Appendix C: The Current Oversight System: History and Description (Research Involving Human Participants V1)
History
By the early 1900s, concern about the involvement of human participants in research was part of the American political agenda, and since that time it has remained a topic of discussion among policymakers, most notably as medical research expanded in the 1940s and 1950s, although discussions during that period were rarely converted to policy (ACHRE 1995, 83 - 129). In the late 1940s, however, formal statements of what was required to ensure ethically sound research began to emerge. These early declarations came largely in response to atrocities committed by Nazi investigators, mostly physicians, who were tried before the Nuremberg Military Tribunal.1 A key task of the prosecutors in this case was to distinguish between the Nazi experiments and U.S. wartime research, both of which used human beings. With the trial looming, and prompted by its liaison to the Nuremberg prosecutors, the American Medical Association adopted its first code of research ethics (AMA 1946), which influenced the American judges' own set of standards for ethical research (ACHRE 1995, 133 - 135; Moreno 1999, 75). In an unusual move, as part of their decision the judges presented ten basic principles for research using human participants, now known as the Nuremberg Code.2,3 However, adherence to such ethical standards was not automatically assured by the development of formal codes of ethics. For example, many saw the Nuremberg Code as an appropriate response to Nazi war crimes but unnecessary for American medicine (Rothman 1991, 62 - 63). Additionally, the Nuremberg Code is difficult to implement because, among things, its first principle, 'the voluntary consent of the human subjects is absolutely essential,' would appear to allow for no exceptions. This absolute requirement may reflect the code's origins in deliberations about research with healthy rather than sick participants and with medical research as opposed to other types of research. Moreover, despite its principled stringency, the Nuremberg Code embodies a deep trust of the research community and gives little weight to the inherent conflicts of interest that might be involved. Investigators alone would be responsible for obtaining informed consent and deciding whether their research met the code's principles.
Although the Nuremberg Code received little attention in the immediate aftermath of the trial, it was not entirely ignored. In 1953, U.S. Secretary of the Department of Defense (DOD), Charles Wilson, issued a Top Secret memorandum establishing policy for research related to atomic, biological, and chemical warfare (Wilson 1953). The policy incorporated the principles of the Nuremberg Code and two additional protections, prohibition on research involving prisoners of war and a requirement that the Secretary of the appropriate military service approve research studies.
Later that year the National Institutes of Health (NIH) Clinical Center opened and established a policy requiring independent review of research and participants' written consent, at least for research involving patient volunteers and/or 'unusual hazard' (NIH 1953). In 1954, these protections of independent review and written informed consent were extended to all NIH intramural research involving 'normal volunteers.'4 These bold statements of policy did not lead immediately to dramatic shifts in actual research practices. The DOD policy remained largely Top Secret and was not disseminated to investigators (ACHRE 1995, 108), and at the NIH Clinical Center, procedures for independent review were rarely invoked (Rothman 1991, 56).
Moreover, both the DOD and NIH policies were limited by confusion over the definition of research. It is not clear whether the Nuremberg Code was meant to apply to research with patients as participants or only to research with healthy individuals. As a result, until 1961, the NIH Clinical Center policy did not require independent review for most research with patients.5 In part, policymakers were concerned about intruding into the doctor-patient relationship. More generally, though, until the late 1960s, concern about human protections seemed unnecessary to many observers. The development of penicillin, the conquest of polio, and the emergence of new medical devices and procedures, all apparently unmarked by inappropriate conduct bolstered the public prestige of and trust in the biomedical research community.6 In 1962, fetal abnormalities linked to maternal use of thalidomide shook public confidence in the regulation of drug-related research. In response, Congress passed the Kefauver-Harris amendments to the Federal Food, Drug, and Cosmetic Act, requiring the Food and Drug Administration (FDA) to evaluate new drugs for efficacy in addition to safety.7 The amendments also specifically required the informed consent of participants in the testing of investigational drugs, but this requirement was weakened by vague language outlining permissible exceptions. Nonetheless, the Kefauver-Harris amendments gave FDA broad authority to regulate drug-related research.
Other events soon influenced NIH policy. A 1962 NIH-commissioned study found that few institutions had their own policies for the protection of research participants (ACHRE 1995, 174; Faden and Beauchamp 1986, 158). The potential for problems was borne out when, in early 1964, newspapers began to describe an NIH-funded study at the Brooklyn Jewish Chronic Disease Hospital in which investigators had injected cancerous cells into elderly patients. The investigators claimed to have obtained informed consent, but many of the patients were incapacitated or did not speak English, and those able to give consent were not told that the cells to be injected were cancerous (Faden and Beauchamp 1986, 161; Jonsen 1998, 143).
In response (and against the recommendations of a committee appointed to examine the issue), NIH Director James Shannon argued that the institutes should take more responsibility for research ethics (Faden and Beauchamp 1986, 208). At Shannon's request, the Public Health Service (PHS) issued a policy for extramural projects (PHS 1966). The initiative was important, but the policy was primarily procedural. It required independent review of research by a committee of the investigator's institutional associates', but offered little guidance about the content of that review (PHS 1966, 475). The policy did not originally specify the composition of the review committee, but an accompanying memo stated that a group of people from different disciplines, familiar with the investigator but 'free to assess his judgment without placing in jeopardy their own goals,' would be required (Stewart 1966, 474). Importantly, it marked a shift away from sole 'reliance on the judgment and virtue of the individual researcher' in the assessment of the ethics of research.8 At NIH, the PHS policy was implemented through the Institutional Relations Branch of the Division of Research Grants. The branch addressed this policy in the way it handled other matters of institutional relations, by negotiating 'assurances of compliance' with the PHS policy from each institution receiving funding. For enforcement, the branch could withhold, or, more likely, threaten to withhold funds.9 The NIH Institutional Relations Branch later became the NIH Office for Protection from Research Risks (OPRR) and assumed a lead role in the protection of research participants within the Department of Health and Human Services (DHHS). In June 2000, OPRR was moved out of NIH to the Office of the Secretary, DHHS, becoming the Office for Human Research Protections (OHRP).10 However, in 1966, the PHS 'Policy for Clinical Investigations with Human Subjects' applied only to extramural research, and the Division of Research Grants dealt only with NIH grantees. Also in 1966, the NIH Clinical Center strengthened its separate system of independent review (Faden and Beauchamp 1986, 209). At the same time, FDA issued guidance to clarify the requirements for and exceptions from informed consent as specified in the Kefauver-Harris amendments (Faden and Beauchamp 1986, 204).
While NIH and FDA were revising their policies for the protection of human subjects, Henry Beecher published a damning indictment of contemporary research practice in the United States (Beecher 1966). He presented 22 examples of 'unethical or questionably ethical studies' published in major medical journals. The article was influential largely because it showed that abuses were occurring in research conducted by mainstream investigators (Rothman 1991, 75). A review of published studies conducted in Great Britain revealed similar abuses (Pappworth 1962).
Several years after Beecher's article, one of the studies he had discussed became a subject of particular controversy, an investigation of hepatitis involving the injection of a mild strain of the virus into children at the time of admission to the Willowbrook State School for the Retarded in New York. Parental consent was obtained, but the consent form may have been misleading, and desperate parents may have been unduly influenced by the availability of preferential and later exclusively research-related admissions to the institution. One notable feature of the case was that the Willowbrook research had been reviewed and approved by the Armed Forces Epidemiological Board, which funded the research, as well as a local review committee for human experimentation (ACHRE 1995, 178; Faden and Beauchamp 1986, 163 - 164).
The debates about the Willowbrook State School experiments became part of a more general concern that local institutional review was not adequately protecting individuals who participated in research (Faden and Beauchamp 1986, 211). In 1971, five years after the PHS policy was put into place, the then Department of Health Education and Welfare (DHEW) developed more detailed guidance and justification for review committees in the form of the 'Yellow Book' (DHEW 1971).
In the summer of 1972, the New York Times published details of the Tuskegee Syphilis Study, sponsored by PHS since the early 1930s (Heller 1972). Although a formal protocol never existed, the study intended to trace the natural history of syphilis in poor African American males living in Macon County, Alabama. Participants were not told of the purpose of the study; in fact, they were misled into believing that they were being treated for syphilis. Throughout this project, research-related procedures, such as lumbar punctures, were described as 'special free treatments.' Investigators continued the study even after penicillin became widely available and prescribed for the treatment of syphilis. In exchange for participation, the men received some unrelated health care, free meals, and transportation, and later in the study, to encourage autopsy, a $50 burial stipend (Jones 1981).
Following media attention about the study, a PHS Advisory Panel was formed to examine whether it was justified at its inception or after penicillin became generally available, to recommend whether the study should be continued, and to determine whether existing human research protection policies were adequate. The study was found to be ethically unjustified; it was halted, and surviving participants were offered treatment. In addition, the Advisory Panel determined that existing procedures for protecting research participants were not adequate. They recommended that 'Congress should establish a permanent body with the authority to regulate at least all Federally-supported research involving human subjects' (Tuskegee Syphilis Study Ad Hoc Advisory Panel 1973, 23).
In 1973, the Senate Labor and Public Welfare Committee began a series of hearings on human experimentation (Jonsen 1998, 92 - 98). Interest was intensified by controversy over NIH-funded research involving aborted fetuses (Cohn 1973). A number of bills were circulated, including one that would have created a National Human Experimentation Board.11 However, it became clear that there was not enough support for such a body, and a compromise was reached. The proposal for a national oversight board was dropped in exchange for an agreement that DHEW would issue regulations governing research with human subjects (ACHRE 1995, 181).12 DHEW quickly developed regulations based on existing 'Yellow Book' policies. The regulations were issued by DHEW in May of 1974,13 and the National Research Act was signed in July of that year.14 The National Research Act also established the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (National Commission) to provide ethical and policy analysis related to conducting human research. The National Commission produced ten reports and is best known for the Belmont Report (National Commission 1979) (see Appendix D), which identified three fundamental ethical principles applicable to research with human participants' respect for persons, beneficence, and justice, which translated respectively into provisions for informed consent, assessment of risk and potential benefits, and selection of participants.
The Belmont Report was important primarily because it linked desired ethical standards and practices and existing concerns to fundamental ethical principles. DHEW regulations already contained specific provisions for obtaining and documenting informed consent and guidance on assessing risk and benefit. The report recommended that additional attention be given to the equitable selection of participants. In response to the Belmont Report, DHHS and FDA simultaneously revised their regulations. Thus, the two sets of regulations were unified in significant ways. In January 1981, the DHHS Secretary signed the revised regulations (45 CFR 46; 21 CFR 50, 56).15 The revisions, however, did not incorporate many of the National Commission's recommendations. The regulations still placed their greatest emphasis on obtaining and documenting voluntary informed consent, while giving minimal attention to the assessment of risk and potential benefit or the selection of participants. Moreover, the regulations were not supplemented with the substantive ethical rationale that the Belmont Report provided, leaving the regulations less detailed and potentially more difficult to interpret. By 1981, the recommendations in the National Commission's report on fetal research were codified as a separate Subpart of the DHHS regulations (Subpart B),16 as had the recommendations from their report on research with prisoners (Subpart C).17 However, their recommendations regarding children and those institutionalized as mentally infirmed were not implemented.
In 1981, the President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research (President's Commission) was established. In its first of two biennial reports on research, the President's Commission examined the general structure of research protections (President's Commission 1981). The second biennial report (President's Commission 1983) focused on their implementation. (See Exhibit C.1.) Agency responses to the President's Commission recommendations were mixed. In 1983, DHHS promulgated regulations governing research with children (Subpart D).18 OPRR took steps to improve interpretation and implementation of the regulations, such as sponsoring regional workshops, issuing regulatory guidance in the form of OPRR Reports, and chairing the Human Subjects Research Subcommittee of the Committee on Science, National Science and Technology Council, Office of the President.
Perhaps the most promising area of agency action was in the standardization of regulations across agencies and departments. The White House convened an interagency ad hoc committee to develop what would become the 'Common Rule' (the Federal Policy for the Protection of Human Subjects [Federal Policy]), a set of identical regulations codified by various agencies. Initially, the group worked under the Federal Coordinators Council for Science, Engineering, and Technology. The standardization process was slow. In addition, in a time of severe budget constraints, few were willing to issue new regulations and establish new offices, and many departments requested extra protections or specific exceptions from any proposed rule.19 Nevertheless, in 1991, the regulations known as the Common Rule were simultaneously published in the Federal Register by 15 departments and agencies.20 The Common Rule expanded the scope of regulated research and provided some standardization across departments, with DHHS, primarily through OPRR, playing a key role in its development.
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Description of the Federal Regulatory Structure
This history has resulted in a complex and sometimes overlapping, but also incomplete, structure for the protection of human research participants. Each codification of the Common Rule by a department or agency is equivalent to 45 CFR 46.101 - 46.124 (Subpart A), the DHHS codification. The DHHS codification is cited throughout this report when referring to the 15 sets of regulations promulgated by federal departments that comprise the Common Rule.21
The Office of Science and Technology Policy (OSTP) did not codify the Common Rule, even though it signed the Federal Policy, because it does not conduct or sponsor research. The Common Rule also regulates research conducted or sponsored by two other agencies that are not signatories to the Common Rule but that are bound to DHHS regulations and therefore to the Common Rule either through public law (the Social Security Administration),22 or Executive Order (the Central Intelligence Agency).23 Thus, the Common Rule has 15 codifications and 16 signatories, and it covers 18 federal agencies '17 by force of law. Its structure is depicted in Figure C.1.
The Common Rule applies to all research involving human participants 'conducted, supported or otherwise subject to regulation by any federal department or agency which takes appropriate administrative action to make this policy applicable to such research.' Thus, it specifically allows agencies with regulatory authority (notably, FDA) to apply the Common Rule to regulated research (45 CFR 46.101(a)). However, DHHS does not require FDA to apply the Common Rule to the research FDA regulates. FDA also has its own regulatory authority over research involving food and color additives, investigational drugs for human use, medical devices for human use, biological products for human use being developed for marketing, and electronic products that emit radiation (e.g., microwave ovens, laser printers, sun lamps, diagnostic x-ray equipment). FDA also regulates research intended to support a change in the labeling of marketed products. To this regulated research, FDA applies its own set of regulations (21 CFR 50, 56) that are generally, but not entirely the same as the Common Rule (45 CFR 46 Subpart A). However, FDA is bound to DHHS regulations when it conducts its own research.
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Exhibit C.1: Recommendations of the President's Commission's First Biennial Report Protecting Human Subjects (1981)
- All federal agencies should adopt the regulations of DHHS (45 CFR 46).
- The Secretary, DHHS, should establish an office to coordinate and monitor government-wide implementation of the regulations.
- Each federal agency should apply one set of rules consistently to all its subunits and funding mechanisms.
- Principal investigators should be required to submit annual data on the number of subjects in their research and the number and nature of adverse events.
- The National Commission's recommendations on research involving children and the mentally disabled should be acted upon promptly.
- 'Private' research organizations receiving direct congressional appropriations should be required to follow federal regulations for the protection of human subjects (President's Commission 1981).
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Recommendations of the President's Commission's Second Biennial Report Implementing Human Research Regulations(1983)
- Congressional committees with oversight responsibilities for biomedical and behavioral research should monitor the progress of the administrative agencies in responding to the recommendations of the Commission's 1981 and 1982 reports on protecting human subjects.
- An Ethics Advisory Board should be reestablished within DHHS either through congressional action, as part of the authorization of the NIH and Alcohol, Drug Abuse and Mental Health Administration (ADAMHA) research programs, or by the DHHS Secretary.
- Federal agencies should clarify the meaning of certain procedural requirements of present regulations, particularly what is meant by 'IRB review.'
- A uniform system for implementing all federal rules to protect human subjects should be established under a single office and should include both assurances of regulatory compliance provided in advance by research institutions and periodic site visits to the institutions. Federal agencies that do not already do so should, as soon as practicable, identify the IRBs responsible for the initial and continuing review of research for which they have regulatory authority.
- The prospective review of institutional assurances of compliance with applicable regulations should consider the amount and types of research that each IRB anticipates reviewing and should determine that requirements regarding IRB composition are met, that sound procedures have been established for the IRB's review of the research, and that the institution understands its responsibilities for protecting human subjects.
- A broad educational and monitoring program covering the protection of human subjects and designed to reach investigators, IRB members, and research administrators should be conducted. Among the various activities included in the program should be site visits of research institutions using experienced IRB members and staff as site visitors (President's Commission 1983).
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Recent Events
Since the creation of the Common Rule, government agencies, Congress, academic scholars, and the private sector have called attention to problems with the current oversight system and have recommended or taken steps to improve it.
Government Activities
In 1994, the Advisory Committee on Human Radiation Experiments (ACHRE) was created to investigate reports of federally sponsored human research involving radioactive materials conducted between 1944 and 1972 and to assess the current state of protections for research participants. Concerning the latter charge they found, 'evidence of serious deficiencies in some parts of the current system' (ACHRE 1995, 797). Specifically, ACHRE was concerned with variability in the quality of IRBs, persistent confusion among human participants regarding whether they were involved in research or therapy, and insufficient attention to the implications of diminished decisionmaking capacity in the consent process. Several of the committee's recommendations addressed the protection of the rights and welfare of human research participants in the future and are directly related to the present report. (Relevant recommendations are reproduced in their entirety in Exhibit C.2.)
Congressional Interest
In general, Congress has been a generous and enthusiastic supporter of biomedical research, but at the same time some members of Congress have expressed concerns about the adequacy of oversight of human research.24 In recent years, several congressional committees have held hearings on various aspects of protection, including overall DHHS oversight of human research, oversight of gene therapy trials,25 privacy in health research,26 the administration of investigational drugs to members of the armed forces,27 and the use of placebo-controls and washout periods in clinical trials.28 Legislation to strengthen the system of protection has been introduced, although none has been enacted. In addition, the Children's Research Act of 200029 included provisions to extend protections for children participating in research.
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Exhibit C.2: ACHRE Recommendations Relevant to This Report
Recommendation 9: The Advisory Committee recommends to the Human Radiation Interagency Working Group [the cabinet-level group to which ACHRE reported] that efforts be undertaken on a national scale to ensure the centrality of ethics in the conduct of scientists whose research involves human subjects.
Recommendation 10: The Advisory Committee recommends to the Human Radiation Interagency Working Group that the IRB component of the federal system for the protection of human subjects be changed in at least the five critical areas described below.
- Mechanisms for ensuring that IRBs appropriately allocate their time so they can adequately review studies that pose more than minimal risk to human subjects. This may include the creation of alternative mechanisms for review and approval of minimal-risk studies.
- Mechanisms for ensuring that the information provided to potential subjects 1) clearly distinguishes research from treatment, 2) realistically portrays the likelihood that subjects may benefit medically from their participation and the nature of the potential benefits, and 3) clearly explains the potential for discomfort and pain that may accompany participation in the research.
- Mechanisms for ensuring that the information provided to potential subjects clearly identifies the federal agency or agencies sponsoring or supporting the research project in whole or in part and all purposes for which the research is being conducted or supported.
- Mechanisms for ensuring that the information provided to potential subjects clearly identifies the financial implications of deciding to consent to or refuse participation in research.
- Recognition that if IRBs are to adequately protect the interests of human subjects, they must have the responsibility to determine that the science is of a quality to warrant the imposition of risk or inconvenience on human subjects and, in the case of research that purports to offer a prospect of medical benefit to subjects, to determine that participating in the research affords patient-subjects at least as good an opportunity of securing this medical benefit as would be available to them without participating in research.
Recommendation 11: The Advisory Committee recommends to the Human Radiation Interagency Working Group that a mechanism be established to provide for the continuing interpretation and application of ethics rules and principles for the conduct of human subject research in an open and public forum. This mechanism is not provided for in the Common Rule.
Recommendation 13: The Advisory Committee recommends that the Human Radiation Interagency Working Group take steps to improve three elements of the current federal system for the protection of the rights and interests of human subjects' oversight, sanctions, and scope: 1) oversight mechanisms to examine outcomes and performance, 2) appropriateness of sanctions for violations of human subjects protections, and 3) extension of human subjects protections to nonfederally funded research (ACHRE 1995, 816 - 826).
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Footnotes
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References
- Advisory Committee on Human Radiation Experiments (ACHRE). 1995. Final Report. Washington, D.C.: U.S. Government Printing Office.
- American Medical Association (AMA). Judicial Council. 1946. 'Supplementary Report of the Judicial Council of the American Medical Association.' Journal of the American Medical Association 132:1090.
- Beecher, H.K. 1966. 'Ethics and Clinical Research.' New England Journal of Medicine 274(24):1354 - 1360.
- Cohn, V. 1973. 'Live-Fetus Research Debated.' Washington Post, 10 April, A-1.
- Department of Health, Education, and Welfare (DHEW). 1971. The Institutional Guide to DHEW Policy on Protection of Human Subjects. Washington, D.C.: U.S. Government Printing Office.
- Faden, R.R., and T.L. Beauchamp. 1986. A History and Theory of Informed Consent. New York: Oxford University Press.
- Harris, S.H. 1994. Factories of Death: Japanese Biological Warfare, 1932ñ1945, and the American Cover-Up. New York: Routledge.
- Heller, J. 1972. 'Syphilis Victims in U.S. Study Went Untreated for 40 Years.' New York Times, 26 July, A-1.
- Jones, J.H. 1981. Bad Blood: The Tuskegee Syphilis Experiment.
- New York: The Free Press.
- Jonsen, A.R. 1998. The Birth of Bioethics. New York: Oxford University Press.
- Moreno, J.D. 1999. Undue Risk: Secret State Experiments on Humans. New York: W.H. Freeman.
- National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (National Commission). 1979.
- Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research. Washington, D.C.: U.S. Government Printing Office.
- National Institutes of Health (NIH). 1953. Group Consideration of Clinical Research Procedures Deviating from Accepted Medical Practice or Involving Unusual Hazard. In Final Report, Supplemental Vol. I, 321 - 324. Washington, D.C.: U.S.
- Government Printing Office.
- Pappworth, M.H. 1962. 'Human Guinea Pigs: A Warning.'
- Twentieth Century Autumn:66 - 75.
- President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research (President's Commission). 1981. Protecting Human Subjects. First Biennial Report on the Adequacy and Uniformity of Federal Rules and Policies, and of their Implementation, for the Protection of Human Subjects.
- Washington, D.C.: U.S. Government Printing Office.
- ... 1983. Implementing Human Research Regulations. Second Biennial Report on the Adequacy and Uniformity of Federal Rules and Policies, and of their Implementation, for the Protection of Human Subjects. Washington, D.C.: U.S. Government Printing Office.
- Public Health Service (PHS). 1966. Clinical Investigations Using Human Subjects. In Final Report, Supplemental Vol. I, 475 - 476. Washington, D.C.: U.S. Government Printing Office.
- Rothman, D.J. 1991. Strangers at the Bedside: A History of How Law and Bioethics Transformed Medical Decision Making. New York: Basic Books.
- Shuster, E. 1997. 'Fifty Years Later: The Significance of the Nuremberg Code.' New England Journal of Medicine 337(20):1436 - 1440.
- Stewart, W.H. 1966. Clinical Research Investigations Using Human Subjects. In Final Report, Supplemental Vol. I, 473 - 474.
- Washington, D.C.: U.S. Government Printing Office.
- Tuskegee Syphilis Study Ad Hoc Advisory Panel. 1973. Final Report. Washington, D.C.: DHEW.
- Wilson, C. 1953. Memorandum for the Secretary of the Army, Secretary of the Navy, Secretary of the Air Force. In Final Report, Supplemental Vol. I, 308 - 310. Washington, D.C.: U.S. Government Printing Office.
Cite this page:
"Appendix C: The Current Oversight System: History and Description (Research Involving Human Participants V1)"
Online Ethics Center for Engineering
5/23/2007
National Academy of Engineering
Accessed: Wednesday, February 08, 2012
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