Research practitioners eagerly anticipate finalization and publication of the revised U.S. Federal Policy for the Protection of Human Subjects, known as the Common Rule, which is scheduled to be released in September 2016. Many experts speculate that the revised policy may not be published as expected, yet there appears to be consensus that change in the rules governing human subjects is inevitable; the question remains as to what will be the final rulemaking and the impact on research practice. More than five years have passed since the impending change was announced in an Advance Notice of Proposed Rulemaking (ANPRM) on July 26, 2011 [FR 2011; 76(143): 44512-44531]. After consideration of substantive public debate, the U.S. Department of Health and Human Services and 15 other Federal Departments and Agencies published a Notice of Proposed Rulemaking (NPRM) with prospective revisions to the Common Rule on September 8, 2015 [FR 2015; 80(173): 53933-54060]. Stakeholders have carefully reviewed the proposed revision, provided essential feedback during an extended open comment period, and continued to consider the implications of potential new requirements as they await publication of a final rulemaking.1,2
One area of proposed change for a revised Common Rule involves requirements for informed consent of research subjects. Most significantly, stricter new requirements for the content and manner of providing information to prospective subjects aim at assuring that subjects are appropriately informed before they agree to participate in a research study. Other major changes that directly relate to informed consent include requirements for the use of stored biospecimens in secondary research (even when de-identified) and public posting of consent documents.3
Although it is expected that the proposed policy language may evolve into what will be the final rule, it is nonetheless important for research practitioners to have an understanding of the rationale for the proposed new requirements and the potential impact on their research practice. Informed consent is a vital part of human subject protection, and compliance with regulatory standards regarding the process of informed consent during the conduct of clinical research is not only a legal requirement, it is an ethical imperative. As regulators and stakeholders consider the need for transformative practices, there is a need for all parties to think through logistics required and potential limitations to implementing new policy.4
The NPRM represents significant change to the human subject protection law in the United States, and as introduced, proposes revisions to “modernize, strengthen, and make the policy more effective.”1,2 The NPRM extends the scope of the Common Rule, currently intended for use of research practitioners involved in the conduct of U.S. federally supported trials, to apply to all clinical trials regardless of funding source which are conducted by a U.S. institution that receives federal funding for research involving human subjects. Although the NPRM is not intended to apply to FDA-regulated research, FDA has communicated intent to harmonize with the final rule. In the NPRM Common Rule Public Town Hall Meeting conducted on October 20, 2015, Joanne Less from the Office of Good Clinical Practice at FDA reported, “FDA has been involved in the rulemaking effort with the other agencies.” Less reiterated interest in the public comments as it conducts a parallel rulemaking effort, stating, “We [FDA] will continue to participate in that process, and we will also be engaged in our own rulemaking effort."4
Form and process change
The NPRM proposes to impose stricter new requirements and outlines changes to the form and process of informed consent. See Table 1 for a listing of what would change under the proposed rule. The information that must be provided to ensure informed consent, codified in 45 CFR part 46 Subpart A, outlines the basic and additional elements of informed consent and is currently consistent with those required for FDA-regulated research under 21 CFR part 50. The general requirements call for investigators to responsibly and ethically obtain “legally effective” informed consent, with obligation to provide potential research subjects with the information necessary to make an informed decision as to whether to participate in a clinical trial. Critics of current day informed consent practices argue that the elements of informed consent are typically provided to research subjects in overly lengthy documents that often contain extra information and technical language, making it more likely to obfuscate lay people than inform them. Moreover, many institutions and research sponsors require additional content to be included that makes the consent forms even longer and more complex, resulting in documents that have become legalistic in ways that appear to protect those entities. The overriding concern is that the most relevant information to a subject’s decision to participate in a clinical study gets buried among the copious detail presented within the consent form.
There is general agreement that a need exists to improve the forms, rendering them more organized with sufficient detail, resulting in documents that are easier to understand through their use of “language understandable to the subject.”1 Shortening and simplifying consent forms will prove to be a challenging task as there are regulatory, legal, and institutional requirements to be met, especially in the setting of complex research. There can be no shortcuts in providing essential information, and there needs to be a complete disclosure of all reasonably foreseeable research risks and study procedures, which often requires extensive listing of information, including the potential for informational or privacy risk (e.g., unauthorized access or use of subject information).
The order in which the information is presented to a prospective subject also gives rise to the potential for confusion on the subject’s part as to what the most important information is for making a decision. The NPRM proposes the requirement for investigators to first present the core information about the research that is most relevant [as required by the rule] before presenting other supplemental information, “with appropriate detail as a reasonable person would want to know in order to make an informed decision,” followed by an opportunity to discuss that information.1 The essential information would be written in a shorter form that could then be augmented by supplemental information that would be placed in an appendix to the consent document. In this way, the “main” consent form would not be an excessively long document that overwhelms a study subject, or worse, buries important information among lengthy and detailed text. Notably, within the proposed rule, there is no restriction on the amount of supplemental (less important) information that can be provided in the appendices.
The NPRM proposes four additional elements of informed consent that basically represent practices that were not routine in 1991 when the Common Rule was first promulgated. The NPRM revisions are intended to enhance human subject protection. The updated regulatory framework is needed not only because of trending increased trial complexity, but clinical researchers are also now able to harness advantages of technology, access data, and use advancing scientific discovery to ask and answer important medical questions in innovative ways, which the considerations made 25 years ago could not address. The NPRM revisions are proposed to offer not only increased protections, but also to promote public trust through increased transparency, provide opportunities for advancing research practice with greater efficiency, and provide regulatory direction for new methodologies and possibilities.5,6
Under the NPRM, the introductory language to 45 CFR Part 46.116 would be clarified to state that if a Health Insurance Portability and Accountability Act of 1996 (HIPAA) authorization is combined with a consent form, the authorization elements required by 45 CFR part 164.508 must be included in the consent document and not the appendices. As such, when consent for research participation is combined with authorization, the authorization elements should be considered one of the required elements of consent.
Additionally, three more new elements of informed consent that pertain to issues reflecting recent advancements in science and research would be required. These elements inform prospective subjects of the chance that the situations described could occur and what might happen, with the intent to reduce the potential for confusion. The NPRM proposed new elements are as follows:
Biospecimens and broad consent
Under the NPRM, the proposed rule would reclassify all biospecimens as human subjects and generally require informed consent for the use of stored biospecimens in secondary research (e.g., remaining specimens that were collected as part of routine healthcare), even if the investigator is not provided with identifying information or a way to identify the person associated with the biospecimen. As proposed, the consent required for secondary research use of data and biospecimens could be obtained through broad consent (i.e., consent for future, unspecified research studies) to the storage and eventual research use of biospecimens. As proposed, a broad consent template would be provided by the regulators.1,6,7
The reforms regarding secondary research on stored biospecimens would require researchers to inform research subjects through the addition of the three new elements of informed consent that the biospecimens might be used for commercial profit, tell them whether they will be informed of new clinically relevant findings, and ask them if they are willing to be re-contacted for future research.7 As proposed, secondary research on stored biospecimens designed to only use information about the person that is already known would be allowed without consent as an exclusion to the requirements of the Common Rule.
Other major provisions affecting informed consent: IRB waivers, multisite single IRB review, exclusions and exemptions
The requirement for informed consent applies to all human research, but there may be regulatory provisions stipulating special circumstances that might allow for waivers, special approvals, exclusions, and/or exemptions. Major provisions within the NPRM include conditions in which special circumstances would apply.
The NPRM, as proposed, permits Institutional Review Boards (IRBs) “to waive the requirement for informed consent, but the requirements for approval of such waivers would be very strict, and such waivers will only occur in rare circumstances.”1
Additionally, a new mandate is proposed for U.S. institutions engaged in cooperative research to rely on a single IRB for multisite research studies taking place within the United States, with certain exceptions. The NPRM also includes a proposal that would require IRBs that are otherwise not affiliated with or operated by an assurance-holding institution (‘‘unaffiliated IRBs’’) to comply with the Common Rule. If a single IRB reviews proposed research for multiple centers, the IRB would be responsible for reviewing and improving informed consent forms and associated methodologies for all centers, which should provide for greater efficiency in trial management and oversight.
Another major provision involves exclusion from coverage under the Common Rule certain categories of activities that should be deemed not to be research, are inherently low risk, or where protections similar to those usually provided by IRB review are separately mandated. Proposed exclusions would also allow for the use of biospecimens without consent in certain limited circumstances. The exclusions address certain research activities that are sufficiently low-risk and nonintrusive whereby the protections provided by the regulations could be viewed as an unnecessary use of time and resources, yet the potential benefits of the research are substantial.1
The proposed revision also provides for additional categories of exempt research to accommodate the scientific landscape and to better match the level of review to the level of risk involved in the research. Determinations will be able to be made for studies to be exempt without requiring administrative or IRB review. Certain exempt and all nonexempt research would be required to provide privacy safeguards for biospecimens and identifiable private information.
There is a new proposed requirement for a one-time posting of clinical trial consent forms on a federal website (yet to be designated) for each federally supported trial. The consent form must be posted by either the awardee or the federal department conducting the trial within 60 days after the recruiting period is completed. Some research practitioners have questioned the benefit of posting consent forms after the fact when subjects have already been consented. The purpose of the posting is not to inform prospective subjects; instead, the posting requirement would make the consent forms publically available in an attempt to increase transparency and encourage consent form authors to write clearly and concisely with the notion that the consent form would be subject to public scrutiny. Over time, consent forms posted would be available as examples, aiding the development of best practices among authors with regard to the development of consent forms.
Although this proposed requirement for posting appears to be somewhat straightforward, it is not without controversy. Elisa Hurley wrote in the PRIM&R Blog post, Amp&rsand, “This requirement may reinforce the perception that a consent form is, if not the only acceptable way to obtain informed consent, the most important part of the consent process. However, when done properly, informed consent involves a robust and purposeful discussion that allows time for questions and that utilizes tools, such as visual aids, aimed at fostering subject comprehension.” Hurley astutely points out that, “The posting requirement also perpetuates the use of standard, written consent forms at a time when such a model is rapidly becoming outdated.” As new technologies and innovative methods of obtaining consent are being built into research programs to enhancing subject understanding, she cautions that “a regulation that requires posting a standard form may in the end stifle such innovation, a result that contradicts DHHS’ stated goal of modernizing the regulations governing human subject research.”8
Impact on practice
The process of obtaining informed consent is one of the most critical responsibilities of all research practitioners. Although the principal investigator of a clinical trial is legally obligated to ensure proper and effective consent of all research subjects, there are many players involved in making sure that the process is done properly and in compliance with all applicable requirements. There are many roles that are impacted by the proposed new requirements — from sponsor representatives who may draft template language, to clinical investigational site personnel who write site-specific forms and obtain consent from research subjects, to the IRB members who review consent forms submitted for approval.
Organizations will need to update and revise standard operating procedures (e.g. SOPs for developing, approving, obtaining, and monitoring) and associated template forms to align with new requirements and, upon implementation, ensure thorough training for all personnel involved in activities pertaining to informed consent. Education will be a critical component of putting the new rule into practice as a major goal of the Common Rule revision is to strengthen the process of informed consent in an unfamiliar, novel way. Proposed changes impact the “what” and the “how” with regard to standard procedures for providing information to research subjects and documenting informed consent; research practitioners will need to transform current processes to be able to focus on the most important information from a subject’s decision-making perspective and then determine how best to communicate supplemental information.
One of the more challenging aspects will be determining what information is most relevant as a required element of informed consent and what information is otherwise best suited to be included in an appendix. Investigators will need to differentiate between details that cover the required elements versus those which could be viewed as extraneous. It is also difficult to write a concise consent form that contains all essential information in a manner that is understandable to a subject, yet the goal must be to include all of the key information in the least confusing way so that a subject can make an educated decision about whether to participate in a study. Existing boilerplate language may no longer be appropriate, and research practitioners will need to rethink how best to present the research and obtain informed consent without excessive detail.
The use of supplemental materials and methodologies may also offer great options for communicating research information in a more meaningful way. Many have already taken innovative steps in using technology solutions to deliver information and test comprehension using eConsent tools and other study-specific applications. Technology continues to transform research practice on an enterprise level and it should be expected that informed consent change can be enhanced by greater use of technology solutions.
Change often comes at a cost, and the logistics of implementing change will require time and resources to plan for and comply with the new requirements. The revamping effort should proceed while keeping in mind that process improvements geared toward advancing patient protections should pay off in terms of strengthening the informed consent process. New roles may emerge as the responsibilities expand for developing, obtaining, documenting and posting forms for informed consent. We can also expect that the additional requirements regarding the provisions for the secondary use of data and biospecimens will require tracking systems and processes to manage which specimens have consent and those which do not.9
How can research practitioners best prepare for upcoming regulatory changes regarding informed consent? While in the stage between the issuance of the NPRM and the final rule, there is no clear path as it is likely that the federal agencies may consider alternative options in the final rulemaking process. However, it is important to be alert to regulatory updates and commentary from stakeholders that may provide insight as to impending changes and best practices. We must also consider that in a presidential election year, there is a possibility that a final rule may not be published, and even if the next administration will pursue the changes as proposed at all.10
Once a final rule is published, the compliance dates will be specified therein with provision for time for practice changes to be implemented. It is anticipated that from the date of publication, compliance would be required within one year for most of the rule. The compliance date for the provisions related to the reclassification of biospecimens as human subjects, however, is projected to be set at three years after publication of the final rule. Until the revised rule goes into effect, informed consent would generally be required before research use of biospecimens not covered by an exclusion.
Compliance with regulatory requirements is not open for debate, but proposed changes are cause for research practitioners to evaluate their own current and best practices with regard to the reason for the proposed changes. Does the current process of informed consent uphold the principles of informed consent as intended and in relation to current day research? Are there changes that could, and should, be made to improve research subject comprehension and decision-making? Many times when regulatory draft guidance is published, stakeholders take action to establish processes and procedures that align with agency current thinking. This does not appear to be the case with the NPRM, as the proposed changes represent a significant departure from what is routinely done in the conduct of clinical research. Going forward, some of the proposed changes will require stakeholder collaboration as well as agency action (e.g., a template for broad consent for research with biospecimens and a repository for consent form positing). Research practitioners can expect published guidance and industry opinions for further instruction as to how consent forms are to be written in order to comply with the requirements of a revised policy. In the meantime, there are steps that may be taken in readiness of anticipated changes and to strengthen human subject protections through informed consent.
A recent blog post from Schulman IRB was dedicated to ways to begin implementing the changes to informed consent outlined in the NPRM while still conforming to current Common Rule requirements. The authors posed that, “Increasing transparency and better informing subjects is something we can all support.” Schulman IRB proposes the following actions that can be taken immediately to achieve improvements to informed consent:
To bridge between the current all-inclusive informed consent forms and those which will contain only the required elements, consider restructuring the informed consent document so that critical information needed for decision-making is presented clearly and early on in the document. In addition, existing informed consent forms can undergo an internal review to determine what pieces of information are associated with required elements and which are not, in an effort to identify what changes might be needed to what otherwise is the standard quo. Having a greater command of the required elements will make it easier on the research practitioner to restructure the informed consent forms within the one year compliance timeframe.
Already good clinical practice, using language that is understandable to the subject is critical to ensuring comprehension. A person cannot be fully informed if they were unable to understand the advanced medical or research terminology contained within a consent form. Once the consent forms are published on the publically accessible federal repository, readability is sure to be highly scrutinized. Readability of the informed consent can also be eased by examining format and structure. Simple things like using a befitting font size and type can improve the attention-holding abilities of a document. The opinion of a proofreader, ideally a lay person, should be sought in determining if the flow and format of the document is appropriate.
Over time, more digital natives will be enrolled as subjects in clinical trials. These individuals tend to learn very well through electronic systems and means, such as videos and interactive programs on a smartphone, computer, or tablet. Interactive electronic systems may help to maintain the attention of potential subjects through the informed consent process. The traditional paper informed consent form and in-person discussion approach may not be the best method to ensure full comprehension of the study by these individuals. An interesting question arises, however, to as how the informed consent “document” will be posted for public review at the end of the study.
Research practitioners have an opportunity to stay ahead of the regulatory curve while waiting for the final rulemaking by making voluntary improvements to strengthen the process of informed consent where possible and meet the ethical mandate to make the process more meaningful.
Recognizing that there may be changes in the final rule, the proposed revision tightens requirements to make the informed consent more meaningful with updates to both the forms and processes. Provisions of the current Common Rule provide limited information about the content of the informed consent form or how the form should be written. The revised regulation, as proposed in the NPRM, specifies how consent forms should be written and what information should be included. Ideally, informed consent forms will be shorter and less confusing than they tend to be now. In addition, the changes under consideration would bolster and enhance informed consent through a more focused process and by promoting greater transparency. Although there may be logistical challenges in implementing a revised Common Rule, streamlined requirements offer positive trade-offs. Under the proposed revision, the review and approval of proposed consent forms should be greatly facilitated, and individuals contemplating participation in research would be more consistently informed and have increased comprehension of the clinical study and their role as a research subject.
By Lynn D. Van Dermark and Bridget Browder
This article was reprinted from Research Practitioner, Volume 17, Number 5, September-October 2016.