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Key Policies and Resources



		Adverse Event Reporting

		Clinical Trial Design

		Clinical Trials Monitoring

		Human Data and Specimens in Research

		Human Subjects Regulations

		Informed Consent

		Models of IRB Review




Adverse Event Reporting

	Department of Health and Human Services:

		Department of Health and Human Services: Protection of Human Subjects. Code of Federal Regulations, 45 CFR 46 Official HHS Federal Code of Regulation for human subject protection in research

	Office of Human Research Protections:

		Reviewing and Reporting Unanticipated Problems and Adverse Events- Educational Video Dr. Michael Carome, OHRP Associate Director of Regulatory Affairs, is interviewed and discusses the criteria for determining if, in the context of human subjects research, an experience, incident, or outcome is an unanticipated problem involving risk to subjects or others, as described in the HHS regulations at 45 CFR part 46. He discusses the differences between adverse events and unanticipated problems and appropriate responses for investigators, IRBs, and institutions when encountering an unanticipated problem. He also discusses prompt reporting requirements and the difference between external and internal unanticipated problems, what to do in the case of multi-center research, and what information that should be reported to OHRP.

		Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or others and Adverse Events (2007) Provides guidance on HHS regulations for the protection of human research subjects at 45 CFR part 46 related to the review and reporting of unanticipated problems involving risks to subjects or others and adverse events. In particular, this guidance clarifies that only a small subset of adverse events occurring in human subjects participating in research are unanticipated problems that must be reported under 45 CFR part 46. The guidance is intended to help ensure that the review and reporting of unanticipated problems and adverse events occur in a timely, meaningful way so that human subjects can be better protected from avoidable harms while reducing unnecessary burden.

	National Institutes of Health:

		Guidance on Reporting Adverse Events to Institutional Review Boards for NIH-Supported Multicenter Clinical Trials (June 11, 1999) Provides guidance to investigators engaged in NIH-supported multi-center clinical trials to promote effective reporting of adverse events to the appropriate IRBs. Highlights investigator responsibility, communication between DSMBs and IRBs and expectations of the NIH program staff that review multicenter clinical trials.

		National Cancer Institute (NCI) Cancer Therapy Evaluation Program (CTEP) Adverse Event Reporting Guidelines Worldwide standard dictionary for reporting acute adverse events to help accurately evaluate new cancer therapies. This resource provides common terminology for adverse event reporting applicable to all oncology clinical trials, a grading or severity scale for each adverse event and instructions and guidelines necessary to carry out such reporting.

	Food and Drug Administration:

		Guidance for Clinical Investigators, Sponsors, and IRBs: Adverse Event Reporting to IRBs, Improving Human Subject Protection (January, 2009) This guidance is intended to assist the research community in interpreting requirements for submitting reports of unanticipated problems, including certain adverse events reports, to the institutional review board (IRB) under Title 21 of the Code of Federal Regulations (21 CFR) part 56 (Institutional Review Boards), part 312 (Investigational New Drug Application), and part 812 (Investigational Device Exemptions). Specifically, the guidance provides recommendations for sponsors and investigators conducting investigational new drug (IND) trials to help them differentiate between those adverse events that are unanticipated problems that must be reported to an IRB and those that are not. The guidance also makes suggestions about how to make communicating adverse events information to IRBs more efficient.
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Clinical Trial Design

	National Institutes of Health System (GeMCRIS)

		Considering Usual Medical Care in Clinical Trial Design: Scientific and Ethical Issues November 14-15, 2005, Meeting Proceedings Meeting proceedings from a NIH sponsored meeting to discuss clinical trial design issues that arise in the use of comparison groups that represent some form of current medical practice. The meeting was attended by more than 300 people from government agencies, academic medical centers, and industry.

	Food and Drug Administration:

		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.

		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.

		Emergency Use of Unapproved Medical Devices Information Sheet (September 1998) An information sheet that defines an unapproved medical devise, the requirements for emergency use and exception from informed consent.

	International Conference on Harmonization:

		Harmonized Tripartite Guideline: Statistical Principles for Clinical Trials (E9)(February 5, 1998) This guideline is intended to harmonize statistical methodology principles applied to clinical trials in Europe, Japan and the United States. It is meant to give direction to sponsors in the design, conduct, analysis and evaluation of clinical trials of an investigational product and in determining its efficacy and safety.

		ICH Harmonized Tripartite Guideline: Choice of Control Group and Related Issues in Clinical Trials (E10)(July 20, 2000) Describes general principles for choosing a control group to demonstrate efficacy in clinical trials. It describes the types of control groups most commonly used and the interpretation issues associated with demonstrating efficacy.
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Clinical Trial Monitoring

	European Medicines Agency:

		Guideline on Data Monitoring Committees An overview guide to highlight the key issues involved when sponsors include Data Monitoring Committees as part of their trial management. Includes information pertaining to assessing the need for and establishing a DMC, as well as the responsibilities, working procedures and possible methodological implications of DMC analyses.

	Food and Drug Administration:

		Guidance for Clinical Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees March 2006 Discusses the roles, responsibilities and operating procedures of Data Monitoring Committees (DMCs) and the advantages and disadvantages of different models for the operation of DMCs. Describes potential concerns regarding operation of DMCs that may arise in specific situations.

		"Monitoring of Clinical Investigations" (January 1998) This guideline describes acceptable approaches to monitoring clinical investigations. Existing requirements for sponsors of clinical investigations involving new drugs for human and animal use (including biological products for human use) and medical devices under 21 CFR Parts 312 and 511, and 812 and 813, respectively, require that a sponsor to monitor the progress of a clinical investigation.

	National Institutes of Health:

		Policy for Data and Safety Monitoring (June 10, 1998) This National Institutes of Health (NIH) document provides guidance to investigators engaged in NIH-supported multi-center clinical trials to promote effective reporting of adverse events to the appropriate IRBs.

		Further Guidance on a Data and Safety Monitoring for Phase I and Phase II Trials (June 5, 2000) Provides guidance for monitoring data and safety of Phase I and Phase II trials. Especially, for studies that have multiple clinical sites, are blinded or employ particularly high-risk interventions or vulnerable populations.

	Office for Human Research Protections:

		Guidance on Continuing Review (January 15, 2007) Continuing review of human subjects by IRBs is required based on research risk, but take place no less than once per year. This document provides guidance on what constitutes for substantial meaningful continuing review, includes considerations for continuing review for multi-site trials, and procedures necessary to expedite the review process.

	World Health Organization:

		Operational Guidelines for the Establishment and Functioning of Data and Safety Monitoring Board These Operational Guidelines are intended to provide international guidance to health research sponsors for the establishment and functioning of data and safety monitoring boards (DSMBs). The guidelines are based on a review of the existing guidance and requirements for DSMBs from national and international organizations, as well as on observations of existing practices of DSMBs in countries and institutions around the world.
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Human Data and Specimens in Research

	Department of Health and Human Services

		Protection of Human Subjects. Code of Federal Regulations, 45 CFR 46 Official HHS Federal Code of Regulation for human subject protection in research.

		HIPAA Privacy Rule (Standards for Privacy of Individually Identifiable Health Information) at 45 CFR Parts 160 and 164 The Office for Civil Rights enforces the HIPAA Privacy Rule, which protects the privacy of individually identifiable health information. This is a valuable resource for consumers and covered entities to help understand the Privacy Rule, the HIPAA Simplification Statute and Rules, and the process to ensure the enforcement of the Privacy Rule.

	Food and Drug Administration:

		Protection of Human Subjects. Code of Federal Regulations, 21 CFR Parts 50 and 56 Official FDA regualtion for human subject protection in research.

		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 StaffApril 25, 2006 Guidance that applies to specimens that were previously collected for other unrelated research and that are not individually identifiable. Outlines circumstances where the FDA intends to exercise enforcement discretion to the informed consent requirement for use of specimens in FDA-regulated IVD studies.

	National Institutes of Health:

		Guidance on "Protecting Personal Health Information in Research: Understanding the HIPAA Privacy Rule" (April 14, 2003; revised 7/13/04) This booklet provides researchers with a basic understanding of the Privacy Rule and how it may affect health research. It also addresses how researchers may be directly or indirectly affected by the Rule when their research requires the use of, or access to, an individualâ€™s identifiable health information.

		Guidance on "Research Repositories, Databases and the HIPAA Privacy Rule" (July 2, 2004) A fact sheet that discusses the Privacy Rule and its potential to affect the creation of research databases and repositories, and research that uses identifiable health information in repositories and databases.

		Guidance on "Institutional Review Boards and the HIPAA Privacy Rule" (July 8, 2004) A fact sheet that describes the Privacy Rule's requirements relating to an IRB and approvals of research-related requests for Authorization waivers or alterations and how those requirements relate to the functioning of an IRB under 45 CFR part 46, 21 CFR parts 50 and 56, and other Federal laws and regulations applicable to an IRB.

		NIH Requirements for the Research Use of Stored Human Specimens and Data Information Sheet Outlines what actions must take place in the Intramural Research Program (IRP), such as prospective and continuing NIH IRB review and approval, before IRP researchers may use stored identifiable specimens or data for research purposes.

	Office for Human Research Protections:

		Research Use of Human Biological Specimens and Other Private Information-Educational Video Ms. Julie Kaneshiro, OHRP Policy Team Leader, is interviewed and discusses the challenges and complexities of the application of the HHS regulations at 45 CFR part 46 to activities involving biological specimens and other private information. Ms. Kaneshiro discusses how to assess whether an activity constitutes non-exempt human subjects research. She clarifies when the HHS regulations do and do not apply to an activity and when an institution is engaged in human subjects research. This is an advanced topic video and is best suited to viewing by individuals already possessing a basic understanding of the HHS regulations for the protection of human subjects.

		OHRP: Engagement of Institutions in Research, guidance memorandum issued October 16, 2008 Guidance for research conducted and supported by HHS involving institutions engaged in non-exempt human subjects research for assurance of compliance and certifying institutional review board (IRB) review and approval. Includes scenarios describing instances intuitions are considered engaged and not engaged in human subjects research and IRB review considerations for cooperative research, where multiple institutions are involved in a human subject research project.

		OHRP: Guidance on Research Involving Coded Private Information or Biological Specimens, issued October 16, 2008 Provides guidance for when research conducted and supported by HHS involving coded private information or specimens is considered research involving human subjects (45 CFR part 46). References applicable HIPAA Privacy Rule requirements and explains that under certain limited conditions, research involving only coded private information or specimens is not human subject research.

		Guidance on "Issues to Consider in the Research Use of Stored Data or Tissues" (November 1997) Identifies issues to consider for the collection, storage and distribution of human tissue repositories. Provides guidance in the areas of IRB review, informed consent, oversight, and submittal and usage agreements.

		International Compilation of Human Subject Research Protections This is a list compiled of approximately 1,100 laws, regulations, and guidelines that govern human subject research in 92 countries, as well as standards from a number of international and regional organizations.


		Disclaimer: Though this Compilation contains information of a legal nature, it has been developed for informational purposes only and does not constitute legal advice or opinions as to the current operative laws, regulations, or guidelines of any jurisdiction. In addition, because new laws, regulations, and guidelines are issued on a continuing basis, this Compilation is not an exhaustive source of all current applicable laws, regulations, and guidelines relating to international human subject research protections. While reasonable efforts have been made to assure the accuracy and completeness of the information provided, researchers and other individuals should check with local authorities and/or research ethics committees before starting research activities.



	Public Responsibility in Medicine and Research:

		PRIM&R Human Tissue/Specimen Banking White Paper - Full Text This paper is organized into two parts and was produced by the PRIM&R Human Tissue/Specimen Banking Working Group, comprised of PRIM&R and Partners HealthCare Systems, Inc., with the support from the Clinical Research Policy Analysis and Coordination (CRpac) program and the National Cancer Institute (NCI) Cancer Diagnosis Program. The first section of the paper discusses the challenges associated with the collection, storage, distribution and use of human specimens and data in research. It also outlines some recommendations to the federal regulatory and funding agencies. The second part of the paper includes human tissue/specimen banking educational materials, points to consider and relevant discussions.

		PRIM&R Human Tissue/Specimen Banking White Paper - Toolkit Excerpt Part 2 of the paper: Tools for investigators, IRBs and repository managers
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Human Subjects Regulations

	Department of Health and Human Services

		Department of Health and Human Services: Protection of Human Subjects. Code of Federal Regulations, 45 CFR 46 Official HHS Federal Code of Regulation for human subject protection in research

		Secretary's Advisory Committee on Human Research Protections (SACHRP) OHRP, DHHS, Recommendations and Communications to the HHS Secretary. SACHRP is charged to "provide expert advice and recommendations to the Secretary and the Assistant Secretary for Health (ASH) on issues and topics pertaining to or associated with the protection of human research subjects."

	Food and Drug Administration:

		Protection of Human Subjects. Code of Federal Regulations, 21 CFR Parts 50 and 56 Official FDA regualtion for human subject protection in research.

		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 May 2006 Provides guidance to assist clinical investigators, Institutional Review Boards (IRBs), sponsors, and other interested parties in understanding the Food and Drug Administration's process for handling clinical investigations that include children as subjects and have been referred to FDA for review under 21 CFR 50.54.

		Comparison of FDA and HHS Human Subject Protection Regulations The FDA and HHS human subject protection regulations are both federally mandated, but are not the same. This resource highlights their differences in terms of scope and definitions.

	Office for Human Subjects Protections:

		International Compilation of Human Subject Research Protections This is a list compiled of approximately 1,100 laws, regulations, and guidelines that govern human subject research in 92 countries, as well as standards from a number of international and regional organizations.


		Disclaimer: Though this Compilation contains information of a legal nature, it has been developed for informational purposes only and does not constitute legal advice or opinions as to the current operative laws, regulations, or guidelines of any jurisdiction. In addition, because new laws, regulations, and guidelines are issued on a continuing basis, this Compilation is not an exhaustive source of all current applicable laws, regulations, and guidelines relating to international human subject research protections. While reasonable efforts have been made to assure the accuracy and completeness of the information provided, researchers and other individuals should check with local authorities and/or research ethics committees before starting research activities.



		Office for Human Research Protections: 1993 IRB Guidebook Intended for new IRB members and investigators, it provides basic information on the background and purpose of the IRB review system.
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Informed Consent

	Department of Health and Human Services:

		Department of Health and Human Services: Protection of Human Subjects. Code of Federal Regulations, 45 CFR 46 Official HHS Federal Code of Regulation for human subject protection in research

	Department of Human Research Protections:

		Office for 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)

		OHRP FAQs - Informed Consent Helpful guidance by OHRP that includes 35 questions and answers about informed consent.

	Food and Drug Administration:

		Protection of Human Subjects. Code of Federal Regulations, 21 CFR Parts 50 and 56 Official FDA regulation for human subject protection in research.

		Guidance on Informed Consent for In Vitro Diagnostic Device Studies Using Leftover Human Specimens that are Not Individually Identifiable Guidance that applies to specimens that were previously collected for other unrelated research and that are not individually identifiable. Outlines circumstances where the FDA intends to exercise enforcement discretion to the informed consent requirement for use of specimens in FDA-regulated IVD studies.

		A Guide to Informed Consent 1998 This document provides guidance on the informed consent process and the information required by each of the eight basic elements of 21 CFR 50.25(a), and each of the six elements of 21 CFR 50.25(b), for studies that are subject to the requirements of the FDA regulations

		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.

		Draft Guidance for Institutional Review Boards, Clinical Investigators and Sponsors: Exception from Informed Consent Requirements for Emergency Research July 2006 This guidance applies to research studies involving FDA regulated products (drugs, biological products, and medical devices). It assists sponsors, clinical investigators, and Institutional Review Boards (IRBs) in the development and conduct of research in emergency settings when an exception from the informed consent requirements is requested under Title 21, Code of Federal Regulations, Section 50.24 (21 CFR 50.24) and understanding their responsibilities for communicating with, and submitting information to, FDA.

		Exception From General Requirements for Informed Consent-FDA's Interim Final Rule at 21 CFR 50.23(e) January 27, 1981 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.

		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.

	National Institutes of Health:

		NIH Points to Consider Research Involving Individuals With Questionable Capacity to Consent This document is intended to provide investigators and institutional review boards (IRBs) with points to consider (a) in fulfilling ethical and Federal regulatory requirements to ensure the protection of the rights and welfare of research subjects who-due to impairments in their capacity to give informed consent-may be vulnerable to coercion or undue influence and (b) in maintaining appropriate awareness of the ethical challenges associated with research involving this vulnerable population.

		Annotated Compendium of NIH-developed Informed Consent Resources

		NCI: A Guide to understanding Informed Consent A guide to help clinical trial participants and investigators understand the informed consent process. It outlines why informed consent is important and what to expect during the process, such as clear explanation and comprehension of patient's rights and responsibilities, as well as possible risks and benefits.

		NIH-National Cancer Institute "Simplification of Informed Consent Documents" This web source provides a definition of terms used in the informed consent process, gives basic information on the HHS and FDA code of regulations pertaining to the requirement of informed consent and provides recommendations and a template for informed consent documents.

		Office of Biotechnology Activities: Informed Consent in Gene Transfer Research This guidance, developed by the Recombinant DNA Advisory Committee (RAC), is intended to serve as a resource and learning tool for investigators involved in gene transfer studies. Each section of the guidance describes different aspects of the informed consent process and includes excerpts from the NIH Guidelines, topic discussion, main points and summary, sample language with examples of how to implement the points made in the discussion sections and lastly, tools and background materials.
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Models of IRB Review

		National Conference on Alternative IRB Models: Optimizing Human Subjects Protections November 20-21, 2006 Summarizes the findings of a national conference held in Washington, D.C. on November 19-21, 2006 called, "The National Conference on Alternative IRB Models: Optimizing Human Subject Protection." Its purpose was to enhance the protection of human subjects of research by encouraging the use of alternative Institutional Review Boards (IRB) models under appropriate circumstances.

		Alternative Models of IRB Review: Workshop Summary Report (November 2005) Summarizes findings from the Alternative Models of IRB Review workshop held November 17-18 2005. Describes issues associated with the use of alternatives to local Institutional Review Boards (IRBs) and plans for informing future committee action.

	Department of Health and Human Services:

		Office for Human Research Protections Guidance on "Knowledge of Local Research Context" Describes the standards that should be met to ensure IRBs posses sufficient knowledge of the local research context, operate efficiently and ensure the protection of human subjects

		Office for Human Research Protections Guidance on "The Use of Another Institution's IRB" Clarifies procedures for local IRB review of NIH multicenter clinical protocols and informed consent documents.

		Office for Human Research Protections: 1993 IRB Guidebook Intended for new IRB members and investigators, it provides basic information on the background and purpose of the IRB review system.

	Food and Drug Administration:

		Guidance on "Non-local IRB Review" (1998) Provides basic knowledge for non-local IRBs. IRBs may review studies that are not performed on-site as long as the 21 CFR parts 50 and 56 requirements are met.

		Food and Drug Administration Guidance on Using a Centralized IRB Review Process in Multicenter Clinical Trials (2006) Guidance to assist sponsors, institutions, institutional review boards (IRBs), and clinical investigators involved in multicenter clinical research and using a single central IRB, to meet the requirements of 21 CFR part 56.

		Guidance for Industry-IRB Review of Stand-Alone HIPAA Authorizations Under FDA Regulations (October 21, 2003) Guidance to assist sponsors, institutions, institutional review boards (IRBs), and clinical investigators involved in multicenter clinical research and using a single central IRB, to meet the requirements of 21 CFR part 56.

	World Health Organization:

		"Operational Guidelines for Ethics Committees that Review Biomedical Research" (2000) Guidelines to establish an international standard for ensuring quality and consistency in ethical review of biomedical research.
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