Criteria for IRB Approval

The Children's Hospital of Philadelphia has chosen not to apply all of the requirements of the Common Rule (45 CFR 46) to all human subjects research under the institution's Federal Wide Assurance (FWA). Research that is funded by the federal government must meet all of the requirements of the Common Rule. In addition, research that is regulated by the FDA must adhere to its regulations for the protection of human subjects and other relevant FDA regulations (e.g., 21 CFR 50, 54, 56, 312, 314, 812, and 814).

The IRB's basic approach to all research, regardless of funding adheres to the principles outlined in the regulations. The IRB's SOPs delineate the ways in which it deviates from the federal regulations for non-federally funded, non-federally regulated research.

CHOP's human research protection program received initial certification in 2010 by the American Association for Human Research Protections Programs (AAHRP) (analogous to JCAHO accreditation for hospitals) and received 5-year certification in 2013. AAHRPP's standards meet and often exceed the federal regulatory requirements. The IRB's Policies and requirements therefore, not only adhere to the federal regulations, but when necessary, to the additional requirements imposed by AAHRPP.

Ethical Requirements for Conduct of Human Subjects Research

"What Makes Clinical Research Ethical"
  1. Social or Scientific Value
  2. Scientific Validity
  3. Fair Subject Selection
  4. Favorable Risk - Benefit
  5. Independent Review
  6. Informed Consent
  7. Respect for Potential and Enrolled Subjects

From JAMA 283:2701-11, 2000.

National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research was formed in 1974 n the wake of the Tuskegee scandal. The Commission provided a variety of reports which formed the foundation of our current research regulations.

The Belmont Report is the most famous of the National Commission's reports and it provides the basis for the ethical justification for conducting human subjects research. The Report establishes the ethical principles of Respect for Persons, Beneficence and Justice as essential for ethical human subjects research. Anyone conducting human subjects research should read this report in its entirety.

Emanuel and his colleagues propose 7 criteria that establish a framework for determining whether or not a proposed research activity satisfies the ethical requirements (panel to the right) articulated in the Belmont Report. Emanuel places great emphasis on the social value and scientific validity of clinical research. One of main points of this paper is that studies that are without value expose subjects to risk and inconvenience without any corresponding prospect of benefit to science, society or the participants. This article is an essential read for clinical investigators.

Basis of IRB Approval

The Federal regulations incorporate all of these concepts including the requirement for independent review of research. The IRB (Institutional Review Board, also known as an (REC) Research Ethics Committee) is the independent review committee that must review and approve all clinical research. The criteria in the panel below summarizes the Federal regulatory requirements. "Procedures consistent with sound research design" not only demands that the investigator demonstrate they are capable of conducting the study and producing scientifically valid results. Many protocols submitted to the IRB, particularly those that are investigator initiated provide insufficient evidence of sound scientific design to permit the IRB to approve the research.

Criteria for IRB Approval of Research

45 CFR 46.111 and 21 CFR 56.111
(a) ...IRB shall determine that all of the following criteria are followed

  1. Risks to subjects are minimized by using:
    i) procedures consistent with sound scientific design and which do not unnecessarily expose subjects to risk
    ii) whenever appropriate by using procedures already being performed on subjects for diagnostic or treatment purposes
  2. Risks to subjects are reasonable in relation to the anticipated benefits ...
  3. Selections of subjects is equitable ...
  4. Informed consent will be sought from each prospective subject or the subject's legally authorized representative ... as required by #46.116.
  5. Informed consent will be appropriately documented ... to the extent required by §46.117
  6. When appropriate, the research plan makes adequate provision for monitoring the data collected to ensure the safety of subjects
  7. When appropriate, there are adequate protections to protect privacy of subjects and to maintain the confidentiality of data.

(b) When some or all of the subjects are likely to be vulnerable to coercion or undue influence, such as children, prisoners, pregnant women, mentally disabled persons, or economically disadvantaged persons, additional safeguards have been included in the study to protect the rights and welfare of the these subjects.

Regulations: Limits of IRB authority
  • 45 CFR 46.109 (a) IRB review of research An IRB shall review and have authority to approve, require modifications in (to secure approval), or disapprove all research activities covered by this policy.
  • 45 CFR 46.113 Suspension or termination of IRB approval of research. An IRB shall have authority to suspend or terminate approval of research that is not being conducted in accordance with the IRB's requirements or that has been associated with unexpected serious harm to subjects.
  • For a more complete discussion of IRB approval with required modifications see OHRP's Guidance on IRB Approval with Conditions.

Actions Available to the IRB

IRBs should limit their actions to those incorporated into the regulations. It is tempting to succumb to mission creep and to impose requirements on investigators above and beyond the IRB's charge. For example, an IRB may try to impose requirements on issues such as whether or not an investigator may include a subject or their data as part of an analysis. This decision is beyond the IRB's scope. While the IRB cannot make an investigator dispose of data, or impose conditions on research conducted outside of an approved protocol, investigators may not claim that the research had IRB approval for these activities when seeking to publish or use the data. It is up to the Institutional Official and others at the institution responsible for the oversight of research to impose sanctions and conditions that go beyond the IRB's authority.

In additions to the actions listed in the box to the right, the IRB may also impose conditions on the research such as the frequency of continuing review, it may audit the study or it may observe the conduct of the research or the consent process.

Summary:

The IRB is not only required to assess the risks and benefits of the research, it must also ensure that the risks of the research have been minimized. Even when the research is only minimal risk, the risks may not have been minimized. For example, the data management proposal might include identifiers in the database when they aren't required or blood tests might be unnecessarily require extra blood draws. Careful planning is the key to minimizing risk

Summary:

In order to fulfill its mission of protecting research subjects, the IRB must ensure that all risks have been minimized and that they are reasonable in relation to the anticipated benefits.

Summary:

The requirement for equitable selection flows from the ethical principle of justice. Justice is intended in the sense of distributive justice where no group is unduly burdened or will unfairly benefit from the research. Originally this was interpreted as requiring protection of vulnerable groups but with the onset of the AIDS epidemic it became apparent that some groups did not have equal access to clinical trials. This led to a transformation where advocates for minorities, women and children have demanded equal access (and equal benefit) from clinical trials.

Summary:

Informed consent is not a document, it is a process that begins with recruitment and continues until the subject's participation in the research is completed. Even then, if the subject's private identifiable information continues to be used, the investigator has an obligation to inform the subject of changes in the research.

Summary:

All studies require a data safety monitoring plan. Many investigators only consider safety monitoring in their plan but both data and safety must be ensured. Only research studies that collect and secure valid data are considered ethical. Conclusions based on faulty, invalid data fails to contribute to scientific knowledge and benefits no one.

Summary:

The federal regulatory requirement to ensure (7) When appropriate, there are adequate provisions to protect the privacy of subjects and to maintain the confidentiality of data overlaps with the privacy and confidentiality protections in HIPAA. With the advent of HIPAA people often confuse privacy and confidentiality and just as frequently over think the need for one or the other.

Summary:

Additional regulatory protections apply to several categories of vulnerable subjects including children, pregnant women and the fetus, and prisoners. In addition, some groups need additional protections such as adults with diminished capacity.

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