NYU School of Medicine IRB Newsletter

This article is the first in a series exploring the informed consent process with respect to human subject research. Future articles in this series will cover the requirements of the informed consent process in the US and varied approaches to informed consent process throughout the world, how the IRB can assist research teams in the development of different methods of informed consent processes for unique consent situations and cultural norms and different attitudes towards informed consent.

Cultures, religions and languages vary widely in the United States. This diversity has not, however, led to a flexible consent process that addresses the varying cultures, religions and languages found here. While other industrialized nations are working towards creating more useful informed consent approaches, the U.S., confronted with very specific federal regulations, has done little to address the diversity of its own population. The "melting-pot" of America is not well-represented in the informed consent process.

What is Informed Consent in Research?

Informed consent is defined as the process of presenting information to potential research subjects in order to enable each person to voluntarily decide whether or not to participate in a research study. The process of obtaining informed consent must comply with the requirements of 45 CFR 46.116. The documentation associated with informed consent must comply with 45 CFR 46.117, requiring that the consent process be documented with written consent forms approved by the IRB. The written presentation of information is used to document the basis for consent and for the subjects' future reference1.

A Basis for Consent

Consider the following question: How does the written consent document act as "A Basis for Consent":

It is proof that the requirements were completed as set forth in 45 CFR 46.116
It is evidence that the subjects were told about the study's purpose, duration, experimental procedures, alternatives, risks, and benefits in "lay language" (i.e. understandable to the people being asked to participate)
It is the documentation for liability purposes and assures authorities that proper signatures were received prior to the commencement of experimental procedures
It is assurance that protects and assists subjects of the many different cultural, educational, and socioeconomic backgrounds and helps subjects decide whether or not to volunteer for research
None of the above
All of the above

The answer is: none of the above. None of the answers above necessarily ensure that a consent document has acted as the basis of consent. Neither do any of the answers demonstrate that adequate consent has been obtained from a given subject.

Can We Guarantee Adequate Consent has Been Achieved?

soothing yet meaningless illustration (you're welcome)

First, it may be helpful to review the federal regulations on Informed Consent in research involving human subjects. The federal regulations at 45 CFR 46.116 require that specific information be given to all subjects in a written document in order to ensure that the subjects are presented with the appropriate details regarding the study. Information that must be provided includes: (1) a statement that the project is research; (2) requirements of the subject; (3) the benefits the subject will receive; (4) any foreseeable risks to the subject; (5) alternatives to participation in the study; (6) a statement describing the extent to which the subject's Protected Health Information ("PHI") will be protected; (7) a statement discussing whether or not compensation will be provided to the subject for a research related injury; (8) contact information for questions relating to the study; (9) a statement of the rights of a research subject; (10) a statement that participation is voluntary and that the subject may withdraw at any time, and (11) any additional requirements as they apply to the study. These additional requirements may include: (a) a statement describing the termination of a subject's participation; (b) a statement describing any additional costs the subject may receive as a result of participation in the study; (c) a statement describing the consequences of withdrawal from the study and how a subject should withdraw from the study; (d) a statement describing when and how significant new findings will be conveyed to the subject, and (e) the approximate number of subjects involved in the study. Again, remember the required information must be documented by the use of a written informed consent form approved by the IRB and the document must be signed by the subject.

Federal regulations leave little flexibility when it comes to consenting subjects—and place a great deal of emphasis on the consent document. While guidance from the Office of Human Research Protection (OHRP) states that informed consent is a process (not just a form), and should be designed to educate the subject population in terms that they can understand, the guidance states that information must be presented in a written format2. The guidance is ambiguous in terms of fostering real understanding between the researcher and their subject, but the regulations are quite rigorous in terms of what minimum consent materials must be in place.

Following the federally mandated written requirements raises the concern that a large segment of the population may not receive adequate information with respect to the research being undertaken. Perhaps the narrow federal regulations and vague OHRP guidance is the reason that researchers struggle to write meaningful informed consent for subjects—sometimes resulting in poor study enrollment, limited comprehension and a distrust of research.

Alternative approaches to presenting and/or documenting informed consent may be necessary in certain types of research. However, neither the regulations nor guidance issued by the federal provide any direction in this area. To remain in compliance with the regulations—including proper written documentation—and deliver adequate informed consent so that subjects know:

they are in a research study
understand all the risks and potential benefits
understand the alternatives
etc

is often a struggle, and does not necessarily guarantee adequate consent.

Can the 'Basis of Informed Consent' be Served by Other Means of Documentation?

There is some confusion in the research community—including IRBs—over the various aspects of what constitutes informed consent. Some believe that informed consent is complete when the subject reads the document and signs it. Some believe that the discussion that takes place between the researcher and subject is the most important element, and ensures the subject has been properly enrolled. Others place priority on the written contents of informed consent document.

Ideally, the basis of informed consent is achieved through a well written consent document approved by an IRB in language easily understood by the subject along with discussion with the subject regarding the research, presentation of the document to the subject, allowing the subject the opportunity to ask questions, allowing the subjects to take the document home (where feasible) for discussion with family and caregivers, and having the subject sign the consent form with the Investigator present. Information should be presented throughout the research study to facilitate a dialogue with the subject and allow them to ask questions. Finally, results of the research should be relayed to the subjects. Educating subjects, minimizing their fear and uncertainty: this is the goal of the basic informed consent process.

The typical informed consent process starts with a discussion between the research subject and the research team. The subject is given a informed consent form and the subject is asked to sign the consent form as proof of the discussion and their agreement to participate in research. No matter how well written your form is, you should question your subject's comprehension:

has the subject really understood what is to be done?
does the subject really know they are in research study?
did the documentation serve as the basis of this process, or did the research team and the formal and informal discussions that took place with the subject serve as the basis of informed consent?

Research on the consent process—including how it fairs in the medical research arena—is being conducted throughout the world. Consent procedures and documentation that differ from the approached outlined in the U.S. regulations are being explored outside the US. These 'outside the box' studies are finding better methodologies which may enhance the standard consent process.

Thinking "Outside the Box"

A recent study evaluated different interventions used to improve research participants understanding of information disclosed in the informed consent process. Studies published during 2004-2006 were evaluated and the researchers concluded that efforts to improve understanding through the use of multimedia and enhanced consent forms have had limited success. Having the research team or a neutral educator spend more time talking one-on-one to study participants appears to be the most effective available way of improving research participants' understanding3.

Another recent study assessed a continuous consent process in which information is given to research participants at different stages in a trial. The continuous consent approach to obtaining informed consent gives subjects information at more than one point in the trial so that they will assimilate the information better. The continuous consent process was used in the Total Body Hypothermia (TOBY) trial, a randomized controlled trial (RCT), investigating the use of whole-body cooling for neonates with evidence of perinatal asphyxia. The process was divided into three main elements.

Element 1: If the baby is born in a non-cooling centre, the parents are given preliminary information about the trial, including a preliminary information leaflet, while the baby is assessed for eligibility. (If deemed appropriate, the leaflet may also be given to parents of babies born in a cooling centre, or preliminary information may be offered more informally.)
Element 2: If the baby is eligible, a second, more comprehensive, information leaflet is given to the parents and further discussion takes place. At this point, parents are asked for their written consent and randomized.
Element 3: During the intervention period, the consultant neonatologist meets the parents to ensure that they understand the trial procedures and wish to continue participating in the trial. It is made clear that the parents remain free to withdraw their baby from the trial.

The study found an improvement in consent validity at the point of signature to that at the post-signature phase for each parent. At the point of signature (element 2), 22 of 30 (73%) mothers and 8 of 27 (30%) fathers had major or serious problems with the validity of their consent. In the post-signature phase, (element 3), there was a drop in serious problems with the validity of consent to 7 of 29 (24%) mothers and 4 of 26(15%) fathers4.

A study involving HIV-seronegative volunteers recruited into a longitudinal cohort to study rates of high-risk sexual behavior and incidence of HIV-1 infection gave all volunteers information about the consent form during two educational sessions. In the first session, groups of 5 to 10 volunteers viewed an educational video on the essential elements of the consent form. In the second, the volunteers met one-on-one with a social worker. Volunteers' comprehension was then evaluated orally by 16 true-false questions and 4 open-ended questions. Volunteers who failed the first evaluation received additional education and had a second evaluation.

Of two hundred fifty volunteers that received education, 186 (74%) passed the first evaluation. Of the 64 who failed, 47 returned for a repeat one-on-one education session and a second evaluation. Among these 47, 39 (83%) passed, and 8 (7%) failed the second evaluation. In total, 225 (90%) of 250 individuals passed either the first or second evaluation and were eligible to enroll in the study. The researchers concluded that informed consent using an educational video ensures good comprehension with additional educational sessions necessary for some subjects with lower educational level5.

Research is being conducted on varying approaches to informed consent processes and data is emerging to support the notion that different approaches not only improve enrollment but increase comprehension.

In the next IRB Newsletter we will discuss how the IRB can assist research teams in the development of different methods of informed consent processes for unique research consent situations.