Attachment C: SACHRP Comments on FDA draft guidance “Use of Electronic Informed Consent in Clinical Investigations: Questions and Answers”

On March 9, 2015, the Food and Drug Administration (FDA) issued the draft guidance “Use of Electronic Informed Consent in Clinical Investigations:  Questions and Answers.”  At the same time, OHRP also asked for commentary on the FDA guidance.  The Federal Register summary states:

In this issue of the Federal Register, the Food and Drug Administration (FDA) is announcing the availability of draft guidance for industry, clinical investigators, and institutional review boards entitled “Use of Electronic Informed Consent in Clinical Investigations—Questions and Answers.” The draft guidance provides recommendations for clinical investigators, sponsors, and institutional review boards (IRBs) on the use of electronic media and processes to obtain informed consent for FDA-regulated clinical investigations of medical products, including human drug and biological products, medical devices, and combinations thereof.

To enhance human subject protection and reduce regulatory burden, the Department of Health and Human Services Office for Human Research Protections (OHRP) and FDA have been actively working to harmonize the agencies' regulatory requirements and guidance for human subject research, and the FDA draft guidance document was developed as a part of these efforts. Although the document is issued by FDA and is drafted as guidance that would apply to FDA-regulated clinical investigations, OHRP is considering whether to adopt the positions and recommendations proposed in this guidance for research regulated under the HHS protection of human subjects regulations, 45 CFR part 46, and to issue a joint OHRP and FDA guidance document on this topic when the final guidance document is developed. OHRP asks for public comment about whether a joint guidance document would be useful for the regulated community. In particular, OHRP is interested in public comment regarding whether FDA's draft guidance would be appropriate for all research regulated under 45 CFR part 46, including research studies other than clinical investigations or clinical trials, such as social and behavioral research studies. If different guidance should apply to social and behavioral research, or other non-FDA-regulated studies, OHRP asks that the public comments address how the guidance should differ from the proposed guidance for FDA-regulated clinical investigations.

OHRP specifically welcomes feedback regarding when it might or might not be appropriate, for studies other than clinical trials, for OHRP to recommend that researchers verify that the person signing the informed consent form is the subject participating in the research.

OHRP and FDA will consider these comments in deciding whether to issue a joint OHRP/FDA guidance document on this topic when the final guidance document is developed.[1]

SACHRP offers the following comments for the agencies’ consideration.  Comments that apply solely to FDA or OHRP will be noted as such.  All other comments are applicable to both agencies.

SACHRP commends the agencies for proactively addressing the complicated issue of electronic informed consent (eIC) for human subjects research.  This is an increasingly relevant issue as communication in all fields is conducted more often through electronic means as opposed to the traditional use of paper, and numerous stakeholders have identified eIC as a potential vehicle for improving the consent process.

Question 2, page 4, lines 129-132 states, “In addition, if the consent process is not personally witnessed by study personnel, the computerized system should include a method to ensure that the person signing the informed consent is the subject who will be participating in the research study (or the subject’s LAR).”  It would be useful if FDA provided examples of some types of methods that would meet this requirement, particularly to the extent that this requirement is driven by 21 CFR 11.100(b), which states, “Before an organization establishes, assigns, certifies, or otherwise sanctions an individual's electronic signature, or any element of such electronic signature, the organization shall verify the identity of the individual.” Examples might include verification of a state issued ID or other identifying documents, use of personal questions, or biometric methods, or visual methods such as skype or a similar application. There has been a significant amount of debate about what methods of verification meet this regulatory requirement.  SACHRP encourages FDA to use a risk-based approach to determining the appropriate methods of verification for the consent process.  Alternatively, if FDA is not basing this recommendation on 21 CFR Part 11, a statement to that effect would be valuable.  

As drafted, the guidance is heavily based on the requirements of 21 CFR Part 11.  OHRP should consider what laws it will consider as binding for research under its jurisdiction, as FDA is the only HHS agency that has adopted 21 CFR Part 11.  For instance, in question 10, page 6, lines 248-250, the guidance states, “The Electronic Signatures in Global and National Commerce Act (E-248 Sign Act) (Public Law 106-229) addresses what constitutes a valid electronic signature, and provides that a signature may not be denied legal effect because it is in electronic form.”  It will be useful in OHRP’s version of the guidance to identify this or other applicable laws that will in OHRP’s opinion be legally binding.  OHRP should clearly indicate that they do not require eIC to conform to 21 CFR Part 11 for research that is not also FDA regulated.

Question 6, page 5, lines 183-185 states “The procedure for eIC may include an electronic method to capture the signature of the subject or the subject’s LAR (e.g., an encrypted digital signature, electronic signature pad, voice print, digital fingerprint).”  FDA should clarify if any of these electronic methods to capture the signature of a subject do not have to meet the requirements of 21 CFR Part 11.  For instance, a common interpretation is that a signature made with a finger or digital pen, which looks the same as a signature made on paper with a pen, need not meet the requirements of Part 11 and can be considered the equivalent of a hand signature rather than an electronic signature.  Confirmation of whether or not that interpretation is correct will be valuable to the regulated community.

Question 7, page 6, lines 204-206 states, regarding the assent of children, “The language and presentation of information must be understandable to the child, and the documentation of assent should be handled in the same way as documentation of informed consent/parental permission.”  This would seem to impose a higher burden of documentation of consent than currently exists in 21 CFR 50.55(g) and 45 CFR 46.408(e), which both state that “When the IRB determines that assent is required, it must also determine whether and how assent must be documented.”  This is a lesser standard of documentation than is required for informed consent/parental permission.  The agencies should clarify that the same predicate rule requirements for assent apply to electronic assent.   In addition, SACHRP recommends that the sentence be modified to say “The language and presentation of information must be understandable to the child, and the documentation of assent, when required by the IRB, should be handled in the same way as documentation of informed consent/parental permission.” SACHRP recommends that FDA clarify that the intent is not to alter existing regulatory requirements for documentation of assent.

Question 8, page 8, lines 219-221, states regarding provision of a copy of the consent document to the subjects, that “The copy (e.g., printed paper document or email with an e-copy) should include a transcript of any audiovisual presentations provided during the eIC process.”  The agencies should clarify that if the copy is provided in electronic format, such as via email or through a link to a website, then it is also acceptable for the audiovisual presentation to be provided to the subject directly for future viewing, and that it is not a requirement in such case to also provide a transcript of the audiovisual presentation.  A transcript may in fact be less useful than an electronic version, given that a transcript may not adequately capture graphics such as a depiction of randomization in clinical research.

Question 8, page 6, lines 223-227 states, “Should an e-copy be offered, subjects should be informed of the risks of storing or viewing the consent document on a personal electronic device (PED), especially if that PED is shared with other users or is lost, hacked, or subject to a search warrant or subpoena. Unlike paper copies, which the subject may refuse to retain or may destroy, e-copies delivered directly to the subject’s PED may not be able to be permanently removed.”  This seems excessive, as paper copies are equally open to being viewed by others if stored in a shared file folder or desk, and can be copied or stolen as easily as an electronic version.  SACHRP recommends that the agencies remove this statement.  However, should researchers or sponsors intend to use an eIC device to record (video or audio) the consent process and retain the recording, this should be disclosed to potential subjects.

Question 11, page 7, lines 257-267, discusses the IRB’s responsibilities in the eIC process.  While Question 11 clearly states that “the IRB must review and approve the eIC and any amendments to the eIC,” the agencies should also address whether it is acceptable for an IRB to review and approve a paper copy of the consent form that will later be converted to electronic form.  Currently some parties involved in the creation of eIC documents believe that the IRBs is only required to review the paper copy, and not the subsequent eIC.  It would be useful for this question to be clearly and proactively addressed to avoid confusion.  IRBs should be required to approve the complete eIC, to ensure that the presentation of materials (e.g., use of interactive graphics, animations, etc.) contribute to an effective informed consent process and do not unduly influence potential subjects.  FDA and OHRP could require the same standard that is used regarding IRB review of final versions of written, audio, video and electronic versions of subject recruitment materials.

Overall, SACHRP recommends that FDA utilize a risk-based approach to the application and interpretation of Part 11 as it applies to eIC.  For example, minimal risk research may warrant more flexibility in the application of Part 11 requirements.

Overall, SACHRP recommends that OHRP should also use a risk based approach to eIC, particularly given that OHRP oversees a significant amount of research that is of minimal risk.  For instance, for minimal risk questionnaire research conducted over the internet which is eligible for a waiver of documentation of consent, it may not be necessary to identify or verify the identity of the subjects.

Finally, SACHRP would like to encourage OHRP and FDA to continue to issue joint guidance and to proactively harmonize guidance to the extent possible.  This is very important to the administrative efficiency of the conduct of research.  In the case of this FDA draft guidance, SACHRP notes again that it is heavily based on the requirements of 21 CFR Part 11, which applies only to FDA and not to agencies with research regulated by 45 CFR 46.  For this reason, SACHRP believes much of the FDA draft guidance cannot be applied to research regulated by 45CFR46 as is.  However, as FDA revises this draft guidance in consultation with OHRP, it may be possible to reorganize the guidance so as to separate those questions and answers that are not based on 21 CFR Part 11 from those that are based on 21 CFR Part 11.  This would allow use of those portions of the guidance that were not based on 21 CFR Part 11 to be used as a guidance for research regulated only under 45 CFR 46.  If it is not possible to separate significant portions of the revised guidance based on 21 CFR Part 11, then SACHRP recommends that separate guidance documents be developed for FDA regulated research and for research  regulated by 45 CFR 46.

[1] Federal Register / Vol. 80, No. 45 / Monday, March 9, 2015 / Notices, pgs. 12496-12497.

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