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Adverse Event Reporting
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Clinical Trials Monitoring
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Models of IRB Review
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Human Specimens and Data
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Human Subjects Regulations
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Informed Consent
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Clinical Trial Design
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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 these goals is the Federal Adverse Event Task Force (FAET), an interagency body composed of representatives of the National Institutes of Health, Food and Drug Administration, Office of 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 these data in promoting the safety and integrity of their clinical research activities, and identifying opportunities for greater interagency harmonization.
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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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Pertinent Resources, Policies, and Regulations
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Department of Health and Human Services:
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Human Subjects Regulations
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OHRP Draft Guidance on "Reporting and Reviewing Adverse Events and Unanticipated Problems Involving Risks to Subjects or Others"
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Food and Drug administration:
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Adverse Event Reporting Requirements
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National Institutes of Health:
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NCI CTEP Adverse Event Reporting Guidelines
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Genetic Modification Clinical Research Information System (GeMCRIS)
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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 and potential harms minimized, while ensuring that a trial continues for an adequate period of time to answer its scientific questions, but is discontinued if the design of the study is no longer appropriate.
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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 (DSMB - see “Pertinent Resources, Policies, and Regulations” below). 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 July 2002 on continuing review that addresses the role of DSMBs and IRBs, but despite these clarifications, local IRBs have different perceptions of their roles and some have required that unblinded interim data from other multicenter trial sites be provided to them. In October 2005, OHRP issued draft guidance for public comment related to the review and reporting of adverse events and unanticipated problems that addressed what interactions should occur between IRBs and DSMBs; the comments on this guidance are being considered by OHRP and coordinated with the FDA. 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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Pertinent Resources, Policies, and Regulations
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European Medicines Agency:
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Guideline on Data Monitoring Committees
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Food and Drug Administration:
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Guidance for Clinical Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees, March 2006
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National Institutes of Health:
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Policy for Data and Safety Monitoring (June 10, 1998)
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Further Guidance on a Data and Safety Monitoring for Phase I and Phase II Trials (June 5, 2000)
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Office of Human Research Protections:
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Guidance on Continuing Review, Including Considerations for DSMBs and Similar Committees
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World Health Organization:
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Operational Guidelines for the Establishment and Functioning of Data and Safety Monitoring Boards
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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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Pertinent Resources, Policies, and Regulations
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Department of Health and Human Services:
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Office of Human Research Protections Guidance on "Knowledge of Local Research Context"
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Office of Human Research Protections Guidance on "The Use of Another Institution's IRB"
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Office of Protections from Research Risks Report on "Local IRB Review of Multicenter Clinical Trials"
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Alternative Models of IRB Review: Workshop Summary Report (November 2005)
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National Conference on Alternative IRB Models: Optimizing Human Subject Protection (November 2006)
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Food and Drug Administration:
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Guidance on "Non-local IRB Review" (1998)
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Food and Drug Administration Guidance on Using a Centralized IRB Review Process in Multicenter Clinical Trials (2006)
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National Institutes of Health:
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NCI Central IRB
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Human Specimens and Data
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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. CRpac is working to promote more consistent policies across the NIH by developing a trans-NIH policy framework for NIH funded research with human specimens and data; and across the Department of Health and Human Services, through an inter-agency taskforce (the HELPS Taskforce). 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; and
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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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Pertinent Resources, Policies, and Regulations
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Department of Health and Human Services:
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Protection of Human Subjects. Code of Federal Regulations, 45 CFR 46
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HIPAA Privacy Rule (Standards for Privacy of Individually Identifiable Health Information) at 45 CFR Parts 160 and 164
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Food and Drug Administration:
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Protection of Human Subjects. Code of Federal Regulations, 21 CFR Parts 50 and 56
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Guidance on Informed Consent for In Vitro Diagnostic Device Studies Using Leftover Human Specimens that are Not Individually Identifiable - Guidance for Sponsors, Institutional Review Boards, Clinical Investigators and FDA Staff
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National Institutes of Health:
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Guidance on "Protecting Personal Health Information in Research: Understanding the HIPAA Privacy Rule" (April 14, 2003; revised 7/13/04)
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Guidance on "Research Repositories, Databases and the HIPAA Privacy Rule" (July 2, 2004)
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Guidance on "Institutional Review Boards and the HIPAA Privacy Rule" (July 8, 2004)
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Office of Human Research Protections:
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Guidance on "Issues to Consider in the Research Use of Stored Data or Tissues" (November 1997)
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Guidance on "Engagement of Institutions in Research" ( January 26, 1999)
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Guidance on "Research Involving Coded Private Information or Biological Specimens" ( August 10, 2004)
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International Compilation of Human Subject Research Protections
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Human Subjects Regulations
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Variability in Application of Regulatory Requirements
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There are two principal sets of regulations governing 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 Department of Health and Human Services (DHHS) and 17 other 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 having difficulty interpreting and applying. Some of these terms and concepts are pivotal to discerning how to apply the regulations. These terms and concepts include:
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"Minimal risk"
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"Minor increase over minimal risk"
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"Disorder"
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"Condition"
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"Human subject"
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"Research"
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The lack of consistent interpretation of regulatory language by IRBs creates unnecessary variability and uncertainty in the review of research. Examples of research where applying the above terms and concepts can be difficult includes research:
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Involving children
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Using human specimens and data
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Collecting data on third parties
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Such uncertainty can result in a lack of clarity on the part of investigators and IRBs about how to comply appropriately with the regulations. This in turn can led to gaps in human subjects protections and unnecessary barriers to research.
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On behalf of the NIH research community, the CRpac program is working to help clarify interpretation of federal regulations for human subjects research. CRpac serves as a centralized resource for the NIH community in several ways. First, CRpac collects and coordinates NIH comments on important policy processes at other agencies, such as FDA and OHRP. 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 and scientific challenges in human subjects research.
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Pertinent Resources, Policies, and Regulations
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Department of Health and Human Services:
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Department of Health and Human Services: Protection of Human Subjects. Code of Federal Regulations, 45 CFR 46
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Guidance for Clinical Investigators, Institutional Review Boards and Sponsors Process for Handling Referrals to FDA Under 21 CFR 50.54: Additional Safeguards for Children in Clinical Investigations
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Office of Human Research Protections: 1993 IRB Guidebook
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Food and Drug Administration:
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Protection of Human Subjects. Code of Federal Regulations, 21 CFR Parts 50 and 56
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Significant Differences in FDA and HHS Regulations for the Protection of Human Subjects
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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 will conduct a comprehensive review and assessment of the communication tools that can be used to enhance the informed consent process; this review will include the broad spectrum of products including pamphlets, videotapes, compact discs, web-based programs and other tools that have been evaluated for their effectiveness. Resource materials produced will 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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Pertinent Resources, Policies, and Regulations
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Department of Health and Human Services:
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Protection of Human Subjects. Code of Federal Regulations, 45 CFR 46
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Office of Human Research Protections (OHRP) Policy Guidance - Informed Consent (Provides a variety of useful OHRP reports and documents on the informed consent process, including tips for researchers and a checklist of elements to include in informed consent documents)
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OHRP FAQs - Informed Consent
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Food and Drug Administration:
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Protection of Human Subjects. Code of Federal Regulations, 21 CFR Parts 50 and 56
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Guidance on Informed Consent for In Vitro Diagnostic Device Studies Using Leftover Human Specimens that are Not Individually Identifiable
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A Guide to Informed Consent
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Exception from Informed Consent For Studies Conducted in Emergency Settings: Regulatory Language and Excerpts from Preamble (1998 - This document provides guidance on the narrow FDA regulatory exception to the requirement for informed consent to allow research on life-threatening conditions for which available treatments are unproven or unsatisfactory, and where it is not possible to obtain informed consent, while establishing additional protections to provide for safe and ethical studies)
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Exception From General Requirements for Informed Consent-FDA's Interim Final Rule at 21 CFR 50.23(e) (The Food and Drug Administration (FDA) issued this interim final rule to amend its medical devices regulations to establish a new exception to the general requirements for informed consent, to permit the use of investigational in vitro diagnostic devices to identify chemical, biological, radiological, or nuclear agents without informed consent in certain circumstances. The exception applies when investigational in vitro diagnostic devices are used and the investigator is unable to obtain timely informed consent from subjects (or their legally authorized representatives) whose specimens are being tested, and delay in diagnosis could be life-threatening to the subject)
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Applicability of 45 CFR part 46 to Clinical Investigations Conducted Under FDA's Interim Final Rule at 21 CFR 50.23(e) (This document addresses how to determine whether the HHS regulations at 45 CFR part 46 are applicable to the activities covered by the Food and Drug Administration's (FDA's) interim final rule, "Medical Devices; Exception From General Requirements for Informed Consent" (21 CFR 50.23(e)). This guidance only applies to clinical investigations that are conducted or supported by HHS)
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National Institutes of Health:
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National Cancer Institute: A Guide to Understanding Informed Consent
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Office of Biotechnology Activities: Informed Consent in Gene Transfer Research
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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. In the meantime, a proceedings of the meeting is available.
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Pertinent Resources, Policies, and Regulations
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National Institutes of Health:
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Proceedings from the conference, "Considering Usual Medical Care in Clinical Trial Design: Scientific and Ethical Issues"
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Food and Drug Administration:
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Guidance for the Use of Bayesian Statistics in Medical Device Clinical Trials - Draft Guidance for Industry and FDA Staff (May 23, 2006) - This draft document discusses important statistical issues and provides guidance on statistical aspects of the design and analysis of clinical trials for medical devices that use Bayesian statistical methods; it does not describe the content of a medical device submission.
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Guidance on Emergency Use of an Investigational Drug or Biologic (1998) - The emergency use of test articles frequently prompts questions from Institutional Review Boards (IRBs) and investigators. This information sheet addresses three areas of concern: emergency Investigational New Drug (IND) requirements; IRB procedures; and informed consent requirements.
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International Conference on Harmonization:
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Harmonized Tripartite Guideline: Statistical Principles for Clinical Trials (E9)
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IHarmonized Tripartite Guideline: Choice of Control Group and Related Issues in Clinical Trials (E10)
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