A Survey on Including Risks in the New “Key Information” Section of an Informed Consent Form

Clinical Researcher—December 2018 (Volume 32, Issue 10)

PEER REVIEWED

Katelyn Le, MS; Stacy Kopka, MS; Doreen Chaitt, RN, MPH; Jerome Pierson, RPh, PhD; Martha Nason, PhD; Tracey Miller, RN, CCRP

 

 

[Note: Since the writing of this article, the Secretary’s Advisory Committee on Human Research Protections (SACHRP) of the U.S. Department of Health and Human Services has released recommendations on writing Key Information. The recommendations can be found online at https://www.hhs.gov/ohrp/sachrp-committee/recommendations/attachment-c-november-13-2018/index.html.]

Informed consent forms (ICFs) are growing longer and more complex.{1–4} The forces behind this trend may be well-intentioned, such as the desire to disclose more accurate and complete information{1}; however, it raises questions about whether important information is buried in lengthy documents, as well as whether ICFs can be structured to better emphasize the information that is most relevant to a study participant.

Recent updates to what is generally known as the Common Rule for protection of human subjects in research are in part meant to respond to this trend. Among these updates is the introduction of a new section called “Key Information”—every ICF now must open with the most important information that potential subjects would want to know when deciding to join a study. But what exactly should this new section contain?

This question is crucial to us, a group of writers and reviewers who work with investigators to develop ICFs (the program was described in a 2013 issue of the ACRP Monitor{5}). For groups like ours, it is important to explore how best to implement the new regulations in a way that promotes consistency across different ICFs.

As an initial step, we wanted to understand how to objectively decide which risks to provide as Key Information. A survey was conducted to investigate how institutional review board (IRB) members, medical monitors, and principal investigators (PIs) view which risks should be considered Key Information. The hypothesis was that cohorts would have differing viewpoints on selecting these risks.

While the findings of this exploratory study demonstrate variability in viewpoints, they also suggest a number of points of consensus to consider when writing Key Information.

A Refresher on Key Information

The Revised Common Rule was issued by the U.S. Department of Health and Human Services in January 2017 and is set to go into effect January 2019. It updates the original 1991 Common Rule regulations to address various issues in modern human subjects research, such as the trend toward longer, more complex ICFs. The addition of the new Key Information section is one such change meant to “combat the growth in length and complexity” of ICFs and stop important information from being “buried.”{6}

As described in the Revised Rule, the consent should give the “information that a reasonable person would want to have in order to make an informed decision” (Title 45 CFR Part 46.116(a)(4) in the Code of Federal Regulations). To do this, ICFs now “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 why one might or might not want to participate in the research” (part 46.116(a)(5)(i)).

The Rule’s preamble (XIV.A.4) suggests that this section may generally include the following information:

  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.”

Identifying the Most Important Risks

It has been suggested that descriptions of study-related risks and discomforts are one particularly significant factor in bulking up ICFs,{1} and risks will likely pose similar challenges to writing “concise and focused” Key Information sections. The regulation provides flexibility in exactly what information to include; the preamble suggests including the “most important risks,” like what a doctor might tell a patient in the clinical context with an emphasis on how those risks are changed in a research study (XIV.A.4). The language gives only a rough idea of the length of the “concise and focused presentation.”

Although such language gives flexibility to individual projects, it challenges efforts to consistently implement the rule across multiple projects. The subjectivity of this language may make it difficult to reach a consensus on which risks to include in Key Information. In the absence of specific guidance on writing Key Information, a survey was designed to explore outstanding questions about including risks in this new section.

A Survey on Risks in Key Information

A digital survey tool was created using a PDF form and disseminated and returned via e-mail. The survey opened with a brief introduction to the Revised Common Rule and the new Key Information section. Next, the survey presented a four-page ICF Potential Risks section, which included 39 discrete risk ideas, from an IRB-approved ICF for a Phase I study of a licensed monoclonal antibody in HIV patients.

This ICF language was chosen because it is representative of studies at our institute (early-phase trials of investigational agents), and includes a variety of risks to differentiate characteristics such as frequency, seriousness, and certainty. Additionally, the survey included IRB-approved risk language for select standard (non-experimental) study procedures: bone marrow biopsy, apheresis, and venipuncture.

Respondents were asked to review the sample ICF Potential Risks section and use the digital highlighter tool in a PDF viewing program to mark the risk ideas that they would move to Key Information (see Figure 1). Respondents were instructed to focus on risk ideas, not exact wording, with the understanding that language would in practice be revised to fit into a standalone Key Information section.

An open‑ended question asked respondents to explain what factors influenced their decisions in selecting key risks. Also, the survey included multiple choice demographic questions.

Figure 1: Excerpt from a Completed Survey

Respondents used the highlighter tool in a PDF-reading program to identify the risks they would move to the new Key Information section. Text that was not highlighted would remain in the main Risks and Discomforts section of the ICF.

To capture the viewpoints of a variety of stakeholders in human subjects research at our institute, the survey was distributed to three cohorts: all primary IRB members (n: 9), all medical monitors (n: 3), and a convenience sample of PIs (n: 17, N: 29). There were nine responses (response rate: 31%). Respondent demographics are presented in Table 1.

Table 1: Survey Respondent Demographics (N=9, response rate=31%)

Role Medical monitor 3
PI 1
IRB member 5
Time in Research < 5 years 1
5–10 years 1
11–20 years 3
> 20 years 4
Age 40–49 years 3
50–59 years 2
60–69 years 4
Sex Male 4
Female 5

An honest broker deidentified responses before analysis. The surveys were then analyzed by counting and categorizing the risks addressed in the highlighted text.

What Did Respondents Consider Key?

Out of the 39 total risk ideas, there were only seven that most respondents (more than half) agreed to include; all seven were related to the study agent (see Figure 2).

Every respondent highlighted at least one risk of the study agent. The seven risk ideas that most respondents highlighted were the study agent’s most common side effects, most serious known risks, risks that are important to the study population, and the possibility of unknown study agent risks. Interestingly, this last risk idea is not a specific “most important risk,” but rather a disclosure of theoretical risk. Perhaps respondents felt it important to include as a “reasonably foreseeable risk” an acknowledgement that the study agent is experimental and not all risks can be foreseen.

Figure 2: Respondents Who Thought Each Risk Idea in the Sample ICF Should be Moved to the New Key Information Section

All but one of the IRB members thought the general risks of monoclonal antibodies as a class should be in Key Information, but no medical monitors or PIs did (see Figure 2).

The survey population was not large enough to compare subgroups, so we cannot conclude that there is a significant difference in viewpoints between IRB members and other groups. This finding does, however, support the initial hypothesis that people in different roles in human subjects research will have differing interpretations of Key Information, which is not surprising since one would expect each cohort to review the consent with a different purpose in mind.

Nevertheless, possibly due to the small sample size, this was the only risk idea for which there was a clear difference in response between cohorts. For many of the other 38 risk ideas, individual responses were too variable to identify trends within cohorts. Conceivably, studying a larger population could help identify cohort-specific preferences, but it is also possible that individuals within a single cohort have such differing perspectives that it is impossible to identify trends about what should comprise Key Information.

Of the 39 total risk ideas presented, all but two were chosen as Key Information by at least one respondent (see Figure 2).

This means that almost 95% of the risk ideas in the sample ICF were chosen by at least one respondent. Thus, respondents together thought most of the study risks should be included in Key Information. This may support an argument for considering all study risks as “most important” for a potential subject’s decision.

Of the 39 total risk ideas, each respondent chose an average of 12 risks (range 6 to 19).

Interestingly, the highest and lowest numbers of chosen risk ideas were both from IRB members. These numbers are the result of an artificial task, since respondents were only asked to highlight risks they would move to Key Information, not to write the actual Key Information section. However, differing interpretations of the regulation’s language (for example “concise and focused presentation” of “most important” information) do not define how short this section should be. The Revised Common Rule’s preamble does mention that length may depend on the length of the entire ICF, with longer ICFs having longer Key Information.

What Guided Respondents’ Decisions?

When asked what factors influenced their decisions, most respondents mentioned that they considered the severity/seriousness and frequency of the risks. Other factors respondents mentioned were complexity, certainty, and the study population.

Complexity was one topic with divergent implications. For example, one respondent indicated an intention to avoid complexity in Key Information and reserve complex ideas for the main body of the consent (“big concepts [first]…details later”); however, a different respondent preferred to use the Key Information section to address the most complex issues (things anticipated to take the “most time to explain or subjects would most want to know/talk about”).

Also, multiple respondents included discussions of why they did or did not include risks of procedures. Two respondents said that they would include study procedure risks to essentially “kill two birds with one stone”—first to highlight the types of study procedures required on the study and secondly to mention the risks. From these reactions, it appears that when writing Key Information sections, it will most likely be necessary to introduce and briefly explain the study procedures before presenting the risks of those procedures.

Writing Key Information

These findings highlight the variability in viewpoints of research professionals, both between and within cohorts, on selecting risks as Key Information in the absence of more specific guidance. The Revised Common Rule’s language was meant to lend flexibility to the specific contexts of a given study. For example, the content of Key Information will likely differ between Phase I and Phase III studies, since a Phase III study would have more risk information to reference, would be focused primarily on efficacy rather than safety, and in some cases may involve a different study population (e.g., patients versus healthy volunteers).

However, this regulation introduces more subjectivity—and perhaps even bias—into the process of identifying the “most important” risks. Additional official guidance may help minimize variability and facilitate the consistent writing of this new section.

In some situations, a discrete, standalone Key Information section may not be needed. The preamble to the Revised Common Rule acknowledges that institutions may determine that, for simple studies with short ICFs, the requirement for Key Information may be fulfilled by arranging the content so that the “most important” information (such as the required elements of consent) come first, followed by other language and disclosures less relevant to decisions about participation.

This simple solution would avoid repeating content and making broad judgments about which information will be most important to participants. Conversely, in longer ICFs for more complex studies, information would be summarized upfront in Key Information and then provided in greater detail later in the document. For studies with long lists of possible risks, this may mean concisely presenting the most common and severe risks upfront, followed by a comprehensive description of all reasonably foreseeable risks later in the ICF.

In situations where a standalone Key Information section is warranted, the results of this survey suggest considering the following points:

  • Focus on the risks of the study agent (or other investigational procedure).
  • Mention the possibility of unknown risks in the population being studied.
  • Include the risks that are the most frequent and/or serious.
  • Anticipate variability in this section based on the protocol specifications (for example, study population, phase, prospect for benefit, treatment alternatives) and the perspectives of reviewers.

Conclusion

This survey was exploratory and limited in nature. It used a small sample at a single institution and, though the overall response rate was within the expected range for electronic surveys,{7–10} the cohort response for PIs was lower than expected (6%).

Respondents could only consider the information provided, which excluded other ICF sections and study documents that may also have affected choices about the content of the Key Information section. In addition to risks, there may be other factors that a “reasonable person” would find important when deciding to participate, which may affect the length and scope at which risks are discussed upfront.

In the future, the authors of this survey plan to design a larger survey examining risks and the Key Information section in a broader population including research subjects.

This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

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Katelyn Le, MS, (katelyn.le@nih.gov) is a medical writer with Clinical Monitoring Research Program Directorate of the Frederick National Laboratory for Cancer Research, sponsored by the National Cancer Institute in Rockville, Md.

Stacy Kopka, MS, is a medical writer manager with the Clinical Monitoring Research Program Directorate of the Frederick National Laboratory for Cancer Research, sponsored by the National Cancer Institute.

Doreen Chaitt, RN, MPH, is director of the IRB Office and deputy director with the Office of Clinical Research Policy and Regulatory Operations, Division of Clinical Research, at the National Institute of Allergy and Infectious Diseases.

Jerome Pierson, RPh, PhD, is director of the Office of Clinical Research Policy and Regulatory Operations, Division of Clinical Research, at the National Institute of Allergy and Infectious Diseases.

Martha Nason, PhD, is a mathematical statistician with the Biostatistics Research Branch, Division of Clinical Research, at the National Institute of Allergy and Infectious Diseases.

Tracey Miller, RN, CCRP, is a protocol navigation manager with the Clinical Monitoring Research Program Directorate of the Frederick National Laboratory for Cancer Research, sponsored by the National Cancer Institute.