Final Rule

Background
  • First major revision to 45 CFR 46 since 1991
  • Regulation for human subjects research for 16 Federal Agencies that support the Common Rule
  • Revised regulations take into account advancements in science & technology, as well as a rapidly changing research landscape.
  • Originally scheduled to take effect January 19, 2018; now in effect as of January 21, 2019.
  • 45 CFR 46 Federal Policy for the Protection of Human Subjects: Final Rule This version includes an extensive preamble with discussions about and explanations for each change.
  • 45 CFR 46 (published January 17, 2017) This version just includes the Final Rule (does not include the preamble).

On January 19, 2017, DHHS issued a Final Rule to the Federal Policy for the Protection of Human Subjects that extensively updates the Common Rule - 45 CFR 46 - for the first time since 1991. Not all of the changes proposed in the 2015 Notice of Proposed Rule-Making were included in the Final Rule. The promulgated changes are intended to add flexibility and to reduce regulatory burden. Whether or not the goals will be actually achieved remains to be seen.

Implementation Date for the Final Rule

Although the implementation of the new regulations were delayed (see below); they are now in effect as of January 21, 2019.

Changes due to the Final Rule apply to the following:

  • New studies submitted after the implementation date (January 21, 2019);
  • New studies that have not obtained IRB approval prior to the date of implementation; and
  • Most existing studies at the time of their next IRB review (e.g. with the next amendment or continuing review).

What are the most important changes?

Changes to Definitions

The definition of who is a human subject has been expanded to include both identifiable data and identifiable biospecimens. From a pragmatic perspective, this isn't really a change; most IRBs already considered identifiable biospecimens as part of an individual's identifiable private information. The change makes this requirement explicit rather than implicit.

A definition of "clinical trials" has also been added. "Clinical trial means a research study in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other active control intervention) to evaluate the effects of the interventions on biomedical or behavioral health-related outcomes."

Changes to Exempt Criteria

Certain categories of minimal risk research are currently exempt from the regulatory requirements of 45 CFR 46. The Final Rule modifies the existing categories, adds several new categories and also adds limited IRB review to several categories. The most important change is to Category 4. Category 4 previously only applied to the use of existing data or specimens and limited the use to (1) sources that were either publicly available or (2) to data/specimens recorded by the investigator in such a manner that subjects could not be identified, directly or through identifiers linked to the subjects. The revised Category 4 now permits the use of both existing and prospective data and biological specimens that are collected as part of clinical care or during another research study. The change also allows investigators, when HIPAA applies, to record identifiers for data (but not biological specimens).

Broad Consent

Broad consent is a new concept in the Final Rule. It is defined by as consent for storage and then use for secondary research of identifiable private information or biospecimens. Individuals have the opportunity to either opt-in or opt-out from having their identifiable data and leftover specimens used for future research. The research use of data/specimens stored under broad consent would be eligible for a determination of exemption after a limited IRB review. The IRB cannot waive the requirement for consent for an individual who declined broad consent. This potentially limits the use of data and specimens in future.

Implementation of broad consent must take place at an institutional level and requires a mechanism to track each individual's choice - opt-in or opt-out. At present, OHRP has not provided any guidance for implementation of Broad Consent. There are substantial obstacles for institutions who want to implement broad consent. Each individual's choices must be tracked regarding who did and who did not consent. And it is not clear what should happen if an individual makes different choices at different points in time, adding further complexity. Lastly, CHOP investigators would be required to exclude the data derived from those who decline Broad Consent from all future research. (How would an investigator know that the individual opted out previously when approached by a different investigator?) In consequence, CHOP is not pursuing implementation of Broad Consent at this time.

Changes to Requirements for Continuing Review

Under the Pre-2018 Common Rule, all non-exempt federally funded and FDA regulated research requires continuing review and approval by the IRB at least once a year. The CHOP IRB has allowed the extension of the review period for non-federally funded, non-FDA regulated, minimal risk studies, when appropriate. The Final Rule will do away with the requirement for annual review altogether for certain categories of minimal risk research. On a case-by-case basis the IRB can impose additional continuing review requirements.

For more information about these requirements, see Continuing Review.

Single IRB Review

The Final Rule mandates single IRB review for all federally funded cooperative research. This will go into effect January 19, 2020. 45 CFR 46.114 has been expanded to include the requirement for single IRB review for all Cooperative Research which means research that involves more than one institution.

45 CFR 46.114(b)(1)“Any institution located in the United States that is engaged in cooperative research must rely upon approval by a single IRB for that portion of the research that is conducted in the United States." Since the NIH has already mandated single IRB review for research that it funds (all competing grant applications for due dates on or after January 25, 2018), this will not be a major change for many institutions. However, this requirement will then apply to the other federal departments and agencies that have adopted the Common Rule.

Changes to Informed Consent

The Final Rule adds requirements intended to make the informed consent form more focused and understandable. 45 CFR 46.116(a)(4) adds a new standard for what level of information should be in the consent form. "(4) The prospective subject or the legally authorized representative must be provided with the information that a reasonable person would want to have in order to make an informed decision about whether to participate, and an opportunity to discuss that information." To accomplish this, there is now a requirement that a concise statement explaining the research precede the body of the consent form.

Other changes include new elements that must be in the informed consent. These relate to future use of identifiable information/biospecimens, disclosure of profit from commercial use (if applicable), return of research results and information related to genome sequencing. These elements have generally been included in CHOP's consent forms already but the regulation formalizes the requirements for their inclusion. CHOP IRB’s consent templates reflect these updated requirements.

Changes to Waiver of Consent Criteria & Waiver of Documentation of Consent Criteria

There are new requirements added to the criteria for waiver of consent at 45 CFR 46.116(f)(3). If a subject has declined broad consent, the IRB cannot subsequently waive the informed consent requirements for that individual.

There is now a new option at 45 CFR 46.117(c)(1)(iii) to waive documentation of consent if the subjects or legally authorized representatives are members of a distinct cultural group or community in which signing forms is not the norm, provided the research presents no more than minimal risk of harm to subjects and there is an appropriate alternative mechanism for documenting that informed consent was obtained.

Posting of Informed Consent Document

There is a new regulation at 45 CFR 46.116(h) that requires the posting of clinical trial consent forms.

(h) Posting of clinical trial consent form.

  1. For each clinical trial conducted or supported by a Federal department or agency, one IRB- approved informed consent form used to enroll subjects must be posted by the awardee or the Federal department or agency component conducting the trial on a publicly available Federal Web site that will be established as a repository for such informed consent forms.
  2. If the Federal department or agency supporting or conducting the clinical trial determines that certain information should not be made publicly available on a Federal Web site (e.g. confidential commercial information), such Federal department or agency may permit or require redactions to the information posted.
  3. The informed consent form must be posted on the Federal Web site after the clinical trial is closed to recruitment, and no later than 60 days after the last study visit by any subject, as required by the protocol.
  4. At CHOP, the Office of Research Compliance will assist investigators to ensure compliance with this requirement.

Changes to Consent Requirements for Screening

Consent is no longer required for screening subjects for eligibility, if the procedures are limited to: (a) obtaining information through oral or written communication with the prospective subject or legally authorized representative, and/or (b) obtaining identifiable private information or identifiable biospecimens by accessing records or stored identifiable biospecimens.

This change aligns the requirements of 45 CFR 46 with the FDA's requirements and guidance regarding screening prospective subjects. Investigators will now be allowed to approach individuals, ask them questions to determine if they are eligible or review their existing medical records or biospecimens – e.g. existing blood tests, urine tests, radiographic imaging, etc. Subjects will still need to consent prior to having any prospective procedures performed to determine eligibility – e.g. new blood tests, urine tests, radiographic imaging, etc.

While consent is no longer required for these screening activities, if HIPAA applies to the research, then either HIPAA authorization or a waiver of HIPAA authorization will still be required. If HIPAA authorization is required, a stand-alone HIPAA authorization should be used.

What has the CHOP IRB done to implement the revised regulations?

  • Changes have been made to eIRB. For example, investigators may have to answer additional questions when submitting a request for an exempt determination. There is a new activity to update the study status every two years for minimal risk research (see "Changes to Requirements for Continuing Review" above).
  • New consent form templates (complying with the new requirements) have been posted to the IRB website.
  • Both the IRB website as well as the IRB SOPs have been updated to reflect the revised regulations.
  • Training sessions for investigators, study staff, IRB members and IRB staff were conducted. The IRB held joint workshops with the Office of Research Compliance and gave presentations at faculty meetings for all CHOP Departments and the Divisions in the Department of Pediatrics. Additional presentations to other groups are scheduled.

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