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Responsible Research: A Systems Approach to Protecting Research Participants 7 Improving an Evolving National Human Research Participant Protection System The preceding chapters have outlined various steps that can be taken to improve the protection of research participants throughout the research process. Chapter 6 described how protection programs could improve quality and clarify roles within a program to enhance performance. This chapter focuses on the relationship of individual Human Research Participant Protection Programs (HRPPPs) to a larger protection system—one that includes sponsors, regulatory agencies, journal publishers, and policy makers. The intent of this discussion is not to be comprehensive—other groups have assessed the overall system of protections in recent years (ACHRE, 1995; NBAC, 2001b; OIG 1998a,b,c,d,e, 2000a,b,c)—but rather to highlight issues that should be recognized and addressed to improve the functioning of the protection system as a whole. In particular, this final chapter discusses the need for independent advice to be provided from the public to the federal policy makers responsible for oversight of the protection system. It also discusses the requirement for a publicly accessible clinical trials registry for those interested in considering participation. Several emerging and evolving areas of policy directly related to human research are then considered, including discussions regarding how the developing debate over patient privacy might affect protection programs in future years, the role of scientific publishers in responsibly communicating research results, and considerations relevant to research to counter bioterrorism.
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Responsible Research: A Systems Approach to Protecting Research Participants THE NEED FOR BETTER ADVICE AND GUIDANCE AT THE FEDERAL LEVEL Complexity, opacity, and contradiction abound in interpretations of the rules and regulations that apply to human research; these confound clear communication between agencies and institutions. Federal regulations are complex and subject to broad interpretation. Although the language of the Common Rule1 deserves a careful and comprehensive reassessment for clarity and relevancy, revising it would be time consuming and difficult, because each signatory agency must agree to the changes. Eventually, Congress will need to take the necessary steps to broaden and strengthen the federal oversight system and to modify the Common Rule where needed. In the interim, however, several steps can be taken to promote its uniform interpretation and clarify its intent. The committee applauds the emphasis of the Office for Human Research Protections (OHRP) on “protection without over-reaction” and the increased emphasis on providing education and engaging in discussion. However, agencies such as OHRP and the Food and Drug Administration (FDA) should do more to clarify the existing regulations and to provide illustrative guidance to institutions. This could occur through a number of approaches: agencies (and perhaps the accreditation bodies) could place this information on the Web, conduct workshops, visit institutions to provide education, begin the process of developing best practices through case studies (see Recommendation 3.8), and compile and disseminate examples of acceptable and unacceptable scenarios. Clear guidance from the funding agencies and recognition that the situations that face research organizations are more alike than different would help dissipate the self-protective, over-reactive climate found in many research organizations today. Because it is not uncommon for multiple points of contact to occur between agencies and research organizations, it is even more important that readily accessible information is available to research organizations and that their staff members make frequent use of it. A body such as the Federal Demonstration Partnership2 could assess the effectiveness of the communication and interaction between the relevant oversight and funding agencies and the academic research organizations. 1 45 CFR 46, Subpart A. 2 The Federal Demonstration Partnership was convened by the Government-University-Industry Research Roundtable to provide a forum where universities, research institutions, and federal representatives come together to assess university-government research collaborations. See www.fdp3.org.
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Responsible Research: A Systems Approach to Protecting Research Participants Independent Advice Recommendation 7.1: Congress should authorize and appropriate funding for a standing independent, multidisciplinary, nonpartisan expert Committee on Human Research Participant Protections whose membership would include the perspective of the research participant. Before the creation of OHRP in June 2000, the Office for Protection from Research Risks (OPRR) existed within the National Institutes of Health (NIH). Concerns were raised in a document commissioned by the then-Department of Health and Human Services (DHHS) Assistant Secretary for Health regarding the propriety of OPRR’s location within NIH, with the majority of NIH-funded research subject to OPRR oversight (OPRR Review Panel, 1999). A determination was made to rename OPRR and move it to DHHS’ Office of Public Health and Science (OPHS) in order to eliminate any concerns regarding the appearance of potential impropriety or conflict of interest. It also was decided that OHRP should receive independent advice from the communities it serves. Thus, DHHS created the National Human Research Protections Advisory Committee (NHRPAC) to provide expert advice and recommendations to the Secretary of DHHS, the Director of OHRP, and other departmental officials on a broad range of issues and topics pertaining to or associated with the protection of human research subjects.3 NHRPAC’s charter reads in part as follows: The Committee will provide advice on the development and management of collaborations and communications between HHS and its operating and staff divisions and other pertinent elements of the federal government; the biomedical, academic, and research communities; non-governmental entities; and other organizations as necessary to further the interests of the human subjects protection enterprise. The Committee will provide counsel on opportunities to improve public awareness of the function and importance of human subjects protection activities (DHHS, 2001b). In order for NHRPAC to achieve these goals, it is crucial that it be sufficiently independent of the regulatory agency that it advises. NHRPAC currently is administered by OHRP, with a budget controlled by the OHRP Director. However, for NHRPAC to receive candid and constructive input from researchers, research organizations, and participants and to provide 3 As this report went to press, it was reported that DHHS had disbanded NHRPAC (Weiss, 2002; Otto, 2002c). This underscores the need for Congressional direction in the establishment of a nonpartisan, independent advisory committee focused on the policy issues relevant to ensuring the protection of research participants, as discussed in this chapter.
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Responsible Research: A Systems Approach to Protecting Research Participants advice to other “pertinent elements of the federal government” as well as nongovernment entities, its position within the DHHS bureaucracy should be modified. In its capacity as an advisory committee, NHRPAC should be established as an independent entity within OPHS under the aegis of the DHHS Assistant Secretary of Health. To ensure the public’s trust, it should have its own budget and be impartial and free from the appearance or existence of impropriety or undue influence.Any perception on behalf of the public or other federal agencies that NHRPAC is not an independent entity free to identify and examine concerns regarding the protection of research participants could cast doubt on its credibility. Assuring the ability of NHRPAC to provide independent advice to the federal government is a necessary first step to strengthening the voice of public stakeholders in the development and evolution of human research policy. To most effectively ensure that OHRP and the entire protection system receive independent advice, Congress should establish a nonpartisan, multidisciplinary, independent body of experts that could operate with total independence and provide balanced representation of the perspectives of participants, scholars in a range of scientific disciplines and bioethics, and IRB experts. The Institute for Laboratory Animal Research (ILAR) provides an example of a successful model for providing such advice. ILAR is a standing committee in the National Research Council at the National Academies that provides independent, expert advice and guidance on the care and use of laboratory and other animals in research. It also provides guidance on relevant accreditation standards.4 A similar independent body could be useful to the ongoing development of protections for research participants. The potential for conflicts in the current configuration of OHRP and NHRPAC justifies this proposal of an alternative model, which would provide ongoing advice and guidance on the scientific (clinical and social/ behavioral), technological, and ethical issues related to participant protection, including quality improvement, accreditation standards, conflict of interest, resource needs, and system performance changes over time at the federal oversight and organizational levels. THE NEED FOR PUBLIC INFORMATION REGARDING ONGOING CLINICAL RESEARCH According to central tenets of ethical research, the community of individuals that stands to benefit or be harmed by research should 1) have an 4 The Guide for the Care and Use of Laboratory Animals (NRC, 1996) is produced and updated by ILAR and is heavily utilized by the Association for Assessment and Accreditation of Laboratory Animal Care in its accreditation program.
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Responsible Research: A Systems Approach to Protecting Research Participants opportunity to comment on the research design and operation; 2) have an opportunity to participate in the research; 3) reasonably expect that the research will not involve unnecessary duplication; and 4) have access to study findings. It is difficult to justify denying the public knowledge about existing research, particularly if it is publicly funded. Even in the context of classified research sponsored or funded by the government, the protection of Research Ethics Review Board5 (Research ERB) review should be provided (ACHRE, 1995). Secrecy often has led to abuses of human rights. The pharmaceutical and other industries cite the need for protection of proprietary interests, and in a capitalist economy this claim is generally respected (DHHS, 1999). The potential for profit, however, should never overshadow the rights of individuals and the public to have access to information, particularly in the high-risk area of clinical trials. Therefore, systems for providing access to information about clinical research that are responsive to both industry and public needs should be developed. Recommendation 7.2: The Department of Health and Human Services should facilitate the establishment of a central registry for all clinical trials. Protection programs should provide the basic information for submission to the registry. Section 113 of the FDA Modernization Act of 19976 requires that Phase 2, 3, and 4 clinical trials conducted under an Investigational New Drug application (IND) be included in a publicly available registry for access by patients, researchers, and health care providers, if that drug or biologic product is intended to treat a serious or life-threatening disease. The provision stipulates that the information in the databank must include a brief description of the clinical trial, the purpose of the investigational treatment, patient eligibility criteria, locations of clinical trial sites, and either central or site-specific contacts for the trial. The law also requires that the language of the databank entries be readily understandable by the public. In 2000, the National Library of Medicine (NLM) established a clinical 5 Recommendation 3.1 calls for “Institutional Review Boards” (IRBs) to be named and referred to within research organizations by a title reflective of their focus on the ethics underlying participant protection activities. The committee has adopted the term “Research Ethics Review Board” (Research ERB) for this purpose. Therefore, Research ERB refers herein to the committee’s idealized protection program, and IRB to descriptions of the current system. 6 P.L. 105-115, 1997.
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Responsible Research: A Systems Approach to Protecting Research Participants trials registry,7 which originally included principally NIH-sponsored trials, but has expanded to include data from other registries8 and serves as the FDA-required site for submissions about clinical trials subject to Section 113’s registry requirement. The database also includes a Protocol Registration System, a Web-based data processing program for sponsors to register the relevant FDA-regulated studies. The first version of the system, publicly available in February 2000, contains more than 4,000 records, most of which are trials sponsored by NIH. The NLM system design and implementation have been guided by several principles. First, all stages of system development focused on the needs of the primary target audience—patients and other members of the public. Second, broad agreement was obtained on a common set of data elements for submission. Third, the system was designed in a modular and extensible way, and search methods that take extensive advantage of the NLM’s Unified Medical Language System were developed (McCray and Ide, 2000). The NLM registry is an important first step toward providing high-quality clinical trial information to the public. However, no truly centralized system exists for disseminating information about clinical trials of drugs or other interventions, making it difficult for consumers and health care providers to identify ongoing studies in which consumers could participate. In the absence of a centralized mechanism, hundreds of registries or accessible databases of ongoing studies have been created in the last several years, and their numbers are growing (Anderson et al., forthcoming).9 Many of these registries are established by medical centers hoping to recruit patients. Others are funded by publishing companies with strong links to drug companies (e.g., CenterWatch Trial Listings, published by Thomson Publishing Company) or by the government (e.g., the NLM registry). Although many are high quality, in the absence of common oversight, there is always a risk that inaccurate or misleading data could lead to inappropriate participant recruitment or enrollment in trials (Crocco, 2002). Despite the vast contribution these registries have made to inform those who are interested in trials, their content, quality, and information vary widely. For example, although an interested party may learn that a trial is available for a given condition, the drug name, study location, and phase of 7 www.clinicaltrials.gov. 8 These registries include the AIDS Clinical Trials Information System, the Physician’s Data Query, and the Rare Diseases and National Institute of Aging Databases. 9 A sampling of online registries, some of which are tailored to specific criteria, include www.clinicaltrials.gov; www.centerwatch.com/patient/trials.html; www.trialscentral.org/; www.controlled-trials.com/; www.wiley.co.uk/wileychi/genmed/clinical/DATABASE/db/genesearch.cgi; www.actis.org/intltrials.html; www.update-software.com/National/.
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Responsible Research: A Systems Approach to Protecting Research Participants testing may not be provided. Often, the patient interested in participating in a listed study may be required to self-identify to the research entity before learning more about the design details. Eric Manheimer has shown that a patient with prostate or colon cancer who wishes to participate in a drug trial would have to spend many hours searching dozens of online registries to compile a list of potentially appropriate Phase 3 trials for either condition and would still not have a complete list (forthcoming). In addition to having access to information, consumers should expect that any research in which they are asked to participate could lead to the generation of new knowledge or knowledge required to confirm inconclusive or insufficient information from other sources. Yet with no central listing of all research projects undertaken, either completed or ongoing, studies may be unnecessarily duplicated. Antman, Lau, and colleagues provide several examples of randomized clinical trials that were conducted long after knowledge about a treatment’s efficacy should have been accepted (1992).10 Treatment recommendations in textbooks and review articles have also reflected a failure to keep track of initiated and completed research, in some cases leading to decades elapsing between the production of reliable efficacy evidence and recommendations for general use (ibid.). Further, as the United States moves increasingly toward an evidence-based health care system, access to trial findings is vital. Results of far too many trials will never be known, because perhaps half of all initiated studies are never published, and selective publication occurs of studies based on the strength or direction of findings (Egger and Smith, 1998). Because it is nearly impossible to identify unpublished studies (Hetherington, 1989), any summary or systematic review of existing research is therefore most likely to rely on published research. If a disproportionate number of trials showing an effective intervention are published, then research reviews could result in overestimated effectiveness of interventions, which could lead to inappropriate patient care policies. In addition, patients who consent to participate in a clinical trial do so believing they are contributing to the advancement of scientific knowledge. If the trial’s results are never disseminated, the investigator-participant trust is broken, creating an ethical breach. For these as well as other reasons, observers have called for decades for a comprehensive registry of all initiated studies (Chalmers, 1977). More recently, the Institute of Medicine (IOM) Committee on Medicare Payment for Participation in Clinical Trials has made the same recommendation (2000a). In 2002, the DHHS Office of Inspector General (OIG) released a report 10 For example, this is what happened in the case of thrombolytic drugs for secondary prevention of myocardial infarction. Tens of thousands of patients were unnecessarily randomized believing they were contributing to new knowledge.
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Responsible Research: A Systems Approach to Protecting Research Participants that assessed the role of clinical trial Web sites in fostering understanding about informed consent and the role of Research ERBs in overseeing the information on these sites (OIG, 2002). The study found that clinical trial Web sites are emerging as an important recruitment strategy and show promise as a means of increasing knowledge about informed consent. However, these sites sometimes provide inaccurate information about the clinical trial process, exclude key information in trial listings, and fail to disclose policies that address the use of personal information that is collected by the site. Based on these findings, the OIG recommended that FDA and OHRP jointly provide guidance to Research ERBs regarding their responsibility for reviewing Web sites, facilitate the adoption and use of voluntary standards for clinical trial Web sites, and encourage clinical trial Web sites to undergo periodic review by independent bodies. Although the OIG report encourages the adoption of voluntary standards across sites to improve the quality and consistency of registry entries, the inaccessibility of information caused by the need to search multiple databanks is not addressed. One possible mechanism for facilitating central registration would be through a federal system using Research ERBs. This model would not require investigators to submit additional registration materials to multiple Web sites. Instead, basic material submitted to the Research ERB would serve as the backbone of the registry.11 If all human research studies are reviewed and approved by a Research ERB, as recommended by this committee (Recommendation 2.1), this strategy would allow comprehensive registration of initiated clinical trials. The committee recognizes the challenges involved in designing, initiating and maintaining such an endeavor, as well as the resources that would be required, but believes that clinical trials are of such public concern and benefit that the effort should be pursued. The creation of a comprehensive clinical trials database that is soundly structured for public use would ensure that information about all clinical trials undertaken would be available to contribute to generalizable knowledge regardless of whether their results are viewed as positive or negative by investigators, sponsors, or publishers. 11 Basic material submitted for approved protocols might include disease target, a general description of the intervention, trial site locations, and contact information to learn more about the study. One option would be to adopt at a minimum the same inputs required for compliance with Section 113 of the FDA Modernization Act (P.L. 105-115, 1997). It should be noted that the basic information submitted to the registry would not need to include trial results.
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Responsible Research: A Systems Approach to Protecting Research Participants COMMUNICATING RESEARCH RESULTS: A ROLE FOR PUBLISHERS Scientific journals and other outlets for disseminating research results serve as an integral part of the protection system (Altman, 2002), as has been evident since 1966, when Henry Beecher published an article presenting 22 examples of “unethical or questionably ethical studies” that had appeared in mainstream medical journals (Beecher, 1966). As the major distribution channel of research results and as an important contributor to the professional advancement of scientists (through publication of their work), scientific journals are obligated to publish research that meets high ethical standards and offers unique contributions to the field (i.e., research that does not constitute an unnecessary or unjustified replication of previous work) and for which the authors have attested to their compliance with regulatory and ethical standards (e.g., Research ERB review, disclosure of relevant conflicts of interest). Several journals have already taken positive steps in this regard (see Box 7.1), and there has been recent improvement in the percentage of published papers citing compliance with IRB and informed consent procedures in major medical journals (Yank and Rennie, 2002). The committee encourages other publications to pursue similar standards. THE IMPACT OF THE HEALTH INSURANCE PORTABILITY AND ACCOUNTABILITY ACT OF 1996 REQUIREMENTS AND PRIVACY ISSUES ON HRPPPS The regulatory landscape regarding patient privacy has continued to evolve in recent years. Clearly, among the most important issues that should be faced when conducting research involving human participants are protecting the privacy of information and assuring confidentiality. Thus, programs should keep abreast of the relevant policy developments. Private information is defined in the Common Rule to include ...information about behavior that occurs in a context in which an individual can reasonably expect that no observation or recording is taking place, and information which has been provided for specific purposes by an individual and which the individual can reasonably expect will not be made public (for example, a medical record).12 Confidentiality becomes an issue when information disclosed by an individual (such as a research participant) to a particular person or persons for a specific purpose is further disclosed to other individuals or institutions for other purposes without the participant’s authorization (IOM, 2000c). 12 45 CFR 46.102(f).
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Responsible Research: A Systems Approach to Protecting Research Participants Box 7.1 Sample Journal Policies Regarding Research Participant Protections International Committee of Medical Journal Editors (ICMJE) Protection of Patients’ Rights to Privacy Patients have a right to privacy that should not be infringed without informed consent. Identifying information should not be published in written descriptions, photographs, and pedigrees unless the information is essential for scientific purposes and the patient (or parent or guardian) gives written informed consent for publication. Informed consent for this purpose requires that the patient be shown the manuscript to be published. Identifying details should be omitted if they are not essential, but patient data should never be altered or falsified in an attempt to attain anonymity. Complete anonymity is difficult to achieve, and informed consent should be obtained if there is any doubt. For example, masking the eye region in photographs of patients is inadequate protection of anonymity. The requirement for informed consent should be included in the journal’s instructions for authors. When informed consent has been obtained it should be indicated in the published article. Ethics When reporting experiments on human subjects, indicate whether the procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional or regional) and with the Helsinki Declaration of 1975, as revised in 1983. Do not use patients’ names, initials, or hospital numbers, especially in illustrative material. When reporting experiments on animals, indicate whether the institution’s or a national research council’s guide for, or any national law on the care and use of laboratory animals was followed. SOURCE: www.icmje.org/index.html#top. NOTE: Hundreds of journals have agreed to the ICJME requirements, including Journal of the American Medical Association, New England Journal of Medicine, British Medical Journal, Lancet, American Journal of Medicine. A full list of the journals is available at www.icmje.org/jrnlist.html. British Medical Journal Patient confidentiality and consent to publication If there is any chance that a patient may be identified from a case report, illustration, or paper we ask for the written consent of the patient for publication. Patients are almost always willing to give such consent. Black bands across the eyes are wholly ineffective in disguising the patient, and changing details of patients to try to disguise them is bad scientific practice. SOURCE: bmj.com/advice/. Journal of the American Medical Association (JAMA) Ethical Requirements. For experimental investigations of human or animal subjects, state in the Methods section of the manuscript that an appropriate institutional review board approved the project. For those investigators who do not have
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Responsible Research: A Systems Approach to Protecting Research Participants formal ethics review committees (institutional or regional), the principles outlined in the Declaration of Helsinki should be followed. For investigations of human subjects, state in the Methods section the manner in which informed consent was obtained from the subjects. Patient Descriptions, Photographs, and Pedigrees. Include a signed statement of informed consent to publish (in print and online) patient descriptions, photographs, and pedigrees from all persons (parents or legal guardians for minors) who can be identified in such written descriptions, photographs, or pedigrees. Such persons should be shown the manuscript before its submission. SOURCE: www.jama.ama-assn.org/info/auinst.html#a3. Lancet Patients’ consent and permission to publish—Studies on patients or volunteers require ethics committee approval and informed consent, which should be documented in your paper. Where there is an unavoidable risk of breach of privacy—e.g., in a clinical photograph or in case details—the patient’s written consent, or that of the next of kin, to publish must be obtained and enclosed with your submission. Consent must be obtained for all Case reports and Clinical pictures. A consent form is available at image.thelancet.com/consent/consentform.pdf. SOURCE: www.thelancet.com/authorinfo. Privacy and confidentiality are vital issues throughout all stages of research design and implementation. Research projects should be designed to intrude on the privacy of research participants no more than is necessary, and the confidentiality of information obtained during a research project should be protected throughout the project as well as after it is completed. Although privacy and confidentiality issues are involved in all forms of research involving human participants, they are particularly important with respect to health services and social science research, because in these forms of research (as compared to clinical research), privacy and confidentiality threats are often the primary risks to human participants. Two years ago, IOM completed a project considering privacy and confidentiality issues in health services research (IOM, 2000c). The report of the Committee on National Statistics/Board on Behavioral, Cognitive, and Sensory Sciences and Education panel advising this committee also identified confidentiality as a major issue in social and behavioral science research and offered five recommendations related to confidentiality (Appendix B, recommendations 1-5). Recent regulations promulgated pursuant to the Health Insurance Portability and Accountability Act of 1996 (HIPAA) expand considerably the regulatory obligations of health plans and providers that conduct research
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Responsible Research: A Systems Approach to Protecting Research Participants involving human participants.13 This rule (referred to in this report as the “Privacy Rule”) will go into final effect in April 2003.14 The Privacy Rule applies to individually identifiable health information held by a health plan, a health care clearinghouse, or a health care provider that transmits any health care information electronically.15 It does not, therefore, apply to social science research conducted outside of health care institutions, and it may not even apply to clinical research that is not conducted by health care providers.16 The definition of research found in the Privacy Rule is intentionally identical to that found in the Common Rule: “Research means a systematic investigation, including research development, testing, and evaluation, designed to develop or contribute to generalizable knowledge.”17 The Privacy Rule supplements and does not replace the Common Rule for regulating research. Federally funded research must, therefore, comply with both. Privately funded research conducted within health plans or by providers must comply with the Privacy Rule, even though it is not covered by the Common Rule. Researchers must also comply with state laws that are more stringent than the Privacy Rule; these state laws are specifically protected from preemption under the Rule.18 The Privacy Rule permits information to be used or disclosed for research only under the following conditions: First, if information used in research is not individually identifiable, it is not protected health information and is not subject to the Rule.19 The revised Rule also provides for “Limited Data Sets,” from which sixteen specific identifiers have been deleted, for research purposes if the covered entity obtains from the data user a data use agreement that limits use of the data and prevents further disclosure.20 Second, if use or disclosure of protected health information is authorized by the research participant, it may be used or disclosed to the extent of that authorization.21 Third, protected health information may be 13 The DHHS Standards for Privacy of Individually Identifiable Health Information; Final Rule, 65 Fed. Reg. 82461, et seq., adopted on December 28, 2000. See also, explaining the Rule, technical guidance regarding research found at www.hhs.gov/ocr/hipaa/research.html. Amendments to the Rule were published on August 14, 2002 (DHHS, 2002). 14 Small health plans have a year longer to comply with HIPAA, which also includes special transition provisions for ongoing research (45 CFR 164.532). 15 45 CFR 160.102(a), 164.501. 16 Health care provider is defined by cross reference to the Medicare statute, but also includes “any other person or organization who furnishes, bills, or is paid for health care in the normal course of business” (45 CFR 160.103). 17 45 CFR 164.501. 18 45 CFR 160.203. 19 Standards for de-identified data are found at 45 CFR 164.514. 20 45 CFR 164.514(e). 21 45 CFR 164.508.
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Responsible Research: A Systems Approach to Protecting Research Participants used or disclosed for research without authorization for certain purposes explicitly authorized by the Rule, including research conducted on decedents and review of patient information for preparing research protocols.22 Fourth, protected health information may be used or disclosed for research without authorization if authorization is waived by an Institutional Review Board (IRB) or a privacy board (see below), as permitted by the Rule.23 The HIPAA Privacy Rule imposes a new task on Research ERBs— granting waivers to permit the use and disclosure of identifiable health care information without authorization by the research participants from whom the information was generated. The Rule also permits authorization waivers to be granted by new entities, called “privacy boards,” which include members of varying backgrounds who are competent to review privacy issues, have at least one nonaffiliated member, and do not allow members to review research with which they have conflicts of interest.24 It appears that privacy boards have been created to review research that is not subject to Research ERB approval, such as nonfederally funded research, and Research ERBs will normally review privacy issues for research otherwise subject to their jurisdiction. Research ERBs and privacy boards can alter or waive authorization if specific criteria are met (see Box 7.2). Research ERBs must follow Common Rule procedures in determining authorization for waivers and alterations.25 Privacy boards must review authorization waivers or alterations at meetings during which a majority of the board, including an unaffiliated member, is present and approves the waiver by a majority vote. However, the chair or one or more members of the board may authorize a waiver in an expedited review procedure when the research involves no more than a minimal risk to privacy.26 The waiver must be signed by the chair or other member designated by the chair of the privacy board or IRB.27 The preface to the original Privacy Rule notes that waivers will rarely apply in clinical trials, since the researcher normally will have contact with the participant and could request authorization. The primary use of the waiver process will therefore be in health services research, in which large numbers of records are reviewed retrospectively. Although Research ERBs have a legitimate role in deciding whether research using identifiable information should be permitted without participant authorization, the practical application of the waiver criteria is likely 22 45 CFR 164.612(i)(1)(ii) & (iii). 23 45 CFR 164.512(i)(1)(i). 24 45 CFR 164.512(i)(B). 25 45 CFR 164.512(i)(2)(iv)(A). 26 45 CFR 164.512(i)(2)(iv)(B) & (C). 27 45 CFR 164.512(i)(2)(v).
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Responsible Research: A Systems Approach to Protecting Research Participants Box 7.2 Health Insurance Portability and Accountability Act of 1996 (HIPAA) Waiver Criteria (under modifications to the HIPAA Privacy Rule) The use of disclosure of the information involves no more than minimal risk, based on the presence of at least: an adequate plan to protect identifiers from improper use or disclosure; an adequate plan to destroy identifiers as soon as possible consistent with the research unless there is a health or research reason to retain them, or retention is otherwise required by law (the preface specifically recognizes that FDA or International Organization for Standardization requirements may prohibit the destruction of identifiers) (65 Fed. Reg. at 81698); and there are adequate written assurances that protected information will not be reused or disclosed except as required by law, for research oversight, or for other research for which the use or disclosure of protected health information would be authorized by the Rule. The research could not practicably be conducted without the alteration or waiver. The research could not be practicably conducted without access to and use of the protected health information [45 CFR 164.512(i)(2)(ii)]. to be problematic. In particular, it is not clear whether the Privacy Rule uses the term “minimal risk” in a manner consistent with the way the term is used in the Common Rule, though the preface to the revised final Rule asserts this intention.28 The fact that expedited review is permitted by privacy boards under the Privacy Rule when minimal risk is involved suggests that the two Rules are not using the term consistently. It is also important that other obligations under the Privacy Rule not be indiscriminately transferred to Research ERBs. Someone within a health care plan or a provider that conducts research involving de-identified data (or limited data sets) must be responsible under the Privacy Rule for determining if data have been properly de-identified in conformity with the Rule’s complex requirements. Someone also must be responsible for assuring that authorizations to use or disclose information for research contain the elements specified by the Privacy Rule. The Rule does not specify, however, that these functions must be performed by a Research ERB. Given the limited resources of Research ERBs in most settings and the committee’s goal of refocusing their attention on the ethics of research, it would be inappropriate to assign these compliance responsibilities to a Research ERB (see Chapter 6). 28 67 Fed. Reg. at 53230.
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Responsible Research: A Systems Approach to Protecting Research Participants Although it is not this committee’s task to comment in detail on the Privacy Rule, it agrees that the Rule’s basic organizing principle is sensible. In particular, identifiable information concerning research participants should not be used or disclosed without either informed authorization from the participant or pursuant to a judgment from a Research ERB or equivalent body that 1) identifiable information is necessary for a particular research project, 2) it is impracticable to obtain consent from all participants, and 3) privacy risks are minimal. The committee’s concern, expressed in Chapter 6, that the Research ERB should not be burdened with responsibilities tangential to its focus on ethics would suggest that policing compliance with the Privacy Rule might be better handled elsewhere in the organization, such as in a compliance office. RESEARCH EFFORTS TO COUNTER TERRORISM The terrorist attacks of 2001 have had a profound impact on American society, prompting an increased emphasis on the need to conduct research to counter terrorism. Although such research will focus on myriad security and related issues, issues involving humans—including drug, vaccine, and prophylactic trials—deserve particular attention in the context of this report. The United States previously has conducted investigations into protective and therapeutic methods to combat the effects of various threat agents. However, based on the President’s proposed budget for FY 2003, NIH plans to designate $1.48 billion to bioterrorism-related research and infrastructure—an increase of $1.47 billion from FY 2002 (NIH, 2002a). Of that amount, $977 million would fund bioterrorism research activities.29 This is a massive increase in funding, and NIH is not the only federal agency that will be conducting such research. Recommendation 7.3: Groups addressing bioterrorism response mechanisms and research should pay special attention to the protection of research participants in their studies. Protection of human participants in research to counter bioterrorism presents special challenges that relate particularly to the understanding of a trial’s risks and benefits as described during the informed consent process. A relevant example is that of research on smallpox vaccines. The outpouring of volunteers for trials of different dilutions of available smallpox vaccine for immunogenicity after September 11 likely occurred for several reasons: the belief that the vaccine would provide protection, the knowledge that most of the population has no immunity to smallpox, the atten- 9 These figures are subject to change during the Congressional appropriations process.
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Responsible Research: A Systems Approach to Protecting Research Participants tion paid to the disastrous effects that would result from the release of smallpox in a bioterrorist attack, and, significantly, a lack of understanding of the true risks and experimental nature of the trials (Argetsinger, 2001; Connolly and Goldstein, 2001). On the other hand, experience with the anthrax situation in October 2001 indicated reluctance to participate in the use of antibiotics by those exposed to anthrax, even though the antibiotics likely helped prevent further illness (Brookmeyer and Blades, 2002; Double Exposure, 2001). Because the duration of treatment to prevent pulmonary anthrax was unknown, those being treated were participants in an informal investigation of a different use of approved drugs. The already difficult process of obtaining fully informed consent for an effort that could be considered somewhere between a study and an application of a therapeutic measure not yet approved by FDA was further complicated by the fact that people had few options. The anthrax vaccine had been approved in the 1970s and used prophylactically in the military and by laboratory workers and veterinarians. However, before the anthrax incidents of 2001, it had not been used post exposure, and thus, it was treated as an IND under FDA regulations, which meant that informed consent documents had to be signed. Press reports citing concerns of “experts” about experiments similar to the Tuskegee syphilis studies and confusing recommendations made by public health officials resulted in public misunderstanding of the status of anthrax vaccines for therapeutic use and loss of public trust in official pronouncements. Of the 10,000 people who had the option of taking the vaccine post exposure, only 130 chose to do so; another 1,168 took only the antibiotics as part of the study administered by the Centers for Disease Control and Prevention (Stolberg, 2002). Again, obtaining truly informed consent was difficult. A further concern regarding research in these circumstances is that current products have generally been developed and approved for a healthy, young population and may have unknown effects when used in the population at large. The defensive research on prophylactic or therapeutic products against agents such as anthrax in the past was targeted mainly to those in the armed forces. Vulnerable groups, such as pregnant women, children, the elderly, the chronically ill, or the immune-compromised, were not included. If new prophylactic and therapeutic products are to be developed for use in the general population, additional research will be needed regarding the effects of these products in all populations. With the increased emphasis on bioterrorism research, all parties involved should understand that the basic ethical principles underlying the involvement of human participants apply, no matter how urgently needed the research may be. Studies involving bioterrorism, some of which will be classified, will be carried out within a climate of public fear (Spieler, 2002), and in times of crisis, potential participants may be more prone to minimize
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Responsible Research: A Systems Approach to Protecting Research Participants known and stated risks, especially considering the desire to protect one’s self and family, and this could override the informed aspect of consent. Additionally, in times of uncertainty and fear, the full range of civil liberties sometimes is not respected or enforced in order to enhance security, and the government’s support of individual autonomy can decrease if resources are scarce and the need for data is great. Thus, the coercion of individuals to participate in trials that would support national needs could be tolerated under extreme conditions (ACHRE, 1995; Moreno, 2000). In May 2002, FDA amended its New Drug and Biological Product regulations so that certain human drugs and biologics that are intended to reduce or prevent serious or life-threatening conditions may be approved for marketing with research evidence of effectiveness from appropriate animal studies, if human efficacy studies are not ethical or feasible (FDA, 2002b). This so-called Animal Rule—part of FDA’s effort to help improve the nation’s ability to respond to emergencies, including terrorist events— will apply when adequate and well-controlled clinical studies in humans cannot be ethically conducted because the studies would involve administering a potentially lethal or permanently disabling toxic substance or organism to healthy human volunteers. The new rule has postmarketing and labeling restrictions, however, and it does not apply if the product could be approved on the basis of any other standard under FDA’s jurisdiction. Although human participants are used for safety trials before approval, this modification of regulations is appropriate given the need to develop products to counter bioterrorism. Because questions will inevitably arise the first time these drugs and vaccines are used in practice, HRPPPs should be particularly vigilant in such situations. Classified Research The Advisory Committee on Human Radiation Experiments (ACHRE), formed by former President William Clinton to investigate past classified radiation experiments involving humans, has addressed the special concerns of classified research, and its efforts should serve as a guide to conducting ethical classified research (ACHRE, 1995). In its expansive report, ACHRE made a number of recommendations regarding the ethical aspects of classified research. Most relevant to this discussion is the recommendation that the informed consent requirement in classified research should not be waived and that an independent panel of nongovernmental experts should approve classified research (see Box 7.3). Under proposed legislation, these recommendations would be enforceable by law.30 30 A Bill to Amend the Public Health Service Act with Respect to the Protection of Human Subjects in Research. H.R. 4697. 107th Congress, 2nd Sess. (2002).
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Responsible Research: A Systems Approach to Protecting Research Participants Box 7.3 Advisory Committee on Human Radiation Experiments Recommendations for Balancing National Security Interests and the Rights of the Public Recommendation 15: 15a: The Advisory Committee recommends to the Human Radiation Interagency Working Group the adoption of a federal policy requiring the informed consent of all human subjects of classified research and that this requirement not be subject to exemption or waiver. In all cases, potential subjects should be informed of the identity of the sponsoring federal agency and that the project involves classified information. 15b: The Advisory Committee recommends to the Human Radiation Interagency Working Group the adoption of a federal policy requiring that classified research involving human subjects be permitted only after the review and approval of an independent panel of appropriate nongovernmental experts and citizen representatives, all with the necessary security clearances. This panel should be charged with determining (1) that the proposed experiment has scientific merit; (2) that risks to subjects are acceptable and that the balance of risk and potential benefit is appropriate; (3) that the disclosure to prospective subjects is sufficiently informational and that the consent solicited from subjects is sufficiently voluntary; and (4) whether potential subjects must have security clearances in order to be sufficiently informed to make a valid consent decision, and if so, how this can be achieved without compromising the privacy and voluntariness of potential subjects. Complete documentation of the panel’s deliberations and of the informed consent documents and process should be maintained permanently. These records should be made public as soon as the national security concern justifying secrecy no longer applies (ACHRE, 1995, p.828). In 1997, President Clinton issued a memorandum that required all agencies subject to the Common Rule to promulgate final rules regarding the protection of human participants in classified research. The same memorandum also prohibited agencies from conducting such research until those changes were incorporated into the Common Rule (Clinton, 1997). Although the changes have been accepted by 13 of the departments and agencies subject to the Common Rule, the Central Intelligence Agency and the Department of Defense are among those that have not signed off on the alterations (Spieler, 2002). The power to classify research has generally been reserved for security agencies, but in December 2001, President Bush extended the power to classify information as secret to the Secretary of DHHS (Mitchell, 2001). The documents that could be classified include those related to bioterrorism and preparedness of response. Thus, recent comment that federal regula-
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Responsible Research: A Systems Approach to Protecting Research Participants tions governing classified human research should be implemented as soon as possible is very timely (Spieler, 2002). Federal agencies such as DHHS and groups including The National Academies, the Center for Strategic and International Studies, and the RAND Corporation have and will continue to address the various aspects of bioterrorism threats. As outlined in this section, research in these circumstances, and classified research in general, involves special considerations if it is to be carried out ethically. National pressure to prepare for possible attacks involving biological or chemical agents is significant, and those exploring and recommending responses to bioterrorism should consider the protection of research participants in classified and terrorism-related research to be of the highest priority. SUMMARY When the original system for the protection of human participants in research was created, the typical study was conducted at a single research institution by a single investigator or a small team of investigators. There might have been one IRB, formed from volunteers at the research site to ensure an independent review of proposed research. Today, however, some research involves scores or even hundreds of centers and tens of thousands of participants, with multiple investigators, review boards, and institutions possibly involved. In addition, with the dramatic increase in privately funded research, a separate system of independent IRBs has been created. The recommendations made in this report aim to improve the system of protections as a whole, as it has not adequately adapted to the vast growth in the scale and complexity of research. Trust in the human research enterprise demands that the system responsible for protection be credible and accountable. To be credible, the system requires ongoing independent advice, with input from a population that is as diverse as possible. Regulatory agencies, such as OHRP, would benefit from ongoing review of and advice regarding the policies, practices, and needs of the national protection system. To be accountable, information about new and ongoing clinical trials should be available in a centralized, user-friendly, and accessible database. After research is completed, results should be published in a manner that makes the value of the research and its compliance with ethical norms clear. Emerging social issues will continue to influence the nature and direction of research involving humans. The potential for growth in research directed at countering terrorism or that is classified for national security requires extraordinary vigilance to ensure that public and social goals do not inappropriately and unfairly trample human rights and protections in research. Finally, the issue of privacy will continue to be debated in Ameri-
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Responsible Research: A Systems Approach to Protecting Research Participants can society, especially in medicine and the health care system. Because protection programs are mandated to protect the rights and welfare of research participants, it is essential that they keep abreast of developments in the changing landscape of privacy regulations as they relate to health care and research.
Representative terms from entire chapter: