REGULATIONS and GUIDANCES

HISTORICAL PERSPECTIVE

There are 2 major milestones that occurred in the development of laws and guidelines that govern the conduct of clinical trials internationally.

The Nuremburg Code (1947): This code was a result of discovery of human experimentation during World War II and the Nuremburg trials which followed. The code contains 10 points which define necessary components of medical experimentation using human subjects, including voluntary consent of subjects, investigations of scientific merit, avoidance of unnecessary harm to subjects, experiments conducted by qualified people, and the right of subjects to withdraw from the experiment. The Code includes 10 elements which should be considered when designing and executing an experiment:

·  Voluntary consent of the human subject.

·  Designed to produce fruitful results.

·  Designed and based on animal studies and knowledge of the natural history of disease or problem under study so anticipated results justify the experiment.

·  Conducted to avoid unnecessary harm and suffering.

·  No experiment is conducted that is expected to result in death or disabling injury.

·  Degree of risk should never exceed the problem’s humanitarian importance.

·  Proper preparations should be made to protect the subject against injury, disability or death.

·  Experiment should be conducted by scientifically qualified persons.

·  The human subject should be able to bring the experiment to an end.

·  The scientist must be able to terminate the experiment if there is reason to believe continuing will result in injury, disability or death.

Declaration of Helsinki (1964): Issued by the World Medical Association (WMA) , the Declaration of Helsinki is a statement of ethical principles to guide physicians and other participants in medical research involving human subjects, including medical research on identifiable human material or identifiable data forms , and form the basis for human research ethics internationally. All physicians are morally bound to follow the principles. The declaration is based on the Nuremburg Code and added that the interest of the subject should always be given a higher priority than the interests of society and that every subject in clinical research should get the best known treatment. Its core principles are respect for the individual, the individual’s right to self-determination, and the right of the individual to make informed decisions. This document is modified every few years, most recently in 2013.

UNITED STATES

There are laws that govern the conduct of clinical research in the United States. The Legislative Branch of the federal government is responsible for U. S. laws. Congress creates laws and passes bills. The President then signs those bills into law. Federal laws are published in the United States Code (USC) and are legally binding.

Federal regulations are issued by the Executive Branch (i.e., agencies such as Department of Health and Human Services). They explain how the agency intends to carry out a law. Federal regulations are created through a process known as rulemaking and published in the Code of Federal Regulations (CFR). If an agency needs to add, revise, or delete a regulation, they publish a proposed rule in the Federal Register and ask for public comment. After review of the feedback, changes are made, and the final rule is published in the Federal Register with dates that the regulation becomes effective and enforceable. All regulations are legally binding.

Guidances are issued by the various agencies, published in the Federal Register, and provide more information or guidance on how a particular regulation is implemented. Gudiances are not legally binding.

Belmont Report: A series of highly publicized abuses in research led to the enactment of the 1974 National Research Act (Public Law 93-348), which created the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. One of the charges to the National Commission was to identify the basic ethical principles and guidelines for the conduct of biomedical and behavioral research involving human subjects. In 1978, the Commission published “Ethical Principles and Guidelines for the Protection of Human Subjects of Research,” also known as the Belmont Report. The report identifies three principles for the ethical conduct of research involving human subjects:

  1. respect for persons
  2. beneficence, and
  3. justice.

Research conducted or supported by the Department of Health and Human Services (HHS)

(This includes all NCI sponsored or funded clinical research)

The Office for Human Research Protections (OHRP) provides leadership in the protection of the rights, welfare, and wellbeing of subjects involved in research conducted or supported by the U.S. Basic regulations governing the protection of human subjects in research supported or conducted by the Department of Health and Human Services were first published at 45 CFR Part 46 in 1974. The current version of the regulations includes five subparts:

·  Subpart A (issued in 1974, revised in 1981 and 1991 and technical amendments in 2005): Basic set of protections for all human subjects of research conducted or supported by HHS.

·  Subpart B (issued in1975 with most recent revised in 2001): Provides additional protections for pregnant women, human fetuses, and neonates involved in research.

·  Subpart C (issued in 1978): Provides additional protections pertaining to biomedical and behavioral research involving prisoners as subjects.

·  Subpart D (issued in 1983): Provides additional protections for children involved as subjects in research.

·  Subpart E (issued in 2009): Registration of institutional review boards (IRBs).

OHRP Guidances are found at: http://www.hhs.gov/ohrp/policy/index.html

Federal Policy for the Protection of Human Research Subjects

In 1991, the “Federal Policy for the Protection of Human Research Subjects,” informally known as the “Common Rule” was issued by 15 federal departments and agencies. The Common Rule was based on the HHS 45 CFR Part 46 Subpart A, and includes identical language in the separate regulations of those departments and agencies. Three departments and agencies have not issued the Common Rule but apply all parts of 45 CFR Part 46:

·  Central Intelligence Agency,

·  Social Security Administration, and

·  Department of Homeland Security.

Other departments and agencies have adopted one or more of the other HHS subparts and some have their own additional human subject protection regulations. Click on the link for a complete listing of the agencies that follow the Common Rule.

Research regulated by the Food and Drug Administration (FDA)

The Food and Drug Administration (FDA) is an HHS agency that regulates clinical investigations of products under its jurisdiction, such as drugs, biological products, and medical devices. FDA regulations are published in title 21 of the CFR.FDA’s human subject protection regulations include:

·  21 CFR Part 11: Electronic Record/Electronic Signatures

·  21 CFR Part 50: Protection of Human Subjects, specially informed consent

o  Subpart D: Provides additional protections for children

·  21 CFR Part 54: Financial Disclosure clinical Investigators

·  21 CFR Part 56: Institutional Review Boards

·  21 CFR Part 312: Investigational New Drug Application

·  21 CFR Part 314: Applications for FDA Approval to Market a New Drug

·  21 CFR Part 601: Biologics Licensing

·  21 CFR Part 812: Investigational Device Exemptions

FDA Information Sheets of Interest to the CTN

General Information Sheets

·  Charging for Investigational Products - Information Sheet

·  Cooperative Research - Information Sheet

·  Exception from Informed Consent Requirements for Emergency Research

·  Informed Consent, A Guide to - Information Sheet

·  Institutional Review Boards Frequently Asked Questions - Information Sheet

·  Non-local IRB Review - Information Sheet

·  "Off-Label" and Investigational Use Of Marketed Drugs, Biologics, and Medical Devices - Information Sheet

·  Payment to Research Subjects - Information Sheet

·  Recruiting Study Subjects - Information Sheet

·  Screening Tests Prior to Study Enrollment - Information Sheet

·  Sponsor - Investigator - IRB Interrelationship - Information Sheet

Drugs and Biologics

·  Emergency Use of an Investigational Drug or Biologic - Information Sheet

·  Evaluation of Gender Differences in Clinical Investigations - Information Sheet

·  Statement of Investigator (Form FDA 1572) - Frequently Asked Questions – Information Sheet

·  Treatment Use of Investigational Drugs - Information Sheet

·  Waiver of IRB Requirements for Drug and Biological Product Studies - Information Sheet

Devices

·  Medical Devices, Frequently Asked Questions About - Information Sheet

·  Significant Risk and Nonsignificant Risk Medical Device Studies - Information Sheet

FDA Operations

· FDA Inspections of Clinical Investigators - Information Sheet

· FDA Institutional Review Board Inspections - Information Sheet

FDA Guidances of interest to the CTN

General Guidances

·  21 CFR 50.54 - Additional Safeguards for Children in Clinical Investigations, Process for Handling Referrals to FDA Under

·  Clinical Holds, Submitting and Reviewing Complete Responses to

·  Data Monitoring Committees for Clinical Trial Sponsors, The Establishment and Operation of Clinical Trial

·  Data Retention When Subjects Withdraw from FDA-Regulated Clinical Trials

·  Exception from Informed Consent Requirements for Emergency Research

·  Financial Disclosure by Clinical Investigators

·  Financial Relationships and Interests in Research Involving Human Subjects

·  Investigator Responsibilities — Protecting the Rights, Safety, and Welfare of Study Subjects

·  Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims

·  ICH Guidances adopted by the FDA

IRB and Informed Consent

·  Adverse Event Reporting to IRBs - Improving Human Subject Protection

·  Centralized IRB Review Process in Multicenter Clinical Trials, Using a Central IRB

·  HIPAA Authorizations Under FDA Regulations, IRB Review of Stand-Alone

·  Informed Consent Elements, 21 CFR 50.25(c), Questions and Answers

·  IRB Continuing Review After Clinical Investigation Approval

·  IRB Registration, Frequently Asked Questions

·  IRB Responsibilities for Reviewing the Qualifications of Investigators, Adequacy of Research Sites, and the Determination of Whether an IND/IDE is Needed

Drugs and Biologics

·  Exploratory IND Studies

·  IND Exemptions for Studies of Lawfully Marketed Drug or Biological Products for the Treatment of Cancer

·  Safety Reporting Requirements for INDs (Investigational New Drug Applications) and BA/BE (Bioavailability/Bioequivalence) Studies

Electronic Data

·  Computerized Systems Used in Clinical Trials

·  Electronic Records; Electronic Signatures - Part 11, Scope and Application

THE INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE (ICH)

ICH is a coalition of regulatory authorities and representatives from the pharmaceutical industry whose goal is cooperation among the groups in Japan, Europe and the U. S. (FDA represents the U. S.) to protect the rights and welfare of the clinical subjects. They have establish global standards for the conduct of clinical research - a consolidated guideline that sets minimal standards for clinical trials (CT) to ensure the quality and integrity of the data and identifies and defines responsibilities of key personnel/groups involved in clinical trials.

The guidelines are divided into 4 major categories of standards are:

•  Quality guidelines

–  chemical and pharmaceutical Quality Assurance

•  Safety guidelines

–  in vitro and in vivo pre-clinical studies

•  Efficacy guidelines

–  clinical studies in human subject

–  E2: data management

–  E6: Good Clinical Practice (GCP) Guidelines

•  Multidisciplinary guidelines

–  cross-cutting topics that do not fit into one of the above categories

Adoption and implementation of ICH GCP guidelines vary between the founding countries:

·  EU implemented the ICH GCP guideline as a legal directive in 1996

·  Japan translated the document and legally enacted its version in 1997

·  U.S. FDA adopted the E6 guideline as a guidance document.

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