Introduction
On July 15, 2014, FDA released for public comment the draft guidance entitled, “Informed Consent Information Sheet; Guidance for IRBs, Clinical Investigators, and Sponsors.” The charge of the Secretary's Advisory Committee on Human Research Protections (SACHRP) is to:
[P]rovide expert advice and recommendations to the Secretary, through the Assistant Secretary for Health (ASH), on issues and topics pertaining to or associated with the protection of human research subjects. The Committee will work to advise the Secretary on how to improve the quality of the system of human research protection programs, including the responsibilities of investigators, institutional review boards (lRBs), administrators, and institutional officials, and the role of the Office for Human Research Protections and other offices within the Department of Health and Human Services.
In accordance with this charge, SACHRP offers the following commentary on FDA’s draft guidance. Page references are to the PDF version of the draft guidance posted on FDA’s website. Unless otherwise indicated, SACHRP’s recommendations are addressed solely to this FDA draft guidance, and should not be applied to non-FDA-regulated human subject research.
SACHRP would like to commend FDA for issuing the draft revised update to the informed consent guidance, and the effort to harmonize this guidance with other existing draft and final guidance and OHRP guidance.
Commentary
In section III.A.2, page 5, it states, “Careful wording is needed in order to avoid overstating potential benefits that may contribute to a subject's therapeutic misconception.” It would be useful to the regulated community if FDA would provide some examples of such wording, in order to set a standard.
In section III.A.2, page 5, it states, “Furthermore, statements such as "FDA has given permission for the clinical investigation to proceed" or "FDA has approved the clinical investigation" should be avoided, because such statements may contribute to the misimpression that the investigation has FDA's endorsement.” In the current version of the FDA Information Sheets, it also states that “FDA also believes that an explicit statement that an IRB has approved solicitation of subjects to participate in research could mislead or unduly induce subjects. Subjects might think that, because the IRB had approved the research, there is no need to evaluate the study for themselves to determine whether or not they should participate.” If this is no longer FDA’s guidance, it may be useful to state this explicitly so that the regulated community understands that this is a change in FDA’s position, which will encourage IRBs and other parties to remove this proscription from current standard operating procedures.
In section III.A.3, page 5, FDA encourages that information that is given to subjects be understandable. However, in the next section, III.A.4, pages 5-6, addressing exculpatory language, the examples of exculpatory and not exculpatory language are at a college reading level according to readability tests such as the Flesch-Kincaid, Gunning-Fog, Coleman-Liau, and SMOG.
In section III.B.1, page 7, the guidance says that:
FDA recommends that potential subjects first be informed of the care a patient would likely receive if not part of the research and then be provided with information about the research. This sequence allows potential subjects to understand how the research differs from the care they might otherwise receive.
FDA should clarify whether or not this information about “care a patient would likely receive if not part of the research” (hereafter in this paragraph referenced as “other care”) should be included in the written consent form, or whether this could or should be provided to subjects orally or through an addendum to the consent form or other written documents besides the research consent form. SACHRP recommends that information about other care not be included in the written consent document, and that emphasis be put on the oral consent process carried out by the investigator and research team. SACHRP notes that as part of any treatment relationship, common law and professional standards already require that physicians discuss realistic treatment options with a patient. That duty of care precedes any research duty, and must be fulfilled, whether or not study enrollment is offered. Researchers should assure that research is offered after, or in the context of, discussion of treatment alternatives.
With this background, SACHRP makes the following recommendations regarding the inclusion of other care in the research consent form. First, including this information about other care in the consent form will significantly increase the length and complexity of the consent form. Second, subjects may confuse the additional data about other care with information about the research. Third, it would be very difficult to draft a consent form with language about other care because subjects are often in different stages of disease and treatment options, potentially with confounding diseases or medical histories, and it is unlikely a single document can adequately anticipate all the potential situations a subject might be encountering. Fourth, in some cases the other care will already have been discussed with the subjects. SACHRP also recommends that documentation of the discussion of other care be similar in scope to the current clinical documentation standards. If FDA decides that oral presentation of the information about other care is not an acceptable approach, and instead takes the position that information about other care should be included in written documents separate from the consent form, then SACHRP recommends that FDA clarify whether it expects the IRB to review those documents.
Also in section III.B.1, page 7, this sentence follows the citation above: “The information provided should also inform prospective subjects about the potential consequences of these differences in care.” SACHRP was unclear about the intent of this sentence. If the intent is to provide subjects with information about the potential outcome of the study, then it will be difficult to say much more about the consequences than you may or may not get better. The intent of research is to determine whether or not an intervention is safe and efficacious, and like clinical care is not always successful, On the other hand, if the intent of this sentence is to provide information to the subject about the outcome, such as ”you will have to wear a prosthesis the rest of your life,” then FDA should clarify that. SACHRP recommends FDA use more precise language, or provide examples, or remove this sentence. Finally, if this language is kept, then it should be qualified as “major consequences” rather than any potential consequences.
In section III.B.2, page 8, the guidance includes this sentence: “All possible risks do not need to be described in detail in the informed consent form, especially if it could be overwhelming for subjects to read.” The regulatory criteria for the inclusion of risks in the consent form is that they be “reasonably foreseeable.” The draft sentence is confusing because it could be interpreted to mean that some reasonably foreseeable risks don’t need to be included if there are many of them. Also, it contradicts the rest of section III.B.2. SACHRP recommends that FDA tie this issue to the existing regulatory language regarding foreseeable risks, and not bring in the concept of “overwhelming” separate from that regulatory language, FDA may find it more productive to provide more direct guidance on the meaning of “reasonably foreseeable.” This could say that the reasonably foreseeable risks are not all possible risks that could occur, but rather are those risks that a reasonable person would find meaningful to his or her decision to participate in the research.
In section III.B.4, page 10, FDA discusses the disclosure of alternative treatments. One paragraph states that:
When disclosing appropriate alternative procedures or courses of treatment, FDA believes a description of any reasonably foreseeable risks or discomforts and potential benefits associated with these alternatives must be disclosed. Where such descriptions or disclosures can contain quantified comparative estimates of risks and benefits (e.g., from the clinical literature), they should do so. The agency does not believe that imposing such a strict requirement for every case would be realistic or appropriate.[19] Where such well-defined estimates are not possible, the agency believes that a description of the risks and benefits will be sufficient.
Similar language was supported by the FDA in the 1981 Preamble at 21 CFR Part 50, at comments 27 and 28. Also, the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) E6 document includes similar language. ICH GCP section 4.8.10(i) states that the consent form should include an explanation of “(i) The alternative procedure(s) or course(s) of treatment that may be available to the subject, and their important potential benefits and risks.”
SACHRP strongly recommends that FDA abandon this position, for several reasons. First, it will make consent forms very long when the research involves a disease with many options for treatment. For instance, disclosing the risks and benefits of all drugs approved for the treatment of arthritis would take many pages. Similarly, for some cancers there are dozens of potential treatment options, particularly if one considers different drug combinations in addition to radiation and surgical procedures. Second, disclosing the risks and benefits of the research against all of the risks and benefits of alternative courses of treatment might dilute the risks and benefits of the research. Third, the disclosure of the risks and benefits of alternative procedures or treatments in the same document as the risks and benefits of the research intervention may increase the likelihood of subjects suffering from therapeutic misconception.
SACHRP notes that FDA says that the “reasonably foreseeable risks or discomforts and potential benefits associated with these alternatives must be disclosed.” [emphasis added]. SACHRP recommends that “must” be changed to “should” in this sentence, and that FDA qualify that the risks and benefits of alternative procedures should be disclosed to subjects when the information is meaningful to the decision to participate. SACHRP believes that the use of “must” in the entire first paragraph of section III.B.4, on page 9, is appropriate. However, the use of “must” in the paragraph cited above, on page 10, is not a necessary interpretation of the regulatory language in 21 CFR 50.25(a)(4). SACHRP does want to note that it believes that alternative treatments, and their risks and benefits, should be discussed with each potential subject, with emphasis on the best clinical options for the individual.
SACHRP notes that the issues discussed above in section III.B.4, page 10, regarding the disclosure of risks and benefits of alternative treatments, are similar to the issues discussed in section III.B.1, page 7, regarding the provision of information about “care a patient would likely receive if not part of the research” (“other care”). For both issues, either oral disclosure during the consent process or the use of written documents separate from the consent form could be used. FDA should provide consistent guidance on these two related issues.
Finally, footnote 16 in this section of the draft guidance says, “FDA notes that OHRP may hold a different interpretation of “appropriate alternative procedures or courses or treatment” as noted in their regulatory correspondence.” SACHRP recommends that FDA and OHRP harmonize their approach to this issue to the extent differences exist. It is difficult for the regulated community to follow conflicting guidance on the same regulatory issue, particularly when so much clinical research falls under the authority of both FDA and OHRP through HHS funding or through voluntary application of the HHS regulations to all research by an institution through the FWA process.
In section III.B.5, pages 10- 11, the guidance states that “The consent process must also note the possibility that FDA may inspect records (21 CFR 50.25(a)(5)), and should not state or imply that FDA needs permission from the subject for access to the records.” SACHRP recommends that FDA consider whether this sentence should be modified with the addition of the italicized language: “The consent process must also note the possibility that FDA may inspect records (21 CFR 50.25(a)(5)), and should not state or imply that FDA needs additional permission from the subject for access to the records. ” When subject provide consent to participate in research, if the consent form appropriately discloses that FDA has the right to inspect their records, they have given their permission for this to occur as a condition of participation in the research.
In section III.B.6, pages 11-12, the guidance provides two examples of language that can be included in the consent form to disclose that compensation for injury is not planned. Both examples are at a college reading level according to readability tests such as the Flesch-Kincaid, Gunning-Fog, Coleman-Liau, and SMOG.
In section III.B.7, page 12, FDA states:
If contact information changes during the clinical investigation, then the new contact information must be provided to the subject. (21 CFR 50.25(a)(7).) This may be done through a variety of ways, for example, a card providing the relevant contact information for the clinical investigation.
SACHRP recommends that FDA clarify that the word “card” here refers to a card provided to subjects in a manner that ensures the protection of privacy and confidentiality. This is particularly true when the research involves a stigmatized disease, such as HIV.
In section III.C.5, page 15, the guidance addresses the regulatory requirement that as appropriate a statement that significant new findings developed during the course of the research which may relate to the subject's willingness to continue participation will be provided to the subject. (21 CFR 50.25(b)(5).) The guidance states:
FDA encourages the inclusion of this statement in the consent form for clinical investigations where knowledge of risk is limited, for example, clinical investigations of the first use in humans, novel therapies, and new molecular entities, or complex clinical investigations that involve significant risk.
SACHRP recommends that FDA not limit this statement to clinical investigations where knowledge of risk is limited. There are many types of new information that might affect a subject’s willingness to continue participation in a research study that do not involve risk, such as new conflict of interest disclosure or notice that the investigator is moving to a new location. This inclusion of the significant new findings language should be encouraged in most clinical investigations.
In section III.E.2, page 17, FDA addresses alternative methods of obtaining informed consent. It defines the traditional means of obtaining informed consent as the face-to-face interview using paper consent forms and acknowledges that new technologies are becoming available that may serve as an alternative to the traditional process. The draft guidance furthers describes the FDA’s willingness to consider alternative methods. This willingness is more reactive or passive in that FDA will respond to parties that are interested in pursuing alternative methods once those parties contact FDA. SACHRP feels that the proposed guidance is an opportunity for FDA to be proactive and provide direction to the research community and help shape the conversation around use of non-traditional methods to informed consent. These alternative or non-traditional methods will continue to be used more and more in research. FDA could proactively provide direct feedback on such aspects as follows and for example:
- Guidance as to best practices in incorporating the required elements of informed consent into technology enabled methods
- Identification of good examples of alternative methods of informed consent
- Current issues or barriers to overcome potential limitations that it has identified with alternative methods of informed consent
In section III.E.3, page 18, FDA addresses the dating of the consent form. The last sentence in this section states, “Although FDA regulations do not require the subject's copy to be a signed copy, FDA recommends that a copy of the signed consent form be provided.” FDA should consider whether it would be appropriate to reference ICH GCP 4.8.11, which states “Prior to participation in the trial, the subject or the subject's legally acceptable representative should receive a copy of the signed and dated written informed consent form and any other written information provided to the subjects.” It is not clear why this FDA draft guidance does not reference applicable sections of ICH GCP document ‘‘E6 Good Clinical Practice: Consolidated Guideline’’ (ICH E6), which FDA adopted for use as guidance for industry in 1997 (62 FR 25692, May 9, 1997). Many sponsors want IRBs and investigators to comply with ICH E6 so that the results of the research may be submitted to government agencies outside of the United States. FDA could facilitate IRB and investigator compliance with ICH by referencing relevant sections such as in this case, further enhancing the global drug approval process.
In section III.E.4, page 19-20, FDA addresses the short form. FDA notes that “The information presented orally is to be the same quantity and quality of information as when a long form is used.” Occasionally, investigators and sponsors propose the use of the short form for research involving emergent conditions such as stroke and cardiac arrest. It would be helpful to the regulated community if FDA explicitly stated that the short form does not provide any advantages over the long form in clinical investigations of emergent conditions, and in fact may be more complicated to use due to the additional signature requirements.
Also in section III.E.4, page 20, FDA addresses who may be an appropriate witness to the oral presentation of information when the short form is used. FDA “recommends that an impartial third party, not otherwise connected with the clinical investigation (for example, clinical staff not involved in the research or a patient advocate), serve as the witness.” An issue that occasionally arises is whether or not the subject’s family member may serve as the witness. It would be helpful if FDA addresses this issue directly. If FDA agrees that an adult family member can be an impartial witness, this could be added to the parenthetical statement after patient advocate. SACHRP supports the interpretation that an adult family member can serve as a witness in this role, where there is no reasonable concern that the proposed witness is not acting in the best interest of the individual.
In section IV.C.5, pages 20-29, the guidance addresses responsibilities for informed consent, and has separate sections for the IRB (section A), the clinical investigator (section B), the sponsor (section C), and the FDA (section D).
In section A, page 22, FDA provides the following guidance for IRBs:
Investigators must use an IRB-approved written consent form when documenting informed consent, in accordance with 21 CFR 50.27, except as provided in 21 CFR 56.109(c). Thus, the IRB should review the adequacy and appropriateness of all wording in the consent materials, as well as the overall length and presentation of information. Consent forms that are long, complex, legalistic, and have a high reading level may overwhelm potential subjects and may inhibit reading of the full document and understanding of the relevant information.
The IRB should ensure that technical and scientific concepts and terms are explained, or common terms substituted, so that the anticipated subject population can understand all provided information (21 CFR 50.20).[40] Pictures or diagrams may be used to improve understanding of medical terms or how an investigational product functions. IRBs may wish to evaluate, through subject interviews, how well the consent materials communicate critical information.
This is excellent guidance, but it is directed at the wrong party. IRBs do not write consent forms; clinical investigators and sponsors write consent forms. It is very inefficient to make the IRB responsible for re-writing submitted consent forms that are inappropriately written at a college reading level. The IRB is the last procedural review conducted prior to beginning a clinical investigation. It will be far more efficient both time-wise and administratively if the consent form is written in understandable language before it is submitted to the IRB, while the clinical investigator or sponsor are concurrently fulfilling other necessary actions such as submitting protocols to FDA and arranging for sites to conduct the research.
Therefore, this guidance needs to be directed at clinical investigator and sponsors in sections B and C, as the individuals that write consent forms are usually either investigators or individuals who are under the control of investigators or sponsors. FDA should proactively require that consent form writers draft consent forms using the principles and tools for health literacy and numeracy. In addition, or alternatively, FDA should recommend the use of readability tests such as the Flesch-Kincaid, Gunning-Fog, Coleman-Liau, and SMOG when drafting consent forms to ensure that the consent form is at an 8th grade level. .
There are several proactive steps beyond the issuance of this informed consent guidance that FDA can take to assist these parties in meeting this requirement. First, FDA should develop a webpage that provides tools, guidance and training on the principles of health literacy and numeracy. Examples of similar websites at HHS agencies are the Centers for Disease Control (CDC) webpage on health literacy, and Centers for Medicare and Medicaid (CMS) website. FDA already has at least one website dedicated to plain language. Perhaps this website could be expanded or modified to address consent form understandability in particular.
Second, FDA should include notice with every issued IND and IDE that the principles of health literacy and numeracy must be applied to in the drafting of consent forms for the clinical investigations conducted under those INDs or IDEs. Third, it would be helpful if the consent form drafters informed the IRB that the principles of health literacy and numeracy and readability tests were considered and implemented in the writing of that consent form.
SACHRP considers these to be the most important recommendations we are making regarding this draft guidance, and implementation could do more to improve the consent process in the United States than any other action FDA can take. FDA has jurisdiction over the majority of clinical research conducted in the United States, and could use this jurisdiction to transform the way in which consent forms are written in the United States. The development of these resources would also provide tools for individuals writing consent forms for research that is not regulated by FDA. There are certain issues which are most effectively led by the government, such as the promotion of inclusion of more women and children in research as effected by FDA and NIH in the 1990s. The development of understandable consent forms is one of those issues.
In section IV.A.3, page 24, the guidance addresses IRB review procedures, and in the second paragraph focuses on expedited review of changes in research. The guidance says:
Some changes may be reviewed and approved by expedited means, as provided for by 21 CFR 56.110. For example, an IRB may decide expedited review is appropriate for changes to the consent form that reflect minor changes in the protocol or recruitment plan, such as new advertising for subjects following initiation of the clinical investigation when the advertisement incorporates wording from the approved consent form and the advertisement can be easily compared to the approved consent form.
The example should be changed. Most new advertising materials qualify for expedited review, even if they do not directly incorporate wording from the consent form. See SACHRP October 13, 2011 letter to the HHS Secretary, Attachment B, “SACHRP Recommendation regarding definition of a minor change in research under 45 CFR 46 and 21 CFR 56.” In that recommendation, SACHRP recommends that OHRP and FDA adopt the following definition of a minor change in research that can be reviewed through the expedited procedure: “Minor changes in approved research that can be approved through expedited review procedures are changes that neither materially increase risk, nor materially decrease benefit, nor materially decrease scientific merit.” It is very rare for new recruitment materials not to meet that standard.
In section IV.B. page 25, the guidance discusses the investigator duties that arise when a revised consent form is necessary due to changes in the protocol or new information. The guidance notes that the IRB should determine the need to re-consent enrolled subjects. The guidance states:
To diminish confusion about the change, the investigator may use a prepared summary of the change to aid in an informative presentation to the enrolled subject. However, this summary does not constitute the revised informed consent document.
FDA should clarify whether the “prepared summary of the change” refers to a consent form addendum, as this is a common term used by the regulated community, or if it is a different type of document. Also, FDA should clarify that if this “prepared summary of the change” is a consent form addendum, then the main consent form also must be revised. Finally, FDA should explicitly state whether or not the IRB must review this “prepared summary of the change.”
In section V.A, page 29, the guidance addresses review of patient records, and in the second and third paragraphs focuses on review of patient records to determine whether a site has a sufficient number of patients and to determine whether a patient is eligible for a clinical investigation. Both of these paragraphs have footnotes (50 and 51) which state:
For a clinical investigation that is conducted or supported by HHS, the activities described here generally would be considered research involving human subjects, but could be exempt under 45 CFR 46.101(b)(4). If the study is not exempt, the requirements for obtaining and documenting the informed consent of the subjects (or the requirements for waiving the informed consent requirements) under the HHS regulations would need to be satisfied in order for these activities to be conducted.
SACHRP recommends that this footnote not be included, as SACHRP has previously recommended that OHRP not consider such activities to be research. See SACHRP October 13, 2011 letter to the HHS Secretary, Attachment C, “SACHRP 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.” In that document, “SACHRP recommends that OHRP abandon the guidance that IRBs approve a waiver of consent under 45 CFR 46.116(d) for all activities conducted prior to consent, as exemplified in the guidance entitled “Clinical Research and the HIPAA Privacy Rule.”” Several reasons are provided. Also, SACHRP understands the current OHRP position on exemptions to be that if any part of a research study is not exempt, then the entire study is not exempt. This footnote contradicts that position.
In section V.B.2 page 31-34, FDA addresses informed consent procedures when enrollment of subjects who do not understand English is unexpected. SACHRP agrees with the draft FDA guidance approach, and recommends for consistency that OHRP consider adopting this approach for clinical trials greater than minimal risk not under FDA jurisdiction.
In section V.D page 34-35, the guidance addresses obtaining and documenting consent by physically challenged subjects, for example, physically unable to talk or write or has hearing or visual loss. FDA may wish to clarify that such subjects do not need to have consent provided by a legally authorized representative (LAR) even if they cannot physically sign the consent form. Sponsors, investigators and IRBs sometimes believe consent from an LAR is necessary in such cases, and it would be helpful for FDA to clarify that it is not necessary if the subject is mentally capable.
In section V.F page 39, the guidance addresses the enrollment of children who are wards of the state. Regarding clinical investigations approved under 21 CFR 50.51 (i.e., research involving no more than minimal risk) or 21 CFR 50.52 (i.e., research involving greater than minimal risk but presenting the prospect of direct benefit), FDA recommends that “Before enrolling any child who is a ward in a clinical investigation, IRBs should ensure that each child has a guardian and/or advocate with the background, experience and commitment to act in the best interest of the child.” SACHRP recommends that FDA not include this recommendation regarding clinical investigations conducted under 21 CFR 50.51 and 21 CFR 50.52. While requiring an IRB to review the background of each guardian and/or advocate will provide a further level of protection to these children, it is also likely to have the effect of discouraging the inclusion of such children in clinical investigations approved under 21 CFR 50.51 or 21 CFR 50.52 due to the additional administrative burden. Because clinical investigations under these regulatory provisions are by definition either minimal risk or include a prospect of direct benefit equivalent to that prospect the children would face in clinical care, they are highly unlikely to involve any undue risk or exploitation of this vulnerable group. In fact, in some situations a clinical investigation conducted under 21 CFR 50.52 will offer a prospect of benefit available only in that clinical investigation which is better than available clinical care. The National Commission for the Protection of Human Subjects in Biomedical and Behavioral Research carefully addressed the issue of research with children in its 1977 report entitled “Research Involving Children.” SACHRP believes that the National Commission reached the optimum balance of ethical principles in regard to research with children who are wards of the state, and that FDA should maintain the approach outlined in the 1977 report and the current FDA regulations.
If FDA decides to keep this suggestion as drafted, then FDA should clarify whether or not it will require that the IRB review the background of each guardian and/or advocate, or whether the IRB can delegate this decision to other parties such as the clinical investigator. This question will eventually arise if this section is maintained as drafted.
In section V.K page 41-42, FDA addresses the reporting of aggregate results of clinical investigations to subjects. SACHRP recommends that FDA explicitly state that when results are returned to subjects after the study has been closed with an IRB, the IRB does not have to review the documents provided to subjects, just as the IRB does not have to review study results posted to ClinicalTrials.gov after the study has closed. Furthermore, the individuals are technically no longer subjects, and there is not an open clinical investigation. However, if results are returned to subjects while the study is still open with the IRB, then the IRB must review and approve the documents provided directly to the subjects.
SACHRP also recommends that if feasible, FDA also address how clinical investigators and sponsors can avoid illegal promotion of medical products when providing aggregate results to subjects, as this would greatly contribute to sponsor’s comfort with providing such results to subjects. SACHRP believes that routine provision of aggregate results to subjects will improve subjects’ satisfaction with the research process and help to promote public support of research.
As noted earlier in this recommendation, one implication of this draft guidance is that before the research informed consent begins, a clinical informed consent process should occur. The clinical informed consent process is the responsibility of the clinician treating a patient and may, if appropriate, include participation in research as an option. The research informed consent process is conducted by investigators (who may or may not also be the treating clinician). This FDA draft guidance is directed at investigators, sponsors, and IRBs, not clinical care providers. In addition, this is a topic that is not unique to FDA regulated trials and it is SACHRP’s observation that confusion exists about the relationship between the clinical and research informed consent processes. For this reason, SACHRP encourages FDA to work with other stakeholders, such as OHRP, NIH, industry and professional societies to explore ways to better educate clinicians and researchers about the importance of clinical informed consent as a necessary precedent to the research informed consent process.
Conclusion
SACHRP thanks FDA for this valuable update to the FDA Information Sheet on informed consent, and hopes that the agency finds these comments useful.
