www.cioms.ch/frame_current_membership.htm, 20 December 2002.

21. Council for International Organizations of Medical Sciences: these guidelines are binding only for signatories.

22. As the European Union has not yet enacted a uniform European regulation in the area of tissue research, the legal approaches to be considered in each Member State are different. Hence, they are to be found in different legal contexts varying from country to country. See C. Trouet and D. Sprumont, ‘Biobanks: Investigation in Regulation’, Baltic Yearbook of International Law, Volume 2, 2002, 3-19.

23. Act on Biobanks in Health Care Chapter 3, section 5.

24. E. Rynning, ‘The new Swedish Act on biobanks in health care – privacy versus freedom of research revisited’, 14th World Congress on Medical Law, 11–15 August 2002, Book of Proceedings II, at 231.

25. Décret No. 2000-156 du 23 février 2000 relatif à l’importation et à l’exportation d’organes, de tissues et de leurs dérives, de cellules du corps humain, à l’exception des gamètes, et de produits de thérapies génetique et cellulaire, et modifiant le code de la santé publique, Journal Officiel, février 2000, p.3077-3080.

26. See Report from N. Lenoir, ‘Aux frontières de la vie: une éthique biomédicale à la française’, Doc. Fr., Paris 1991, Part II, at 120 and following.

27. These laws are currently under revision.

28. H. Nys and A. Baeyens, ‘De Franse bio-ethiekwetgeving A. De Bescherming van het menselijk lichaam’ (The French bio-ethical laws: protection of the human body), Brussels, Federale Diensten voor Wetenschappelijke, technische en culturele aangelegenheden, 1996, at 3.

29. Article 3.

30. European Society for Human Genetics: Data Storage and DNA Banking for Biomedical Research; European Association of Tissue Banks: EATB General Standards for Tissue Banking, EATB Ethical Code; British Association for Tissue Banking: General Standards for Tissue Banking.

31. In December 1999 an Inquiry Panel was appointed to investigate the removal, retention and disposal of human organs and tissues following post mortem examination at The Royal Liverpool Children’s Hospital and the extent to which the Human Tissue Act 1961 (HTA) had been complied with. This Inquiry resulted in the Redfern Report.

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