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Significant Differences in FDA and DHHS Regulations

August 2009

Human subject research is regulated at the federal, state, and local level.  The two principal federal agencies with human research oversight, the Department of Health and Human Services (DHHS) and the Food and Drug Administration (FDA), have promulgated regulations which are not always consistent with one another.  The chart below identifies some of the differences between the DHHS and FDA regulations that affect human subjects, investigators and the study team, sponsors, research institutions, funding agencies, and Institutional Review Boards.

DHHS

FDA

Definition of Research

 “…a systematic investigation, including research development, testing, and evaluation, designed to develop or contribute to generalizable knowledge."

"...any experiment that involves a test article and one or more human subjects, and that either must meet the requirements for prior submission to the Food and Drug Administration."

Definition of Human Subject

"Human subject" means a living individual about whom an investigator (whether professional or student) conducting research obtains (1) data through intervention or interaction with the individual, or (2) identifiable private information.

"Human subject" means an individual who is or becomes a participant in research, either as a recipient of the test article or as a control. A subject may be either a healthy individual or a patient.

Regulations on Human Subject Research

Part 45, parts A, B, C, and D.  Regulations provide special protections for children, pregnant women/fetus/neonates, and prisoners.

(some of the many applicable regulations)

Part 50 (protection of human subjects): Subpart A (definitions), Subpart B (informed consent), Subpart D (children)

Note:  No subparts for prisoners or pregnant women/fetus/neonates

Part 54 (financial disclosure by clinical investigators)

Part 56 (Institutional Review Boards)

Part 11 (Electronic Records, signatures)

Part 312 (Investigational New Drug Application)

Part 809 (In Vitro Diagnostic products for human use)

Part 812 (Investigational Device Exemption)

Emergency Use: IRB Review

DHHS regulations state that they are not intended to limit the provision of emergency medical care.

No special “emergency” IRB review procedure is provided.

FDA provides exemption from the prospective IRB review requirement for "emergency use" of test article in specific situations.

FDA “Emergency Use” provides procedure for IRB clearance of investigational product use, when possible, prior to use in emergency clinical setting.

Exempt Research

DHHS exempts certain categories of research and provides for a Secretarial waiver.

FDA provides for sponsors and sponsor-investigators to request a waiver of IRB review requirements (but not informed consent requirements).  The FDA has a limited number of categories which are exempt (56.104/105)

Waiver of IRB Review

DHHS has no provision for waiving IRB review for human subject research that is not exempt.

On the application of a sponsor or sponsor-investigator, the FDA may waive any of the requirements contained in these regulations, including the requirement for IRB review, for specific research activities or for classes of research activities, otherwise covered by these regulations. 56.105

Updating IRB Membership

DHHS requires that the Institution submit IRB membership rosters to the OHRP and update any changes. 

Effective July 14, 2009, 21 CFR 56.106 requires registration of each IRB in the U.S. that reviews clinical investigations. Registration is through the OHRP electronic IRB registration site.

Waiver of Parent/Guardian Permission in Minimal Risk Studies  (45.404)

For minimal risk studies involving children, the IRB may waive the requirement for consent if the research meets the criteria of 46.116(d) or is designed for conditions or a population for which parent/guardian permission is not a reasonable requirement to protect the subjects (examples include neglected and abused children).

Waiver of parental permission is not allowed for FDA regulated research.

Waiver of Parent/Guardian Permission in studies posing more than minimal risk to subjects and offering direct benefit to children participating.  (45.405)

For benefit studies with more than minimal risk involving children, the IRB may waive the requirement for consent if the research is designed for conditions or a population for which parent/guardian permission is not a reasonable requirement to protect the subjects (examples include neglected and abused children).

Waiver of parental permission is not allowed for FDA regulated research.

Waiver of Parent/Guardian Permission in Studies – a minor increase over minimal risk and no benefit to children participants (45.406)

For studies not offering the prospect of direct benefit and that involve only a minor increase over minimal risk involving children, the IRB may waive the requirement for consent ONLY IF the research is designed for conditions or a population for which parent/guardian permission is not a reasonable requirement to protect the subjects (ex. include neglected and abused children).  If parental permission is sought, both parents must provide consent (some exceptions.)

Waiver of parental permission is not allowed for FDA regulated research.

Dating consent forms

DHHS regulations do not explicitly require consent forms to be dated.

FDA explicitly requires that consent forms be dated as well as signed by the subject or the subject's legally authorized representative. 50.27(a)

Waiver of Documentation of Informed Consent

DHHS allows for waiver or alteration of the requirement for a signed informed consent document in certain minimal risk studies and when the principal risk is a breach of confidentiality.

FDA does not permit waiver of documentation. Obtaining informed consent is “deemed feasible” except in two situations (clinical emergency and emergency research.  21 CFR 50.23, 50.24. 

Waiver of Informed Consent/Consent not Required

Waiver permitted under 46.116(d) if:

  • The research involves minimal risk
  • The waiver will not adversely affect the rights and welfare of subjects
  • The research could not practicably be carried out w/out the waiver
  • Where appropriate, subjects will be provided w/ additional information

Exceptions to informed consent requirements 21 CFR 50.23:

  • Subject is confronted with life-threatening situation necessitating use of test article
  • Informed consent not possible because of an inability to communicate with, or obtain legally effective IC from the subject
  • No time to obtain consent from LAR
  • No alternative method of approved therapy available that provides equal or greater likelihood of saving subject’s life
  • IRB approves emergency research without requiring IC.

            21 CFR 50.24

Costs of Research

Informed consent document must include disclosure of any “additional costs to the subject that may result from participation in the research.” 46.116(b)(3)

  • Disclosure of “additional costs” in the IC document
  • Costs of IND product are not chargeable to the subject without FDA permission
  • Costs of IDE product are chargeable to the subject, and are controlled by regulation.

Inspection of Study Records

DHHS reserves the right to inspect records of studies it funds at a reasonable time and in a reasonable manner; it does not require that subjects provide informed consent for that inspection.

FDA explicitly requires that subjects be informed that FDA may inspect the records of the study because FDA may occasionally examine a subject's medical records when they pertain to the study. 50.25(a)(5)

Responsibilities of Investigators

Defers to the IRB to determine competence of the investigator(s)

  • Provides expectations and responsibilities (IND -312.60; 812.100-110)
  • Form 1572 signed by IND holder

Record Retention

Note:  HIPAA requires records to be retained for up to 6 years after the last subject has completed study activity.

Records must be kept for 3 years after completion of research.

Specified recordkeeping and record retention (2 years after marketing application approved, investigation is discontinued.)

“Problem” and AE Reporting

PI must report “any unanticipated problems involving risk to subjects or others” or “any serious or continuing non-compliance”

Drug: PI must report to sponsor “any adverse effect that may reasonably be regarded as caused by, or probably caused by, the drug”

Device: PI must report “unanticipated adverse device effects” (812.150)

Sanctions

DHHS regulations do not list sanctions; however, the OHRP may withdraw the assurance between the institution and the government, and prevent the conduct of federally sponsored research at that institution.

  • FDA regulations provide sanctions for non-compliance with regulations.  56.120, 124.
  • The FDA had procedures for “disqualification” of a clinical investigator. (312.70, 812.119)
  • The FDA has a process of “debarment” which can prevent individual investigators from participating in FDA regulated research.

AAHRPP

 

 

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