Recently, researchers have witnessed a vast change regarding the protection of research participants in the clinical research environment. Although federal regulations (particularly the “Common Rule”1) governing human participant research have not changed substantially since 1981, the level of enforcement and the implementation of those regulations have increased dramatically. For example, in June 2000, the Office of Human Research Protections (OHRP) was created within the U.S. Department of Health and Human Services (DHHS) to succeed the Office for Protection from Research Risks. In the 10 years preceding this announcement, Office for Protection from Research Risks had issued 40 determination letters noting violations of a research institution's multiple project assurance.2During the first 18-month period of OHRP's existence, however, 289 determination letters were issued.3The increased enforcement of compliance activity within DHHS, as well as the escalating legal environment, has increased institutional anxiety concerning clinical research.4Whereas clinical researchers previously had modest institutional oversight procedures, these procedures have increased substantially in the form of multiple Institutional Review Boards (IRBs),5conflict-of-interest committees,6scientific oversight committees, and other entities.
Recent accounts of adverse events—including deaths—among patients enrolled in clinical studies have created a public demand for increased protection of patient safety and greater regulation of research institutions.7-9The increased oversight burden threatens to compromise the efficiency of the clinical research enterprise, however, and there is a perception in the clinical research community that regulations are onerous, which may serve as a disincentive for physicians and students who are contemplating careers in clinical research.10The desire to maximize both efficiency and participant protection ranks high on the priority list of many clinical researchers. As such, in a June workshop conducted by the Clinical Research Roundtable (CRR), the issue “Streamlining the Clinical Research Enterprise” was discussed with regard to whether the perceived regulatory burden is due to regulations or to other components of the clinical research enterprise. The CRR is a group of stakeholders in clinical research who represent diverse interests such as academia, industry, government, health care purchasers, and not-for-profit foundations. It convenes regular meetings held by the Institute of Medicine. This report details the discussion that took place during the CRR's June workshop and concludes with our recommendations for further action.
PERSPECTIVE OF INVESTIGATORS AND RESEARCH INSTITUTIONS
Contrary to certain reports in the popular media, the vast majority of clinical biomedical researchers are eager to comply with regulations that are designed to protect the welfare and safety of research participants. Given the current regulatory and legal environment, however, investigators find themselves in need of more assistance in navigating the various institutional and regulatory requirements that are in place, particularly when requirements seem to conflict with each other (e.g., multiple IRB determinations) and the domain of a given regulation is not widely known or understood. Examples of the latter situation include uncertainty about which drugs require that Investigational New Drug applications be submitted with the U.S. Food and Drug Administration (FDA), which protocols are exempt from IRB review, and which aspects of study design require oversight. In general, clinical investigators have a strong desire to meet federal, institutional, and other regulations; they simply need support in fulfilling regulatory requirements on a study-by-study basis.
The 2001 National Bioethics Advisory Commission recommended that education programs be developed by institutions involved in clinical research to promote better understanding of regulations and ethics among its researchers, administrators, IRB members, and other institution members involved in the research process.2Moreover, the federal government, in conjunction with academic and professional societies, should promote and enhance education in research ethics related to human research participants as a key part of investigator education.
Administrators at research institutions keenly feel the need to support investigators in complying with increasingly complex regulations. Many research institutions have already implemented centralized structures to assist individual investigators with regulatory compliance. Such structures include a central office of research support staffed by individuals who are trained to answer questions and provide assistance with various aspects of protocol development, IRB infrastructure for ethical review, and templates forms or other materials required in the regulatory process that are adapted as the regulations themselves evolve. Maintenance of these structures requires an ongoing commitment of resources, however, which may impose an economic burden on research institutions, particularly smaller ones that cannot take advantage of economies of scale in terms of research support. Furthermore, the support structures themselves can become so complex that they become inefficient.
Research institutions also need assistance from regulatory agencies—in the form of training, accessible information, and open dialogue—to stay well informed and up-to-date with respect to current regulations and regulatory guidance documents. Research institutions, like individual investigators, understand that regulations governing clinical research that involves human participants are aimed at protecting individual participants, and they desire to comply fully. As the complexity of this activity continues to increase, however, more resources must be devoted to this task, which imposes an increasingly greater burden on U.S. biomedical research institutions.
PERSPECTIVE OF REGULATORY AGENCIES
Regulatory agencies, including the FDA and the OHRP, are charged with the task of protecting human participants in research studies and, in the case of the FDA, ensuring the quality of data used to support regulatory decisions. In general, the public is very supportive of clinical research; however, disturbing, widely publicized breakdowns in the system have occurred from time to time. Minority communities in particular have had reason in the past to distrust the motives of the research community.11Public trust in the clinical research enterprise is essential, and the pressure on regulatory bodies to fulfill their mandates effectively and completely is tremendous.12,13
In general, regulators perceive that researchers are substantially more compliant with regulations today than they were 30 years ago. For example, the percentage of FDA investigations that resulted in the initiation of official action dropped from 20% in 1997 to 3% in 2000.14Furthermore, leaders of regulatory agencies and research institutions report a willingness to work with each other and maintain an open dialogue. Some institutions seem to be reluctant to devote more resources to the process of research participant protection. Because many players are involved in participant protection, this attitude can lead to differing interpretations of the Common Rule and disparities in enforcement.2The primary challenge for the future is to remove inconsistencies and weaknesses in systems of regulatory compliance and regulatory guidelines for the protection of human research participants.
Federal agencies have implemented a number of initiatives to advance clinical research and facilitate the protection of human research participants. The National Institutes of Health (NIH) has developed on-line research ethics training modules for researchers and also allows “just-in-time” IRB review, whereby IRBs are not required to review a new protocol until after the protocol receives an NIH score within a fundable range.15The NIH also has initiated a series of program grants to enhance institutional research participant protection programs, including support for IRB review, protocol tracking, training, and similar initiatives. The NIH's General Clinical Research Center, under the direction of John Gallin, is developing a system that will help to streamline the human research participant protection process.16In addition, the NIH has instituted a human research participant advocate position as part of its General Clinical Research Center grant network.
The OHRP supplements these programs by coordinating research participant regulations within the DHHS, as well as by providing training modules, ensuring that institutions that receive federal research funds comply with regulations, communicating with other government agencies, and evaluating DHHS policies and procedures for their effectiveness in promoting research participant protection. For its part, the FDA continually evaluates the efficacy of regulations and promotes good clinical practice as well as systems that support research participant protection. Topics of particular focus include dealing with the increase in large multicenter trials, ensuring quality in international studies, and clearly delineating which studies should and should not be monitored according to FDA protocols.
AREAS FOR EVOLUTION AND IMPROVEMENT
Investigators and Research Institutions
The perceived increased burden of complying with FDA, OHRP, and institutional regulatory requirements in addition to other professional duties puts a noticeable strain on investigators. Individual investigators and their institutions are working to ensure that the process of human research protection is more transparent and thorough than before. The heightened public concern regarding issues such as participants' right to privacy and institutional or investigators' financial conflicts of interest are driving many of these changes. To achieve success, investigators and research institutions must forge proactive relationships and partnerships with regulatory agencies and reach out to include the public in all aspects of the research process. In addition, investigators and research institutions must accommodate the regulatory process by streamlining and adapting research protocols. Clinical trials and other research studies should be designed so that compliance with research participant protection regulations makes sense and is understandable to people without specific scientific knowledge. Simplicity rather than complexity should be the goal in study design and in preparing consent forms whenever possible. Not only are simple protocols and consent forms easier to review from an ethical perspective, but also participants comprehend the purpose and the risk-to-benefit ratio of such studies more readily. The community of participants should be consulted as often as possible, even during the selection of research questions and study design. Such input enhances acceptance of the research project and is likely to increase the number of participants in the study as well.
Potential adverse events and other consequences of research should be thought through in advance. Such an approach conserves resources while maintaining public trust in biomedical research in general and removing incentives to add further regulations to a burden already far too complex for the ordinary investigator to navigate alone. Institutions should improve central support systems for investigators to facilitate regulatory compliance. Specifically, institutions should consider providing their investigators with the following services:
Mandatory, meaningful training of participants, investigators, study coordinators, and IRB members
A sufficient number of IRBs to ensure thorough, efficient ethical review of all protocols, which may require a roster of investigators with specific expertise
A sufficient number of dedicated IRB administrative staff members
Standardized language and procedures for IRB submissions, consent forms, conflict-of-interest disclosures, and adverse event reporting
Well-publicized offices with staff who are capable of answering questions about the regulatory process
An adequate number of staff trained to perform certain mandatory tasks, including completing Investigational New Drug applications and other paperwork to be submitted to external regulatory agencies
Consultants or staff to deal with information technology needs
Information systems consistency across studies to facilitate information sharing
High-level administrative officials to oversee the clinical research process
The involvement of community groups in an advisory capacity at the start of the regulatory review process
Expanded assistance to investigators with regard to patient recruitment, data collection, investigational new drug monitoring, and financial support
Such initiatives cannot be undertaken without funding, and although funding agencies do have a responsibility to ensure that studies can be conducted without undermining patient safety, research institutions also must accept that human research participant protection merits dedicated institutional funding as well.
Regulatory and Funding Agencies
Similarly to the burdens that individual investigators face, the resources of funding and regulatory agencies are under increased strain in the current regulatory environment regarding human research participant protection. Nevertheless, such agencies have an obligation to render new regulations, guidance, and determination letters clearly interpretable for individual investigators, research participants, the public, and institutional administrators. Confusion exists with regard to those guidance documents that describe what must be done to remain in compliance with regulations and those that merely offer suggestions on how to comply. Regulatory agencies should invest resources to develop a clear, centralized source of information that is accessible to and understandable by relatively inexperienced clinical researchers and the lay public and that contains the majority of essential information needed for such individuals to develop and perform protocols in compliance with federal regulations. To the extent possible, such information should be presented in plain English rather than in the legal language in which most regulations are written. In addition, regulatory agencies need to have a sufficient number of staff who are dedicated to communicating with institutional research support office staff, thereby enabling those support staff to provide adequate support to investigators. The functions of such regulatory agency staff members should include the training of institutional research support staff, being available to answer questions from various research support offices, and ensuring that the regulatory guidelines are applied in individual investigator or institutional research studies.
In addition to the general need for support from and communication with regulatory bodies, researchers and institutional representatives at the CRR meeting also identified a number of specific areas that they thought that regulatory and funding agencies should address. These areas of concern included regulations that, in their current state, hinder the efficiency of clinical research but do not add proportional value in terms of protecting human participants in clinical research. To address these concerns, the CRR recommended that the following steps be taken:
Develop a consistent definition of, as well as a mechanism to more effectively differentiate, high- and low-risk protocols such that studies involving low risk to research participants would bear less regulatory and ethical review burden.
Make progress toward enabling the review of large multicenter studies by a centralized IRB rather than by local IRBs with equal authority and often contradictory recommendations that ultimately may damage the scientific merit of such studies.
Clarify and refine regulations pertaining to international studies such that local ethical standards can be respected without compromising the safety of study participants.
Consider the development of methods to speed the approval of new drugs and devices, including the use of mandatory postmarketing Phase IV studies rather than multiple prelicensure Phase III studies.
Promote the creation of mechanisms to fund the infrastructure of human research participant protection.
Enhance procedures to streamline the dual processes of scientific and ethical review, because concern exists that study sections and IRBs operate as separate, noncommunicating layers of review, each of which tends to encroach on the other's mandate (i.e., study sections consider ethical issues, IRBs make recommendations on the basis of scientific merit).
In general, the existing regulatory process for the protection of human research participants seems to work well. Participants in the large majority of clinical research studies do not experience significant adverse events. Investigators want to protect research participants and comply with federal regulations, and regulatory agencies are willing to help them do so. Nevertheless, two opposing goals drive the current regulatory structure. The primary goal, acknowledged by both researchers and regulators, is to protect research participants and thereby maintain public trust in the clinical research enterprise. The secondary goal is to maximize the efficiency of that enterprise. Researchers and research institutions generally think that the primary goal of patient safety is being met, but they are overburdened, and work needs to be done toward maximizing participant protection efficiency.
The following are some other conclusions derived from the CRR workshop:
The current regulatory and legal environment surrounding human research participant protection is here to stay. Researchers should accept this fact and work within their institutions to streamline the research enterprise.
Individual investigators are not so much upset with the current regulatory environment as they are lost in it. Institutions must improve their support for researchers and participants in this area.
Investigators should spend more time involved in activities that are aimed at protecting human research participants. Research institutions should set up and maintain centralized research support services, including an adequate number of members on and sufficient infrastructural support of IRBs.
Institutions that fund clinical research must study the possibility of funding activities (e.g., IRB review) that are aimed at complying with research participant regulations. If resources are not devoted to this task, the safety and well-being of research participants and ultimately the public's trust in the research enterprise will be compromised.
Researchers and regulators must communicate and cooperate with each other as they seek to maximize the safety of research participants as well as the efficiency of the clinical research enterprise. By continuing this collaborative effort, the interests of all who devote themselves to the improvement of human life through clinical research—as participants, researchers, administrators, funders, or regulators—can be served.