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Chapter 2: A Proposal for Oversight (Research Involving Human Participants V1)

Introduction
Purpose of Oversight
Functions and Responsibilities of the Oversight System
Scope and Structure of a Revised Oversight System
Exhibit 2.1: Responsibilities of Those Involved in the Oversight System
The Need for a Unified, Comprehensive Federal Policy
Definition of Research Involving Human Participants
Summary
Footnotes
References

Introduction

This chapter proposes an enhanced system of U.S. oversight of research involving human participants, specifically addressing its purpose and functions, the parties involved, and its scope and structure. The chapter also focuses on the definitions of research and human participant, terms that are crucial to delineating the scope of the oversight system. Although some of the components of the proposed system already exist in total or in part within the current system, certain alterations and additions are required. Specifically, what is needed is a more effectively coordinated system:

in which coverage, in terms of protections, is not dependent on source of funding;
that can propose and implement reforms in a timely manner;
that can issue uniform interpretations of regulations, across the government and the private sector, and that can make the rules work both for medical and non-medical research;
that relies on certification and education to better ensure ethical research and that promotes guidance in lieu of regulation;
that streamlines review in a manner commensurate with research risks;
that better reflects the ways in which participants may become vulnerable and the ways this can be avoided;
that can facilitate multi-site review efforts and specialized review mechanisms;
that continues to rely on decentralized review and monitoring, overseen by a more coordinated collection of adverse event reporting;
that has a wide array of enforcement tools that can be tailored more effectively to the nature of the problems encountered; and
that facilitates studying compensation possibilities for those injured in the course of research.

Discussion and recommendations pertaining to each of these criteria are found in this and subsequent chapters of this report. The most significant change proposed is that of consolidation - that is, where there are now multiple sets of overlapping regulations, the National Bioethics Advisory Commission (NBAC) suggests a unified comprehensive policy in the form of a single set of regulations and a single source of guidance and interpretation. This consolidated structure would allow for much needed regulatory flexibility and, in certain areas, a greater use of guidance with less regulation. Of course, an effective oversight system consists of more than governmental regulation. Indeed, it should be devoid of excessive regulation, relying, when appropriate, on the ethical behavior and commitments of all individuals and entities - federal and nonfederal - engaged in research involving human participants.

Purpose of Oversight

For many involved in the oversight system, the bureaucratic procedural requirements (as opposed to ethical principles) that characterize the current federal regulatory system for human research have become synonymous with the purpose, intent, and implementation of the oversight system itself. As a result, some investigators and Institutional Review Board (IRB) members perceive the regulations as lacking an ethical foundation and view them merely as a set of formal procedural requirements,some of which protect human participants (e.g., informed consent), but others of which have little to do with such protection (e.g., assurances of compliance and record keeping).1 2 Unless the regulations and guidance appear ethically substantive, investigators will view them simply as irritating obstacles to doing important, socially valuable work, while IRB members, who are responsible for applying the rules, will become frustrated with investigators' resistance. In such cases, when the largely procedural requirements are perceived as ineffective in improving protections, some investigators might avoid submitting research protocols to IRBs or fail to disclose certain aspects of the protocol (Ferraro et al. 1999; Liddle and Brazalton 1996), behavior that could place participants at risk and compromise public trust in the oversight system.

Some of this frustration could be alleviated if all who are involved in the human research enterprise recognize that the overarching purpose of the system should be to ensure the protection of the participants in a manner that encourages and facilitates research that is consistent with accepted ethical principles. There is no necessary conflict between the goal of promoting research and its benefits and that of protecting human research participants. In previous reports, NBAC has reinforced the importance of these dual goals (NBAC 1999a, 1999b). In a paper prepared for NBAC, for example, Harold Vanderpool articulated this perspective:

The purposes of protecting human subjects and enhancing the benefits of biomedical and behavioral research are fully justifiable, although their balance should be critically and periodically reassessed. It is a mistake to assume that the relationship between these purposes has to be a zero sum game, whereby increased protection for subjects subtracts from the conducting of research.3

As discussed in Chapter 1, a credible system for the protection of research participants promotes research by encouraging public support and participation. In addition, by requiring careful consideration of the implications of study design on the ethical acceptability of a protocol and independent review prior to the involvement of human participants, the oversight system often leads to improvements in research design. The system also can promote research by providing a prospective mechanism for discussion and review of controversial research, moving many innovative research studies forward.

Protection of human participants should never be an afterthought. Rather, it should be a factor in decision-making by everybody involved throughout the conception, design, review, and performance of human research. The oversight system should act to forbid research designs that are clearly unethical. In areas of less ethical certainty, the system should ensure protection of research participants by providing mechanisms for applying accepted ethical principles and seeking independent review and public input to resolve issues of uncertainty. But the system should allow the majority of research, for which there is clear ethical acceptance, to proceed with minimal delay. An oversight system succeeds to the extent that it encourages the protection of participants in all aspects of research, but does not create any unnecessary barriers to the conduct of research.

Although the need to protect human research participants is a well-accepted norm, controversy arises over the amount of protection that should be required. Jonathan Moreno provides a useful framework for considering the levels of protectionism that are needed. Weak protectionism requires that participants be provided at least the protection of informed consent, but it relies on the virtue and commitment of the investigators to provide that protection without any external involvement by an outside entity. In moderate protectionism, the investigators remain responsible for providing protection, including obtaining informed consent from participants, but the research study undergoes an independent external review. A system of strong protectionism would greatly reduce reliance on the investigator for providing substantive protections to participants by, for example, increasing the use of third parties for monitoring the conduct of the research.4 The current system of requiring prior approval of research by IRBs and informed consent by participants is a moderately protectionist approach that is appropriate because it can protect participants while not imposing inappropriate delays in initiating ethically sound research.

Functions and Responsibilities of the Oversight System

The oversight system should include several interrelated but distinct functions and responsibilities. It should establish clear and effective policies in the form of regulations or guidance; provide education and assistance to all parties; require review of research to determine whether it is ethically acceptable; monitor ongoing research and the operation and behavior of institutions, IRBs, and investigators; enforce requirements; and maintain public accountability.

Policy: Regulation and Guidance

Establishing policy by providing regulations or guidance provides a necessary framework for the entire oversight system. It also provides leadership by setting the direction, approach, and tone. Policies must be established by the federal government in order to ensure uniform protection of research participants regardless of the source of the research funding. In addition, whether issued as regulations or nonbinding guidance, policies must be presented in an understandable form.

Regulations alone are unlikely to be sufficient to address all types of research (e.g., clinical trials, surveys, records review studies, studies using stored human biological materials, behavioral experiments, or oral history studies). Therefore, guidance, because it establishes standards of acceptable practice while allowing for reasoned deviations, can be used to supplement regulations by indicating how substantive ethical principles can be implemented in particular circumstances.5 Moreover, guidance can be particularly helpful in areas of emerging research where the ethical standards and associated procedures are not entirely clear or well developed. In such situations, thoughtful discussion within the framework of existing guidance may be sufficient to allow innovative research to move forward, and if not, new guidance can be developed promptly.

No matter how well regulations and guidance are written, situations will arise in which it is unclear how ethical principles should be applied or regulations should be interpreted.

Policy interpretation and consultation, provided by a federal oversight office, would be particularly helpful to IRBs struggling with especially complex or difficult research studies.

Education

Understanding basic ethical principles and how they apply in various research situations is the best way to avoid inadvertent harm to the rights and welfare of participants. Education can also prepare individuals to understand and resolve ethical issues, especially novel ethical problems, as they arise in specific research studies. (Educational programs are discussed in more detail in Chapter 3.) An effective oversight system helps make education available to all relevant parties. Investigators, IRB staff and members, contract research organizations (CROs), institutional officials, and sponsors (public and private) are the primary audiences for education. Educational activities, however, should be tailored to the particular role of each party in the research enterprise and be relevant to different types of research.

It is also important to educate prospective participants and the general public. Education directed at these audiences should strive to increase the public's awareness of the system's functions and operations, which can encourage informed decisionmaking by prospective participants, increase public input regarding policies for the protection of research participants, and increase and sustain the willingness of the public to participate in and support the research enterprise.

Review of Research

In the United States, independent review of proposed research to determine whether it is ethically acceptable is largely performed by local IRBs and is one of the primary means by which the current system provides protection to research participants.6 Such review should be responsive to the nature of risk and commensurate with the level of risk involved. For example, the risks and potential benefits arising in a clinical trial are generally different from those arising in a study using existing data. Likewise, social science and humanities research raises risks and potential benefits that differ from those raised by clinical research. Harms may vary from physical to psychological, social, or legal. Within each of these domains, the risk of harm may range from low to high. Review criteria and mechanisms should be matched to the ethical issues arising from the research. IRBs, as full committees, should review research involving more than minimal risk; however, IRBs should be able to develop procedures other than full board review for research involving no more than minimal risk.

Research involving difficult ethical considerations, such as highly innovative interventions or technologies, should be reviewed by a body with particular expertise and experience in these special issues, in addition to the local IRB, unless the local IRB is especially qualified to review such research. Several options should be available for providing such heightened review, including specially trained and accredited local IRBs or specially created regional or national review bodies. Often, these special bodies would be reviewing classes of research rather than individual research protocols in order to assist in the development of guidance to local IRBs regarding the criteria for approval. For example, NBAC previously recommended the use of a special standing panel to review research studies involving persons with mental disorders that may affect their decisionmaking capacity and a national-level review for certain types of stem cell research (NBAC 1998; NBAC 1999a). However, because national or special review panels could increase delays or even prevent some research from being conducted, steps must be taken to ensure that the system does not impose undue delays on the approval of ethically sound research.

IRB Review of Research Involving No More Than Minimal Risk

IRBs should be allowed to use procedures that are more expeditious than full board review for research that involves no more than minimal risk. Such procedures should also be permitted for handling other research-related matters, such as determining whether an activity is research and subject to oversight, reviewing minor proposed changes to an approved protocol, conducting some types of continuing review, and reviewing some reports of unanticipated problems. Under the current system, the expedited review process is akin to the procedures proposed here, which are intended to replace the expedited review process and to expand the activities that could be handled by the IRB more expeditiously than through a full board meeting. Generally, IRBs should be able to use more efficient procedures to handle most, if not all, research-related issues, with the exception of protocols involving more than minimal risk.

Such procedures would differ from the current expedited review in several ways:

All research involving no more than minimal risk would be eligible for review under these more expeditious processes (see Chapter 4).
The IRB chair or a designee would not need to carry out these more expeditious processes. Instead, NBAC proposes that a minimum requirement of review be carried out by a certified IRB professional who may be a member of the IRB or an IRB administrator. The individual(s) conducting the review might act alone, ask for advice from an IRB member or from a consultant, or refer the protocol for full IRB review. IRBs may also choose an individual or a small group of IRB members to conduct such reviews. However, those responsible for reviews must be certified. (Chapter 3 discusses certification in more detail.)
The full IRB would not need to be informed of approvals granted through this process.
These procedures would be used to review research involving human participants that is currently exempt from the Common Rule, but that is deemed to be covered by the oversight system. One of the advantages of including research that is now exempt is that it would allow institutions to track their human research portfolios.
IRBs would use more discretion in reviewing research involving little or no risk so that they can move such research quickly through the IRB process. Using these proposed procedures, IRBs would review minimal risk research in accordance with all regulatory requirements; however, they would have discretion with respect to applying the requirements so that the required levels of scrutiny and protections are commensurate with the risks associated with the research. The use of such procedures should take less time than full IRB review and would reduce the workload of the full board and expedite the review process.

Monitoring

The monitoring of activities is an important component of an effective oversight system. One type of monitoring should occur at the federal level, with the federal oversight office (see discussion later in this chapter) monitoring the implementation of oversight activities by federal agencies. Such monitoring should include, for example, ensuring that all federal agencies sponsoring or conducting research follow appropriate policies, regulations, and guidance and report violations, noncompliance, and other unanticipated problems. The federal oversight office should also ensure that accrediting or certifying bodies apply standards applicable to assessing a core set of competencies that has been approved by the federal oversight office and should also play a role in monitoring sponsors and institutions from the private sector when these entities are not monitored either by another federal agency (for example, the Food and Drug Administration [FDA], which oversees research involving investigational new drugs) or by an accrediting body. The goal is to ensure that all parties involved in the various aspects of research protect research participants, both at the time studies are initially approved and throughout the research process. The efforts of the federal oversight office should complement but not duplicate the activities of the accrediting and certifying bodies.

A second type of monitoring involves establishing mechanisms to ensure that institutions, IRBs, and investigators are following regulations and guidance. This type of monitoring is described further in Chapter 3 as verification of compliance. Responsibility for verifying compliance should be shared by different parties. For example, accrediting bodies should be responsible for monitoring accredited institutions and independent IRBs. However, institutions should also establish procedures to monitor their IRBs. They could, for example, have an internal audit process for reviewing, on a sample basis, whether IRB decisions are consistent with regulatory requirements. Institutions also should implement such procedures to determine whether investigators are complying with regulatory requirements and conducting research according to IRB-approved protocols.

The third type of monitoring assesses the progress of research through conducting continuing review of ongoing research and monitoring the safety of research participants and whether unanticipated problems or events occur. Investigators, IRBs, sponsors, or those acting on behalf of sponsors, such as CROs or Data and Safety Monitoring Boards, generally carry out these activities. Monitoring should provide the information needed to evaluate whether the oversight system is achieving its purpose. If gaps exist between purpose and performance, monitoring should help to identify their nature, magnitude, and location and should ensure the development of measures to close them. The results of monitoring might also show a need for changes in policy, additional or enhanced education, or enforcement measures.

Enforcement

The provision of enforcement measures makes all parties aware that the system must be taken seriously and ensures the public's continuing trust. Monitoring is used as an additional mechanism to prevent harm to participants, to promote improved practices, and to assess whether any violations are inadvertent or intentional. When investigators are unwilling or unable to provide appropriate protection to participants, enforcement should stop individuals and possibly their institutions from conducting human research. Enforcement should complement policy, education, and monitoring of compliance to ensure that research participants are protected; however, it should not be the primary focus of an oversight system.

Sanctions are necessary in serious cases of noncom-pliance or in the case of repeat offenses. Most sanctions involve administrative action by a government agency against an individual or organization for failure to comply with regulatory requirements. The oversight system should include a range of sanctions, including halting research at an institution; de-accrediting an IRB or institution; requiring special training and probation accompanied by mentoring; disqualifying or debarring an investigator from conducting research involving human participants; removing the investigator from a particular research study; issuing letters of reprimand to investigators, IRBs, or institutions; conducting special monitoring of investigators or IRBs; refusing to publish the research results that do not meet all the ethical obligations to human participants (NBAC 1999b); and levying civil monetary penalties. However, enforcement also might include judicial action. Regulatory agencies have the authority to initiate and conduct such actions, but in a broader sense, enforcement includes all the ways in which the oversight system induces actions that support the purposes of the system. Thus, many parties carry responsibility for enforcement, including regulators, sponsors, institutions, IRBs, professional societies, editors of scientific publications, and accrediting and certifying bodies.

Accountability

The proposed oversight system is strengthened when its policies, interventions, and outcomes are open to public view and input. In addition, dissemination of results of research studies and of research protection creates a public record that can form the basis for trust. Easily accessed systems for registering concerns and complaints help to bring problems to the attention of those who can resolve them and offer necessary safeguards to those who believe they have been harmed in the course of research participation.7 See Exhibit 2.1 for a description of the responsibilities of those involved in the oversight system.

Scope and Structure of a Revised Oversight System

Scope of Oversight

In 1997, NBAC unanimously adopted a resolution that "[n]o person in the United States should be enrolled in research without the twin protections of informed consent by an authorized person and independent review of the risks and benefits of the research." NBAC adopted this resolution based on the conviction that the entitlement to an independent review of risks and potential benefits and the opportunity to exercise informed consent are grounded in civil and human rights. Whether or not participants in currently unregulated research are harmed in greater numbers or to a greater degree than those in regulated research is not and cannot be known because of a lack of data at the national level. Nonetheless, protecting the rights and welfare of all participants is necessary to maintain public trust in the research community as well as to guard against the actual harm of research participants.

However, not all research participants are protected by the Common Rule (see Figures 2.1 and C.1). Some institutions conduct research that is not covered by the Common Rule or regulated as research by FDA, and unless those institutions voluntarily commit to reviewing.

Exhibit 2.1: Responsibilities of Those Involved in the Oversight System

Participants:: Even though investigators are obligated to adequately inform participants about research, competent participants have a responsibility to become knowledgeable about a prospective research study and to use the information to make an informed decision about participation. During the research study, participants are responsible for staying informed about the research, following the study procedures, reporting problems encountered in the course of research, and informing investigators when they move in order to facilitate additional contact that may be necessary, as long as they voluntarily remain in the study. It is important to remember that participants also have the right to discontinue their participation at any time during the study, so they only have a limited, or qualified, responsibility to follow the study procedures.
Investigators:: Investigators have an obligation to ensure that research studies are scientifically and ethically sound, are reviewed and approved by an IRB prior to conducting the study, are conducted in accordance with an approved protocol, and receive appropriate safety monitoring and continuing review. They are also obligated to acknowledge when errors occur or problems develop and to report them to appropriate parties, such as the IRB. The FDA regulations contain a specific definition of investigator, which "...means an individual who actually conducts or leads a clinical investigation...or, in the event of an investigation conducted by a team of individuals, is the responsible leader of that team" (21 CFR 50.3 (d)).
Institutions:: Institutions engaged in research may be public or private entities. They are usually organizations (e.g., universities, medical schools, insurance companies, research firms, pharmaceutical companies, or dedicated research facilities) that employ investigators, but may also be facilities in which research is conducted (e.g., hospitals, prisons, schools, community-based organizations). For some research there may be more than one relevant institution involved; for example, when a university-affiliated investigator conducts research in a prison or in an educational, industrial, or corporate setting, or when a pharmaceutical company conducts a clinical trial at multiple sites. By either employing investigators or allowing research to be conducted in its facilities, each institution engaged in research must take responsibility for the ethical conduct of that research. Moreover, each institution has an obligation to ensure that the research is conducted in accordance with all applicable federal and state laws, regulations, and procedures. Institutions that employ investigators also have responsibilities for education, monitoring, and enforcement. Moreover, institutions in which research is conducted often have other obligations to participants;for example, as patients or students.
IRBs:: IRBs serve as a principle component of that part of the research enterprise charged with protecting research participants. IRBs are responsible for reviewing human participant research to ensure that the proposed study is ethically acceptable prior to initiation of the study. Once research begins, IRBs have a responsibility to monitor the progress of the approved research with the primary goal of protecting participants, but also to ensure that the research is proceeding according to the approved proposal. This is usually accomplished through the process of periodic review.
Sponsors:: Sponsors are the governmental and private organizations that fund (through grants and contracts) research. Sponsors have responsibility for the manner in which studies are conducted. When sponsors are federal agencies, they share responsibilities with the federal oversight office for guidance development, education, monitoring, and enforcement. However, all sponsors share responsibilities for educating their employees and the investigators who conduct their research. Sponsors are responsible for ensuring that their research has scientific merit and is ethically justifiable prior to funding. For certain types of research (e.g., high-risk research), sponsors are responsible for ensuring that additional oversight protections are provided that allow expert and public vetting of the proposed research. They are also responsible for ensuring that investigators and relevant institutions monitor ongoing progress, and they may have monitoring responsibilities of their own. In conjunction with the federal oversight office, sponsors also may have some enforcement responsibilities. In contrast to the use of terms in this report, FDA regulations use the term "sponsor"/em> in a more narrow sense. It means a person who initiates a clinical investigation, but who does not actually conduct the investigation� A person other than an individual (e.g., corporation or agency) that uses one or more of its own employees to conduct a clinical investigation it has initiated is considered to be a sponsor (not a sponsor-investigator), and the employees are considered to be investigators (21 CFR 50.3(e)). In contrast, the FDA regulations state that the term "sponsor-investigator" means an individual who both initiates and actually conducts, alone or with others, a clinical investigation� The term does not include any person other than an individual, e.g., corporation or agency (21 CFR 50.3 (f)).
Professional Societies and Advocacy Organizations:: These organizations are valuable resources in the education process that should encourage their members to seek out educational opportunities, inform them of professional codes relating to the ethical conduct of research, and provide relevant materials to them.
Accrediting and Certifying Organizations:: Although there are many accrediting and certifying organizations, programs for accreditation and certification of those involved in human research are new or just developing, although the need for such programs has long been recognized (IOM 2001; President's Commission 1983, 114 - 121).
Editors and Publishers:: As arbiters of scientific quality, scientific editors and publishers are obligated to ensure that the data they publish were collected and analyzed according to the ethical standards set forth by the oversight system (NBAC 1998, NBAC 1999b).
Congress:: Congress is responsible for providing the authorizing language and appropriations for research programs and agencies that support the oversight system. Through its governing authorities, Congress can monitor the performance of federal officials and institutions conducting federally regulated research.
State Regulators:: Although some states have separate statutes and regulations governing human research,8 federal and state regulatory systems are not structurally connected. When federal and state regulations are applicable to a research study, the more protective provisions must be met (45 CFR 46.101(f); 21 CFR 56.103(c)). A state may require greater protection, but it cannot allow less protection than is mandated by the federal requirements. such research according to the Common Rule, participants might not be protected. The commitment to protect participants should not be voluntary, nor should requirements be adhered to for only some human research (e.g., private organizations following federal requirements for FDA-regulated research, such as an investigational new drug study, but not following federal requirements when conducting an epidemiological study). All research participants should be protected by the oversight system, and the system should apply to all U.S. investigators and sponsors who conduct research domestically and internationally.

Extending current protections to all privately funded research and making uniform all federal regulations and guidance cannot be accomplished within the current oversight system, which has no authority to act on behalf of the entire federal government and for the benefit of research participants. A unified, comprehensive federal policy promulgated and interpreted by a single office would facilitate the extension of the same protections to all humans participating in research.

Recommendation 2.1:

The federal oversight system should protect the rights and welfare of human research participants by requiring 1) independent review of risks and potential benefits and 2) voluntary informed consent. Protection should be available to participants in both publicly and privately sponsored research. Federal legislation should be enacted to provide such protection.

The Need for a Unified, Comprehensive Federal Policy

A credible oversight system requires that all federal agencies and private organizations follow the same federal policy in the forms of regulation and guidance. Institutions should not be forced to comply with inconsistent regulations when research falls into the jurisdiction of multiple agencies, such as when an a National Institutes of Health (NIH)-sponsored clinical trial involves an investigational new drug regulated by the FDA. Currently, under this circumstance, institutions must follow the Department of Health and Human Services (DHHS) regulations (45 CFR 46) and the FDA regulations (21 CFR 50, 56), which are not entirely consistent with each other.

Because research inevitably raises new issues that require responsive policy development and revision, amending multiple sets of regulations, as would be required in the Common Rule, is not a viable long-term option. To achieve consistency and flexibility, there must be a single set of regulations promulgated and interpreted by a single office.

The legal authority of the current oversight system is not sufficient to expand coverage to all research conducted by the private sector as proposed here or to promulgate a unified policy, specifically as one set of regulations. Recent actions by the Office for Human Research Protections (OHRP) reflect both the initiatives of an office committed to improving human participant protections and its limitations in implementing broad, consistent change across departments and agencies. However, no matter how beneficial or needed the new initiatives may be in order to improve protections, OHRP does not have the authority to function as the lead organization for other departments, and it cannot require other departments to adopt new initiatives or ensure consistency in oversight across departments and agencies.

The creation of such an oversight system would require legislation that expands the authority of the current system to cover the private sector beyond the areas now regulated by the FDA and that creates a single office to oversee the system. Although an executive order could extend protections to all departments and agencies, it could not extend protections beyond federally sponsored or regulated research.

To ensure a uniform, comprehensive system of protection, a single, independent office should be created. Such an office is referred to in this report as the National Office for Human Research Oversight (NOHRO). Once established, NOHRO should be given authority to be the lead office for implementing and enforcing the oversight system for research involving human participants.

Recommendation 2.2:

To ensure the protection of the rights and welfare of all research participants, federal legislation should be enacted to create a single, independent federal office, the National Office for Human Research Oversight (NOHRO), to lead and coordinate the oversight system. This office should be responsible for policy development, regulatory reform (see Recommendation 2.3), research review and monitoring, research ethics education, and enforcement.

Figure 2-1. Involvement of Human Subjects in Research
Federally Funded	Not Federally Funded and Not Subject to FDA	Federally Funded and Not Subject to FDA
Food, Drug, and Cosmetic Act	Assured institutions that do not voluntarily pledge all activity to 45 CFR Part 46. Source: Office for Protection from Research Risks	Some Department of Labor
Food and Drug Administration	Some colleges and universities not receiving federal research funds	Some Nuclear Regulatory Commission
Informed consent	Some in vitro fertilization clinics	Some National Endowment for the Humanities
Institutional Review Boards	Some weight loss or diet clinics
Public Health Service Act	Some physician offices, some dentist offices, and some psychotherapist offices
DHHS 45 CFR Part 46, Subpart A "Institutional Assurances Informed consent Institutional Review Boards", Subpart B "Pregnant Women," Subpart C "Prisoners," Subpart D "Children" = 1991 Federal Policy for the Protection of Human Subjects	Some legal services clinics
	Some corporate and industrial health, safety and fitness programs.
	Some developers of genetic tests
	Some websites

Source: Office for Protection from Research Risks

Recommendation 2.3:

A unified, comprehensive federal policy embodied in a single set of regulations and guidance should be created that would apply to all types of research involving human participants (see Recommendation 2.2).

If these particular recommendations are not implemented, the federal government should find alternative approaches for realizing the intention of these and subsequent recommendations in this report.

Advantages and Disadvantages of a Single, Independent Office

Advantages

Elevating the government entity that oversees research involving human participants to agency status with government-wide authority gives the federal commitment to protect research participants high public visibility. Empowered with the authorities mentioned above, the office would be more likely to achieve the desired outcomes. Clear, consistent regulations and guidance tailored to various types of research would be developed and modified when needed. Most important, the office would be capable of prompt, decisive action in response to new research issues. NBAC envisions the office implementing a dynamic, evolving, and flexible system of oversight. Even on its first day of operation, the new office would be an improvement over the current system, because it will provide a focal point for oversight and a source for information that does not now exist. It also could begin promptly to develop policy, both regulation and guidance.

NOHRO would also eliminate the inertia that occurs in the current system because of the lack of a lead office with authority to direct federal agencies to carry out a task. One way in which NOHRO could facilitate both protection of research participants and the promotion of research is by introducing mechanisms for review of research that involves complex ethical issues. These mechanisms might include requesting a federal agency to set up a special review body or working with local institutions in conjunction with a federal agency that is sponsoring a particular research program.

If the proposed office were located within a department rather than given agency status, special provision would need to be made to force other departments and agencies to follow the policies set by that lead agency. Empowering such a lead agency within one department with authority over operations of other departments at the same administrative level presents a difficult arrangement at best. For example, staff of the other agencies may be subject to competing expectations and demands from their own agencies as well as the proposed office.

Another concern of locating NOHRO within a single department is that it could be perceived both externally and within the department as responsive primarily to that department's interests, views, and the type of research it sponsors or conducts, to the exclusion of other types of research carried out primarily by other departments. For example, OHRP, located in DHHS, has interpreted regulations and developed policy generally in response to the conduct of biomedical research. Furthermore, housing an oversight office within a department that conducts or supports human research could create a conflict of interest. Such a potential conflict provided at least part of the reason for the recommendation to relocate the Office for Protection from Research Risks from NIH to the DHHS Office of the Secretary (OPRR Review Panel 1999). But this degree of separation may still be insufficient, because NIH is part of DHHS, and the new office is still regulating an organization on which it relies for budgetary and other support. The potential conflict of interest is thus attenuated, but not eliminated.9 10 The ability to act without approval from the agencies it regulates is essential to both the perception and reality of NOHRO's effectiveness.

Disadvantages

Establishing an independent office might have disadvantages. Most notably, an independent office would necessarily be smaller than the departments and agencies affected by the policies it develops and thus might lack some of the political support it would need to be effective.11

Creating an independent office could also lead to increased bureaucracy by adding another layer of oversight. NBAC opposes the creation of another office that merely adds regulations that do not provide additional important protections. However, the new office should reduce unnecessary bureaucratic burden by eliminating some duplicative procedures currently existing under the Common Rule. For example, issuing assurances of compliance and registering IRBs should be centralized in the new office (see Chapter 4). The use of such centralizing rulemaking procedures eliminates the requirement that every federal agency bound to the Common Rule institute its own rulemaking procedures in order to revise the Common Rule or make new regulations.

The scarce resources that are currently available to support the oversight system would be insufficient to create and operate the new office. As discussed in Chapter 7, new funds should be appropriated to support the office. Although there might be short-term costs, in the long run, the investment in oversight could ultimately make more funds available for research by reducing the duplication in the current oversight system and streamlining a number of functions.

Another potential disadvantage of an independent office is that its staff may be isolated from those who are involved in the daily conduct of research. However, mechanisms could be established that would make an independent office accountable to the research community, including the IRB community, participants, and the public. First, the office should establish a standing advisory committee to assist in policy development and interpretation with representation from the appropriate federal agencies; the private sector; the research community, including all the major disciplines (e.g., clinical, public health, social sciences, humanities) that conduct such research; the IRB and ethics communities; and the public. Ad hoc advisory committees should be established to deal with specific issues of ethics and review of research. Interacting with the research community will help the office understand and appreciate the nuances in conducting research and deal effectively with emerging ethical issues. At the same time, this office should be closely tied to the IRB community so that it can address issues, problems, or challenges facing IRBs. NOHRO also should develop mechanisms for public input, not only into rulemaking procedures, but also into guidance development procedures. This might include establishing a process for seeking input into decisions involving interpretations of regulations or guidance. The office should also be required to make annual reports to Congress on the status of oversight for research involving human participants.

Two examples of this model of independent, government-wide regulatory bodies, both of which were formerly located within agencies performing the activities they regulated, are the Office of Government Ethics (OGE) and the Nuclear Regulatory Commission (NRC). OGE was formerly part of the Office of Personnel Management and has authority over all federal agencies. NRC was part of the Department of Energy and has authority over both the public and private sector. The creation of OGE and NRC corrected some problems that NBAC has also observed occurring in the current oversight system for research.12 These offices act independently and are free from the interests of other agencies. They are able to make rules and promulgate guidance, visit and audit those they oversee, govern pertinent activity within other federal departments and agencies, and operate with adequate resources, including staff.13

Operating Mode of NOHRO

A lead federal office should not carry out the day-today work of protecting research participants. Once created, it would be imperative for the office to review with all federal agencies their current responsibilities and tasks so that overlapping activities could be avoided or harmonized. Individual federal offices would be responsible for interacting with the lead office and for implementing the oversight system within their departments or agencies. When appropriate, the office should delegate authority to departments or agencies, especially when the implementation of the function will vary by department. For example, departments must have authority to manage the implementation of the human research oversight system in their extramural programs. OHRP should continue to monitor compliance and investigate allegations of noncompliance, provide education, and work with the DHHS agencies in administering their extramural research programs. In fact, OHRP should be able to expand its activities to cover the 11 agencies within DHHS in which they have not had much of a presence.

Generally, NOHRO should be directly responsible for policy development and interpretation through regulation and guidance. Rulemaking and guidance development should occur with input from federal departments, the private sector, academic and research institutions, IRBs, and the public. Education is a shared function, best carried out by other parties in the oversight system, such as academic and other research institutions, public and private sponsors, and professional societies. However, NOHRO should serve a coordinating role, ensuring consistency in educational standards and acting as a catalyst for educational program development.

NOHRO would not only ensure that review of research continues to occur through IRBs, but would also provide the leadership and policy needed to ensure consistency across IRBs. Its role in this function would be to 1) register those institutions and IRBs authorized to review and conduct research using human participants and work with credentialing bodies to develop mechanisms to accredit institutions and certify investigators, IRB members, and IRB staff and 2) coordinate reviews by specially accredited IRBs or specially created regional or national review bodies.

Other responsibilities would include the following:

defining the criteria of research studies that should receive additional review;
defining the criteria for when review should be conducted by a specially accredited IRB or a specially created regional or national review body versus review by a local IRB;
determining the mechanism for communication between local IRBs and the additional review body so that the latter is informed about locally relevant information and the former about deliberations of the additional review body; and
exploring whether there is a need to serve a mediation or arbitration function when IRBs disagree over the review of the same research study.

Monitoring is another shared function that is best carried out by those entities closest to the conduct of research, such as sponsors and institutions or accrediting bodies. NOHRO's role should be to set policy and institute procedures for monitoring the federal agencies that sponsor research.

Although the lead office should have final authority for enforcement, this function should be shared with federal departments, institutions, and accrediting bodies. NOHRO should set policy describing the types of non-compliance, types of sanctions, and use of various types of sanctions to address noncompliance. It should have the authority to conduct investigations to detect regulatory noncompliance and should delegate authority to federal agencies to investigate allegations of noncompli-ance. Federal agencies, accrediting bodies, and institutions should be held accountable to report violations to NOHRO, which should investigate serious violations and repeat offenders.

Regulation of Research Involving Human Participants Sponsored by the Private Sector

NOHRO's authority would extend to research conducted or sponsored by the private sector. Although FDA would continue to regulate research conducted in support of licensure of drugs, medical devices, biological products, or food and color additives, private institutions conducting human research and IRBs would be required to register with NOHRO and to be accredited, and investigators, IRB staff, and IRB members would be required to be certified. Sanctions would apply to both the public and private sectors.

Definition of Research Involving Human Participants

Terminology for Those Who Participate in Research

Thus far, NBAC has defined the scope of the oversight system in terms of the parties that should be covered and the functions to be carried out. This section addresses another aspect regarding scope - that is, which activities should be covered by the oversight system. This involves careful consideration of how to define the terms 'human participant' and 'research'. Various terms are used to describe individuals who participate in research, including 'subjects, respondents, observed, interviewees, informants, participants,' and 'volunteers'.

The term 'subject' is generally used in scientific disciplines in which studies involve experimenting on humans. It connotes the fact that the individual is 'subjected' to an action by the investigator and highlights an important aspect of the nature of the relationship between the investigator and the individual who is the subject of the experiment. No other term more accurately portrays the relationship and the unequal balance of power between the investigator and the individual in the research. 'Subject' sometimes portrays another aspect of the relationship between the investigator and the individual, referred to as passivity.

The term 'subject' traditionally is used in clinical research and was previously used in psychology (it continues to be used by some of the other social science disciplines). Disciplines in which the primary scientific method is the survey tend to use the term 'respondent' or 'interviewee', while disciplines employing purely observational methods may use the term observed (as a noun).

The current federal regulations for protecting those who volunteer for research use the term 'subject', because at the time the regulations were drafted in 1981, the term was commonly used in clinical research, it had validity in describing the relationship between the investigator and the individuals being studied, and sensitivities regarding the term were less recognized. In the past two decades, two other terms have been used - 'participants' and 'volunteers'. In fact, the American Psychological Association began using the term 'participant' in the 1970s (Faden and Beauchamp 1986, 184ñ185). Both terms reflect the commitment to the ethical principle of respect for persons and the aspiration to make 'subjects' more fully protected in the process. Individuals who participate in research are assumed to do so based on their own free will. Thus, the term'participant' is used. 'Volunteer' is even more specific because it makes explicit that participation is voluntary and frequently unpaid.

Neither of these terms is completely satisfactory in describing those who participate in research. 'Volunteer' cannot readily be applied to children or others who may have diminished decisionmaking capacity and may not be able to give informed consent.'Participant 'may seem overly broad and referring to anyone involved in the research. However, the term is likely to be confusing only to those unfamiliar with conducting research. In the literature on this topic, only those individuals who are participating in research as subjects or respondents, for example, are called participants.

Perhaps more important, some individuals who participate in research find the term 'subject' offensive. The term can be perceived as dehumanizing (Ferré and Jones 1997), and several professional organizations have stopped using it. At least two professional societies representing the social sciences use the term 'participant',14 as do Public Responsibility in Medicine and Research and the Applied Research Ethics National Association. Internationally, there is a trend toward using the term 'participant'. France,15 , Uganda (National Consensus Conference on Bioethics and Health Research in Uganda 1997), the United Kingdom (MRC 1998), Australia (NHMRC 1999), and the Joint United Nations Programme on HIV/AIDS (UNAIDS 2000) have adopted ethics guidelines, statements, or codes that refer to human subjects as participants. Others have suggested that subjects should not be thought of as research material or passive individuals but 'simply as persons' and should be encouraged to be active in their participation in research (Veatch 1987, 4).

NBAC believes that the terminology should be changed to 'human participant'.* Even though the term 'subject' has validity, it seems appropriate to change it in order to be more respectful to the individuals who participate in research and to emphasize that individuals should be active, not passive, in the decision to enroll in research studies.

*Commissioner Capron, joined by Commissioners Backlar and Cassell, offers the following observation: "Although I do not believe that we should employ the word participant in place of the traditional term, subject, I recognize that no term is perfect. The traditional term carries a connotation of being under the rule of (and being obedient to) the investigator, which seems to deny a central tenet of research ethics, namely that patients and volunteers are autonomous agents, free to choose whether to participate and to withdraw from a study. Human participant, the term chosen by the Commission, overcomes that problem because it suggests a willing partner in the enterprise, but it fails to convey the fact that among those who participate in the research enterprise, those being termed participants are the ones subject to manipulation and observation and are usually the ones bearing the risk of the research. Participant might be fine as a term of aspiration, but it is premature to adopt the term, because today too many patients and volunteers who are enrolled in research studies are still not free and equal participants in the research; indeed, changing the term could send a false signal that less vigilance is needed to protect human subjects or that investigators and IRBs need not expend further effort to move to a system in which the people being studied are truly research participants."

Defining Research Involving Human Participants and Determining What Is Covered by the Oversight System

Many activities involve interactions between people in which one party does something to another party (manipulates) and in the process of that interaction obtains or analyzes data. For example, physicians diagnose and treat patients, public health officials investigate disease outbreaks in the population, journalists conduct interviews, teachers test students, credit card companies obtain credit information, police officers question suspects and witnesses, the Internal Revenue Service (IRS) audits citizens' tax returns, and investigators conduct various activities with participants in research. All of these activities involve not only human interaction, but also the collection or analysis of data about individuals. Yet, it is intuitively if not explicitly clear that only some of these activities should be regulated under the proposed system of oversight.

The proposed oversight system is not intended to protect the rights and welfare of individuals in all activities involving interactions between people in which one party manipulates another party and in the process of that interaction obtains or analyzes data. To do so would be impractical and inappropriate, because other systems of protection exist to provide those protections in particular circumstances (e.g., state laws related to disease reporting, the legal system for suspects and witnesses in court proceedings, or ethics codes for the practice of medicine).

Research Versus Practice

Drawing the line between research that should be regulated and that which should not be can be difficult. During each of the town meetings conducted by NBAC, questions were raised about the definition of research. For certain professionsósuch as medicine, public health, psychology, social work, and educationóboth practice and research activities are conducted, and the line between the two types of activities can be easily blurred, leading to genuine disagreement or difficult judgments. In other professional areas, there may be only practice activities, but the methods used in these activities are similar to those used in research. For example, the survey methods used in political polls are the same as those used in health research surveys.

As discussed in Appendix C, the United States began to seriously focus on regulating research after the Nazi war crimes trials and the opening of the NIH Clinical Center. Given the historical context, the focus was on differentiating clinical research from clinical practice. Thus, the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (National Commission) was charged16 with distinguishing between research and practice in medical, behavioral, and social interventions and produced eight papers addressing this issue (Campbell and Cecil 1979; Gallant 1979; Goldiamond 1979; Levine 1979; London and Klerman 1979; Robertson 1979; Sabiston 1979; Tropp 1979). Because the National Commission focused its attention on medicine, it used a framework of �he individual versus the group." The basic element of this distinction was that the practice of medicine referred to activities designed solely to enhance the well-being of the specific patient, while research, often using many individuals, was designed to develop or contribute to generalizable knowledge.

Of great interest to the National Commission were ways in which to classify innovative therapies or practices (London and Klerman 1979; Robertson 1979; Sabiston 1979). It was widely recognized that a common practice in medicine involved physicians trying therapies or administering drugs in a manner that differed from generally accepted practice standards. Such innovative practices were considered not to be research because they are generally not carried out in a systematic fashion and they do not generate generalizable knowledge. In addition, there is no built-in conflict of interest between the physician and the patient, because it is presumed that the sole interest of the physician is to provide potential benefit to the patient. However, the National Commission recommended that innovative practices be studied under a research protocol as soon as it became appropriate to study them systematically (National Commission 1979). NBAC agrees with the views and recommendations of the National Commission regarding the handling of innovative therapies.

Missing from the National Commission's deliberations, however, were activities outside clinical or behavioral settings. For example, public health and certain types of research in the humanities and social sciences (e.g., oral history) were only minimally addressed in the National Commission's reports. Thus, a definition of research emerged that differentiated clinical practice from clinical research, but did little to help differentiate practice from research activities in other areas.

The National Commission offered its definition of research in the Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research (Belmont Report) as an "activity designed to test an hypothesis, permit conclusions to be drawn, and thereby to develop or contribute to generalizable knowledge (expressed, for example, in theories, principles, and statements of relationships"). The Belmont Report states further that research is �sually described in a formal protocol that sets forth an objective and a set of procedures designed to reach that objective." Practice is defined as �nterventions that are designed solely to enhance the well-being of an individual patient or client and that have reasonable expectation of success�(National Commission 1979, 2). Although the definition of practice is explicit that interventions are undertaken to benefit individuals, in the definition of research, it is implicit that some, if not all, benefit is to the investigator and to society through the potential advancement of scientific understanding or knowledge.

When the federal regulations were revised following the publication of the Belmont Report, the definition in the Belmont Report was incorporated, but only to a limited degree. Since 1981, the regulatory definition of research in 45 CFR 46.102 has been as follows: �esearch means a systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge." This regulatory definition has been used to identify the universe of activities covered under the Common Rule, but does not include the important distinguishing concept of who benefits from the activity. Clinical practice activities directly benefit those receiving them; the relationship between the professional and the individual is presumed to be unambiguous with the intent presumed to be that of benefiting the individual. In research, however, the relationship between the investigator and the individual is different; investigators use those participating in research to generate knowledge that is of primary benefit to society. Thus, a potential conflict of interest always exists between investigators' desire to pursue knowledge and their obligation to protect the rights and welfare of research participants.

Another shortcoming of the current definition is the use of the term 'generalizable.' By not including a fuller definition of generalizable knowledge that would include, for example, theories, principles, statements of relationship, or attempts to develop answers to a particular question, the term is left to be defined by those attempting to apply the research definition to their activities. For example, without clarifying what is meant by generalizable knowledge, journalistic activities, marketing surveys, political polls, or police investigations could be included in the definition of research because they involve using individuals to gain information for the benefit of those who are gathering the information. However, although these activities generate useful, important information that is of general interest, they normally do not produce new knowledge that can be used to develop or revise theories or principles. NBAC does not consider these activities to fall within the scope of research involving human participants that is subject to oversight.

The current definition of research, though, is even more difficult to use in sorting activities at the boundary between research and practice (e.g., surveillance, program evaluation, quality improvement, innovative therapy, or medical monitoring) or for activities that focus on populations (e.g., public health and health services) rather than on individuals. Public health activities and health services studies are two examples for which the current definition of research is problematic.

Public Health Activities

State and local health departments have broad, legally mandated roles to protect the health of the community through data collection and analysis that target public health actions for disease prevention and control. For many public health practice activities, systematically collected data and scientific methods are used to enhance knowledge. In some cases, the knowledge gained from public health practice could be used to develop or refine knowledge. Although the individuals who participate in these activities rarely benefit directly, the intent of public health practice is always to prevent or control disease and improve health or to improve a public health program or service in a specific population (i.e., the �ublic health patient� (CDC 1999). In public health practice, immediate action is taken based on the analysis of the data to improve the health of the specific population in question. Indeed, carrying out such practices is usually done as part of activity mandated by state statute. These activities are similar to certain medical interventions in which the individual participant does not directly benefit, but others do (e.g., blood donation, skin grafts, organ transplants). In addition, the role of the public health professional usually can be considered more akin to that of the physician than that of the investigator, because the public health professional performs the activities for the benefit of the population being served, just as the physician performs activities for the benefit of the patient.

One could argue that individuals who participate in public health practice activities should be protected because in some sense they are being used just as individuals who participate in research. However, other mechanisms exist to protect the interests of individuals who participate in public health activities. State and local laws address the requirements for informed consent, protections for privacy and confidentiality, procedures for collecting and handling information (e.g., disease reporting and surveillance systems), and penalties for public health professionals when they do not comply with legal requirements.17 Any remaining deficiencies in these protection mechanisms should be evaluated and addressed through state and local laws.

On the other hand, public health professionals also conduct research in conjunction with routine public health practice activities. To provide clarification on applying the current definition of research to public health, the Centers for Disease Control and Prevention (CDC) has developed specific guidance on this matter (CDC 1999), much of which is devoted to clarifying the term designed in a context in which data on populations are routinely and systemically collected and analyzed with the intention of providing an immediate benefit to individuals or their community (practice). This contrasts with activities that are involved in generating knowledge that would have no direct or immediate benefit for the participants or their community, but that would be applicable elsewhere (research).

Public health activities that meet the definition of research involving human participants must be subject to the proposed oversight system; however, public health practice (as defined above) would not be considered research for this purpose. For example, outbreak investigations that do not provide information beyond the scope of the investigation are public health practice and not human participant research. In addition, requirements for disease reporting, monitoring, and other data collection activities conducted under state statute or under recognized public health authority are not research that would fall under the oversight system. However, such data may be used for research purposes, in which case the use, not the initial collection of the data, constitutes research involving human participants and is subject to the oversight system (e.g., use of state cancer registry data for research).

Health Services Research and Program Evaluation

Another area in which it is difficult to apply the definition of research is the delivery of health services. A recent Institute of Medicine report defined health services research as 'the study of the effects of using different modes of organization, delivery and financing for health care services' (IOM 2000, 1). Health services research differs from clinical research in that it concentrates on the study of intervention effectiveness in applied settings, while clinical research concentrates on studying the efficacy of interventions in controlled settings. Eisenberg describes health services research as part of a broader continuum of health-related research, in which the boundaries between biomedical and health services research are blurred (Eisenberg 1998). Yet, some data collection and analysis activities in health services are not intended to generate scientific knowledge, but rather are used as management tools to improve the provision of services to a specific health care population (IOM 2000). These activities, generally referred to as program evaluation or quality improvement, are not intended to have any application beyond the specific organization in which they are conducted. As is true in the area of public health, because populations are the subject of study and because the methods used in program evaluation or quality improvement are the same as those used in research, it is often difficult to determine whether an activity is research that falls under the oversight system.

Definitional issues regarding program evaluation or quality improvement are not limited to health care delivery. They also occur in industrial or educational settings and in social science and operations research. However, if the purpose is to assess the success of an established program, and the information gained from the evaluation will be used to improve that program, the activity should not be considered research involving human participants. Evaluation is a program monitoring tool, and the information gained will immediately benefit the program and/or the individuals involved.

However, when quality improvement involving human participants is undertaken to test a new, modified, or previously untested intervention, service, or program to determine whether it is effective and can be used elsewhere, the activity is human participant research and subject to the oversight system.

Certain Types of Research That Might Not Require Federal Oversight

In some disciplines, especially the social sciences and humanities, it is unclear whether it is appropriate to include certain types of research in the federal oversight system.18 Although no one would question that the systematic investigations undertaken in these disciplines are research, the interpretation of the current regulations and the requirements that IRBs impose on such research may raise concerns.19 The burden on investigators coupled with the lack of any perceived benefit in added protection to participants have led some to suggest that certain types of research in these areas should not be covered under the oversight system.

In fact, intending to avoid unnecessarily burdensome review, the current federal regulations specify six categories of research as exempt from the federal regulatory system. A review of the rulemaking process that occurred when the exemptions were codified indicates that DHHS assumed that most educational, behavioral, and social science research involves little or no risk to research participants and should not be regulated. 20 Although most educational and social science research involves no more than minimal risk to participants, some of these research studies present a significant risk. Because the current regulations do not limit the exemptions only to research involving little or no risk, any kind of research that meets the criteria can be exempted, including, for example, a survey involving sensitive questions. Moreover, some of the exemption categories are used for biomedical research that incorporates the study of behavioral processes and employs behavioral and social science methods.

Further, current regulations specify that when research is exempt from the Federal Policy, the research is exempt from all requirements, not simply from IRB review. It is clear, however, that although requiring IRB review might be not be appropriate, it might be appropriate to require informed consent.

Delineating the criteria for exclusion from coverage is challenging. For the reasons mentioned above, the criteria should not be based on research methods alone. Instead, they should include characteristics of research design that ensure that there is little, if any, risk to participants and that there is a clear and easy opportunity for participants to make an informed refusal to participate. For example, research involving no intervention, the collection of no sensitive information, and no need by investigators to act upon the collected information (e.g., mandatory disclosures) should not be included in the system.

In summary, the definition of covered research can be improved by avoiding the use of terms that are difficult to understand or apply. A clear and accurate definition will help ensure that the federal oversight system will cover activities within its scope. These activities should include those involving the systematic collection or analysis of data with the intent of generating new knowledge, principles, or theories and studies that generate information that revises or improves on an existing principle, theory, or body of knowledge. Some research activities that are conducted in fields that do not rely solely on clinical scientific procedures - such as some types of anthropological or humanities research - should be included under this definition. Among those activities that are considered research, however, some should not be covered under the federal oversight system, especially when they pose little or no risk to participants and allow them to make an informed refusal to participate. Furthermore, although the definition of research need not explicitly state the nature of the relationship between investigators and participants, it should be clear that in those activities defined as research, participants are used at least to some extent by investigators to achieve their research objectives, which might or might not benefit the participants.

In developing one set of regulations and a definition of research, it will be important to harmonize that definition with FDA's definition of regulated activities to ensure that FDA-regulated activities are included. For example, FDA regulations relating to the use of test articles involving experiments with one or more human participants require protections for human participants even if the activity does not involve �esearch�(21 CFR 56.102(c); 21 CFR 312.3(b)).

Who Should Be Protected by the Oversight System?

Under the Common Rule, sequential decisions must be made to determine whether an activity constitutes human participant research. That is, one must first determine whether the activity is research; then, if it is research, one must determine whether it involves human participants. In making this determination, one must establish whether private information is obtained and whether it is individually identifiable (NBAC 1999b), meaning that the 'identity of the subject is or may be readily ascertained by the investigator or associated with the information' (45 CFR 46.102(f)(2)). No definition of �eadily ascertained by the investigator�is provided. Private information includes �nformation 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�(45 CFR 46.102(f)(2)).

This algorithm is often poorly understood (NBAC 1999b). A simpler decisionmaking process could be one that describes human participants who should be covered as those who are exposed to manipulations, interventions, observations, or other types of interactions (e.g., surveys) with investigators or who are identifiable through research using biological materials, medical or other records, or databases.

Different terms are used by various disciplines to describe what occurs in the relationship between investigators and participants. 'Manipulation' or 'intervention' means physical, psychological, or social procedures by which data are collected or by which the participants or the participants' environment are affected as part of the research. 'Interaction' means communication or interpersonal contact between the investigator and the participant.

Investigators include all who are involved in the conduct of a research study, such as scientists, study coordinators, research staff, and data abstractors. Student-initiated research in which the intention of the activity may be as much pedagogical as it is to pursue knowledge is often difficult to classify, 21but students conducting research involving human participants should also be considered investigators. Review of student-initiated research should be commensurate with the risks associated with the research; for example much student-initiated research is likely to involve no more than minimal risk and to be eligible for review using procedures other than full IRB review.

NBAC developed a definition of 'identifiable' in its report on the research use of human biological materials that also applies here, in which coded data are considered identifiable (NBAC 1999b, 17). Coded data were defined as linked or identifiable because, even though they do not include any identifying information, such as names, they have codes that allow the data to be linked to identifying information (NBAC 1999b).

All coded data are identifiable regardless of the how difficult it may be to link the data to identifying information. Even when disclosure of the identifying information is protected under federal or state law and access to the identifying information would be extremely difficult to obtain, the coded data remain identifiable. For example, coded data that are protected under federal confidentiality statutes (e.g., statues adhered to by the Departments of Education and Justice and CDC) should be considered identifiable, and uses of such data for research purposes constitute research involving human participants. Sometimes, investigators who hold coded data will release it to another investigator for use in a research study under a written agreement unequivocally prohibiting release of identifying information to the recipient investigator. 22Even in this instance, the coded data are identifiable, and studies involving such data constitute research involving human participants.

Although all research using coded data involves human participants, the potential to identify individuals varies. Some coded data are easily identifiable (i.e., investigators have access to the key linking the code to identifying information), while other coded data are more difficult to identify (i.e., the recipient of the coded data does not have access to the key), and still other coded data are very difficult if not virtually impossible to identify (i.e., the key is legally protected and cannot be disclosed to investigators). IRBs should consider, when reviewing a particular research study, how easily coded data can be identified and conduct a review that is commensurate with the risks associated with that data. For example, if the coded data are part of a data set that is available for public access, such as those from the National Center for Health Statistics or the Bureau of the Census, the IRB review may consist of nothing more than ascertaining that the data are available to the public and that the owner of the data has taken appropriate steps to protect the coded data (e.g., the confidentiality of the data is protected under federal statute or under state law or a data repository requires the recipient to sign a legally binding agreement stipulating permitted uses of the data and that no identifying information will be released to the recipient).

Research involving the analysis of existing data that are unidentifiable does not involve human participants. NBAC has previously defined two types of unidentifiable data. One type is unidentified, also referred to as anonymous, which are collected from individuals who were not identified at the time of collection. The second type of data is unlinked or anonymized data. Although identifiers were available when the data were collected or stored, at some point, the identifiers were unlinked. Thus, unlinked data lack identifiers or codes that can link the data to identifying information or particular individuals (NBAC 1999b).

Information Revealed About Others

Some research involves interaction with the participant that reveals information about other individuals (e.g., family histories and research on familial interactions). Generally, these other individuals are not considered research participants, although there have been recent discussions about how to consider the rights and welfare of these individuals when constructing appropriate protections (Botkin 2001). NBAC concludes that, in general, these individuals should not be considered human participants in research. Nevertheless, there might be circumstances in which it is appropriate for an IRB to consider whether their rights and welfare are being protected, particularly with regard to confidentiality of data.

Children

Inclusion of children in research raises special issues. Although research with children is not addressed in this report, the proposed system could apply to this population as well. Should this report and its recommendations be implemented, special attention should be given to the ethical standards and regulatory requirements associated with providing adequate protections to children who are research participants.

Embryos and Fetuses

Research involving human fetuses and embryos raises distinct issues. Additional protection exists in the DHHS regulations pertaining to research and related activities involving fetuses, pregnant women, and in vitro fertilization (Subpart B). In 1993, DHHS convened a working group to revise Subpart B. These revisions were published in the Federal Register on January 17, 2001, but are not yet effective. 23

Deceased Individuals

Current federal regulations do not cover deceased individuals, which includes cadavers, biological materials from cadavers, and data from cadavers. NBAC concurs with this position and has in part addressed this issue previously (NBAC 1999b, 29).

As discussed in Chapter 4, when living persons may be affected by research involving the deceased in such a way that the living might experience social, physical, psychological, economic, or legal harm, these risks should be considered by an IRB. Although deceased individuals do not have independent rights and interests that need to be protected, living family members might claim such rights and interests, especially in research in which the living family members may be contacted or in which they or others become aware of the research findings (NBAC 1999b, 49, 73). The burden is on investigators to be sensitive to these issues.

Materials from deceased individuals that are used in a current research study may be obtained from previous research or practice (e.g., specimens collected as part of a surgical procedure). The understanding of individuals at the time they are living with respect to future uses of such materials should be honored following their death (NBAC 1999b, 49). Consent documents should be reviewed to ensure that currently proposed research is not violating the participant's understanding at the time consent was obtained, regardless of whether the materials or data were collected as part of a research study or practice.

This same principle holds true for other types of data. For example, oral histories are often archived, with informed consent from the participant for future research uses, and the data could be used for future research. 24 So that data can be used in an ethical manner after a participant's death, investigators should construct informed consent processes to describe as many potential uses of specimens or data after death that can be anticipated at the time of agreement to participate in the research. In this way, investigators can respect the wishes of participants and at the same time use valuable data repositories.

Decisions Regarding Whether an Activity Is Research and Subject to Federal Oversight

This report does not attempt to offer a regulatory definition of research involving human participants that would be subject to the oversight system that clearly and easily identifies all possible activities that must be included. No regulatory definition of covered research can be written with the sensitivity and specificity needed to ensure that all research activities that should be subject to oversight are always included and all activities that should be excluded from oversight are always excluded. Clarification and interpretation will invariably be required, and ambiguous cases will always arise.

Recommendation 2.4:

Federal policy should cover research involving human participants that entails systematic collection or analysis of data with the intent to generate new knowledge. Research should be considered to involve human participants when individuals 1) are exposed to manipulations, interventions, observations, or other types of interactions with investigators or 2) are identifiable through research using biological materials, medical and other records, or databases. Federal policy also should identify those research activities that are not subject to federal oversight and outline a procedure for determining whether a particular study is or is not covered by the oversight system.

One of the important leadership roles NOHRO should fulfill is to provide guidance on determining whether an activity is research involving human participants and thus subject to oversight. In addition, it should generate a list of activities that are normally treated as human participant research and are therefore subject to oversight as well those that are not. For example, the list of activities not covered by the federal oversight system should include journalism, market surveys, political polls, police investigations, IRS audits, academic examinations, athletic competitions, mandatory disease reporting, outbreak investigations, quality improvement or program evaluation when used as management tools, other defined practice activities in public health, medicine, psychology, and social work, and certain types of research activities posing little or no risk to participants and offering the opportunity for participants to make an informed refusal. NOHRO should initiate a process in which representatives from various disciplines and professions (e.g., social sciences, humanities, business, public health, and health services) contribute to the development of the definition and the list of research activities subject to the oversight system. Based on the recommendations in this report, it is likely that some research that is currently exempt would be covered under the federal oversight system while other, currently exempt research would not be covered.

Moreover, at the local level, institutions should develop policies and procedures for ensuring that a disinterested third party, who is not the investigator, determines whether an activity is research involving human participants and subject to oversight. The third party should be sufficiently knowledgeable about the institution's mission and overall activities to make such determinations, keeping in mind that all disciplines have nuances that make each decision about whether an activity is human participant research unique. Although IRBs or institutional human research oversight offices are obvious locations for this process, other models may be appropriate. In any case, the investigator alone should not make the determination.

Applicability to Various Types of Research

It is NBAC's intention that the definition of research involving human participants be applied in all disciplines. However, because the risks of research differ both qualitatively and quantitatively across the spectrum of research disciplines, the oversight system should ensure that all covered research is subject to basic protections, such as a process of informed consent, except in the specified conditions in which it can be waived; protection of privacy and confidentiality; and minimization of risks. Having potentially included more research under this proposed system, it is more critical than ever that review mechanisms and criteria for various types of research are suited to the nature of the research and the likely risks. This chapter, for example, has described the use of procedures that could accelerate, streamline, or harmonize review, such as less than full board review for minimal risk research and use of specially accredited IRBs or special regional or national review of novel or controversial research to supplement local IRB review. Moreover, more specific guidance for review of different types of research is needed, including guidance regarding review criteria and IRB composition.

Under the proposed oversight system, a wide range of research activities would be covered, from clinical trials to observational studies, with a continuum between them that includes psychological experiments, studies using existing data, and surveys, with the types and degree of risks varying substantially among the different types of research. Thus, review criteria and mechanisms must be appropriate for the particular type of research. To be effective and efficient, the oversight system should encourage flexibility in IRB review; however, the local IRB should implement a common set of ethical principles and standards.

All research studies that are judged to involve no more than minimal risk should be eligible for IRB review using more efficient procedures than a full review, although full board review could be required if deemed necessary by a local IRB. Most social science and humanities research involves no more than minimal risk and can be reviewed using a more efficacious procedure than full IRB review. In addition, many health services research studies, epidemiological studies, and other studies using existing data involve no more than minimal risk and can be reviewed using a less resource-intensive process. However, even within the IRB review category of no more than minimal risk, the risk level varies from virtually none to minimal, and review within the category should be commensurate with the level of risk.

For example, one significant demarcation along the continuum of research is whether it involves interaction with human participants. In research involving the use of existing data or tissues and no interaction with human participants, the primary ethical concerns are threats to privacy and confidentiality (NBAC 1999b). IRBs should pay attention to these types of ethical concerns and have or find the needed expertise, for example, in data management, storage, and transmission; computer security; and other confidentiality protections (e.g., state law). IRBs that review DNA research on stored tissue samples, for example, might have expertise in genetics. The expertise of the IRB or access of the IRB to such expertise (i.e., use of consultants) should be appropriate for addressing the ethical issues the IRB is likely to face in reviewing research. Chapter 4 further discusses IRB review requirements for different types of research.

Recommendation 2.5:

Federal policy should require research ethics review that is commensurate with the nature and level of risk involved. Standards and procedures for review should distinguish between research that poses minimal risk and research that poses more than minimal risk. Minimal risk should be defined as the probability and magnitude of harms that are normally encountered in the daily lives of the general population (see Recommendation 4.2). In addition, the federal government should facilitate the creation of special, supplementary review bodies for research that involves novel or controversial ethical issues.

Summary

A comprehensive and effective oversight system is essential to uniformly protect the rights and welfare of research participants while permitting ethically and scientifically responsible research to proceed without undue delay. To achieve these goals, the oversight system should include several interrelated but distinct functions and responsibilities, including policy development, regulatory reform, research review and monitoring, research ethics education, and enforcement. Many parties are involved in the research enterprise and the system of oversight, including research participants, IRBs, institutions, sponsors, a federal oversight office, state regulators, professional organizations, publishers, Congress, and the public. To function as intended, the system requires that all parties act responsibly, even though the ethical obligation to protect participants lies primarily with investigators, sponsors, and IRBs.

All research participants, regardless of whether the research sponsor is a public or private entity, should be protected by this oversight system, which should apply to both domestic and international research. To accomplish this level and extent of protection, the system must expand beyond its current scope. An independent, single federal office created to lead and coordinate the oversight system would be more effective than the current system and would solve a number of problems. Such an office should promulgate a unified and comprehensive federal policy embodied in a single set of regulations and guidance that can be applied to all types of research involving human participants. Federal protections should be uniform across all sectors of government, academe, and the private sector, but should be flexible enough to be applied in widely different research settings or to emerging areas of research.

Finally, the newly created office should include in its policy a definition of research involving human participants that is subject to federal protections and develop a range of review mechanisms for the various types of covered research. To meet the goal of protecting those who participate in research, the scope and relevancy of protections must be clear to all. Investigators, IRBs, sponsors, and institutions require and must receive unambiguous guidance on the extent to which their research activities are covered by the oversight system.

Footnotes

1 OPRR/FDA Town Hall Meeting: June 16, 2000, Chapel Hill, North Carolina; Vanderpool, H., Testimony before NBAC. June 6, 2000. San Francisco, California.
2 NBAC Town Meetings: February 9, 2000, Houston, Texas; April 5, 2000, Pittsburgh, Pennsylvania; May 3, 2000, Orlando, Florida; June 7, 2000, Chicago, Illinois; August 14, 2000, Portland, Oregon.
3 See Vanderpool, H., "Unfulfilled Promise: How the Belmont Report Can Amend the Code of Federal Regulations Title 45 Part 46 ó Protection of Human Subjects ." This background paper was prepared for NBAC and is available in Volume II of this report.
4 See Moreno, J., "Protectionism in Research Involving Human Subjects." This background paper was prepared for NBAC and is available in Volume II of this report.
5 See Chalmers, D., "Research Ethics in Australia." This background paper was prepared for NBAC and is available in Volume II of this report.
6 See Moreno, J., "Protectionism in Research Involving Human Subjects." This background paper was prepared for NBAC and is available in Volume II of this report.
7 See Chalmers, D., "Research Ethics in Australia." This background paper was prepared for NBAC and is available in Volume II of this report.
8 See Schwartz, J., "Oversight of Human Subject Research: The Role of the States." This background paper was prepared for NBAC and is available in Volume II of this report.
9 See McCarthy, C., "Reflections on the Organizational Locus of the Office for Protection from Research Risks." This background paper was prepared for NBAC and is available in Volume II of this report.
10 See Fletcher, J., "Location of the Office for Protection from Research Risks within the National Institutes of Health: Problems of Status and Independent Authority." This background paper was prepared for NBAC and is available in Volume II of this report.
11 See McCarthy, C., "Reflections on the Organizational Locus of the Office for Protection from Research Risks." This background paper was prepared for NBAC and is available in Volume II of this report.
12 Flack, D., Testimony before NBAC. March 1, 2000. Herndon, Virginia; Ley, J., Testimony before NBAC. March 1, 2000. Herndon, Virginia. See McCarthy, C., "Reflections on the Organizational Locus of the Office for Protection from Research Risks." This background paper was prepared for NBAC and is available in Volume II of this report.
13 See Fletcher, J., "Location of the Office for Protection from Research Risks within the National Institutes of Health: Problems of Status and Independent Authority." This background paper was prepared for NBAC and is available in Volume II of this report.
14 All codes available at American Psychological Association, American Sociological Association, Both sites last accessed December 12, 2000.
15 Law 88-1138 Regarding the Protection of Persons Agreeing to Biomedical Research.
16 Pub. Law 348, 93rd Congress, Title II.
17 NBAC Town Meeting: August 14, 2000, Portland, Oregon.
18 NBAC Town Meetings: February 9, 2000, Houston, Texas; April 5, 2000, Pittsburgh, Pennsylvania; May 3, 2000, Orlando, Florida; June 7, 2000, Chicago, Illinois; August 14, 2000, Portland, Oregon.
19 Wax, M., Testimony before NBAC. April 6, 2000. Washington, D.C.; Sieber, J.E., Testimony before NBAC. April 6, 2000. Washington, D.C.; Abowd, J.M., Testimony before NBAC. April 6, 2000. Washington, D.C.; Shopes, L., Testimony before NBAC. April 6, 2000. Washington, D.C.
20 46 Fed. Reg . 8366-8391.
21 Public Responsibility in Medicine and Research conference on human subjects protections, November 1998,"IRBs and the Shifting Sands of Public Opinion." San Diego, California.
22 OHRP Guidance: "Engagement of Institutions in Research." January 26, 1999; "Issues to Consider in the Research Use of Stored Data or Tissues." November 7, 1997; "Protections for Human Subjects in the NIGMS Human Genetic Mutant Cell Repository: Submission of Non-Identifiable Materials to the Repository." May 22, 1997; "Guidance on Protections for Human Subjects in the National Institute of General Medical Sciences Human Genetic Mutant Cell Repository." May 21, 1997; "Operation of Human Cell Repositories Under HHS Regulations at 45 CFR 46." August 19, 1996. Available at http://ohrp.osophs.dhhs.gov/humansubjects/guidance/reposit.htm Last accessed December 15, 2000.
23 38 Fed. Reg. 3878-3883.
24 K. Ewing and L.K. George, Duke University, to E.M. Meslin, NBAC. February 16, 2001. Letter relating to draft of this report.