Todd W. Rice, MD, MSc
Division of Allergy, Pulmonary, and Critical Care Medicine
Chair, Health Sciences Committee #2, Institutional Review Board
Vanderbilt University School of Medicine, Nashville, TN

Gordon R. Bernard, MD
Melinda Owen Bass Professor of Medicine
Director, Division of Allergy, Pulmonary, and Critical Care Medicine
Assistant Vice-Chancellor for Research
Medical Director, Institutional Review Board Vanderbilt University School of Medicine, Nashville, TN

Introduction

The Belmont Report (http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.html) lists three fundamental principles in the ethical conduct of research involving human subjects, including respect for persons, beneficence, and justice. Informed consent is required by the moral principle of respect for persons and is essential to the principle of autonomy. The common rule states that "a human being may not be involved as a subject in research unless the investigator has obtained the legally effective authorized consent of the subject or the subject's legally authorized representative." Legally effective informed consent contains three elements: information, comprehension, and freedom from undue coercion. In other words, participants must be offered information about the research (i.e. purpose, procedures, reasonably expected risks and benefits, costs, compensation) presented orally or written in a language they can comprehend. They also must possess the capability of understanding the information and voluntarily agree to participate in the study without coercion and with the freedom to retract their approval without fear of penalty or repercussions.

Although a written form is usually utilized, informed consent should be viewed as an ongoing dialogue between the investigator and the research participant or legally authorized representative. Adequate time should be allotted during the consent process for the participant to have any questions answered to his or her satisfaction. The decision of a subject to sign the informed consent form (ICF) and participate in research does not end the consent process. New, pertinent information discovered during the course of the research should be relayed to participants in a timely manner to ensure that they still wish to continue participating in the research study.

Obtaining Informed Consent

Informed consent should be prospectively obtained from the participant prior to the initiation of any research procedures. In the past, investigators utilized a mechanism of deferred consent to conduct emergency research [1]. Criticism of this practice arouse on the grounds that participants could not truly consent for procedures that had already occurred and resulted in the practice being abandoned. Today, the preferred mechanism for obtaining consent involves having the participant sign a written ICF explaining the research. Unfortunately, the written nature of this document, along with the participant's signature, has misled many to believe that the ICF represents a means of limiting liability, like a legal contract. This has dramatically increased the complexity and length of ICFs over time, often rendering the document incomprehensible or too lengthy for the participant to read in detail. The end result is that the consent obtained is not informed. Maximally effective informed consent documents are written in easily understandable verbiage (OHRP recommends documents be written at or below an 8th grade readability level) and are as succinct as possible while still containing the required elements. Studies have found that excessive length of the informed consent document is the major characteristic impeding participant's ability to comprehend the proposed research [2-4].

Informed consent must be obtained from the participant or from a legally authorized representative prior to initiating research activities, including screening procedures performed for determining eligibility. Some populations are unable to provide informed consent, either because they are unable to comprehend (i.e. cognitively impaired) or because they lack the legal authority to consent (minors). For children under the age of 18, parents or legal guardians are the legally authorized representatives who may grant permission to participate in research. Assent from the child, however, may be required depending on the nature of the research and the age and maturity of the child. Certain emancipated minors may give their own consent to participate in research. Examples of possible emancipated minors include pregnant teenagers, those who have children, or those who are married or living on their own. State and local laws should be consulted to determine the criteria for emancipation, however, as these are determined locally. Cognitively impaired adult participants (including many critically ill patients) are also unable to provide informed consent to participate in research. Three types of legally authorized representatives are identified for granting permission for research participation of these individuals. Health care agents, or durable powers of attorney executed while the individual had decision-making capacity, possess the greatest power to make such decisions. Next in line are legal guardians or conservators, who are appointed by a judicial body to make decisions for an individual determined to be incompetent. A surrogate, or identified person designated to make healthcare decisions on behalf of an individual, may be utilized for consent when a health care agent, legal guardian, or conservator have not been previously appointed. Although the surrogate is usually the next of kin, the hierarchy of who can function in this role (i.e. spouse, adult child, parent, sibling, other relative) is determined by state legislation.

What must be included in the informed consent document? Required Elements of Informed Consent (Table 1)

Regardless of who (i.e. participant, parent, legal representative, surrogate) provides it, regulation 46.116 of the Common Rule (45 CFR 46) provides guidance on the required elements for informed consent ( Table 1) (available at: http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm#46.116). Informed Consent documents should be written in the second person (i.e. you are, the risks to you are, etc.) and must contain a statement that the study involves research, an explanation of the purpose of the research, and the expected duration of participation. In cases where the person obtaining consent is also the treating physician, care must be taken to avoid therapeutic misconception [5-7]. In other words, special precautions should be undertaken to ensure the participant understands that the procedures are for the purpose of developing new knowledge (i.e. research) and does not mistakenly believe that they are being performed with the primary goal of providing benefit to the participant (i.e. treatment). Although an individual subject may benefit as a result of participating, the primary goal of the research is to develop new knowledge about the condition. A description of the procedures needs to be included, with specific delineation of the procedures that are being performed solely for research purposes. If protocols are being compared, as often occurs in critical care research, potential subjects should be made aware of the experimental nature of these protocols [8]. Ascribing therapeutic intent to research protocols represents another means of therapeutic misconception.

A statement that participation is voluntary, refusal to participate will involve no penalty or loss of benefits, and that participation may be discontinued at any time without penalty or loss of benefits must also be included in the ICF. A description of all reasonably foreseeable risks or discomforts is required, with special care to avoid minimization. Likewise, any benefits to either the subject or others that may reasonably be expected from the research ought to be described, without overemphasis. The ICF must detail alternative procedures or courses of treatment available. Regulations also mandate a statement outlining the extent to which confidentiality of records identifying subjects will be maintained. This has become increasingly important with the recent passage of the Health Insurance Portability and Accountability Act of 1996 (HIPAA), which assures the privacy of protected health information (PHI) (available at: http://www.hhs.gov/ocr/hipaa). PHI is individually identifiable health information that is, or has been collected or maintained about participants that can be linked back to them, including information that is collected for research purposes. Most institutions or IRBs can provide templated language covering HIPAA and confidentiality of research records.

Research involving more than minimal risk requires an explanation as to whether any compensation and/or medical treatments are available if injury occurs, what those treatments consist of, and where further information may be obtained about the compensation and/or treatments. The ICF must tell participants whom to contact for questions about the research and research subjects' rights and whom to contact in the event of a research-related injury. Federal regulations require additional elements of informed consent, when appropriate, which are detailed in table 2. State or local laws may require further additional information be disclosed in the informed consent (ex: frequency of adverse events, adverse events that may be life-threatening, whether insurance will cover the costs of research, compensation that the investigator is receiving for performing the research, genetic rider, etc.) [9].

Can children give informed consent? Assent and Dissent in Minors

Parents or legal guardians are approached for consent for minors who lack the legal authority to consent for themselves to participate in research. Despite not possessing the legal authority to consent, the principle of autonomy and respect for persons still dictates that minors should be given the opportunity to assent and dissent to their own research procedures, when possible [10]. Although means for determining dissent should be outlined, the lack of dissent should not be misperceived as assent in such matters. Minors participating in research should specifically be asked for their assent, often as a written document in age appropriate language. For older and more mature minors (i.e. 12-17 y.o.), the child's assent form may look identical to the parental ICF. For younger participants, a very simple short form (aged 7-12 y.o.) or script (age less than 7 y.o.) is utilized. The short form often takes the shape of a sample question and answer format, while the script is often a single paragraph covering a very simple explanation of the procedures. Voluntary participation should be stressed in both. In certain circumstances, federal regulations allow the IRB to waive assent for minors, including those under the age of 7 and those for whom research presents the only opportunity for treatment of a life-threatening condition (i.e. cancer, AIDS, etc.).

Surrogate Consent

Many cognitively impaired subjects lack the capacity to consent for themselves. Although traditionally these have been viewed as patients with chronically diminished cognition, those with an acute impairment, including many critically ill patients requiring sedation for mechanical ventilation or with acute delirium, also fall under this designation. When a healthcare agent, durable power of attorney, legal guardian, or conservator has not been previously appointed, a surrogate designated to make health care decisions should be approached for consent. The same person identified to make health care decisions should be the surrogate for making decisions regarding research participation. Surrogates are usually next of kin, but state laws vary on the hierarchy of relatives eligible to act as such surrogates. Furthermore, some states restrict the type of research that can be conducted under surrogate consent. For example, Tennessee state law forbids surrogate consent for research that does not hold out any possible benefit to the participant. The ethical principle of autonomy and self-determination dictates that the acutely cognitively-impaired participant who regains the capacity to make healthcare decisions should be "re-consented" with the full ICF, even if this occurs after research procedures have been completed.

Documentation of Informed Consent

With only a few exceptions, regulation 46.116 of the Common Rule states that "informed consent shall be documented by the use of a written consent form approved by the IRB and signed by the subject or the subject's legally authorized representative." (available at: http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm#46.116) The potential participant or his/her representative should be given an adequate opportunity to read the ICF before signing, even if the form is read to them. If possible, designated potential assignees should be given the opportunity to take the ICF home and ponder the decision. The preferred method for obtaining informed consent from participants who do not speak English is to provide them with an informed consent document translated in a language in which they are fluent. The guidelines allow for an oral presentation as an alternative to the ICF. If an oral presentation is chosen as the means of consent, however, the participant must sign and date a short form written informed consent stating the elements of consent have been provided orally. In addition, the participant must be provided a copy of the signed short form and a written summary of the information that was presented orally. Furthermore, a witness (separate from the person obtaining consent) must be present during the oral presentation and must sign and date both the short form written consent document and the written summary. The person obtaining the informed consent must also sign and date a copy of the written summary of information that is presented orally. Participants who do not speak English should be presented with informed consent documents in a language understandable to them.

Waiver of Informed Consent

Occasionally, an IRB will agree to waive the requirement for the investigator to obtain a signed consent form, allowing the research procedures to occur without the participant's explicit consent. This usually occurs with either retrospective chart reviews or prospective studies collecting data from standard care, but may also rarely be granted for prospective studies of minimal risk procedures performed for research in critically ill patients. For the purpose of research, minimal risk is defined as the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests. Procedures for which an IRB may decide to waive consent include minimal blood draws or non-invasive tests such as ultrasounds, electrocardiograms, or electroencephalograms. The Common Rule dictates that the research must meet all four of the following criteria to qualify for consideration of waiver of consent: 1) the research must not involve more than minimal risk to the participant; 2) the waiver will not adversely affect the rights or welfare of the participant; 3) the research could not practically be accomplished without the waiver (i.e. for retrospective studies it is often impossible to locate all the participants to obtain consent); and 4) if appropriate, the participant will be provided with additional information after participation.

Conclusion

In conclusion, obtaining informed consent is a vital part of respect for persons and preservation of self-determination. This consent to participate in research should be informed, comprehensible, and free of undue coercion. Signatures on written forms are the preferred method of documenting informed consent, but alternatives are allowable. The federal regulations have mandated minimum required elements for the informed consent document, but state, local, and institutional guidelines may expand on these. For critically ill participants, surrogate consent is often obtained. If this is the case, the study participant should be "re-consented" upon regaining the ability for self-determination. The Common Rule occasionally allows IRBs to waive the requirement for obtaining consent, but only for minimal risk procedures and research which could not practically occur if informed consent was required.

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