- IRB: ETHICS & HUMAN RESEARCH
A Consent Form Template for Phase I Oncology Trials
The two primary components of the consent process for research are a consent form and a discussion between the investigator and the potential research participant. Although empirical assessments of consent forms suggest that the majority contain an adequate description of the risks and benefits associated with participating in a given study, important deficiencies remain. Consent forms are characterized by excessive length, a lack of organization, and complex language that is tailored to an above-average reading level and is often confusing—or, worse, misleading—to many readers.1For instance, one study of phase I consent forms found that their average length was 6.4 pages (with a range of 3 to 13 pages) and that 96% of them referred to the investigational agent as “treatment” or “therapy” without including modifying words such as “experimental” or “research.”2Some commentators have alleged that overall, consent forms may do more harm than good by obfuscating the information relayed in the physician consultation.3
Several attempts have been made to simplify consent forms,4and the National Cancer Institute (NCI) has developed guidelines for improving these documents, as well as a template to help investigators and institutional review boards (IRBs) draft and review them.5However, the NCI template aims to be comprehensive and is not specific to phase I trials. Because cancer patients often fail to understand that there is only a small chance of therapeutic benefit from phase I trials, concerns have been raised about whether they can provide fully informed consent to participate.6We believe that a simple, clear consent form is an important component of improving the informed consent process for phase I oncology trials and have therefore developed a shorter, simplified consent form template specific to phase I oncology trials.
The template was developed based on information obtained from a prior study in which we examined the language, length, and organization of 272 phase I oncology consent forms collected from 80% of the NCI-designated cancer centers in the United States and six large pharmaceutical sponsors of phase I trials.7We also used information obtained from cognitive interviewing data that we reviewed during our participation in the drafting of the NCI template. An interactive, consensus-based approach was used to critique and revise our template repeatedly, with an eye towards ultimately increasing the average cancer patient’s understanding of it when recruited to enroll in a phase I trial. We formally evaluated the readability of the template and used tables to present certain information. The template is short, more specific, better organized, and less repetitive than previous models, and is available in both English and Spanish.
Table 1 provides the consent form template in English. Several principles underpinned our aim to construct a short, readable, and useful consent template specific to phase I oncology studies:
- avoiding repetition of specific details in multiple sections;
- using simple tables to organize and visually represent information;
- using simpler language to improve the readability of the consent form;
focusing primarily on phase I oncology trials, but being broad enough to accommodate different categories of agents (cytotoxic agents, biologics, vaccines, etc.);
- organizing information into identifiable sections; and
- framing the section headings as first-person questions asked from the prospective participant’s point of view.
Consent Form Organization
Dividing the information into discrete sections improves the consent form’s readability and can also help investigators structure an organized discussion. The form is divided into sections that cover all of the regulatory requirements governing research with humans, including the purpose of the research; procedures; risks and side effects; benefits; alternatives; costs and study sponsorship; confidentiality; and biological sample storage, if applicable.
Terminology.Careful attention must be paid to the choice of language used in the consent form. Because the mere reference to the investigational agent as a “drug,” “therapy,” or “treatment” without modification could give the impression that the primary objective or expectation of the trial is to treat the patient’s cancer, such unqualified terms should be avoided. We have thus consistently employed the term “research agent.” Using a generic term enables the consent form to accommodate a variety of different types of agents, including cytotoxic drugs, antibodies, vaccines, and other interventions.
Study Purpose.The first section of the consent form should briefly define a phase I trial. In addition to emphasizing the nature of the trial as research, the form identifies the primary objective of the phase I trial as a dose-finding safety study. The consent form further clarifies that the agent’s effectiveness as an anticancer agent will be studied in a subsequent phase II study. No mention of potential benefit or risks is or should be made in the purpose section of the consent form.
Study Procedures.This section explains the dose escalation strategy—that different participants will receive different doses of the agent, and that the dose will be increased until several participants experience significant toxicity. So that prospective participants will better appreciate the significance of dose levels, the template then explains that participants who receive higher doses may have a higher likelihood of experiencing both side effects and clinical benefit than those who receive lower doses. If it is known at the time a patient agrees to participate in a trial which dosing cohort he or she will be assigned to, this section includes a space for the dose level to be described.
The procedures section also includes a listing of diagnostic procedures that will be performed, as well as information about when during the trial they will be done. An example of a timeline chart is provided for presenting this information in a clear and straightforward way, so that prospective participants can visualize the overall chronology of events. Investigators can easily add to the chart as much specific information as is needed.
Risks and Side Effects.The critical features in this section include disclosure of the known or predicted side effects of the research agent, the likelihood of their occurrence (if known), the anticipated time of onset, and whether they are reversible. Although death is an unlikely outcome when new biologics are tested in the phase I setting, it is always a possibility. Thus, the template includes language stating that death is a possible risk, and that unknown or unanticipated side effects could occur. Presenting risk information in a table allows for simplified presentation of all of these elements in a short space. Also, in trials where multiple agents are being studied, prospective participants are likely to care more about their overall risks than about which particular agent may be responsible for which toxicity. The tabulated format integrates the profiles of multiple agents and avoids repeating similar side effects, such as nausea and vomiting.
Benefits.Phase I studies are usually not designed to show antitumor efficacy. Nonetheless, it might be reasonable to indicate in the consent form that a therapeutic benefit is possible from participating in the study. However, it should be explicit that the chances for tumor shrinkage or extended survival are low. The consent form should also clearly state that the main benefit from participating in the trial is to help future cancer patients with the knowledge gleaned from the trial. Because prospective participants often focus most on the mention of response, or cure, repeating the fact that the trial is not designed to be therapeutic is recommended.
Alternatives.The template consent form lists five alternatives in a bulleted list to help prospective participants understand that all options are distinct and to facilitate the investigator’s clarification of each option. While one study found that nearly all phase I consent forms examined listed some alternatives to trial participation, only 56% mentioned palliative/supportive care; surprisingly, only one out of 272 forms examined referred to hospice care.8Because cancer patients considering enrolling in a phase I trial often have cancers that have proven resistant to several different chemotherapeutic regimens, supportive care in general, and hospice care in particular, should be incorporated into the informed consent process, even if patients exploring phase I trials may not be inclined to enroll in them.9
Study Withdrawal.A separate section explains to potential participants that they may withdraw from the study at any time, for any reason. It is vital to clarify that they will not be penalized for doing so and that whatever benefits they were entitled to before enrollment will remain. The consent form should also explicitly state that the investigators may remove a participant from the study due to progressive disease or poor compliance with study requirements.
Trial Costs and Study Sponsorship.Distinguishing between the costs of the research agent, tests, and other procedures unique to trial participation and the costs of routine clinical care helps prospective participants to understand that communication with their insurance company is critical in order to verify what costs the insurer will cover during the trial. This section should also include information about who will reimburse the costs of travel, accommodations, and other incidental expenses incurred during participation in the trial, and whether participants will receive payment beyond these expenses. When relevant, the sponsor of the study should be disclosed, along with an explanatory remark if the sponsor is helping the research team cover the costs of the study. Because a complete listing of consulting fees, honoraria, and the like seems impractical and out of place in a consent form, we recommend mentioning that an ethics or conflict of interest committee has reviewed the relationship between the study sponsor and the research team members and found it acceptable—if this has, in fact, happened.
Confidentiality.The consent form should state that any potential participant’s personal health information will be kept as confidential as possible, but that absolute confidentiality cannot be promised. However, the form should also state that participants’ information will be made available upon request to certain official agencies such as the Food and Drug Administration (FDA) or the NCI; we recommend listing the pertinent agencies in bulleted format. Because there is considerable overlap between the federal regulatory requirements for consent (the Common Rule) and the authorization requirements of the HIPAA Privacy Rule, we integrated the additional requirements mandated by the latter into the consent form to avoid unnecessary duplication and to help streamline this part of the consent process.10The template also suggests that participants inform the research team in writing if they decide to withdraw from the study and specifies that members of the research team may use their personal health information for an indefinite time.
Biological Samples.Almost all cancer studies now collect biological samples for correlative and future research. Language incorporated into this section is based upon extensive study of research participants’ wishes regarding research with biological samples.11Prospective participants can check yes or no concerning whether their blood and/or tissues can be stored for future research.
Spanish-Version Template.This version of the template (available here) was created by a certified medical translator; it was then back-translated for corroboration. We encourage investigators to translate the template into other languages common to their local population.
Studies Using FDA-Approved Agents.Many phase I trials use FDA-approved agents being tested in a novel dosing strategy or in a new tumor type, rather than novel agents that have yet to obtain FDA-approval. When a phase I study involves an FDA-approved agent, several minor changes to the template are called for. First, the risk-benefit ratio of phase I trials of FDA-approved agents appears to be quite different than that of novel agents, as toxicities are more predictable and response rates tend to be substantially higher.12Also, dosing strategies tend to be somewhat more conservative, as the starting dose is usually closer to the eventual recommended phase II dose. Thus, it is imperative to incorporate these differences into the consent form when an FDA-approved agent is being tested in a phase I trial.
The template was analyzed in its entirety for readability using Microsoft Word software and an online readability calculator (data available from the authors).13These readability tools are validated instruments and are often used in the educational realm, as well as in the assessment of insurance documents.14The Flesch Reading Ease Score (FRES) measures the ease of reading, with a higher score indicating that a document was easier to read. The Flesch-Kincaid Grade Level (FKGL) and the Gunning Fog Index (GFI) estimate the grade level of education required to understand a document.
The template generated an FRES of 68.3 and an FKGL of 7.1 (age 12–13) using the MS Word calculator; it generated a similar result using the online calculator. The GFI was 9.0. This is similar to the readability scores measured by the same methods forReader’s Digestmagazine. This template is much more readable—and written four grade levels lower—than the average informed consent document in clinical research (FRES 52.6, FKGL 11.4, GFI 14.1). It is also easier to read than the eighth-grade reading level recommended for consent forms.15The Spanish version was also analyzed with the Fernandez-Huerta readability test, which is scaled from 0–100 and provides a score similar to the FRES. The translation yielded a score of 64.16
It is important to point out the limitations of readability scores. They are purely quantitative estimates of the complexity of a given text and only indirectly gauge how difficult it will be for a heterogeneous population of potential trial participants to understand it.17However, since there is no way to directly test understandability short of a clinical trial, readability statistics are important initial measures by which proposed consent forms should be developed and evaluated, similar to the creation of the NCI template. Ultimately, a direct measure of patient understandability by way of a clinical trial is warranted.
The phase I consent template was developed by individuals who participated in the NCI template development, have an extensive research background in the process of informed consent, and critically reviewed hundreds of consent forms. The template offers the specific advantages of easy readability, shorter length, and trial specificity. Yet the ultimate test of its value is its impact on patient understanding and satisfaction, and we currently are developing a randomized controlled trial to address these questions.
We believe the phase I consent form template has four distinct advantages over other consent forms. First, to our knowledge, it is the first phase I consent form template that meets the recommended maximum eighth-grade reading level. Readability analysis shows that it is about as easy to read asReader’s Digest, and easier thanTimemagazine. Second, it is unique to phase I oncology trials because of the omission of features that are only relevant to phase II and III trials. Thus, it should be easier to use than forms designed for later-stage trials. Because investigators will have to make few modifications in adapting it to a particular phase I trial, this should increase the likelihood that final consent forms will have a very similar readability profile to the template and will retain a reading level below eighth grade. This is often not the case when the longer, more generic NCI template is used in different clinical settings because investigators have to make considerably more additions and modifications to it. Thus, the final consent document derived from the NCI template is often written at too high a reading level, partly because many investigators are not as focused on achieving superior readability outcomes. While a favorable readability score is an important criterion for a consent form template, the likelihood of a finalized consent form retaining a similar readability profile after being applied to a particular clinical trial setting is a more important measure, and one that we believe can be more reliably achieved by a shorter, more specific template that requires less modification by investigators. A third advantage of our template is that it is considerably shorter than the average consent form (3.5 vs. 6.4 pages). Studies have shown that prospective participants are more likely to read shorter, less cumbersome consent forms in their entirety and to retain information at higher rates than when presented with long consent forms.18Finally, as this is the first phase I oncology template translated into Spanish, it will be useful to investigators recruiting cancer patients who have difficulty reading documents written in English.
We thank Esther Mosak for translating and reviewing the Spanish version of the template. We also thank Sam Horng and Elizabeth Horstmann for their efforts in collecting and analyzing phase I consent forms and beginning this project.
The authors of this article are responsible for its contents. No statement in this article should be construed as an official position of the National Institutes of Health, the Public Health Service, or the Department of Health and Human Services.
Shlomo Koyfman, MD,is Resident Physician, Department of Radiation Oncology, Cleveland Clinic, Cleveland, OH;Mary S. McCabe, RN, MA,is Director, Cancer Survivorship Program, Memorial Sloan Kettering Cancer Center, New York, NY;Ezekiel J. Emanuel, MD,is Chief, Department of Bioethics, Clinical Center, National Institutes of Health, Bethesda, MD; andChristine Grady, RN, PhD,is Head, Section on Human Subjects, Department of Bioethics, Clinical Center, National Institutes of Health, Bethesda, MD.
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7. See ref. 6, Agrawal and Emanuel 2003.
8. See ref. 1, Horng et al. 2002.
9. See ref. 6, Agrawal and Emanuel 2003.
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Shlomo A. Koyfman, Mary S. McCabe, Ezekiel J. Emanuel, and Christine Grady, ” A Consent Form Template for Phase I Oncology Trials,”IRB: Ethics & Human Research31, no. 4 (2009): 1-8.