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Adverse Event Reporting
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Clinical Trial Design
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Clinical Trials Monitoring
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Human Data and Specimens in Research
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Human Subjects Regulations
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Informed Consent
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Models of IRB Review
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Adverse Event Reporting
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Reporting of Safety Information
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Tremendous diversity exists among adverse event reporting requirements promulgated by various Federal agencies, as well as among the NIH Institutes. This heterogeneity is a challenge for investigators, IRBs, and sponsors, who may face multiple requirements regarding the content, format, and timing of reports that must be made to different agencies and oversight bodies.
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An important mechanism for achieving the goal of improved harmonization of adverse event reporting is the Federal Adverse Event Task Force (FAET), an interagency body composed of representatives of the National Institutes of Health (the CRpac program), Food and Drug Administration, Office for Human Research Protections, the Centers for Disease Control and Prevention, the Department of Veterans Affairs, the Department of Defense, and the Agency for Healthcare Research and Quality. The purpose of the FAET is to propose specific means for promoting harmonized and streamlined requirements and processes for reporting of adverse events in clinical research. Toward this end, the FAET is conducting a comprehensive, in-depth assessment and analysis of existing federal policies for adverse event reporting, discerning how agencies collect and use data in promoting the safety and integrity of their clinical research activities, and identifying opportunities for greater interagency harmonization. FAET has worked closely with OHRP to develop a comprehensive guidance to ensure review and reporting of adverse events and unanticipated problems occur in a timely and insightful manner to protect human subjects from undue risk and harm.
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To address the diversity of requirements that exist within the NIH, a Trans-NIH Adverse Event Task Force has been established and charged with proposing ways to harmonize the reporting policies of the agency's many Institutes and Centers.
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Key Policies and Resources
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Clinical Trial Design
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Science, Safety, and Ethics of Designing Clinical Trials
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Proper clinical trial design is critical to ensuring the scientific validity of research results, the potential benefits that will accrue to society from the knowledge gained, and the ethics of conducting experimentation on human research participants. Different design choices have different implications for the applicability of research results to clinical practice, and for the risks and benefits to human participants in a trial. For example, in some cases, there is no clear consensus on what comparison arms should be included in a clinical trial testing a new or existing intervention. A classic approach in many trials is to compare an intervention of interest to standard treatment. Yet, whether and how to include such a comparison arm is a complex determination in situations where multiple modalities are used, or where there is a lack of consensus in the professional community regarding which treatment is best.
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The absence of consensus about how to handle such clinical trial design issues has led to controversy and even to the temporary halt of a clinical trial. Thus, the CRpac program aims to create a broad dialogue about these matters and develop "points to consider" as guidance for clinical investigators, ethical review committees, and other stakeholders to inform the design and oversight of future studies.
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As a step toward this end, the CRpac program convened a conference November 14-15, 2005 titled, "Considering Usual Medical Care in Clinical Trial Design: Scientific and Ethical Issues." The planning committee for this activity included experts from NIH, OHRP, FDA, CMS, and AHRQ. Speakers addressed such matters as the fundamental scientific and statistical principles pertinent to clinical trial design, ethical considerations in the selection of comparison arms in clinical trials, and other topics to set the intellectual foundation for discussion. These foundational principles were applied to case studies involving several different areas of clinical practice. The scientific and ethical implications of different design choices were also discussed, and these parameters will be articulated in a draft "points to consider" document for broader consideration by relevant stakeholder communities. A proceedings of the meeting is available.
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Key Policies and Resources
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Clinical Trials Monitoring
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Data and Safety Monitoring Boards and Other Review Mechanisms
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Clinical trials must be conducted at a high standard of quality that assures the research question is answered in a reliable, valid, and unbiased manner, while protecting the rights and welfare of the participating human subjects. Accordingly, the safety of subjects in a clinical trial must be monitored, potential harms minimized, and if the design of the study is deemed no longer appropriate, the trial must discontinue.
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In 1998, NIH issued a policy statement further clarified in 2000 - that each Institute and Center (IC) should have a system for the appropriate oversight and monitoring of the conduct of clinical trials to ensure the safety of participants and the validity and integrity of the data for all NIH-supported or conducted clinical trials. The NIH requirement for data and safety monitoring and IC oversight for all clinical trials - commensurate with the risks, size and complexity of the trial - is separate and distinct from the requirement for study review and approval by an Institutional Review Board (IRB).
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The 1998 and 2000 statements also described when monitoring should be in the form of a Data and Safety Monitoring Board. A DSMB is an independent advisory body of pertinent experts appointed to assess, at regular intervals, the progress of a clinical trial (or several trials), accumulating outcome data, reports of adverse events, and as appropriate, critical efficacy endpoints, in a manner that contributes to the safety of subjects and the continuing validity and scientific merit of the trial. The DSMB provides recommendations regarding study modification, suspension, or early stopping, as appropriate. While all interventional studies are required to have a data and safety monitoring plan, the establishment of a DSMB to perform the monitoring function may be required by NIH or individual IC policy, based on the characteristics of the clinical trial.
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Other Federal agencies are developing policies and guidance related to data and safety monitoring as well. The Food and Drug Administration (FDA) proposed guidance for data monitoring committees in November 2001, and the final FDA guidance, "Establishment and Operation of Clinical Trial Data Monitoring Committees (DMCs)," was issued on March 28, 2006. OHRP issued guidance in January 2007 on continuing review that focuses on clarifying what constitutes for continuing review and addresses considerations for continuing review of multi-center trials monitored by DSMBs. OHRP also issued guidance in January 2007 on review and reporting of adverse events and unanticipated problems that addressed what interactions should occur between IRBs and DSMBs. The Centers for Disease Control and Prevention (CDC) and the Agency for Healthcare Research and Quality (AHRQ) are each considering the development of a data and safety monitoring policy. Internationally, the issue of data and safety monitoring in clinical trials is also being addressed, and the World Health Organization (WHO) and the European Medicines Agency (EMEA) have each issued guidelines on the use of independent monitoring committees as part of clinical trial management.
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Federal guidance on data and safety monitoring activities continues to evolve, while at the same time, IRBs are being urged to be more responsible for subject safety, including monitoring of clinical studies. This situation raises questions about:
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Human Subjects Regulations
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the types of studies that should require DSMBs;
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how DSMBs should fit into overall data monitoring plans;
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the comparability of NIH and FDA standards for DSMBs; and
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the relative roles of DSMBs and IRBs
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The CRpac program is working to coordinate the development of these various policies to promote consistency and harmony to the extent possible.
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Key Policies and Resources
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Human Data and Specimens in Research
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Ethical, Legal, and Policy Issues
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In growing recognition of the importance of human specimens and data to clinical research, the NIH CRpac program is coordinating a high priority effort to address the legal, ethical and policy issues related to such research. The goal is to facilitate research using human specimens while protecting subjects. In order to examine federal regulations and policies in this area and to determine how they may be streamlined, coordinated and harmonized, CRpac is leading a Trans-HHS Taskforce called the Harmonization of the Ethical, Legal and Policy Issues related to Specimens and Data (HELPS) taskforce. CRpac is also working to promote more consistent policies across the NIH Institutes and Centers by developing a trans-NIH policy framework for NIH funded research with human specimens and data. This effort is being achieved through a Trans-NIH Bioethics Committee (T-NBC) on Human Data and Specimen Committee (DSC). The CRpac initiative covers the legal, ethical and policy issues related to collection, storage, use of, and access to human biological materials and associated data for research. The specific plans of the CRpac initiative include:
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Identifying legal, ethical and policy challenges to research using human specimens and data and strategies for overcoming those challenges while protecting human subjects
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Developing an NIH-wide policy framework to facilitate the collection, storage, use of, and access to, these materials in research
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Coordinating the efforts of a trans-HHS HELPS Task Force to review agencies' existing policies and regulations related to specimens and data to determine where harmonization is needed and to develop strategies to achieve greater consistency
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Promoting more uniform interpretation of existing regulations and policy guidance related to human specimens and data
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Guiding the development of NIH positions on international policy instruments and guidances and coordinating with other federal agencies to advance international harmonization
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Human Subjects Regulations
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Optimizing Regulatory Requirements
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Two principal sets of federal regulations govern human subjects protections in research. The Food and Drug Administration (FDA) human subjects regulations are found
in 21 CFR parts 50 and 56. These regulations are similar to, but distinct from, the "Common Rule" implemented by the Department of Health and Human Services (DHHS) and
17 other federal agencies. The DHHS rules, found in 45 CFR part 46, are enforced by the DHHS Office for Human Research Protections (OHRP).
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The FDA and DHHS regulations differ slightly from one another with respect to certain definitions and concepts. Furthermore, both rules employ regulatory terminology
that IRBs often have difficulty interpreting and applying. The lack of consistent interpretation of regulatory language by IRBs creates unnecessary variability and
uncertainty in the review of research.
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Furthermore, since the promulgation of the Common Rule in 1991, the research landscape has changed considerably. There have been major increases in the volume of research,
in multi-site studies, and in health services and social sciences research. New technologies for research - genomics, imaging, informatics - have also been developed and
have altered the methods and aims of research with human subjects.
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In the ANPRM, the federal government proposed seven possible regulatory reforms. More than 1100 comments were received during the public comment period that ended October 26, 2011. Using input from the NIH ICs, CRpac provided information to NIH leadership to inform them about stakeholder interests relating to these issues.
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On behalf of the NIH, the CRpac program is working to meet the needs of NIH's various stakeholder communities as the government considers possible reforms in the federal
regulations for human subjects research and addresses other related issues and challenges. This is accomplished in several ways. First, CRpac collects and coordinates
NIH comments on important policy matters, such as the ANPRM. Second, CRpac staff serve as NIH representatives for interagency policy development activities.
Third, CRpac is a resource for communication and sharing of best practices within the NIH community regarding ethical, regulatory, and scientific challenges in human subjects research.
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Key Policies and Resources
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Informed Consent
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Guidance and Resources
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Fully informed consent is critical to the ethical conduct of clinical research. Although the consent document is only one component of the entire consent process, its content is defined in regulation and is a critical tool to help potential participants understand the risks and benefits of a research project. Over time, as research has increased in complexity, the informed consent document has become lengthy, complex and difficult to understand. Studies have confirmed that the documents are often written at reading levels considerably higher than that of the majority of the U.S. population. Recent research has shown that there can be a large discrepancy between the information in the informed consent document and a participant's understanding.
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An aim of the CRpac program is to develop informed consent resources that will be of assistance to investigators, IRBs, and prospective research participants. Toward that end, the CRpac program has conducted a comprehensive review and assessment of the communication tools that can be used to enhance the informed consent process; this review includes the broad spectrum of products including pamphlets, videotapes, compact discs, web-based programs and other tools that have been evaluated for their effectiveness. The resource materials produced provide an evidence-based set of recommendations for the informed consent process that takes into account the differing information needs of specific populations, the learning needs of specific groups (such as children and those with limited English proficiency) and the types of clinical research being conducted.
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Key Policies and Resources
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Models of IRB Review
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Alternative Review Models
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Institutional Review Boards (IRBs) were established to allow for an evaluation - independent of the research team - of the risks and benefits of proposed research activities to participants. Fundamental to the IRB's evaluation of these characteristics are knowledge of patient populations, local circumstances, and community attitudes about the research being proposed. Consequently, IRBs were initially bodies that were geographically proximal to the research in question and were administered, most commonly, by the institution conducting the research.
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Over time, clinical research became an inherently more complex activity and the desirability of decentralized institution-by-institution review for certain types of research has been questioned for both practical and philosophical reasons. First, for large, multi-site clinical trials, full review of a given protocol was generally carried out by each involved local IRB. These reviews, often numbering in the hundreds, created a time-consuming, and in the view of some, redundant, workload. The notion of having a single IRB - often called a "central IRB" - review a protocol on behalf of multiple sites thus became a popular notion and was appealing to sponsors of trials for reasons related to the inherent efficiency of this approach. In other situations, a commercial IRB may be engaged by an institution or site to conduct review because the local infrastructure or expertise is insufficient to accommodate review institutionally.
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Nonetheless, there remains disagreement about the relative value of IRBs that are administered directly by the institutions conducting the research under review versus by commercial firms, consortia, or other non-institutional entities. For example, while central IRBs offer greater efficiency and perhaps less costs overall, some fear that they are less able to consider truly local characteristics of the research environment and study population. Commercial IRBs also, in the view of some, create the potential for conflicts of interest by the fee-for-service arrangement that generally underpins their business model, leaving the IRB beholden to the client paying for the review service. Institutional IRBs, on the other hand, are also often characterized as being vulnerable to conflicts of interest by virtue of being staffed and funded by the institution proposing the research in question. This characteristic, coupled with the inefficiencies alluded to above, have led some to advocate for greater use of the central IRB model.
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To address this matter, the CRpac program is launching a dialogue on the characteristics and relative benefits of various models of IRB review. The aim is to produce a resource that will help institutions determine the model of review that may work best for particular areas of research. This process will include the convening of a national conference on this topic with other agencies and stakeholder groups.
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Meetings and Conferences
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National Conference on Alternative IRB Models: Optimizing Human Subjects Protections
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