Biomedical research involving human subjects.
The history of medical progress is to a large extent the history of medical experimentation. (1)Introduction
Clinical Investigation
Human subjects are an integral part of medical research investigation. Testing of a potential drug, device, or vaccine in humans is generally required in order to receive Food and Drug Administration (FDA) licensure. FDA approval and licensure are necessary to make the benefits of the new drug, device, or vaccine available to the general public. Human testing is necessary, in part, because the results of animal testing may not be indicative of how a particular drug, device, or vaccine will perform in a human. Testing in human subjects is conducted as part of a clinical investigation. A clinical investigation is an experiment that involves a test article (drug, device, or vaccine) and one or more human volunteers. A clinical investigation is subject to requirements for submission to the FDA, or the results of which are intended to be submitted as part of an application for a research or marketing permit. (2)
Substantial Evidence Requirement
Generally, approval of a potential vaccine by the FDA will only occur if clinical investigation reveals that the test article is both safe and efficacious, meaning that a particular test article will work for its intended purpose. A researcher must produce substantial evidence from the clinical investigation that shows that the vaccine (for example) works in humans. The Federal Food, Drug, and Cosmetic Act (FFDCA) defines substantial evidence as
...evidence consisting of adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and responsibly be concluded by such experts that the drug will have the effect it purports to have. (3)
Common Rule
Biomedical research involving human subjects that is conducted or funded by a federal agency is also regulated by Department of Health and Human Services (HHS) regulations, at 45 CFR 46 (Subpart A) as implemented by the given federal agency. This regulation is known as the "Common Rule," having been adopted by the Department of Defense (DoD) (at 32 CFR §219) and 15 other federal agencies in 1991. While the FDA regulations and the Common Rule are largely harmonized, investigators must be aware of some differences. (4) In addition, if a biomedical research project involving human subjects does not involve an FDA-regulated test article and is not conducted to support FDA licensure, the project will not be regulated by the FFDCA and its implementing regulations.
HISTORICAL EVENTS AND ETHICAL PRINCIPLES
The Nuremberg Code: Voluntary Consent
With the exception of highly-regulated emergency research conducted without informed consent, and some minimal risk research, federal regulations prohibit the use of human subjects for research unless the subject's informed consent or the consent of the subject's legally authorized representative has been obtained. (5) These regulations, and others, embody the ethical principles set forth in the Nuremberg Code, the Declaration of Helsinki, and the Belmont Report. The Nuremberg Code is a set of 10 ethical principles that evolved from the trials of the Nazi doctors in 1947. (6) The key element of the Code focuses on voluntary consent. The Code was derived from international law, international customs, basic humanitarian considerations, and sensitivities of public conscience. (7) It now represents international common law and is applied in US courts. (8)
The Declaration of Helsinki: Informed Consent and Research Study Review
The Declaration of Helsinki was formulated by the World Medical Association in 1964 as a more specific, workable ethical code for medical personnel. The most recent revision of this document occurred in 2008. (9) Prior to that, it had been revised in 2000, and provisions were clarified in 2002 and 2004. It represents a further evolution of the ethical guidelines to be applied by physicians in clinical and nonclinical biomedical research. Like the Nuremberg Code, The Declaration of Helsinki stresses informed consent while adding a requirement for review of the research study. (10)
The Belmont Report: Ethical Guidelines for Protection of Human Subjects
The Belmont Report (11) resulted from study and deliberations of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (1974-1978). The Commission was established by the National Research Act, Pub L 93348 (1974), to identify the basic ethical principles concerning human subjects that should be applied in the performance of biomedical and behavioral research. The Belmont Report sets forth the guidelines that are incorporated into federal regulations for the protection of human subjects. This guidance is applied in the evaluation of research proposals for federal funding.
Other Developments
Other noteworthy actions include the creation of the President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research (1980-1983), the Advisory Committee on Human Radiation Experiments (1994), and the National Bioethics Advisory Commission (1996). The President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research was created by Pub L 95-622, (12) which required all federal agencies to adopt the Common Rule. The deliberations of the Advisory Committee on Human Radiation Experiments resulted in Executive Order 12975, (13) which established the National Bioethics Advisory Commission (NBAC) in response to disclosure of human subject abuses in federally supported radiation experiments. The NBAC's primary goal was to develop clear ethical standards for the protection of human subjects during the conduct of research. The NBAC's charter expired in 2001, and, in that same year, President George W. Bush created the President's Council on Bioethics, which is charged with advising "...the President on bioethical issues that may emerge as a consequence of advances in biomedical science and technology." (14)
ETHICAL PRINCIPLES OF RESEARCH
The consensus within the research and ethics communities is that all research should be conducted in keeping with 3 basic ethical principles: respect for persons, beneficence, and justice. These principles are considered to have equal moral force, although their implementation may be expressed differently in different circumstances.
Respect for Persons
Respect for persons includes respect for the autonomy of the individual. Autonomy is essentially the right of self-determination. Thus, researchers should respect an individual's exercise of self-determination in making decisions about his or her body. The Belmont Report (11) emphasized that researchers must respect the individual by giving weight to his or her informed consent to participate in the study and the weighing of the relative risks and benefits of procedures that will be performed. Respect for persons also acknowledges that vulnerable individuals with diminished autonomy should be protected from harm or abuse. All of the ethical guidelines discussed above focus on autonomy of the subject as a key principle.
Beneficence
The concept of beneficence requires that researchers maximize the potential benefits and minimize potential harms to the subject. In other words, potential risk to the subject must be reasonable in proportion to the anticipated benefits of the research study and the knowledge sought. In addition, the study must be scientifically meritorious, and the researcher must be qualified to conduct the research and competent to protect the subjects from deliberate harm. An individual may choose to participate in a study when death is a probable result. However, the responsibility for the individual must always rest with the medical personnel even though the subject has given consent. Concern for the well being of the individual subject must always outweigh the potential benefit to society as a whole. (9)
Justice
Justice requires the equitable distribution of the benefits and burdens of research among the participants and recipients of the benefits of research. Recruitment of subjects should not be limited to specific categories of persons while the general population reaps the benefits of that group's participation. For example, exclusive use of mentally disabled persons as human subjects because of a perception that they are not socially valuable individuals would be improper. Conducting a study with this group of subjects may be permissible if the study seeks to answer some scientifically valid question about mental disability. Treating a specific group differently should be based upon some morally relevant justification or meritorious scientific inquiry.
Informed Consent
Risk/Benefit Analysis. Whether to participate in a particular research study is a choice the potential subject must make based on adequate and essential information presented during the process of "informed consent." Informed consent requires that sufficient information about the conduct of the research and possible benefits or risks to the subject be presented in such a way that the subject can make a reasoned and informed decision about whether to participate in the research. The standard applied in determining whether there has been informed consent is whether there has been disclosure of all information that a reasonable person would consider material in weighing the potential benefits and risks of participation.
Without Coercion. In keeping with the ethical principles discussed above, it is important to stress the voluntary nature of the subject's participation throughout the informed consent process. The researcher must avoid any action or statement that could be construed as deceptive, applying undue pressure or influence, or seeking to intimidate the potential subject into signing the consent document. The potential subject must be assured of the ability to withdraw from the study at will and without penalty. If payment or other compensation is to be made for participation, such compensation cannot be so enticing as to be coercive or irresistible to the individual.
Documentation. In the general research community, informed consent is usually documented in writing with a signed consent form, but may be obtained orally in certain circumstances. (15) The consent document must address all of the 8 basic elements of informed consent discussed below and may not include any exculpatory language through which subjects are made to waive, or appear to waive, any legal rights they may have. Furthermore, the consent form should be written in nonmedical language that is easily understood by the subject. A translation of the consent form for subjects who do not understand English must also be provided.
Continuing Obligation. It is important to remember that informed consent is a continuous process. The informed consent document is not simply a piece of paper to be executed at the beginning of a study and then filed and forgotten. The researcher has a continuing obligation to notify the subject of any new information or changed circumstances that may affect his or her participation in the study. The researcher's obligation continues even after the study has concluded. (16)
Selected Elements of Informed Consent
There are 8 basic elements of informed consent set forth in the Common Rule. (17) At a minimum, the 8 elements must become part of the informed consent document, but agencies may impose requirements for additional disclosures to the subject. Researchers must provide a statement to the subject that the study involves research, the purpose of the research, the expected duration of the subject's participation, an explanation of the procedures to be performed, and identification of any procedures that are experimental. In addition, there must be a description of the reasonably foreseeable risks to the subject due to his or her participation, as well as benefits anticipated, if any. The subject must also be provided with information about alternative procedures or treatments that might be beneficial to him or her. Confidentiality of medical or research records must be addressed, as well as an explanation of compensation to be provided, if any. The subject must also be informed whether medical care and/or compensation will be provided in the case of injury related to the study. Of extreme importance is the requirement that the subject be made aware that his or her participation is voluntary and that he or she may withdraw from the study at any time without suffering penalties or loss of benefits to which the subject is otherwise entitled. Finally, a point of contact must be provided concerning the subject's participation in the study.
FEDERAL LAW AND DOD REGULATIONS
The body of law governing the use and protection of human subjects in federally funded or conducted research is an amalgam of ethical considerations, international common law, US statutes, and specific regulations promulgated by federal agencies. In 1991, the DoD and 15 other federal agencies adopted HHS regulations at 45 CFR 46 (Subpart A) concerning the protection of human subjects in federal research. As discussed earlier, the adopted regulations are referred to as the Common Rule. (18) The Common Rule applies to all research funded by the federal government, whether intramural or extramural, via grants, contracts, cooperative agreements, or cooperative research and development agreements. The Common Rule incorporates the principles discussed in the Belmont Report (11) and requires institutional assurances of compliance with federal law, the creation of institutional review boards, and informed consent of the subject or the subject's legally authorized representative to participation in the research study.
The HHS also published regulations at 45 CFR 46 Subparts B, C, and D. These Subparts address research activities involving fetuses, pregnant women, and neonates (Subpart B), prisoners (Subpart C), and children (Subpart D). Though these Subparts are not part of the Common Rule, these Subparts are made applicable to DoD research by paragraph 4.4.1. of Department of Defense Directive 3216.02. (19(p3))
10 USC §980 (20) is a federal statute that applies only to research funded by the DoD. 10 USC §980 restricts the DoD's ability to conduct or fund certain research that would otherwise be in compliance with the Common Rule. It requires the following for DoD-funded research involving human subjects: (1) the informed consent of the subject must be obtained in advance; and (2) if a subject is unable to legally give informed consent (eg, children, the mentally ill, unconscious persons, trauma victims), the legal representative of the subject may give the informed consent of the subject in advance, but only if the research is "intended to be beneficial" to the subject. The intent-to-benefit requirement of 10 USC §980 creates a challenge in the conduct of certain placebo research involving children that is otherwise approvable under the Common Rule and the HHS Subpart regulating research with children. The impact of 10 USC §980 on research involving children is discussed later in this article.
10 USC §980 has also historically made it difficult to conduct DoD-funded research involving trauma victims and unconscious subjects because it is often impossible to get informed consent from such subjects or their legal representatives in advance. The National Defense Authorization Act of 2002 amended 10 USC §980 to address this issue. The amendment permits the Secretary of Defense to waive the requirement for advance informed consent:
with respect to a specific research project to advance the development of a medical product necessary to the armed forces if the research project may directly benefit the subject and is carried out in accordance with all other applicable laws. (21)
Paragraph 4.2.2. of Department of Defense Directive 3216.02 (19(p3)) (the implementation directive for 10 USC §980), the Secretary of Defense delegated this waiver authority to the heads of DoD components (eg, Secretary of the Army). Other applicable laws include the FDA regulations governing use of investigational drugs or devices in emergency research without informed consent, (22) or, for research not regulated by the FDA, the equivalent HHS regulation. (23) The waiver may be requested for DoD research intended to improve treatment of battlefield injuries, using new techniques, drugs, or devices, on a research population that may be difficult to identify and/or obtain informed consent from in advance.
Department of Defense Directive 3216.02 also creates certain DoD-unique obligations for research involving human subjects conducted or supported by the DoD (eg, through contract, grant, cooperative agreement, or other arrangement). For example, paragraph 4.4.3 states:
For research involving more than minimal risk to subjects (as defined in 32 CFR 219.102(i)), an independent medical monitor shall be appointed by name. Medical monitors shall be physicians, dentists, psychologists, nurses, or other healthcare providers capable of overseeing the progress of research protocols, especially issues of individual subject/patient management and safety. Medical monitors shall be independent of the investigative team and shall possess sufficient educational and professional experience to serve as the subject/patient advocate. (19(p4))
Additionally, paragraph 4.4.3.2. gives medical monitors
...the authority to stop a research study in progress, remove individual subjects from a study, and take whatever steps are necessary to protect the safety and well-being of research subjects until the IRB [institutional review board] can assess the medical monitor's report. (19(p4)(
Multiple Army regulations may also affect research involving human subjects. Army Regulation 70-25 (16) applies to Army RDT&E* research involving human subjects. Army Regulation 40-38 (24) applies to the research involving human subjects in the Clinical Investigation Program. Both of those Army regulations further govern the Army's research involving human subjects. If Army research involves FDA-regulated products, the conduct of such research is also governed by Army Regulation 40-7. (25)
Institutional review boards (IRBs) are charged with protecting the rights and welfare of human subjects and to ensure that accepted ethical principles are applied in the conduct of research upon humans. The IRBs do this primarily by reviewing research plans (protocols) and serving as biomedical research ethics advisory boards. All Army research studies must be reviewed by an IRB whether the research conducted is intramural or extramural. All protocols must be reviewed prior to beginning the research. Extramural research protocols will usually be reviewed by the institution conducting the research. In the DoD, extramural research and intramural research that is greater than minimal risk must also receive a "headquarters-level" administrative review. This additional review requirement is unique to the DoD, and arises from paragraph 5.3.3. of Department of Defense Directive 3216.02. (19(pp6-7))
Laboratory commanders at the US Army Medical Research and Materiel Command (USAMRMC) have the authority, after IRB approval, to approve minimal risk research. The Commanding General (CG), USAMRMC, has the authority to approve the use of human subjects in other research studies. The Human Subjects Research Review Board (HSRRB) serves under the CG's authority. The HSRRB functions as an IRB for certain categories of research, and performs the headquarters-level review function for other research, which must first have been reviewed and approved by an IRB. The HSRRB has authority to recommend CG approval of research, and may also disapprove, or defer approval of the protocol. It may also recommend approval of the submitted protocol conditionally, requiring modifications or extra protections. In addition, the HSRRB may suspend or terminate an ongoing study. For research within the Clinical Investigation Program, the Clinical Investigation Regulatory Office (CIRO), recently relocated under the USAMRMC, provides the headquarters-level second review. For research, development, test, and evaluation (RDTE) work for which the HSRRB serves as the IRB, the Army Human Research Protections Office provides headquarters-level review.
An institution conducting research must first determine if an activity in question is "research involving human subjects" under the Common Rule, as the Common Rule and its requirement for IRB review do not apply to activities that do not meet that definition. In addition, even if a given activity is determined to be research involving human subjects, the research may be exempt from the Common Rule, and therefore exempt from IRB review. A commonly cited exemption is research involving the collection or study of existing data, documents, records, or specimens, if sources are publicly available or if the information is recorded by the investigator in such a manner that subjects cannot be identified. The determinations of applicability of the Common Rule and/or exemption of research from the Common Rule can be made by the institution in whatever manner it deems appropriate. However, if there is even a possibility that a given activity may be nonexempt research involving human subjects, it is advisable to involve the IRB or the institutional office with human subjects protection expertise in both determinations.
One of the tasks of the IRB is to determine the level of risk of the research. The risk levels are minimal risk and greater than minimal risk. The Common Rule defines minimal risk as the level of risk in which 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. An analysis of risk should include any risks unique to the study and an estimation of their severity and likelihood of occurrence. The risks presented in the protocol should be compared with risks the subject might encounter in the course of his or her daily activities. The risk level is relevant because it may affect the IRB and headquarters-level review processes; a medical monitor is not required for minimal risk research, and certain minimal risk research can be conducted with a waiver of informed consent.
In addition to reviewing the informed consent document, the IRB, CIRO, and the HSRRB will also review the entire protocol to ensure that the risks to the subjects are minimized and in proportion to the importance of the knowledge to be gained. Selection of subjects will also be reviewed to confirm that the pool of subjects is equitable. Recruitment documents and advertisements will be reviewed to ensure that the study is not misrepresented to potential volunteers. Although the IRB and headquarters-level review do not include an independent scientific review, the reviews do consider scientific merit in the risk-benefit analysis.
SPECIAL ISSUES
Women and Minorities
The FDA and the National Institutes of Health (NIH) guidance encourages diversification in clinical trials unless there is a scientific reason for excluding a certain category of human subjects. (26) The FDA has stated that subjects included in clinical studies should, in general, reflect the population that will receive the drug when it is licensed and marketed. Representatives of both genders should be included in clinical trials in numbers adequate to allow detection of clinically significant gender-related differences in drug responses. It is the policy of NIH that women and members of minority groups must be included in all NIH-funded research, unless a clear and compelling rationale and justification establishes that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. Cost is not an acceptable reason for exclusion except when the study would duplicate data from other sources. Women of childbearing potential should not be routinely excluded from participation in clinical research. (27) Similarly, inclusion of minorities in research studies is needed to obtain valid analyses of whether test variables affect members of minority groups differently. With the passage of the National Defense Authorization Act for Fiscal Year 1994, (28) the DoD adopted the essential elements of the NIH guidance. The DoD now requires the inclusion of women and minorities in DoD funded or conducted research.
Vulnerable Populations
Certain categories of study subjects, such as children, incompetents, and prisoners, constitute "vulnerable" populations for whom special protections are warranted. As a general principle, research studies should use subjects that are considered less vulnerable before recruiting more vulnerable populations for participation, unless the research is specifically intended to benefit the vulnerable population being recruited, and the vulnerable population must be involved in order for the research to be successfully conducted.
Children and Incompetents
As previously mentioned, research directed at a specific category of subjects must seek to answer a specific scientific question pertaining to that group. For instance, children would be appropriate subjects for research on infectious diseases that afflict mostly children. The DoD, through Department of Defense Directive 3216.02, (19) requires compliance with HHS regulation 45 CFR 46, Subpart D (Additional Protections for Children Involved as Subjects in Research). This regulation specifies that the minor's assent (in addition to the parent or legal representative's consent) should generally be obtained if the minor is capable of understanding the object of the research study and the procedures to be performed.
As an additional protection for minors and incompetents, DoD researchers are bound by the provisions of 10 USC §980, discussed above. This law states, in relevant part:
Funds appropriated to the Department of Defense may not be used for research involving a human being as an experimental subject unless ... in the case of research intended to be beneficial to the subject, the informed consent of the subject or a legal representative of the subject is obtained in advance. (20)
Because research involving children requires the consent of the child's legal representative, as opposed to consent of the child, who cannot legally consent, the research must intend to benefit the child. Certain research that does not intend to benefit each minor subject would be approvable under the HHS subpart D, in the absence of 10 USC §980.
The required intent to benefit of 10 USC §980 can be met if (1) the test article, drug, vaccine, or device is intended to benefit subjects who receive it; or (2) there are other intended benefits to subjects from the research, such as medical diagnostic testing, health care given during the research, psychological counseling, or nutritional analysis. There must be an intended benefit for each individual subject. It is not necessary for each subject to receive the same benefit, and it is permissible for some subjects to benefit more than others.* The IRB that is reviewing the research is the appropriate body for determining whether there is an intended benefit, and whether that intended benefit is sufficient. An intended benefit must at a minimum be a medical benefit, as differentiated from compensation that may be provided to research subjects. 10 USC §980 has made it challenging, though not impossible, to conduct certain placebo research involving children, because investigators must demonstrate that such research intends to benefit each subject, including those who receive the placebo.
Prisoners
Although there is no per se prohibition on the use of prisoners as human subjects, studies proposing to use prisoners are controversial and should be carefully reviewed. DoD has conducted some research involving prisoners, and specifically adopted Subpart C of the HHS regulations which governs research involving prisoners. However, prisoners of war will not be used as research subjects. (19(p3)) Although prisoner populations may be very attractive to researchers because of their standardized living environment and availability for long-term studies, those populations may be susceptible to coercion or unstated pressures to volunteer or continue in a research study.
Soldiers as Subjects
Soldiers may also be considered a vulnerable population because of the special command authority and restrictions on autonomy imposed by the military environment. Soldiers may have the misperception that they will receive preferential treatment, good performance reports, or other benefits if they volunteer to serve as subjects. Alternatively, they may volunteer because they fear disapproval or retaliation for failure to participate in a command sponsored study. However, participation in any study must be truly voluntary and there are no Uniform Code of Military Justice (28) or administrative actions for declining to participate in or withdrawing from a study. Recognizing the influences of the military command structure, paragraph 4.4.4. of Department of Defense Directive 3216.02, generally prohibits presence of officers and noncommissioned officers at group recruitment briefings of Soldiers under their command. Furthermore, provision for a disinterested ombudsman may be required to monitor group recruitment of service members to ensure that the voluntary nature of participation is stressed. (19(p4))
Others Who Require Special Protection
Other groups face similar pressures or misconceptions concerning participation in clinical studies supported or conducted by their organizations. For example, medical and nursing students may feel pressure to volunteer for studies conducted by their teaching hospitals. Persons with advanced terminal diseases may be more vulnerable to recruitment for riskier protocols as a "last hope." Indigents as a group also require special protection as they may have weakened physical and mental conditions, economic disadvantage, and generally, lack any family or community support in decision-making.
Medical Care
With regard to medical care for research-related injuries, the Common Rule merely requires subjects to be informed if medical care is available, and what costs may be involved. Such medical care, if available, may be billed to the subjects or subjects' insurance and need not be provided free of charge. (30) However, pursuant to paragraph 5.3.4. of Department of Defense Directive 3216.02, (19(p7)) DoD components must "protect human subjects from medical expenses (not otherwise provided or reimbursed)" that are for treatment of research-related injuries from research for which primary involvement is from the DoD.
Given the lesser requirement of the Common Rule and the inability of the federal government under fiscal law principles to commit to paying indefinite medical care costs, this provision has created some conflict with extramural research partners. It has also created some uncertainty within the DoD for components conducting intramural research involving human subjects who are not DoD health care beneficiaries.
The DoD components interpret and address this provision in different ways. For example, the USAMRMC instructs extramural partners to include, after their own Common Rule policy, language in their consent forms informing subjects of the availability of no-cost medical care at Army medical treatment facilities, in accordance with Army Regulation 70-25 (16) and paragraph 3-56 of Army Regulation 40-400, (31) and of a process to seek reimbursement (nonguaranteed) for out-of-pocket, research-related medical expenses incurred. Other DoD component mechanisms for attempting to meet this requirement include limiting enrollment to subjects who are DoD healthcare beneficiaries, and/or seeking DoD component Secretary designee status on an ad hoc or categorical basis for injured subjects who are otherwise not entitled to DoD healthcare.
COMPENSATION RELATED TO PARTICIPATION
It is permissible for research subjects to receive payments or other compensation for participating in a study. Acceptable compensation includes, but is not limited to, reimbursement for transportation costs, other minor or incidental expenses, inconvenience associated with participation, and blood draws. Unacceptable compensation would be that which seems excessive, unwarranted, or appears to be an improper reward to obtain compliance. Compensation that would normally be acceptable may become an unacceptable inducement for a particular person or vulnerable group. Individual situations and cultural considerations must be evaluated in determining whether a particular payment is an improper inducement to participation or at what point a payment might become an improper inducement.
Ability to compensate military service members for research participation has been a source of confusion. A federal law, 24 USC §30 (2002), permits compensation for blood draws, not to exceed $50 per blood draw, to be paid to "on-duty" service members (ie, when the service member is not on leave, and is participating during his or her duty hours). A service member who is participating while on-duty may only be compensated for blood draws, and may not be otherwise compensated for research participation. By permitting compensation for blood draws while on-duty, 24 USC §30 provides an exception to another federal law, the Dual Compensation Act of 1964,32 which prohibits service members from being paid by any source other than their regular military salaries while they are on duty.
"Off-duty" service members (service members on leave, or participating after his/her duty hours) may be compensated in the same manner as nonmilitary research subjects. Off-duty service members therefore may be paid more than $50 per blood draw and may be compensated for research participation generally (not only for blood draws). However, payment to off-duty service members for research participation other than blood draws must not be directly from a federal source (payment from a contractor or other nonfederal source is permissible). In addition, within the Clinical Investigation Program as regulated by Army Regulation 40-38, compensation of off-duty service members may still be limited to $50 per blood draw, with no distinction drawn between on duty and off-duty participants for the purpose of compensation. (24(p7))
Service members should get command permission to participate in research while off-duty. Participation in off-duty research may affect a service member's ability to perform his or her military duties. Principal investigators should confirm that a service member's commander supports the service member's research participation.
SPECIMEN DONATION
If blood, tissue, or body product samples will be drawn during the study, the subject should be informed as to the procedures by which the specimen will be obtained, the amount of tissue or fluid withdrawn, and its use. Withdrawal of blood, for example, should be described in lay terms such as "two teaspoons worth." If specimens will be obtained in the study for possible future use in another protocol, the informed consent document should include a statement notifying the subject of this possibility, and providing an option to permit or forbid such use. The consent document should also notify the subject that the specimen could potentially have some commercial applicability, but also include language that explicitly donates the specimen to the federal government and relinquishes all right, title, and interest in the specimen.
CONFIDENTIALITY AND RECORDKEEPING
Records pertaining to the use of volunteer subjects should include a copy of approved consent documents, a copy of the approved research protocol, minutes of the IRB review, the commander's recommendations, a summary of the research results including any adverse event reporting, and records compiled for the volunteer database. In addition, there will often be identifiable medical information related to the subject, either from a subject's existing medical records, or created by the subject's participation in research .
For intramural RDTE research involving greater than minimal risk, and some other research projects, information about research subjects is entered into a volunteer registry database. The database contains personal information about the individual such that a subject's questions about his or her participation in a particular research study can be answered. In addition, the database is necessary to ensure that the research organization can comply with its obligation to adequately warn volunteers of risks and to provide relevant new information as it becomes available. A statement must be included in the consent form for research as to which information will be entered into the database, notifying the subject that personal information will be collected, the purpose for collection, and duration of time the information will be maintained in the database. The subject must also be notified that representatives of the DoD and FDA (if research is regulated by the FDA) may inspect the records of the research in fulfilling their duty to protect human subjects.
The extent to which records will be kept confidential must also be addressed. If the subject is a Soldier, notice must be given that complete confidentiality cannot be guaranteed, as certain medical conditions must be reported to the Soldier's commander or others. Any system of records must comply with Army Regulation 340-21, (33) the Army Privacy Program, and the Privacy Act of 1974. (34)
In addition, the Health Insurance Portability and Accountability Act (35) (HIPAA) Privacy Rule regulates the use and disclosure of individually identifiable health information, and in the context of research this generally requires an "authorization" to use and/or disclose such information. The authorization can be integrated into or separate from the consent form. The DoD regulation that implements HIPAA is Department of Defense 6025.18-R. (36) Army Regulation 40-66 (37) also discusses HIPAA.
LIABILITY ISSUES
Feres Doctrine
The Feres case generally precludes successful suits by service members for personal injury or death that is incurred incident to service. (38) Medical malpractice cases are generally dismissed because medical care in military facilities is considered incident to service, even if the treatment or surgery was elective. A suit brought for personal injury or death resulting from participation in a research study would have certain similarities to a medical malpractice case and would most likely be barred if brought by a service member.
Tort Litigation
Suits arising from participation in DoD-conducted research studies would most likely be filed pursuant to The Federal Tort Claims Act (FTCA) which waives sovereign immunity to suit in certain limited cases. (39) The FTCA does not prohibit suits for injury or death resulting from the negligence of government employees in conducting the research study. However, a plaintiff would have to prove that his or her injury is the proximate result of participation in the study and that some duty had been violated. Litigation would most likely concern issues of informed consent and the adequacy of the informed consent document. Specifically, allegations might assert inadequate disclosure of risks of personal injury or death. Causes of action may also be asserted that research or commercial interest in specimens was not disclosed or that the investigator was influenced in his treatment of the subject by a conflict of interest. There might also be claims resulting from the personal injury or death itself. Although the informed consent document may generate litigation, if drafted properly the document may serve as written evidence that the subject was warned of and acknowledged the risks associated with his or her participation in the study.
Cobbs v Grant, (40) a California medical malpractice case, discussed the evolution of the negligence theory for inadequate disclosure and failure to obtain informed consent. Legal analysis in previous cases employed a battery theory instead of a negligence theory. The Cobbs court concluded that a battery theory should apply only when the procedure implemented is substantially different from the procedure consented to. The court also stated that inadequate disclosure of risks is really a question of the standard of professional conduct. The "patient's dependence upon and trust in his physician for the information upon which he relies during the decisional process raises an obligation in the physician that transcends arms-length transactions." The court held that an integral part of the physician's obligation to the patient is a duty of reasonable disclosure of the available choices with respect to proposed therapy and of the dangers inherently and potentially involved in each alternative. Recognizing the difficulty of defining "reasonable," the court went on to state that the scope of a physician's communication to the patient must be measured by the patient's need, and that need is whatever information is material to the decision. Therefore, the test for determining whether a risk must be disclosed is its materiality to the patient's decision.
The standard of disclosure was also addressed in Karp v Cooley, (41) a Texas medical malpractice case involving an experimental heart pump. The plaintiff alleged lack of informed consent because the number of animals in which the device was tested and the results of those tests were not disclosed. The plaintiff also claimed that the risk of injury by the mechanical heart and its experimental nature was never disclosed. The court stated that the standard of disclosure was what a reasonable practitioner of the same school of practice and the same or similar locality would have advised a patient under similar circumstances. The court also stated that
Physicians and surgeons have a duty to make a reasonable disclosure to a patient of risks that are incident to medical diagnosis and treatment ... True consent to what happens to one's self is the informed exercise of a choice, and that entails an opportunity to evaluate knowledgeably the options available and the risks attendant upon each.
Failure to disclose research or commercial interest in specimens or investigator conflicts of interest is another area ripe for litigation. In Moore v The Regents of the University of California et al, (42) the plaintiff s cells were extracted and used to create a cell line with potentially lucrative commercial applications. The plaintiff was never told that his cells were being extracted for any purpose other than treatment; neither was he told that there might be some economic interest associated with the use of his cells. The court stated that a reasonable person would want to know whether his physician has an economic interest that might affect the physician's professional judgment. The court held that the plaintiff was not required to prove that his cells had potential commercial value at the time they were extracted. The court also held that
...a physician who is seeking a patient's consent for a medical procedure must, in order to satisfy his fiduciary duty and to obtain the patient's informed consent, disclose personal interests unrelated to the patient's health, whether research or economic, that may affect his medical judgment.
Failure to disclose such interests would give rise to a cause of action for negligence.
CONCLUSION
Use of human subjects in research poses unique ethical questions that become more perplexing as biomedical technology increases in complexity and sophistication. The amalgam of ethical considerations, international common law, statutes and regulations protecting volunteer subjects is also becoming more complex. Scientists must seek to understand the necessity for enforcing protections for human subjects while devising new ways to solve scientific conundrums. Ethicists must endeavor to understand the importance of research in advancing knowledge. Regulators must be conscious of the shared objectives and competing concerns of both groups. A balancing of all interests must continue for successful development of new therapeutic drugs, devices and preventative vaccines for the benefit of all.
References
(1.) Annas GJ. The Rights of Patients: The Basic ACLU Guide to Patient Rights. 2nd ed. Carbondale, IL: Southern Illinois University Press; 1989.
(2.) 21 CFR 50.3(c) (2009).
(3.) Federal Food, Drug, and Cosmetic Act, 21 USC §355 (d) (2009).
(4.) Human Subject Institutional Review Board Guidebook. Office for Human Research Protections. Washington, DC: Dept of Health and Human Services; 1993: chap 2. Available at www.hhs.gov/ohrp/ irb/irb_guidebook.htm. Accessed December 1, 2009.
(5.) 45 CFR 46.116, Subpart A (2008).
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(13.) Executive Order 12975 of October 3, 1995: Protection of Human Research Subjects and Creation of National Bioethics Advisory Commission. 60 Federal Register 52063 (1995). Available at: http:// frwebgate6.access.gpo.gov/cgi-bin/PDFgate.cgi? WAISdocID=946206431230+1+2+0&WAISaction=r etrieve Accessed December 4, 2009.
(14.) Executive Order 13237 of November 28, 2001: Creation of the President's Council on Bioethics. 66 Federal Register 59851 (2001). Available at: http:// frwebgate.access.gpo.gov/cgi-bin/getdoc.cgi? dbname=2001_register&docid=fr30no01-151.pdf. Accessed December 4, 2009.
(15.) 32 CFR 219.117 (2009).
(16.) Army Regulation 70-25: Use of Volunteers as Subjects of Research. Washington, DC: US Dept of the Army; January 25, 1990.
(17.) 32 CFR §219.116 (2009).
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(19.) Department of Defense Directive 3216.02: Protection of Human Subjects and Adherence to Ethical Standards in DoD-Supported Research. Washington, DC: US Dept of the Army; March 25, 2002.
(20.) 10 USC §980 (2004), Limitation on the Use of Humans as Experimental Subjects. Available at: http://frwebgate.access.gpo.gov/cgi-bin/getdoc.cgi? dbname=browse_usc&docid=Cite:+10USC980. Accessed December 7, 2009.
(21.) Pub L No.107-107, 115 Stat 1012 Sec 733 (2001). Available at: http://frwebgate.access.gpo.gov/cgi-bin/ getdoc.cgi?dbname=107_cong_public_laws&docid =f:publ107.107.pdf. Accessed December 7, 2009.
(22.) 21 CFR §50.24 (2009), Exception from Informed Consent Requirements for Emergency Research. Available at: http://www.accessdata.fda.gov/scripts/ cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFR Part=50&showFR=1. Accessed December 3, 2009.
(23.) Waiver of Informed Consent Requirements in Certain Emergency Research, 61 Federal Register 5153151533 (1996) (codified at 45 CFR Part 46).
(24.) Army Regulation 40-38: Clinical Investigation Program. Washington, DC: US Dept of the Army; September 1, 1998.
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(26.) NIH Revitalization Act of 1993, 42 USC §289 (1993). Available at: http://grants.nih.gov/grants/ olaw/pl103-43.pdf. Accessed December 1, 2009.
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(28.) Defense Authorization Act for Fiscal Year 1994, Pub L No. 103-106, 107 Stat 1578 (1993).
(29.) 64 Stat. 109, 10 USC, chap 47.
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(32.) Dual Compensation Act of 1964, 5 USC §3501-3504.
(33.) Army Regulation 340-21: The Army Privacy Program. Washington, DC: US Dept of the Army; July 5, 1985.
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(36.) DoD 6025.18-R: DoD Health Information Privacy Regulation. Washington, DC: US Dept of Defense; January 24, 2003.
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(38.) Feres v United States, 340 US 135 (1950).
(39.) The Federal Tort Claims Act, 28 USC §2671 (2006).
(40.) Cobbs v Grant, 8 Cal 3d 229 (1972).
(41.) Karp v Cooley, 493 F 2d 408 (1974).
(42.) Moore v. The Regents of the University of California et al, 51 Cal 3d 120 (1990).
* Research, development, test and evaluation
* Memorandum from MAJ Dale Woodling, Office of The Judge Advocate General, US Army, dated September 1, 1998. Available at the Office of the Staff Judge Advocate, US Army Medical Research and Materiel Command, Fort Detrick, MD.
Mr Maleson is an Attorney Advisor with the Office of the Staff Judge Advocate, US Army Medical Research and Materiel Command, Fort Detrick, Maryland.
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| Author: | Maleson, Stephen |
|---|---|
| Publication: | U.S. Army Medical Department Journal |
| Geographic Code: | 1USA |
| Date: | Jan 1, 2010 |
| Words: | 7611 |
| Previous Article: | Medical futility. |
| Next Article: | The Medical Affirmative Claims program. |
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