The conduct of research has been transformed by many factors over the past 25 years, resulting in a much larger and more complex enterprise. Changes include shifts in patterns of research investment; growing stresses on academic medical centers and research universities; the emergence of independent IRBs; changing public per-ceptions and expectations about research participation;
new technologies that affect risks and potential bene-fits in research; and growing consideration of the roles of groups and communities in research design and implementation.
Changes in Trends in Research Investment In the past two decades, phenomenal growth has occurred in federally and industry-sponsored biomedical research. Federal expenditures for medical and health
research conducted in the United States and in foreign countries almost doubled from $6.9 billion to $13.4 billion between 1986 and 1995. Roughly half of that funding went to university-based research programs, largely to academic medical centers.12The federal invest-ment in research involving human participants extends well beyond biomedical research and is extremely diverse (see Exhibit 1.1).
Industry expenditures for medical and health-related research conducted in the United States and in foreign countries have been rising even faster than those of the public sector, tripling from $6.2 billion to $18.6 billion during that same period.13 Research conducted in the United States sponsored by one segment of industry, pharmaceutical companies, has experienced particularly rapid growth, rising 14-fold from $1.5 billion to $22.4 billion between 1980 and 2000 (PhRMA 2000). As a result, industry funding is playing an increasingly impor-tant role in the support and conduct of medical and health-related research.
Not surprisingly, the rapid rise in industry investment in research funding has been matched by an accompany-ing rise in the number of clinical investigators connected with this activity. For example, the number of investi-gators participating in FDA-regulated research increased from 5,500 in 1990 to 25,000 in 1996 (Valigra 1997), and the total number of U.S. clinical investigators is now estimated to be between 45,000 and 50,000 (CenterWatch 2000). Thus, the sheer volume and diversity of research have placed new strains on the system designed to oversee the protection of research participants.
Stresses on Academic Medical Centers and Research Universities
Academic medical centers, traditionally the principal sites of clinical research, have experienced certain stresses that offset, in part, the effects of this growth in research funding. In particular, managed care, price competition in health care, and cost containment efforts (e.g., the Balanced Budget Act of 1997)14 have resulted in reduc-tions in net clinical income to academic institureduc-tions. This trend negatively influences their capacity for research and education, because excess clinical revenue traditionally has been the means by which academic medical centers subsidize these activities (Crowley and Thier 1996;
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Exhibit 1.1: The Size and Scope of Federally Funded Research Involving Human Participants
Sixteen federal departments and agencies reported to NBAC that they conduct or support research involving human participants, although some components within departments reported that they do not sponsor or conduct such research (e.g., the DHHS Administration on Aging). Each agency’s research program involving human participants is distinctive in terms of its size, scope, organization, and focus, all of which reflect its primary mission. The following examples illustrate the diverse types of research conducted or supported by federal agencies:
■ The Department of Defense (DOD) conducts biomed-ical and behavioral research involving human partici-pants within each of the military services and through several additional defense agencies, primarily in areas supporting the mission of the department.
■ The Department of Veterans Affairs (VA) operates inpatient medical centers—including short-term hospitals, psychiatric and rehabilitation facilities, and nursing homes—and domiciliary and outpatient facilities. The VA’s largely intramural biomedical research program focuses on the health care needs of veterans.
■ The Department of Energy (DOE) conducts and supports research involving human participants that ranges from diagnostic and therapeutic applications in nuclear medicine to epidemiological and occu-pational health studies and manages the National Laboratories, where many other agencies sponsor biomedical and nonbiomedical research.
■ The U.S. Coast Guard within the Department of Transportation (DOT) conducts studies involving human participants that are currently limited to ship-board crew endurance efforts.
■ The National Aeronautics and Space Administration conducts ground-based and in-flight biomedical research related to space life that involves human participants.
■ The Census Bureau participates in survey and cen-sus design, questionnaire development, geographic support, and data collection, tabulation, analysis, and dissemination.
■ Research studies in the Human Factors Laboratory at the Federal Highway Administration of DOT include investigations of drivers’ responses to highway design features and in-vehicle information systems.
■ A major research program of the Substance Abuse and Mental Health Services Administration (DHHS) develops knowledge about new ways to improve the prevention and treatment of substance abuse and mental illness and new ways to work with state and local governments, as well as providers, families, and consumers, to apply that knowledge effectively in everyday practice.
■ The Health Care Financing Administration (DHHS) sponsors research designed to study or evaluate public benefit or service programs, such as Medicare/Medicaid and the State Children’s Health Insurance Program.
■ In the area of infectious disease research, the Centers for Disease Control and Prevention (CDC, DHHS) conducts studies involving the systematic collection, analysis, and interpretation of outcome-specific data, closely integrated with timely dissemi-nation of these data to those responsible for preventing and controlling disease or injury.
■ The Directorate of Social, Behavioral and Economic Sciences of the National Science Foundation sup-ports research that builds fundamental knowledge of human behavior and of social and economic systems, organizations, and institutions.
■ The Environmental Protection Agency sponsors research on human exposure to environmental agents, which involves the gathering of physiological measurements (e.g., monitoring a subject’s car-diorespiratory performance) or the collection of body fluids, tissue, or expired air from participants.
■ As part of its HIV/AIDS and Pre-Adolescent Awareness Programs in Africa, the U.S. Agency for International Development supports activities to collect information about what is currently taking place in schools as well as information about student sexual awareness and sexual practices. Research efforts aim to demonstrate what kinds of risk behav-iors exist and how curricula can be developed that will enable students to make informed decisions.15 At least 69 federal departments and agencies are not covered by the Common Rule. NBAC was unable to determine which of these departments and agencies might sponsor or conduct research with human partici-pants; however, at least some of them are involved in such activities.
Mechanic and Dobson 1996). In addition, clinical income has been affected by managed care’s scrutiny of patient-related costs, whereby much routine patient care is deemed unreimbursable when associated with a clinical trial or an “experimental” therapy.
One set of responses has been the establishment of revenue-generating centers for clinical research and the development of new relations with industry (Gallin and Smits 1997). Another is the creation of research partner-ships with health maintenance organizations (Donahue et al. 1996). In addition, the burgeoning number of academic investigators competing for funding has stimu-lated many institutions to seek financial support from industry (Henderson 1999). In some cases, this shift to more private funding has changed the nature of regula-tory oversight.
At the same time, industry-sponsored research is spreading between and beyond academic medical cen-ters. In 1998, only 40 percent of industry funding for clinical trials went to academic medical centers, down from 80 percent in 1991 (Henderson 1999). Large amounts of research are now managed by private Contract Research Organizations (CROs), rather than academic investigators, and there has been significant growth in Site Management Organizations (SMOs), which conduct research in dedicated facilities and through various types of physician networks (Association of Clinical Research Professionals 1997). Research also continues to be performed in private medical and diag-nostic practices unaffiliated with an SMO (CenterWatch 1998). Thus, increasingly some avenues of clinical research fall outside the strongest and most experienced part of the current system of oversight.
To find the large numbers of participants needed to enroll in clinical studies, sponsors and CROs often con-duct a single research study at dozens or even hundreds of sites. A study may involve numerous academic centers, as well as community hospitals and private practice physicians. In order to compete, some academic medical centers are forming research networks and attempting to provide services similar to those of for-profit companies (Bodenheimer 2000). Consequently, the traditional bio-medical research model of one research study led by one
investigator at one academic institution now occurs much less frequently than in the past, a situation that complicates and often prolongs the review and approval of research studies (OIG 1998a, 4–5).
The Emergence of Independent IRBs
As clinical research has spread beyond academic insti-tutions, the locus of ethics review also has shifted. In the United States, the committees that review research with the mandate to protect the rights and welfare of human participants—IRBs—have traditionally been located in the institution in which the research is conducted.
However, IRBs also now exist as separate entities that are not part of the organizational structure of an institution that conducts or funds research. Although many labels are used to describe these groups, this report will use the term independent IRBs.16 Independent IRBs, which have existed for more than 30 years and are growing both in size and in the number of protocols they review, usually are for-profit entities that operate on a fee-for-service basis (OIG 1998b). Traditionally, independent IRBs primarily have reviewed industry-funded clinical research, but since 1995 they also have been permitted to review federally funded research.17 It should be noted that some institutionally affiliated IRBs have begun to charge for review of certain types of protocols (e.g., industry-sponsored research), and may even conduct reviews for other, unaffiliated or loosely affiliated groups, thus acting much like independent IRBs.
Changing Public Perspectives About Research Participation
The growth and spread of clinical research also reflects a growing demand by patients for access to clinical trials. People with difficult-to-treat, life-threatening diseases often see clinical trials as offering the benefits of cutting-edge medicine. In this context, trial participation is viewed as a benefit to be sought rather than a burden to be avoided (Kahn et al. 1998). This sentiment was expressed forcefully by HIV/AIDS activists (Rothman and Edgar 1991), some of whom adopted the slogan,
“A Drug Trial Is Health Care Too” (Annas 1990, 35).
Disease-oriented patient activists have also emphasized the collective benefits of research for all individuals with
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a specific condition. Advocacy groups commonly lobby Congress and NIH for more research funding (in particu-lar for clinical trials) for specific diseases and conditions, not only to benefit individual research participants, but also to improve treatment for all who are affected by a given disease or condition.
These calls for access to trials have spurred a “recon-ceptualization of the concept of justice” in clinical research (Brody 1998). That is, although the application of the principle of justice has traditionally focused on fairly distributing the risks of research—selecting partic-ipants equitably meant not targeting individuals consid-ered vulnerable for participation in risky research from which they were unlikely to receive any direct benefit—
applying the principle of justice now focuses also on fairly distributing the potential benefits of research.
Selecting participants equitably means not unfairly excluding certain subgroups of the population from research and working to ensure that the knowledge gained in research applies as appropriate across all groups in society. Routine exclusion of groups—such as women of childbearing age—once seen as appropriate and protective, is now seen as arbitrary and paternalistic.
Therefore, several federal agencies have developed policies to promote, for example, inclusion of women and/or minorities in research, as well as data analysis relevant to these groups.18 Other policies that reflect a growing emphasis on access to participation in research include FDA’s regulations granting an exception from informed consent requirements for some emergency research (21 CFR 50.24), the promotion of the inclusion of children in research,19and the provision of Medicare payment for the routine costs of clinical trials and items and services that are otherwise generally available to beneficiaries.20 New Technologies Posing New Challenges to Risk/Potential Benefit Analysis
Research both produces and is affected by advances in technology. However, although advances in genetics, the rise of the Internet, and the growth of informatics are all providing important new capabilities for research, these advances also can raise new ethical challenges. For exam-ple, although genetic research may pose no physical risk beyond that of drawing blood, it can pose significant
psychological and economic risks if participants—or their insurers or employers—learn that they are predis-posed to an untreatable condition. NBAC has addressed some of these issues in a previous report (NBAC 1999b).
New information technologies can provide opportu-nities for medical, health-related, and social science research while also raising ethical challenges regarding the protection of confidentiality of the resulting data. The computerization of medical records, which greatly facili-tates retrospective analysis of patients’ medical records, has also prompted discussion about the legitimate access to and use of medical records in the new elec-tronic environment (Etzioni 1999; National Research Council 1997). Such new technologies might, in this case, increase threats to privacy by making it easier to identify patients from combinations of seemingly unidentifiable data, such as age and date of hospital admission (Sweeney 1997; Woodward 1999). As with medical records, computerization has prompted discus-sion about the ability to restrict access to and use of employment or school records, financial information, and large survey data sets (Garfinkel 2000; White 2000).
The Internet has also given rise to new research opportunities and risks by allowing investigators to reach a wide pool of participants, although participants’
assumptions about the anonymity, security, and privacy of Internet connections might not be justified. The ease with which investigators can misrepresent themselves online raises new questions about the propriety of decep-tion research carried out in this context. The possibility for online misrepresentation by participants is also of concern; for example, investigators may have no way of knowing whether children are participants in online research and are therefore in need of special protections (Frankel and Siang 1999).
Growing Consideration of Groups and Communities
Social science research also is undergoing a number of important changes that affect the protection of research participants. Beginning with the cardiovascular disease primary prevention trials conducted in various communities and sponsored by the National Heart, Lung, and Blood Institute in the 1980s (Carleton et al.
1995; Farquhar et al. 1985; Jacobs et al. 1986), there has been an increase in the number of research studies con-ducted in community settings (Mittelmark et al. 1993).
As the behavioral and social determinants of more diseases are known (e.g., HIV/AIDS, lung cancer, heart attack, stroke), the focus of intervention strategies has broadened from the individual to the population, and the research setting has in some cases moved into the com-munity (Schneiderman and Speers 2000). For example, research on cigarette smoking once focused on cessation efforts, and interventions were targeted at individuals (DiClemente et al. 1991). Now, with the emphasis on prevention of smoking behavior, research interventions are often targeted at particular populations and carried out at the community level (Cummings 1999). With such community-oriented research interventions, defining the research participants and identifying the appropriate participant protections can be difficult.
Increasingly, research is conducted with communities, not on communities (Bracht 1991; George et al. 1996).
Local community groups and organizations often act as collaborative investigators by sharing responsibility with academic investigators in designing and implementing a research study (Hatch et al. 1993). However, this new collaborative role of the community raises many issues related to research infrastructure and oversight. For example, it is unclear when community groups must have an IRB and how to build capacity within the com-munity to carry out these regulatory responsibilities.
Issues related to just what individual or which group speaks for the community as a whole and how to obtain community input or consent are continuing challenges to conducting such research.