Approved October 19, 2022
In 2009, SACHRP established the Subcommittee on Harmonization with the specific focus of promoting consistency between the HHS and FDA informed consent and human subject protection regulations.
The Subcommittee on Harmonization charge reads as follows:
The Subcommittee will identify and prioritize areas in which regulations and/or guidelines for human subjects research adopted by various agencies or offices within HHS would benefit from harmonization, consistency, clarity, simplification and/or coordination. The Subcommittee will then develop recommendations, for consideration and possible adoption by SACHRP, to harmonize and simplify these guidelines and regulations. The goal of this subcommittee effort is to reduce unnecessary burdens on research efforts, thus resulting in better allocation of research resources and promoting the safety and welfare of human subjects.1
This charge provides the framework for these SACHRP comments. The current version of the HHS regulations and the new FDA regulations as adopted will likely be in place for decades. Therefore, harmonization to the extent possible will reduce regulatory burden for the research community for many years to come. As noted in the NPRM, Congress in Section 3023 of the 21st Century Cures Act “directs the Secretary of HHS, to the extent practicable and consistent with other statutory provisions, to harmonize differences between the HHS Human Subject Regulations and FDA’s Human Subject Regulations . . . in order to, among other things, reduce regulatory duplication and unnecessary delays.”2 Harmonization will also reduce confusion and regulatory burden for studies that are subject to both HHS and FDA human subject protections.3
Page 58738 – New Element of Informed Consent at 21 CFR 50.25(a)(9)
FDA asked for the following public comment:
We request public comment on whether FDA’s proposed new basic element of informed consent at § 50.25(a)(9) would provide adequate notice to potential subjects regarding the possible future research use of their information and biospecimens or whether the Common Rule’s provision at 45 CFR 46.116(b)(9) would better inform potential subjects about the possible future use of their information and biospecimens in research. We further request public comment on whether the research community anticipates challenges in implementing FDA’s proposed new element and whether an alternative approach could lessen such challenges.
45 CFR 46.116(b)(9) reads as follows:
in seeking informed consent the following information shall be provided to each subject or the legally authorized representative: … (9) One of the following statements about any research that involves the collection of identifiable private information or identifiable biospecimens:
(i) A statement that identifiers might be removed from the identifiable private information or identifiable biospecimens and that, after such removal, the information or biospecimens could be used for future research studies or distributed to another investigator for future research studies without additional informed consent from the subject or the legally authorized representative, if this might be a possibility; or
(ii) A statement that the subject’s information or biospecimens collected as part of the research, even if identifiers are removed, will not be used or distributed for future research studies.
FDA’s proposed new regulatory language at 21 CFR 50.25(a)(9) reads as follows:
in seeking informed consent the following information shall be provided to each subject or the legally authorized representative: … A description of how information or biospecimens may be used for future research or distributed to another investigator for future research.
SACHRP recommends that FDA harmonize with the current HHS language and does not introduce the new proposed regulatory language at 21 CFR 50.25(a)(9).
SACHRP appreciates FDA’s effort to harmonize and enhance the basic element of informed consent that was added to the HHS regulations in the 2018 revision. However, SACHRP believes that the value of harmonization outweighs the advantages of the FDA’s proposed new language. First, FDA’s proposed language at 21 CFR 50.25(a)(9) is very open ended, and will in most cases be very difficult for the sponsor or investigator drafting the consent form to complete. Future research with information or biospecimens is often not contemplated at the time of writing the protocol and informed consent form, therefore there will often not be information to provide to the subject. This research is called secondary research because the new questions to be asked become apparent in the future. Further, the goal of the new element in the HHS regulations was solely, and simply, to let subjects know if their information and specimens may be used for further research without their consent. This reflects a common participant concern, particularly after the publicity of the use of Henrietta Lacks’ tissues to create an immortal cell line, that information or specimens might be used without consent in the future. While FDA has attempted to improve the language by making it more open ended, this does not outweigh the value of harmonization across the HHS and FDA consent regulations, in particular when possible future uses may be unknown at the time the present research is being developed. Finally, FDA’s proposed language could lead to IRBs and other parties interpreting the failure to describe future secondary research in the consent form as a prohibition on secondary research without consent, which would restrict the ability to perform such research under the current HHS regulations. Finally, parties in research may be concerned that the conduct of secondary research without consent may be a finding in an FDA inspection if the secondary research was not described in the consent form. This could in turn reduce the ability or willingness to conduct such research, which would impede the current regulatory provisions allowing such research to occur.
Page 58739 – Activities Preparatory to Research
FDA asked for the following public comment:
We request comment on whether FDA’s current policy adequately addresses screening, recruiting, or determining eligibility for an FDA-regulated clinical investigation, or if including the revised Common Rule provision at 45 CFR 46.116(g) would be useful for FDA-regulated clinical investigations.
45 CFR 46.116(g) was revised in 2018 to include the following requirement:
(g) Screening, recruiting, or determining eligibility. An IRB may approve a research proposal in which an investigator will obtain information or biospecimens for the purpose of screening, recruiting, or determining the eligibility of prospective subjects without the informed consent of the prospective subject or the subject’s legally authorized representative, if either of the following conditions are met:
(1) The investigator will obtain information through oral or written communication with the prospective subject or legally authorized representative, or
(2) The investigator will obtain identifiable private information or identifiable biospecimens by accessing records or stored identifiable biospecimens.
SACHRP Recommends that FDA adopt the HHS regulatory language and harmonizing with HHS.
On July 20, 2011, SACHRP issued a “Recommendation regarding application of 45 CFR 46 and 21 CFR 56 to early processes in research, such as identifying potential subjects, contacting subjects and recruiting subjects.” The point of this recommendation was removing the inconsistency among the HHS version of the Common Rule, FDA regulations, and HIPAA regarding activities preparatory to research, and obtaining harmonization on this issue. The HHS regulations were amended in 2018 to specifically address this issue, which was responsive to the SACHRP recommendation. In essence, the HHS regulations were harmonized with the FDA approach, as captured in the 1998 FDA Information Sheet entitled “Screening Tests Prior to Study Enrollment, Guidance for IRBs and Clinical Investigators.”
FDA notes that because the FDA definition of a “clinical investigation” is distinct from the HHS definition of “research,” it is unnecessary for FDA to adopt the new HHS regulatory language. There are several arguments against this position. First, if FDA adopts this language it will change FDA’s position from guidance based on the definition of “clinical investigation” to simple regulatory language. This provides greater certitude that this position is official and can be relied upon by regulated parties. Second, the FDA definition of a clinical investigations at 21 CFR 56.102(c) states that “The terms research, clinical research, clinical study, study, and clinical investigation are deemed to be synonymous for purposes of this part.” This could lead to confusion in the future for individuals trying to understand FDA’s position on the subject of activities preparatory to research. Finally, FDA has now committed to accepting other forms of evidence besides data from clinical investigations for consideration assessing the safety and efficacy of medical products. For instance, FDA has stated it will accept evidence based on real-world data. In addition, FDA has allowed for FDA-regulated research to be conducted under a waiver of consent as provided at 45 CFR 46.116. Therefore, it may be of benefit for FDA going forward to have clear regulatory language on activities preparatory to research rather than relying on guidance based on the definition of a clinical investigation.
Therefore, SACHRP recommends that to further the goal of harmonization it will be far more efficient and understandable for the research community if FDA adopts the new HHS language verbatim, thus obviating the need for a guidance document that reaches the same end as the HHS regulatory language. This will ensure that FDA and HHS regulations are harmonized on this issue for the research community without any question.
Page 58740 – Waiver of Documentation of Informed Consent
FDA asked for the following public comment:
We note that the revised Common Rule also retains an exception to the requirement for documentation of informed consent at 45 CFR 46.117(c)(1)(i) for situations in which the only record linking the subject and the research would be the informed consent form and the principal risk would be potential harm resulting from a breach of confidentiality. FDA’s regulations historically have not included this same exception, and we are not proposing to add it in this rulemaking because we do not believe it is relevant to FDA-regulated research. We are, however, requesting comment on whether this provision is relevant to FDA-regulated research and any examples of situations when it would be useful.
SACHRP Recommends that FDA adopt the waiver of documentation criteria.
It is possible to think of potential examples where this provision could be applied to and FDA- regulated clinical investigation. For instance, an FDA-regulated study evaluating an investigational assay for the detection of monkeypox among a stigmatized group [e.g., men who have sex with men; people with HIV; people who use or inject drugs]. The assay meets the IDE exempt criteria for diagnostic devices at 21 CFR 812(c)(3). Because the assay does not involve invasive sampling procedures and is not being used on its own to guide clinical care, the risks related to the assay may be minimal. In this case, given the proposed study population, the risks of stigmatization due to a potential confidentiality breach are significant and may exceed the risks associated with the assay. This may be a situation where waiving the requirement for documentation of consent reduces the privacy and confidentiality risks and may be in the best interests of study participants.
SACHRP recommends that FDA adopt this regulatory language as FDA moves towards accepting more types of data such as real-world evidence.4 It does not cause any harm to have this provision in the FDA regulations, and on rare occasions may allow such research to go forward with better research participant protection. It is worth noting that FDA regulations already include a provision for waiver of documentation of consent at 21 CFR 56.109(c)(1) for research that presents no more than minimal risk of harm to subjects and involves no procedures for which written consent is normally required outside the research context. Thus, adoption of then new regulatory language does not create novel problems regarding documentation of consent.
Page 58743
- FDA is proposing that the effective date of any final rule that issues based on this proposal would be 180 days from the date of publication of the final rule to allow the regulated community time to prepare to implement the proposed changes. FDA requests comment on this timeframe.
SACHRP agrees this is acceptable.
Pages 58743-58744
- In addition, FDA’s goal is to minimize disruption to FDA-regulated studies that are ongoing when the proposed new requirements would become effective, and we are proposing an implementation strategy to address research initially approved by an IRB before the proposed effective date. For these studies, FDA would not intend to enforce compliance with the following proposed provisions:
- proposed new § 50.20(d) through (e), which would, among other things, require informed consent to begin with a concise and focused presentation of ‘‘key information’’ and would require informed consent information to be organized and presented in certain ways;
- the proposed new basic and additional elements of informed consent at § 50.25(a)(9) and (b)(7) through (9); and
- the proposed revision to § 50.27(b)(2), which would require the key information required by § 50.20 to be presented first to the subject or the subject’s legally authorized representative when informed consent information is provided orally and documented using a short form.
This approach reflects FDA’s concern that, for research an IRB has approved before the proposed effective date, revising the already approved informed consent form and process to comply with the provisions identified above could cause unwarranted burden and, in some cases, delay research. However, nothing in this proposal would prevent sponsors and investigators from updating the consent forms for research that was approved before the proposed effective date to comply with the above listed provisions. We request comment on this proposed approach.
SACHRP agrees this is acceptable.
Page 58744
- The Regulatory Flexibility Act requires us to analyze regulatory options that would minimize any significant impact of a rule on small entities…We have prepared an initial regulatory flexibility analysis and are seeking comment on the data and assumptions used in that analysis.
SACHRP has no comment on this section.
Pages 58747-58748
- In accordance with PRA regulations (5 CFR 1320 at 1320.8(b)(3)(iii)), we provide our estimate in table 7, row 2 of the annual average burden and invite comment on this estimate.
- We maintain our current estimate of one report annually for non-significant risk device studies that do not require submission of an IDE application to FDA, and that preparing the report requires 6 hours, as approved under OMB control number 0910–0078. We note however, this is a longstanding estimate and invite comment specifically with regard to the number of progress reports sponsors and investigators anticipate submitting annually to reviewing IRBs and the burden associated with progress reports under § 812.150 for non-significant risk studies. We do not specifically estimate burden for progress reports to reviewing IRBs for significant risk studies under OMB control number 0910–0078 and therefore invite comment here on how, if at all, the proposed changes would affect the number of progress reports sponsors and investigators anticipate submitting annually to reviewing IRBs and overall burden for these significant risk studies.
SACHRP has no comment on these sections.
SACHRP Recommendation on Biospecimens
SACHRP recommends that the U.S. Food and Drug Administration (“FDA”) clarify in regulation how in-vitro diagnostic research using leftover, de-identified samples ought to be handled in order to harmonize this area of regulation among all parts of HHS. FDA’s investigational device exemption (“IDE”) regulations define a “subject” to include individuals “on whom or on whose specimen an investigational device is used or as a control.”5 FDA has interpreted this to include studies involving prospective collection of specimens and the use of leftover, de-identified specimens.6 This is in contrast to the Common Rule, which would not consider research using leftover, de-identified specimens to constitute research involving a human subject, given that such research does not involve intervention with a living human being or the use of identifiable private information or identifiable biospecimens.7
Under the Notice of Proposed Rule Making pertaining to FDA’s human subjects research regulations (the “HSR NPRM”),8 FDA did not propose alterations to institutional review board (“IRB”) review requirements for in-vitro diagnostic studies using leftover, de-identified specimens – FDA did not, for example, proposed to amend the definition of “subject” under the IDE regulations. Therefore, even if the HSR NPRM is enacted in its current form, FDA regulations will continue to require IRB review for in-vitro diagnostic studies involving remnant, de-identified human specimens, if the results of such studies are submitted to, or held for inspection by, FDA in support of an application for a research or marketing permit.9
Accordingly, the treatment of research involving de-identified specimens continues to be a major point of difference between the Common Rule and the FDA human subjects research regulations. This difference in treatment causes confusion in the regulated community, including for investigators, institutions, sponsors, and IRBs. Such entities often apply the Common Rule framework by default and thus assume that an activity involving only remnant, de-identified specimens will not be subject to IRB review, only later to discover that FDA requires review of such studies. It does not appear to SACHRP that there is a principled reason for the differential treatment of such research by FDA regulations and the Common Rule. Indeed, IRB review of such protocols is often perfunctory, thus not meaningfully adding to human subjects protection. Moreover, the differential treatment imposes additional burdens on researchers developing important public health measures, such as diagnostic tests needed in the ongoing COVID-19 and Monkeypox public health emergencies. SACHRP thus urges FDA to revise its IDE regulations to mirror the Common Rule’s treatment of research involving remnant, de-identified specimens.
Pages 58735 - Need for the Regulation
SACHRP agrees with FDA’s proposals in this section.
Although the NPRM addresses numerous gaps between the revised Common Rule and existing FDA regulations, FDA acknowledges that there are several additional gaps that are either not being addressed at this time or are being addressed through alternative regulatory activities.
As noted in the NPRM:
This proposed rule does not address all of the provisions contained in the revised Common Rule. The Agency has addressed some of these provisions in a previously issued proposed rule and is also considering how other provisions of the revised Common Rule that are potentially relevant to FDA- regulated research, such as provisions related to single IRB review for cooperative research, posting of informed consent forms, broad consent, limited IRB review, exempt research, and public health surveillance activities, could be applied to FDA-regulated research. FDA plans to take additional steps to harmonize FDA’s regulations with the revised Common Rule, to the extent practicable and consistent with statutory provisions.
OHRP has requested SACHRP comment on the FDA’s decision to exclude several of the provisions, specifically: posting consent forms; broad consent; limited IRB review; exempt research, and public health surveillance activities.
At multiple points in the NPRM, the FDA deviates slightly from the exact language of the Common Rule due to nuanced differences between the type and nature of research subject to FDA regulation, which is more narrow than research that is subject to compliance with the Common Rule. The FDA’s focus, which is primarily clinical trials, results in sections of the Common Rule outside the scope of clinical research involving drugs and medical devices. SACHRP finds that in the provisions noted by OHRP, the relevance to FDA-regulated research is limited.
With regard to the Common Rule requirement that 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 (45 CFR 46.116(h)(1)), SACHRP notes that there are potential practical challenges to the FDA’s adoption of this requirement. The majority of FDA-regulated clinical investigations are privately financed. Industry sponsors in seeking to limit the amount of proprietary information that is publicly available are likely to insist on a degree of redaction in these materials that the result would be a document that provides little insight into the manner in which information is conveyed to research subjects. The Common Rule requirements for posting informed consent documents are confusing, and lead to misunderstood information being posted publicly, e.g., posted consent forms are not necessarily the final consent form for a given study or represent the information provided to all participants. Common concerns include administrative burden, limited utility, and risk of litigation or compliance actions among others.
The provisions for broad consent are also inapplicable to most FDA-regulated clinical investigations. Further, the extent to which broad consent has been adopted in Common Rule-regulated research is unclear, but anecdotally uptake is understood to be very low. Exempt research and limited IRB review are both provisions that are largely irrelevant within the sphere if FDA-regulated clinical investigations.
The Common Rule provision that excludes public health surveillance activities10 is also largely inapplicable in the context of FDA-regulated research activities. The majority of public health surveillance activities are publicly funded and do not involve the investigational use of a drug or medical device.
SACHRP concludes that FDA’s decision to exclude these provisions from the current NPRM proposals is logical and will not create confusion within the regulated community.
Endnotes
1https://www.hhs.gov/ohrp/sachrp-committee/subcommittees/index.html
2 87 Fed. Reg. 58735
3 Id.
4 FDA Guidance for Industry, “Submitting Documents Using Real-World Data and Real-World Evidence to FDA for Drug and Biological Products,” September 2022, Procedural.
5 21 C.F.R. § 812.3(p).
6 U.S. Food and Drug Administration, Studies Using Leftover, Deidentified Human Specimens Require IRB Review – Letter to Industry (Oct. 18, 2021), available at: https://www.fda.gov/medical-devices/industry-medical-devices/studies-using-leftover-deidentified-human-specimens-require-irb-review-letter-industry [hereinafter FDA Letter to Industry].
7 45 C.F.R. § 46.102 (“Human subject means a living individual about whom an investigator (whether professional or student) conducting research: (i) Obtains information or biospecimens through intervention or interaction with the individual, and uses, studies, or analyzes the information or biospecimens; or (ii) Obtains, uses, studies, analyzes, or generates identifiable private information or identifiable biospecimens”).
8 Protection of Human Subjects and Institutional Review Boards, 87 Fed. Reg. 58,733 (Sep. 28, 2022) (to be codified at 21 C.F.R. Parts 50, 56, and 812).
9See, e.g., FDA Letter to Industry.
10 “Including the collection and testing of information or biospecimens, conducted, supported, requested, ordered, required, or authorized by a public health authority. Such activities are limited to those necessary to allow a public health authority to identify, monitor, assess, or investigate potential public health signals, onsets of disease outbreaks, or conditions of public health importance (including trends, signals, risk factors, patterns in diseases, or increases in injuries from using consumer products). Such activities include those associated with providing timely situational awareness and priority setting during the course of an event or crisis that threatens public health (including natural or man-made disasters)”. (45CFR46.102(l)(2))
