SACHRP Commentary on the New “Key Information” Informed Consent Requirements October 17, 2018 SACHRP has been asked to provide commentary on questions posed by OHRP in the context of possible OHRP/FDA joint guidance on the new consent requirements at §46.116(a)(5)(i) and (ii). The definition of a “clinical trial” was included as part of the questions from OHRP, and SACHRP was asked to focus on clinical trials in this response. Therefore, this commentary does not address other types of research at this time. SACHRP would like to emphasize that we see these new consent requirements as providing an opportunity to fundamentally change and improve the consent process and the consent form in human subjects research. While the best solutions are not immediately apparent, the new requirements provide the regulatory mandate and the flexibility to test and implement substantial improvements. The process of writing consent forms and obtaining consent had become stagnant and overburdened with competing purposes, with most clinical consent forms following the order of the elements of consent as presented in the regulations. SACHRP would also like to emphasize that although this recommendation focuses more on the concise and focused presentation of the key information as required by §46.116(a)(5)(i), there is also the requirement under §46.116(a)(5)(ii) that “[i]nformed consent as a whole must present information in sufficient detail relating to the research, and must be organized and presented in a way that does not merely provide lists of isolated facts, but rather facilitates the prospective subject's or legally authorized representative's understanding of the reasons why one might or might not want to participate.” Therefore, the key information should not be seen as solely an opening section followed by a standard consent form using the standard format. Rather, these new consent requirements should be used to fundamentally change and improve the consent process as a whole, including the form, to better serve its intended function as described in the Belmont Report. Background Information Provided to SACHRP by OHRP Under the revised Common Rule – §46.102(b) defines “clinical trial” to mean “a research study in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of the interventions on biomedical or behavioral health-related outcomes.” §46.116(a)(4) states “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.” §46.116(a)(5) provides that “Except for broad consent obtained in accordance with paragraph (d) of this section: (i) Informed consent must begin with a concise and focused presentation of the key information that is most likely to assist a prospective subject or legally authorized representative in understanding the reasons why one might or might not want to participate in the research. This part of the informed consent must be organized and presented in a way that facilitates comprehension. (ii) Informed consent as a whole must present information in sufficient detail relating to the research, and must be organized and presented in a way that does not merely provide lists of isolated facts, but rather facilitates the prospective subject's or legally authorized representative's understanding of the reasons why one might or might not want to participate.” The preamble (FR v. 82, no. 12, Jan 19 2017, page 7214) provides the following list of topics that the Common Rule departments and agencies indicated generally would encompass the key information required to satisfy §_116(a)(5)(i): 1. The fact that consent is being sought for research and that participation is voluntary 2. The purposes of the research, the expected duration of the prospective subject’s participation, and the procedures to be followed in the research 3. The reasonably foreseeable risks or discomforts to the prospective subject 4. The benefits to the prospective subject or to others that may reasonably be expected from the research 5. Appropriate alternative procedures or courses of treatments, if any, that might be advantageous to the prospective subject. The preamble language is not legally binding on the Common Rule agencies’ future interpretation and guidance, but is indicative of the Federal agency’s interpretative intent at the time the rule was promulgated. SACHRP Commentary on the Six Questions Presented by OHRP OHRP provided SACHRP with six questions to address. We have taken the approach of jointly answering questions 1, 3, and 4, and then individually answering questions 2, 5 and 6. After these specific answers to the six questions, we have provided general comments. We determined that this was the most effective format for addressing the questions while avoiding repetition and also adding additional commentary. OHRP’s questions are presented in italics. Question 1: How does “key information” vary depending on the clinical trial design being used, the specific research questions being asked, and the populations being asked to participate? For instance, examples of various trial designs that might impact considerations for key information include: (1) a trial where subjects have a terminal disease where current treatment does not fully cure it, and the trial involves randomization between current standard care and a new unapproved treatment that might involve much greater side effects than standard care, but a better chance of a cure; (2) the same type of circumstance, but where the new treatment is already on the market, but being used for a different purpose, and (3) a randomized trial comparing standard care (which is very effective) to an unapproved new drug (e.g., a “me too” drug situation).What are the primary considerations and influences that should be described for the various types of clinical trial designs? Question 3: Are there criteria, thresholds, or standards that can be identified to determine what information should be included as “key” and what are the underlying justifications or principles supporting them? Question 4: Given the wide variety of types and complexities of studies, and drug/device/biologics considerations, what tool(s) or strategies do you recommend to assist investigators and IRBs in determining the key information to be presented up front (e.g., developing a table or algorithm, general points-to-consider)? Response to Questions 1, 3 and 4: Taken together, questions 1, 3 and 4 in essence ask whether there are any considerations, criteria, thresholds, standards, tables, algorithms, or general points-to-consider that could be used to identify key information for a given clinical trial. We will refer to these collectively as “tools.” SACHRP looked at a variety of possible tools to serve this purpose. We concluded that the development of such a tool is not a simple matter. Even when narrowing the focus from all human subjects research to the subset of clinical trials, there is substantial complexity and variability in trial design, types of interventions, disease states, and potential subject populations. Examples of some of those tools are presented in Appendices I through III. Although the committee did not identify a single tool that it felt confident could identify key information for all studies and all participants, that does not mean it is an impossible task. Tools and guidelines can help with consistency in both the writing and review of consent forms, but their development will be an ongoing process. SACHRP recognizes that significant creativity exists within the regulated community and encourages continued efforts to develop and test potential tools. Because there is great variability across clinical trials, there may be great variability in the choice and presentation of key information. Concern about variability should be balanced with recognition of the importance of flexibility. The existing system of drafting consent forms and obtaining consent has become stagnant, and it needs to improve. Appendix I includes a list of initial questions that may be useful for authors of informed consent documents and IRBs when determining what information would be the most appropriate to include as key information. Question 2: Please consider whether the elements of consent listed in the preamble generally should be considered to encompass key information. Should all of the listed elements of informed consent be considered “key information,” or, depending on the design and context of the study, would some of this information not necessarily be “key”? Are there additional recommendations regarding what should also be considered “key,” beyond the listed elements of consent, depending on the design and context of the study? Response to Question 2: Question two asks SACHRP to consider whether the elements of consent listed in the preamble generally should be considered to encompass key information. For reference, “the elements of consent listed in the preamble” are: (1) the fact that consent is being sought for research and that participation is voluntary; (2) the purposes of the research, the expected duration of the prospective subject’s participation, and the procedures to be followed in the research; (3) the reasonably foreseeable risks or discomforts to the prospective subject; (4) the benefits to the prospective subject or to others that may reasonably be expected from the research; and (5) appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the prospective subject. SACHRP recognizes that the elements of consent listed in the preamble may or may not be sufficient to satisfy the requirement for providing key information depending on the study. Although from a compliance perspective, the fact that these elements of consent are listed in the preamble makes them attractive as a safe harbor of sorts, SACHRP believes such a use may not be in keeping with the intent of the regulatory change. There should be flexibility to include other elements of consent, or even additional information that is not a required element of consent, if it would assist a prospective subject or legally authorized representative in understanding the reasons why one might or might not want to participate in the research. In addition, there should be the flexibility to not include one of the elements listed in the preamble when it will not help with understanding or comprehension given the design of the study and the intended population of subjects. Because the key information requirement will apply to a broad range of research studies being conducted with many diverse populations of research subjects, SACHRP does not believe that there are any elements of consent that would never be appropriate as an item of key information. Examples of additional elements of consent or other information that might be key information in certain studies include: • Essential study design elements such as randomization, the use of placebo, crossover design, or washout requirements from current effective treatments • How the treatment in the trial is similar to or different from the clinical care the subject would receive if not in the trial • Significant costs that could be incurred as a result of participation • Compensation for injury • How much time and/or how many research visits are required for participation • Payments to subjects • Impact on the subject’s future clinical care. For example, whether use of an experimental intervention is likely to make a standard clinical intervention ineffective or unavailable after the study • Potential impact on non-participants. Examples include caregivers, family members, children, partners and the public. • Post-trial access to the experimental intervention Regarding item 3 of the preamble list, “the reasonably foreseeable risks or discomforts to the prospective subject,” SACHRP notes that it would be preferable to refer to the most important risks, due to frequency or magnitude, rather than reasonably foreseeable risks. (See response to question 5 below) The preamble puts this in context in FR Volume 82, Number 12, Jan 19, 2017, p. 7213. Question 5: Assuming risk and benefit information must be included, what considerations are relevant and what strategies can be used to determine which reasonably foreseeable risks and potential benefits should be included as key information, and how should they be discussed as key information? Specifically, how do different study designs affect: (1) which reasonably foreseeable risks and potential benefits should be included in the discussion of key information, and (2) how such risks and benefits should be described in the discussion of key information? Response to Question 5: One of the most important factors in deciding whether to participate will be the frequency and severity of risks and benefits, including when there are no risks and no benefits. Key information should not include the full list of risks and benefits. Flooding people with the full list of risks and benefits does not aid in subject understanding. Question 5 asks “what considerations are relevant and what strategies can be used to determine which reasonably foreseeable risks and potential benefits should be included as key information…[?]” SACHRP provides the following considerations: • If the risks or potential benefits are such that a subject would probably use them, without more information, as a criterion to decide whether or not to participate, they are more likely to qualify as key information. Risks with the greatest impact in terms of frequency and/or severity would most likely meet that criterion. • The degree to which the research risks and potential benefits vary from the risks and potential benefits of clinical care that subjects are receiving or will receive will qualify as key information. • In many studies discomforts and inconveniences, rather than risks, might be key information. Examples include, “you will have to avoid exposure to sunlight for four months,” “all of your hair will fall out,” “you will not be able to drink alcohol for six months,” “you should avoid sexual contact” or “you will have 20 study visits.” • If there are no direct benefits to subjects, that should be stated in the key information section. If there are no risks that should also be included in the key information section. • Vague statements about risks and potential benefits should not generally be considered to be key information. Examples include “you may or may not benefit from this research,” “The researchers will try to keep the risks as low as possible,” and “There may be risks which are not known at this time.” The next phrase in Question 5 is “how should [risks and benefits] be discussed as key information?” SACHRP believes it is preferable to place the risks and potential benefits into a pros and cons (or why/why not join) framework, with the possible inclusion of other features such as alternative treatments, in order to provide context that can facilitate potential subjects’ understanding of the risks and potential benefits presented as key information. Implicit in consideration of how best to present risks of harm and potential benefits to potential subjects is the concern that patients who are potential subjects may not fully appreciate that research – even research that has some potential to benefit them directly – has the primary goal of advancing knowledge rather than delivering treatment. Discussing potential benefit may pose a particular challenge. Potential direct benefit to subjects should not be overstated and should be distinguished from the anticipated value or societal benefit of the research in simple and straightforward terms. SACHRP is aware that some IRBs have responded to concerns about potential subjects’ overestimation of direct benefit by minimizing information about potential direct benefit in the consent form, reasoning that subjects will thus be less likely to believe that therapy and research are governed by the same primary goal of advancing the individual patient’s best interest. However, because patients who are potential research subjects often approach clinical trials with the hope of direct benefit, minimal or vague language about potential direct benefit does not correct that misperception. Potential benefits are a legitimate consideration in a individual’s decision to enroll; it is acceptable to include an accurate and specific description of potential benefit as key information. Finally, Question 5 asks, “Specifically, how do different study designs affect: (1) which reasonably foreseeable risks and potential benefits should be included in the discussion of key information, and (2) how such risks and benefits should be described in the discussion of key information?” As discussed above in our response to Questions 1, 3 and 4, different study designs and facts of the study do affect which risks and benefits should be included and described as key information. However, as noted in that response, SACHRP did not find any single tool that was sufficient to identify the key information for every type of clinical trial, and that conclusion also applies to the identification of risks and benefits as key information as targeted here in Question 5. Because there is great variability across clinical trials, there may be great variability in the choice and presentation of key information. SACHRP further notes that existing elements of consent, and traditional approaches to consent, have emphasized benefit and risk, but have not given similar attention to burdens or to the impact of participation in research on an individual’s normal life activities. The flexibility provided by the key information summary should be used to address such impact in addition to providing a more focused overview of risk and benefit. In many cases, impact is certain, but benefits and harms are not. Question 6: Under what circumstances should key information presented up front be repeated in the core sections of the consent form (recognizing that there is no requirement that any such information that is already presented at the front of the consent form needs to be repeated elsewhere in the consent form)? Response to Question 6: The intent of the key information is to create more understandable consent forms, not to shorten or lengthen consent forms. SACHRP supports efforts to decrease the length of informed consent documents to the extent that they promote readability and understanding. However, SACHRP also notes that the new consent requirements at §46.116(a)(5)(i) are additive to the existing elements of consent, that additional elements of consent have also been introduced at §46.116(a)(9) and §46.116(b)(7) to (9), and that none of the currently existing elements of consent have been removed. It is likely that the “concise and focused presentation of the key information” will also add to the length of the consent form. Therefore, SACHRP takes the position that information presented in the key information section need not be repeated in the subsequent sections of the consent document unless that information is necessary to help ensure that the body of the consent remains understandable to the subject, consistent with the goals of §46.116(a)(5)(ii). If repeating information assists subject understanding, then it should be done. If the key information summary contains all the information necessary to fulfill a required element of consent, there may be no reason to repeat this information. Stated more simply, brevity should not sacrifice clarity. Appropriately placed statements or links that reference information contained in other sections of the consent document may help minimize repetition. For studies with simple designs, the consent form itself may be just a few pages, meeting the requirements for being clear and concise and also containing key information in an appropriate format. SACHRP believes that this flexibility should be addressed in the agencies’ guidance on concise consent. SACHRP General Commentary Key Information Beyond the direct answers to Questions 1 through 6, SACHRP also has additional general comments. 1. SACHRP recommends that OHRP (and the other agencies) confirm that there is compliance flexibility going forward, unless and until such time as there is agreement on how to appropriately select and provide key information. OHRP should specifically state that diverging from the preamble suggestions of key information would not incur a compliance risk as long as the full consent document meets the requirements of the regulations. This is critical to encourage the development of creative and potentially better approaches to presenting key information and to improvement of the consent form and process as a whole. Otherwise, researchers and IRBs will be reluctant to deviate from current practices, erring on the side of “more is better” to ensure compliance. SACHRP believes that the changes to the consent form requirements, including but not limited to the addition of the key information summary, should lead to new ways of organizing and presenting the required elements of consent, and also lead to the inclusion of new information that is not a required element of consent as appropriate, in order to best facilitate informed decision making. Writing the consent form should reflect both understanding of the protocol and ability to translate the protocol into information useful to potential subjects. SACHRP recommends that appropriate resources should be dedicated to supporting better consent preparation and research and that the agencies should target both consent form authors and those individuals who obtain consent in guidance on this topic, and carefully consider how to disseminate the guidance to those individuals. 2. SACHRP believes that it is important to regard the key information summary as an opportunity to orient, guide, and assist potential subjects in the decision making process. Therefore, the key information summary should frame the purpose and process of informed decision making from the subject’s perspective. The key information summary should not be regarded as a stand-alone document that provides the potential subject with sufficient information to decide whether or not to participate in the research, thus relegating the rest of the consent form to auxiliary information that provides additive detail. 3. SACHRP also recognizes that flexibility is inherent in the concept of the reasonable person as applied to informed decision making. The reasonable person concept recognizes that it is impossible for researchers to determine what information every individual participant would consider helpful in deciding whether or not to participate. Instead, it asks researchers to include what reasonable people in the same or similar circumstances would want to or need to know. The use of the reasonable person standard to guide drafting of the consent form does not obviate the obligation to respond to the distinct circumstances, preferences, and needs of individual participants; the opportunity for each participant to ask questions that can take into account that person’s own distinct medical history, background, values and personality remains an important part of the consent process. 4. SACHRP notes that e-consent and other formats for presenting consent information may make it easier to provide a concise and focused presentation of the key information, and also to organize and present the information in a way that facilitates comprehension and understanding of the reasons why one might or might not want to participate. When e-consent is used, it will be much easier to use links to connect the information in the key information summary to more complete descriptions later in the consent form, as well as to video and audio presentations of content. In addition, e-consent can use links to outside sources of information, such as websites and dictionaries. New approaches to presenting consent should be tried and assessed. 5. SACHRP recommends that empirical research should be conducted in light of implementation of the new consent requirements. It will be important to determine whether and how different models of the concise summary of key information can best facilitate potential subjects’ understanding, and to use those research results to improve the consent form and process. The posting of consent forms in accord with new rule section §46.116(h) will provide source materials to use in such research. SACHRP encourages funding agencies to provide support for these research efforts, and such research should be generalizable and conducted on a large scale across sites, studies and populations. The research should address both the best means to identify key information, and also how to present that key information to subjects in the consent form and process. A gap in the current research on informed consent is an emphasis on what subjects want and need to know to make an informed decision. Conclusion The revised regulations include new requirements intended to improve the consent form and the consent process. Under the new requirements, informed consent must begin with a concise and focused presentation of the key information that is most likely to assist a prospective subject in understanding the reasons he or she might or might not want to participate, and it must be organized and presented in a way that does not merely provide lists of isolated facts, and there must be an opportunity to discuss that information. As a result, the Common Rule agencies and the regulated community have a significant opportunity to make the informed consent process better for research subjects. SACHRP hopes that all involved parties will take full advantage of this opportunity and work together to advance the application of the ethical principle of respect for persons. Appendix I List of Questions SACHRP developed a list of questions to help writers of consent materials and IRBs to identify the key information for a given trial. The following questions may help authors of consent materials and IRBs identify the key information a prospective subject needs in order to make a well-informed choice about whether to participate: • What are the main reasons a subject will want to join this study? • What are the main reasons a subject will not want to join this study? • What is the research question the study is trying to answer? Why is it relevant to the subject? • What aspects of research participation or this particular study are likely to be unfamiliar to a prospective subject, diverge from a subject’s expectations, or require special attention? • What information about the subject is being collected as part of this research? • What are the types of activities that subjects will do in the research? • What impact will participating in this research have on the subject outside of the research? For example, will it reduce options for standard treatments? • How will the subjects’ experience in this study differ from treatment outside of the study? • In what ways is this research novel? The answers to these questions can be used to help identify the appropriate key information for a given clinical trial. This is not an exhaustive list, and it should not be used as a checklist.