Western Institutional Review Board

Western Institutional Review Board^® (WIRB^®) has the following requirements for obtaining informed consent on behalf of subjects who are not competent, and for determining what constitutes a “Legally Authorized Representative.” This policy statement will review the legal and ethical issues, and outline WIRB’s approach to these issues. Please note that this policy statement reflects board opinion, and that nothing in this policy statement is intended to constitute legal advice. For questions regarding the legal status of an individual subject and the applicability of state law to an individual subject’s enrollment in research, contact a health care attorney admitted to the bar in your state. Please be aware that changes in statutes and regulations occur frequently, and that court decisions may determine or change the interpretation of such statutes and regulations. Legal counsel should always be consulted to determine the current state of applicable law.

Three areas need to be addressed. First are the FDA (21 CFR Parts 50 and 56) and HHS (45 CFR Part 46) human subject protection regulations, and their approach to consent to research by a legally authorized representative. Second is state law on informed consent. Third is the bioethical approach to surrogate consent, which requires a decision based on previously stated wishes of the subject, or substituted judgment, or, as a last resort, consent based on the best interest of the patient.

Stephen Post states that “Law is confounded by dementia.”[1] This is a perfect introduction to the issue of law and research with the decisionally impaired. Many individuals are mentally incapacitated but have not been declared legally incompetent.[2] This is an important distinction that leaves both the FDA regulations and state law with many gray areas of interpretation.

The legal analysis of surrogate consent involves both state law and federal regulations. Therefore, this section will first address the FDA and HHS definition of “legally authorized representative,” then state law, and third return to the FDA and HHS regulations to discuss the federal requirements for informed consent.

no investigator may involve a human being as a subject in research covered by these regulations unless the investigator has obtained the legally effective informed consent of the subject or the subject’s legally authorized representative.

The HHS regulation, at 45 CFR 46.116, is virtually identical. If a subject is not legally competent to consent to participate in a study, the federal regulations require that a legally authorized representative consent for the subject. The definition of “legally authorized representative,” as described in 21 CFR § 50.3 and 45 CFR 46.102(c), is;

an individual or judicial or other body authorized under applicable law to consent on behalf of a prospective subject to the subject’s participation in the procedure(s) involved in the research.

The applicable law is the law of the state, as well as any other local law. Thus, the definition of “legally authorized representative” is determined by state and local law.

If a subject has been declared incompetent, or otherwise has legally transferred authority to consent to another person, then a legally authorized representative, as determined under state law, must consent on the subject’s behalf.

All states have a variety of laws that provide legal authority for an individual to provide legal consent to health care on behalf of an incapable and/or incompetent person.

All states have laws that authorize guardianships for the legally incompetent. These guardians often have broad powers over the health care decisions of their wards. However, in several states guardians are specifically prohibited from enrolling wards in research.

Most states have laws that authorize the establishment of advance directives for health care decisions. However, these directives often are limited to patients in a terminal condition or a persistent vegetative state. Therefore, they may not apply to consent by a legally authorized representative for the enrollment of patients in research.

All states also have laws that authorize a legally competent individual to establish a durable power of attorney in preparation for future incapacity. Durable powers of attorney generally must be established in writing, in accordance with requirements such as witness signatures. The most common problem with using the durable power of attorney to consent to research is that it has to be established in writing, like a will, before the patient becomes incapacitated. As a practical matter, most people do not establish a durable power of attorney before they become incapacitated.

Many states also have law that provides a hierarchy of persons who can make surrogate health care decisions for incapacitated patients. Usually, the ordering descends from guardian down through the holder of a durable power of attorney, spouse, adult children, parents, and various other relatives. These hierarchies may be part of an informed consent statute, a natural death act, or some other type of statute.

There are often additional state statutes addressing the issue of consent for legally incompetent patients, particularly special groups such as the developmentally disabled or the institutionalized. These statutes may or may not be relevant to a particular research protocol.

In addition to statutory sources, judicial decisions may provide legal authority for surrogate consent, or provide interpretation of relevant statutes.

The FDA and HHS definition of a “legally authorized representative” is “an individual or judicial or other body authorized under applicable law to consent on behalf of a prospective subject to the subject’s participation in the procedure(s) involved in the research.” Therefore, there should be a state statute or judicial decision that can be directly cited as providing the authority for the legally authorized representative to make decisions for the incapable potential subject. Furthermore, all of the conditions and standards of the statute or judicial decision must be met.

The FDA and HHS regulations on human subject protection also require certain standards of informed consent. First, they specifically require that a subject or the subject’s legally authorized representative give legally effective informed consent to participation in any research performed under FDA jurisdiction (21 CFR § 50.20; 45 CFR 46.116). The only waivers of informed consent are for the individual emergency use of a test article under FDA regulation 21 CFR § 50.23(a)-(c), emergency room research under FDA regulations 21 CFR § 50.24, or minimal risk research (that is not under FDA jurisdiction) under 45 CFR 46.116(d). There is no waiver of consent that applies to the enrollment of medically incapacitated subjects on the basis of that status alone.

Second, an essential element of legally effective informed consent is comprehension. The FDA Information Sheets state that part of the informed consent process is “ensuring that the subject has comprehended this information.” [3] For consent to be legally effective, it is essential that the person consenting to the research comprehend the information. In addition, comprehension is usually an element of state law on informed consent.

In addition to the consent requirements, the FDA and HHS regulations require that the IRB provide additional safeguards for vulnerable subjects (21 CFR § 56.111(b); 45 CFR 111(b)). Individuals who are incapacitated fit the designation of “mentally disabled persons,” one of the listed categories of vulnerable subjects. Id. Additional safeguards may include stricter than usual consent requirements, additional inclusion or exclusion criteria, or on-site monitoring.

In addition to state and federal law, WIRB expects that investigators will meet ethical standards of surrogate informed consent. In the bioethical literature on the issue of surrogate informed consent, there is a general consensus that there are three methods by which surrogate decision-makers can approach the issue of consent for medically incapacitated patients. These are pure autonomy, substituted judgment, and the best interest standard.

Before discussing these methods, there are two important points to address. First, assessments of patient incapacity and decisions about the clinical care of incapacitated patients usually are made informally, avoiding legal entanglement.[4] The majority of decisions concerning incapacitated patients are made without any official legal action. From an ethical perspective, this is appropriate as long as the decisions made are ethical. However, the ethical standards for surrogate decision-making used in the clinical treatment of incapacitated patients often fail to meet the legal standards of the FDA regulations on research. Therefore, research enrollment procedures may be in compliance with the ethical standards for surrogate decision-making methods for the treatment of medically incapacitated patients, but not FDA and HHS regulatory requirements. This point provides a good example of the difference between law and ethics. WIRB expects that FDA regulations, state law, and ethical standards of informed consent will all be met.

Second, as in law, much of the ethical literature on surrogate consent is based on the extreme case of patients in a persistent vegetative state. These are “clean” theoretical cases because they involve a patient with no quality of life, who cannot participate in any way in the consent process. However, most patients are not so utterly incapacitated, with no hope of recovery of consciousness. Rather, there is a spectrum of incapacity, from slightly incapable to persistent vegetative state. For conscious patients that are somewhere along this spectrum of incapacity, it is often difficult to apply these methods of surrogate consent, and much remains undecided from a theoretical viewpoint.[5] This is especially true when the patient’s level of capacity fluctuates.[6]

Under pure autonomy, decisions are made in accordance with the express wishes of the patient, as written or stated by the patient before the patient was incapacitated. This is only possible when the patient previously considered and specifically discussed the medical circumstances that in fact have come to pass.

Under substituted judgment, the surrogate decision-maker tries to make decisions for the incapacitated patient based on the values and beliefs of the incapacitated patient. These decisions hopefully will be the same decisions the patient would have made if the patient were not incapacitated.

The best interest standard is used when no one is able to base surrogate decisions on the values and beliefs of the patient. This situation can occur when no one who knew the patient is available, or when the patient has never been competent. The best interest standard is based on considerations of benefit to the patient and the quality of life of the patient, rather than on the patient’s autonomy.

In all three of these ethical decision-making methods, if the surrogate decision-maker is deciding whether to enroll a subject in research, the surrogate decision-maker should consider the risks and benefits of the research. The surrogate decision-maker should especially consider the potential lack of benefit when the research contains a placebo arm.

To the degree possible based on capacity, the assent of the subject must be obtained (ICH 4.8.12). If the subject does not wish to participate in the research, the subject cannot be enrolled in the research. The legally authorized representative cannot override an incapacitated subject’s decision not to participate.

At times subjects become incapacitated during the course of a research study. Several considerations apply to this situation. First, subjects may continue to be enrolled in the study if they have agreed in writing to stay in the study after they become incapacitated. Such a written agreement may be a consent form or some type of advance directive. This is acceptable as long as the all conditions of any applicable state law are satisfied. Second, if a legally authorized representative is available and agrees to the continued participation of the subject in the research, the subject may continue to participate in the study. If there is no advance directive and no legally authorized representative is available, then the subject must be disenrolled when the subject is no longer able to participate in the ongoing informed consent process due to the incapacity.

WIRB^® expects that investigators will comply with the FDA regulations and state law, and ensure that the ethical standards for surrogate consent are met. WIRB^® requires that either the subject or the subject’s legally authorized representative as determined by state law give legally effective consent, as required by 21 CFR 50.20 and 45 CFR 116.

Decisions about whether a specific potential subject is capable of enrolling in a given research study is a medicolegal clinical decision that requires exquisite care and assessment by the investigator. The intent of this policy is to provide the framework for making this decision for research under FDA, HHS and WIRB oversight.

Nothing in this policy statement is intended to constitute legal advice. For questions regarding the legal status of an individual subject and the applicability of state law to an individual subject’s enrollment in research, contact a health care attorney admitted to the bar in your state. Please be aware that changes in statutes and regulations occur frequently, and that court decisions may determine or change the interpretation of such statutes and regulations. Legal counsel should always be consulted to determine the current state of applicable law.

[1] Stephen Post, The Moral Challenge of Alzheimer Disease, (Johns Hopkins University Press, 1995) 4.

[2] In this white paper “incapacity” is a medical and psychological term, signifying a patient who cannot make some or all decisions about her own medical care, regardless of her legal status. “Incompetent” is a legal term, signifying a patient whose legal ability to make some or all decisions has been removed through a legal mechanism.

[3] The FDA Information Sheet “Informed Consent Process” (September 1998), 11.

[4] Stephen Post, The Moral Challenge of Alzheimer Disease, (Johns Hopkins University Press, 1995) 68-69.

[5] Beauchamp and Childress, Principles of Biomedical Ethics, (Oxford University Press, 1994) 170.

[6] Stephen Post, The Moral Challenge of Alzheimer Disease, (Johns Hopkins University Press, 1995) 68-69.