The Participant-Investigator Interface
Before further considering the oversight mechanisms that would best protect research participants, it is useful to step back to the initiation of a research study and consider the relevant roles, responsibilities, and interactions of the primary parties: the investigator, who asks a scientific question, and the willing individual, who consents to help the investigator answer the question. Both parties have preconceived expectations of what this relationship will be like and how the exchange between them will proceed. For a productive partnership to occur, i.e., one that results in answering the research question, it is important for both the investigator and the participant to understand and fulfill their respective responsibilities.
This chapter discusses how protections should be incorporated into research from the moment a research question is conceived to the point that individuals are recruited and provide their informed, voluntary consent to proceed. A qualified, properly trained investigator and an informed participant together provide the best opportunity for maximizing participant protections, as the most elaborate protection system imaginable will not work if the investigator does not carry out his or her ethical duties and the research participant does not knowingly and willingly agree to participate.
Efforts to ensure participant protection should begin with the preparations of investigators. After a research question has been posed and a protocol developed and reviewed, the investigator should seek individuals who are willing to participate in the research, a process that hinges on
obtaining the potential participant’s informed consent to enroll in a study. The committee believes that there is a need to improve and standardize the approach to the informed consent process, which underpins the relationship between researcher and participant. Because many groups are currently reviewing various aspects of informed consent and because its complexity requires far more scrutiny than this committee can undertake, the topic is addressed only briefly in this report, as a central element of protection that should be conducted properly and scrutinized by the protection program. An appropriate informed consent process is an exchange between the researcher and the potential participant that is structured appropriately for the research design, the protocol risks, and the participant community in which the study is carried out.
Finally, the roles and responsibilities of research participants are addressed, as well as the need to include the participant perspective within the protection program and to provide basic educational material to potential participants on the general nature of research and the protection program itself.
PREPARATION OF THE INVESTIGATOR AND PROTOCOL DESIGN
The federal regulations do not speak specifically to the knowledge and expertise of the investigator, although they do require that the “IRB shall be able to ascertain the acceptability of proposed research in terms of institutional commitments and regulations, applicable law, and standards of professional conduct and practice.”1 In addition, the necessary qualifications and professional obligations of clinical investigators are defined within the Guideline for Good Clinical Practice developed by the International Conference on Harmonisation (1996, Section 4). The committee suggests that there are common responsibilities incumbent to any investigator who engages participants in research studies, regardless of the scientific discipline or methodology (see Box 4.1).
Regardless of the expertise of the investigator, a poorly designed human research protocol is unethical. If the data cannot be validated or replicated, research participants have been exposed to risk or have volunteered their time for no useful purpose. Thus, research that requires enrolling participants should be conducted only by properly trained individuals.
The question posed by the research protocol should be of sufficient scientific importance to justify the use of human participants and valuable
From the time informed consent is provided until a study is completed, the research investigator plays a pivotal role in assuring participant safety. In some cases, the investigator will have posed the initial research question and will therefore be responsible for the overall research design. In other situations, the investigator may have received a completed research protocol from a sponsor or another investigator. In either case, the investigator is responsible for ensuring that the protocol is properly conducted. The investigator’s responsibilities include the following:
social resources.2 As discussed in Chapter 3, the merit of the scientific question should be established by peer review, or an equivalently rigorous mechanism before comprehensive ethical analysis by the Research Ethics Review Board (Research ERB).3 Issues to consider include whether the
answer to the scientific question will advance knowledge and contribute to the general good, whether the necessary literature searches and background studies have been done, and whether the safety of participants is clearly being considered by the investigator. In a well-designed study, the objectives are defined, the methodology is sound, and the statistical approaches are appropriate to analyze the data and obtain results. The key to ethical protocol design is choosing an approach that addresses the scientific question being asked, the intervention being tested, and the group of participants involved, while at the same time minimizing the risks to the participants. In addition, the final data analysis should provide results that are valid, replicable, and not explained by chance (Saunders et al., 2001).
In designing a protocol, especially a clinical experiment, there should be true uncertainty in the medical community about the value of a particular intervention, a state called “equipoise” (Day and Altman, 2000; Freedman, 1987; Lilford and Jackson, 1995). Equipoise has been defined as the point at which a rational, informed person would express no preference between two (or more) available treatments (Lilford and Jackson, 1995). The results of any trial should be free of bias, which can be caused by flaws in the study design. In clinical trials, bias refers to the tendency of any aspect of the methodology or the interpretation of data to lead to conclusions about the effects of an intervention that are systematically different from the truth, but bias can occur in any type of human research endeavor (FDA, 2001b). Ensuring that the chosen study design avoids bias and generates relevant data is an integral characteristic of clinical research, with a growing literature accumulating to address this point (Gallin, 2002; Meinert and Tonascia, 1986; Sackett, 1983; Spilker, 1991).
If the proposed study will utilize control groups, additional ethical considerations arise, many of which are critically important from the perspective of the participant. Control groups permit investigators to determine whether an observed effect is caused by the experimental intervention being tested or by other factors, such as the natural progression of the disease, observer or participant expectations, differences in the baseline condition of participants, or other treatments or effects (FDA, 2001b). Observing an appropriately selected control group allows the investigator to ascertain what would have happened to study participants had they not received the test intervention or, in clinical situations, what would have happened had they received a different treatment that is known to be effective (FDA, 2001b). In recent years, use of placebo-controls has been
controversial (Weijer et al., 2002). Although the placebo-controlled, randomized, double-blind clinical trial is an authoritative and widely accepted standard for new drug evaluation, some have argued that it is not always ethical to use placebos when a better alternative drug is already available (Freedman et al., 1996). In situations in which the best scientific design is not ethically acceptable, it may be necessary to reconsider the primary research question and to choose one for which an ethically acceptable design can be proposed, or it may be necessary to accept the fact that ethical constraints can create limitations to obtaining scientific knowledge (Levine, 1998; NBAC, 1998; NBAC, 2001a).
Another important design issue with ethical implications is the selection of the population to be studied. For example, in the early phases of drug development, research participants are selected from a small subgroup of the patient population in which the drug eventually may be used (CPMP, 1995). This is done to maximize the opportunity to observe specific clinical effects. By the time the experimental intervention enters Phase 3 trials, the characteristics of enrolled participants should more closely mirror those of the intended users.
Determining sample size is another important component of protocol design and planning. Although many methods and statistical models have been developed to calculate appropriate sample size, the number of participants in a study always should be large enough (but no larger than necessary) to provide a reliable answer to the question(s) posed.
The diverse origins of research proposals influence how their designs emerge and how the protection of research participants is ensured. Clinical studies by industry are undertaken to evaluate one of their products and develop it for Food and Drug Administration (FDA) approval. Large pharmaceutical companies and contract research organizations usually have clinical departments with professional staff who design protocols in association with biostatisticians. Only after the research design, inclusion and exclusion criteria, outcome measurements, statistical powering, monitoring plan, and all other details are determined and approved by FDA and a Research ERB can the recruitment of the first subject begin. The sponsor (the holder of the investigational new drug exemption) is responsible for selecting only investigators qualified by “training and experience” to carry out the project.4
Thus, in order to protect potential research participants, any proposed investigator should, through his or her training, professional commitment, and moral judgment, be able to review what has been done prior to his or her involvement and either accept it, urge modification, or decide he or she cannot be part of it. Faculty members in academic health centers or private physicians may be asked to undertake research initiated in this way.
In contrast, the typical project initiated by an academician is more often motivated primarily by a scientific question rather than by drug development. For biomedical studies, a drug may be involved, but more likely as a probe or perturbation to the system than as an element of proving efficacy and market potential. The investigator in this case is likely to be seeking support from the National Institutes of Health (NIH) or a foundation (or drug company), but the study will not have the elaborate developmental and group participation described for industry. Similarly, NIH will not be monitoring each step of preparation, but will first be involved when a grant application is submitted. The individual investigator is therefore responsible for arranging the same features of research design referred to above and for considering the elements of participant protection.
It should be clear that the investigator working on his or her own to develop a human research protocol needs extensive education and preparation for that role. This is the subject of further discussion below.
Research Ethics Education Goals
The different perspectives between investigators from distinct fields are less important than their commonalities. Anyone studying human beings requires mentoring that is grounded in the science of the discipline, the integrity of research, and the ethics of human investigation. For this reason, the committee believes that formal education, for which numerous programs are now available, with a measured learning achievement should be required of all investigators. The committee does not endorse any single approach, but believes that the research organization should establish standards by which investigators’ initial preparedness, their continuing education, and their adherence to institutional policies and procedures can be assessed. However, it is critical that federal agencies require such education as a basic precondition for carrying out research (Box 4.2) and encourage others research sponsors to do the same.
Educational opportunities within a research organization may include attending seminars, workshops, or Internet-based training. These programs should offer continuing education credits and, when appropriate, a certificate of completion. Topics can be derived from a variety of sources,
National Institutes of Health: In 2000, NIH initiated the requirement that investigators submitting grant applications or contract proposals must complete an educational program on the protection of research participants (NIH, 2000b). The NIH statement stressed the responsibility of institutions to ensure that their clinical investigators and Institutional Review Board (IRB) members receive adequate education and training.
Food and Drug Administration: FDA requires that sponsors select investigators who have appropriate education and training to oversee the conduct of a clinical trial, and the investigator, by signing Form FDA 1572, commits to ensure the sound and ethical conduct of research, including compliance by his or her institutional IRB and research staff [21 CFR 312.53(a)].
Department of Veterans Affairs (VA): Since 2001, the VA has required that all principal investigators, co-principal investigators, and co-investigators submitting research proposals to an IRB and Research and Development Committee provide documentation of participation in an educational program, which must be renewed every three years (Feussner, 2001).
Office of Research Integrity (ORI): ORI has embarked on a similar education requirement for personnel receiving federal funds to do research (DHHS, 2000a). However, the policy is now under the President’s regulatory review plan that suspends implementation of this policy pending additional review. A final ruling on this policy will affect the educational requirements of ORI for clinical investigators (IOM and NRC, 2002).
The International Conference on Harmonisation (ICH): ICH addresses the need for investigator education as a part of Good Clinical Practice in its E6 Guideline. Principle 2.8 states, “Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his or her respective task(s)”; educational requirements also are listed under the investigator guidelines (ICH, 1996).
including faculty, literature searches, professional organizations, consumer groups, and the IRB Forum (formerly mcwirb).5
Additional possibilities include providing support for off-site programs, annual meetings, and tuition reimbursement. A formal mentoring
The IRB Forum is designed to provide a platform for conversations among IRB professionals, via e-mail, about ethical, regulatory, and policy issues involved in research with human participants. Although the forum is not directed at investigators per se, issues commonly arise that would be useful to investigators. The Web site for the group is www.irbforum.org.
program for both young investigators and junior staff also should be considered.
A number of colleges and universities are now offering both undergraduate and graduate degree programs in clinical investigation and research methodology.6 Although most are open to anyone interested in pursuing advanced studies in clinical research, a few programs focus specifically on faculty at academic institutions interested in pursuing a career in clinical research.
Assessing the Knowledge and Competency of Individuals
In order to assess the knowledge base and competency of personnel, research organizations could encourage participation in certification programs and institute a basic core competency program within the institution for all currently employed and newly hired investigators and staff who are directly involved with the conduct of human research. Several institutions (such as NIH, Emory University, and the University of Rochester) currently require that investigators and “key personnel” complete a program of instruction and, at some sites, pass a written test that documents basic competency to conduct a research study. These institutions should be encouraged to collect and share data on their educational program interventions. In addition, adherence to institutional policies and federal laws and regulations governing human research and research integrity should be part of each faculty, staff, and student’s annual performance evaluation. Sanctions for nonadherence and unethical behavior should be unequivocal and effective. Acknowledgment or incentives for consistent performance and exceptional ethical conduct and leadership may also be useful to stimulate the appropriate research culture.
An individual’s knowledge and observance of regulations and ethical considerations should be measurable and sustained. Although the committee strongly encourages, at a minimum, the pursuit of formal education by investigators, all Research ERB members, and administrators (see Chapter 2), content understanding should be documented for those who are required to complete education programs. Updated documentation of the understanding of current policies and practices should be obtained periodi-
Albert Einstein College offers a two-year clinical research training program, resulting in a master of science (MS) degree (www.aecom.yu.edu/crtp/); Northwestern University Graduate School offers an interdisciplinary MS degree in clinical investigation (www.northwestern.edu/graduate/academic/clin-investms.html); and the George Washington School of Medicine and Health Sciences offers an MS in Clinical Research Administration (learn.gwumc.edu/hscidist/DE/Program_DE_cra.htm).
cally, perhaps every three years. In order to be effective, rewards and sanctions should be concrete and consistent, and educational and behavioral endeavors promoting the safety of human research should be closely linked to the institution’s program promoting research integrity.
As a measure to demonstrate competence in the design and conduct of ethically sound research, the National Bioethics Advisory Commission (NBAC) recommends that all investigators, Institutional Review Board (IRB) members, and IRB staff should be certified prior to conducting or reviewing research involving humans. Certification requirements should be appropriate to research roles and to the area of study. The federal government should encourage organizations, sponsors, and institutions to develop certification programs and mechanisms to evaluate their effectiveness. Federal policy should set standards for determining whether institutions and sponsors have an effective process of certification in place (NBAC, 2001b, p.48-49). The committee concurs that it is the responsibility of the research organization to establish the level of initial and continuing instruction appropriate for individuals with different responsibilities.
This committee’s previous report, Preserving Public Trust: Accreditation and Human Research Participant Protection Programs, addressed the utility and potential value of an accreditation program for Human Research Participant Protection Programs (IOM, 2001a). Similar arguments regarding a move toward quality improvement (QI) and stimulating attention to weaknesses can be made for the certification of individual investigators. Certification would increase the likelihood that program principles would be followed by
systematizing the body of knowledge that any investigator would be expected to have,
providing an external mechanism to attest to the investigator’s knowledge and understanding,
stimulating periodic re-review and updates by investigators seeking recertification,
reassuring stakeholders and potential participants that research is conducted appropriately, and
recognizing the skilled research practitioner and screening out the unprepared investigator.
Investigators would be more likely to seek certification if offered an incentive, such as an increased likelihood of qualifying as a study site in multisite studies, or a disincentive, such as exclusion from federally funded or regulated investigations. The committee believes that certification of investigators is a promising approach that deserves immediate and careful
study and deliberation at the national level by the research community, federal policy makers, and professional associations before implementation in a formal or mandatory manner.
Relevant Potential Conflicts of Interest
As an investigator conceives research questions and designs a study to answer those questions, there are multiple points at which unintentional self-interest may bias his or her decision making. The consideration of potential conflicts of interest at this very early stage in the research process is important, as early decisions may significantly affect participant protections provided down the road.
Formulating the research question, for example, may seem to be straightforward if the main considerations are perceived to be only scientific in nature. However, the importance of the research question should demonstrate sufficient possibility of adding to the fund of useful knowledge in order to consider involving volunteers. Merely adding to a company portfolio or to the publications on an investigator’s curriculum vitae, for example, are not useful expenditures of human capital, let alone sufficient reasons to subject research participants to the risks inherent in any research protocol (including instances in which no physical or psychological harm would result). The issue in these cases is a simple balance between the participant’s interests and those of the investigator or institution.
Personal biases and conflicts also can emerge during protocol development. For example, the addition of a placebo arm in a drug study may enable the investigator to use fewer participants, and thus obtain results (and a publication) more quickly than a comparison with an existing drug. However, such a design may or may not be in the best interests of participants, and participants’ rights should trump scientific considerations.7
Conflicts of interest could also lead an investigator to seek out a population simply because it is easy to reach or to seek out individuals because they consciously or subconsciously feel pressure to volunteer. An example is the recruitment of employees, students, or trainees who are in any way associated with the investigator. Rigorous scientific review and appropriate training in the ethics of research with humans can often prevent or identify trouble spots before damage is done. Furthermore, strong organizational leadership and the promotion of a culture based upon ethical norms (as
discussed in Chapter 2), possibly complemented by appropriate accreditation standards, could help to avoid or manage such conflicts.
For this reason, disclosure is the cornerstone of financial conflict of interest guidelines and regulations (AAMC, 2001; AAU, 2001; DHHS, 2001a; NBAC, 2001b; NHRPAC, 2001; 42 CFR 50, subpart F; 21 CFR54). Investigators should understand their obligation to disclose potential financial conflicts of interest to the institution, as required by federal regulations.8 The Public Health Service and National Science Foundation require that investigators disclose payments of $10,000 or more and more than 5 percent ownership in any single entity, while FDA requires investigators to report, among other things, payments of $25,000 beyond the cost of research and equity interests valued at more than $50,000 in sponsor companies. Research organizations, and particularly Research ERBs, should be apprised of the potential conflicts of interest of researchers, their staff, spouses, and dependents, before research is approved. As discussed in Chapter 3, conflicts relevant to research with human participants should be communicated to the Research ERB as a component of the protocol review.
At the conclusion of a research study, investigators should have sufficient control of data and publication to ensure that objective information is shared with the public (Blumenthal, 2001; Bodenheimer, 2001; Davidoff et al., 2001;Yamada, 2001). Sponsor input that limits investigator control over research design and data can create a serious conflict that can be precluded by the institution’s role in the approval of contractual agreements.
Payments to the investigator conditioned on particular research results should not be allowed, and payments to investigators for participant enrollment should be allowed only under limited circumstances, according to the American Association of Medical Colleges (2001). Likewise, the American Medical Association states in its ethical code that “offering or accepting payment for referring patients to research studies (finder’s fees) is unethical” (Council on Ethical and Judicial Affairs, AMA, 2000). Some associations, advisory groups, and government agencies have further declared that investigators and staff responsible for the informed consent process, patient selection, monitoring, management, or data analysis should have no financial stake in a trial (ASGT, 2000; DHHS, 2001a; NHRPAC, 2001). This committee agrees that finder’s fees constitute a serious conflict of interest and should not be allowed for anyone directly responsible for enrolling participants and that individuals who have been identified as having a conflict of interest should not be allowed to carry out functions that could be compromised by their conflicting interest. Further consideration is given in Chapter 6 to financial conflict of interest issues.
THE INFORMED CONSENT PROCESS
Once a protocol has been developed, reviewed, and approved for scientific and ethical acceptability, the investigator must recruit individuals to participate in the research. The voluntary informed consent of the individual is a central element of participant protection. In addition, the informed consent process is a critical means by which investigators can establish the trust and confidence of participants. As such, informed consent can influence and shape long-term relationships with the study population and the general public (Getz and Borfitz, 2002).9
Since the publication of The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research (Belmont Report) and the report on IRBs by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research in 1978, informed consent and IRB review have served as the primary procedural safeguards in human research in the United States (National Commission, 1978, 1979). The centrality of informed consent to the research process was reiterated in a 1982 report by the subsequent President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research, which identified informed consent as an “ethical imperative” to distinguish it from and raise it above the de minimus nature of law or regulation (1982b, p.2).
The continued importance of informed consent as a moral imperative is reflected in the attention it has received as a subject of research on the effectiveness of human research safeguards. A vast literature on informed consent has emerged in recent decades (Erb and Sugarman, 2000; Sugarman et al., 1999, 2001). Indeed, informed consent has been an ongoing subject of investigation by federal advisory committees (the Advisory Committee on Human Radiation Experiments, NBAC, the National Human Research Protections Advisory Committee), bioethics centers, and individual scholars (Faden and Beauchamp, 1986; Moreno et al., 1998; Sugarman, et al., 1999).
However, the safeguards necessary to protect informed consent have been undermined in recent years by several factors, including the advancing complexity of science, threats to privacy, the conflation of institutional risk management with disclosure in consent forms (see Chapter 3), conflicts of interest, the inadequate time available for in-depth consideration of protocols by many IRBs, and the lack of investigators and reviewers sufficiently
trained in biomedical, behavioral, and public health ethics. Other parts of this report discuss the role of the program in promoting informed consent by participants (Chapters 3). This section addresses the process of assuring informed participation at the level of interactions between the investigator and the participant.10
The Concept of Informed Consent
The meaning of the phrase “informed consent” has become distorted over the last two decades as concerns of institutional risk managers have overwhelmed the patient-centered spirit of the Common Rule. In the committee’s view, the intent of this analysis is to recover the original concept of informed consent by disentangling the strands of meaning now woven together under that label, identify and preserve those parts of the current practice needed to empower participants, and rejuvenate and nurture a participant-centered process.
Recommendation 4.1: The informed consent process should be an on-going, interactive dialogue between research staff and research participants involving the disclosure and exchange of relevant information, discussion of that information, and assessment of the individual’s understanding of the discussion.
The ethical ideal of informed consent, grounded in the philosophical concept of autonomy, represents a departure from the paternalistic traditions of medicine revealed in the Hippocratic text, in which physicians were told to direct their commitment to the health and well-being of their patients, but were not instructed to foster their independence of thought or individual choice. In the Hippocratic text, physicians are exhorted to keep patients from “harm and injustice”...not to give a “deadly drug”... and to “come for the benefit of the sick” (Temkin and Temkin, 1967).
In the late 1950s and the 1960s, however, judges began to propose in court opinions that one of the duties of the physician was to share sufficient information or “reasonable disclosure” with the patient so that the patient could choose among available medical options.11 In addition to the idea of
professional duty was the developing legal concept of self-determination. In Schloendorff v. Society of New York Hospital (1914), Judge Cardozo stated that “Every human being of adult years and sound mind shall have the right to determine what shall be done with his own body....” This idea of liberty or self-determination evolved to include decisions about choices in medicine.
Concurrent with the legal development of these concepts, the higher profile of medical ethical analysis and the various rights movements, including the patient rights discussions, led to an ongoing discussion in medicine about the doctor-patient relationship. The result of that discussion, in the context of the legal opinions and scholarship, was the general agreement that paternalism was no longer appropriate as the guiding philosophy of medicine and physician practice. The physician was exhorted to discuss, deliberate, and share with the patient so that this relationship could provide the basis for individually appropriate patient choice.
Finally, in the specific context of research, the iterative set of federal regulations and the related multinational documents made clear that the informed and voluntary consent of the capable research participant was the norm for legally and ethically valid informed consent. Unfortunately, however, this ideal has been trampled by the research power structure and the realities of self-protective behavior often demonstrated by sponsors and research organizations.
The idea of the process of informed consent as one that provides for sharing information with and educating the research participant has fallen prey to the idea of informed consent as a document to be signed by the participant, constructed by the research sponsor or site to comply with the regulations. In medical treatment and clinical research, these documents typically include lengthy descriptions of diagnoses, prognoses, treatment alternatives, risks and benefits of the alternative treatments, the risk of no treatment, the right to refuse, the commitment to provide care even in the face of refusal, and the injury compensation policy of the sponsoring institution. The purpose of the document appears to be compliance with regulations, but the spirit of the document is clearly the articulation of every possible danger so that any subsequent participant complaint can be countered with the argument that the participant had been informed and had accepted this risk. The length, complexity, linguistic sophistication, and generally daunting nature of such documents are not conducive to increasing understanding, but rather serve to overwhelm the patient-participant.
Informed consent should never be focused merely on a written form, which constitutes only a fragment of the process. A structured conversation between the participant and a member of the research team should occur when it is required by the nature of the research, as it usually is in research involving significant risks (Box 4.3). From a purely ethical standpoint, the purpose of the written form is to document and record that the ethically
Items that should be discussed with participants face-to-face:
Items that should be described in a consent form and that participants should have an opportunity to review before agreeing to participate in the study:
relevant information has been discussed. However, whatever role it may play in relation to potential legal liability, a signed form is not sufficient evidence of an ethically valid informed consent.
Informed Consent as an Ongoing Process
Emerging data show that informed consent is most effective as an evolving process, as opposed to a static, one-time disclosure event and/or signing of a consent form. Jeremy Sugarman, an expert on informed consent and the ethics of research involving humans, advised the committee during his testimony that informed consent should be considered an inherent component of the research process itself (not an adjunct exercise) in the
form of an ongoing conversation that occurs at each research encounter or before each intervention (2001). Ideally, the disclosure of information during the informed consent process takes place as a bilateral process involving an exchange of questions and answers between a research participant and a research investigator. This interplay is an important and potentially challenging process, as it requires the person obtaining consent to gauge the appropriate level of language and technical detail suitable for the participant’s understanding (Atkinson, 2000; Coulter, 1999).
Conceptually, informed consent should be construed as an evolving decision making process, rather than as simple “permission.” This model of “ongoing conversation and decision making” allows for reinforcement of previously disclosed information, introduction of new information, and respect for autonomous participant decision making. The act of obtaining written consent is tangential to the process of informed consent and merely provides a mechanism to document and record that ethically relevant communication has taken place.
Particularly in instances of clinical research, investigators face many difficulties in communicating to potential participants the complex set of procedures, side effects, long-term risks, trade-offs relative to alternatives, and other information relevant to study participation. This task is not impossible, however. The challenge is to spend the necessary time and resources to prepare the appropriate language and ensure that communication truly occurs.
Role of Consent Forms
In current practice, so-called informed consent forms are best characterized as consent forms (see Recommendation 3.4). Additional documents (or appendixes to the basic consent form) that contain the boilerplate language directed at the legal protection of the institution rather than informing participants represent disclosure documents. These documents make little contribution to the process of communication and mutual understanding that is central to obtaining ethically valid informed consent. In contrast, the term “informed consent” should refer to the interactive process of education, discussion, and support that permits the potential participant to understand the options and apply a personal scale of values and preferences to those options in order to reach a decision about enrolling in a study.
The present convention, adhered to by investigators and followed by IRBs, is to review the consent form as the mechanism used to obtain informed consent, which is not sufficient as a process of involving and empowering the participant and promoting participant understanding. In the future, it should be up to the research organization’s attorneys to decide whether the consent form and the disclosure documents are legally ad-
equate; that is not the job of the Research ERB (see Chapter 6). Instead, the Research ERB should be expected to review the consent form to determine if it meets the federal standard and to decide whether a shorter, more accessible document might be used as a blueprint for the ensuing conversation with potential participants and as an aid to promoting understanding and choice. If a shorter form were offered, it might be useful to refer the participant to the sections in the full consent form that elaborate on the items in the short form. This would permit the participant to grasp the major procedures and their attendant risks, benefits, and alternatives and then explore them in greater depth. This process would facilitate understanding rather than impede comprehension, which, unfortunately, is often the result of the present use of lengthy consent forms.
Accomplishing the goal of real understanding as a precondition to a meaningful decision to participate will require a sea change in Research ERB and investigator perception and practice. Based on anecdotes and committee member experience, some investigator-participant exchanges are limited to answering questions such as, “What do you think I should do?” Such impoverished interactions utterly fail to link the skill and wisdom of the practitioner with the questions and concerns of the participant.
Disclosure of the nature of the study and its procedures, risks, benefits, and alternatives is a central pillar of the informed consent process. However, although it is necessary, it is not sufficient to support a process with real integrity. Disclosure information, presented comprehensively without overwhelming detail, is a pivotal aspect of the informed consent discussion, as without it potential participants will not have an adequate basis for decision making. Therefore, the committee encourages the development of innovative mechanisms (including written, electronic, or video instruments) to genuinely inform participants and promote understanding as well as record the interaction between the research staff and the potential participant.
In addition to this knowledge, the research professional’s experience, perspectives, opinions, and recommendations are essential. Indeed, it might be more appropriate to label the process “advised consent” rather than “informed consent.” This change would accommodate the interactive and supportive nature of the ideal process that assumes that information is the starting point of a discussion that alternates between participant questions and investigator responses and that helps participants understand the abstractions of benefit and risk in the context of a specific research situation and his or her personal needs and medical history.
An ideal informed consent process might use a brief document to present the basic material first and then offer the potential participant the opportunity to pose additional questions, as well as sufficient time to consider a more comprehensive document that may also be provided. It should
always be stated in the case of nontherapeutic research that the project is research and not therapy. Appropriate help should be available to assist the participant in assuring that he or she understands the relevant issues and receives answers to all questions. In addition, special attention to the informed consent process should be provided for participants with language barriers, diminished capacity, and known vulnerabilities—both to facilitate informed consent and to avoid denying special groups access to human studies.
The Therapeutic Misconception
As mentioned in Chapter 3, in clinical research, informed consent often does not produce an appropriate understanding of the nature of research in participants because of the pervasiveness of the “therapeutic misconception” (Appelbaum et al., 1982; Churchill et al., 1998; King, 1995). The therapeutic misconception refers to the misunderstanding of the differences between research and therapy or treatment; that is, many think they are receiving treatment designed by a physician with their best interests in mind, when in fact the treatment they receive is driven by the demands of a research protocol.
Despite the provision of meaningful disclosures, participants who are ill are often motivated to participate in research by their hope for a therapeutic benefit and their belief that this is why they have been offered participation. At least one study has found that it is no accident that patients hold this belief, because their physicians also have somewhat unrealistic expectations of the therapeutic benefits their patients may receive during research (Daugherty et al., 1995). That study also found that 85 percent of patients decided to participate in a Phase 1 trial for a cancer drug exclusively for reasons of possible therapeutic benefit; the other 15 percent enrolled on grounds of either physician or family advice. None enrolled primarily for altruistic reasons, although 6 percent mentioned some altruistic reason as a secondary consideration (Daugherty et al., 1995).
It can be difficult for patients who are seriously ill or injured and thus who regard the investigational product itself as a potential lifesaving therapy to separate research considerations from possible therapeutic benefit. And, in some cases, access to an experimental protocol might, in fact, provide access to high-quality care that otherwise would likely not be available (Wayne, 2001). Participation in a clinical trial might be the only way that some individuals, particularly minorities, disadvantaged populations, and those with rare disorders can gain access to medical care (Gifford et al., 2002). Whether this situation is unduly manipulative is uncertain, but it is true that those who are seriously ill often see the investigational process as their only hope for therapy, even though an investigational product is not
itself a therapy, and commonly other options exist (Daugherty et al, 1995). The availability of other options, however, is meaningless to a potential participant who believes that the investigational therapy he or she is considering may be considered by at least some experts to be a plausible therapy and therefore a reasonable option.
Considering these complexities, investigators should not abrogate their responsibility to ensure that participants are voluntarily participating in research and that they understand the uncertainty of the potential benefits. Although investigators often face a dilemma when participation in a trial provides otherwise unavailable health care services to individuals, particularly in cases in which the risks are minimal, he or she should remember that the persistence of the therapeutic misconception fundamentally undermines the achievement of meaningful informed consent.
The Need for Research on Informed Consent
A great deal of research has been conducted on the nature and adequacy of various consent procedures in the research and clinical contexts (Sugarman et al., 1999). Some research that has focused on the value of various educational approaches and materials (brochures, videotapes, information sheets) finds that the use of such materials enhances comprehension (Agre et al., 1994; Benson et al., 1988; Fureman et al., 1997). However, several reviews have been conducted regarding the readability of consent forms that have found in general that reading levels are too high to achieve broad comprehension (Briguglio et al., 1995; Grossman et al., 1994; Hochhauser, 1997). Other studies have focused on the ability of individuals to comprehend and remember complex probabilistic information and the effects of health status on comprehension and retention of information. In general, research has shown that in clinical research, both patients and providers place little weight on the value of informed consent (Lidz et al., 1983). Most see it as either a legal document or as a “contract” that is signed once information has been exchanged. And in one study, Getz and Borfitz noted that one out of seven participants reported that they did not even read the consent form before giving their consent (2002). This phenomenon once again highlights the need to distinguish the informed consent process from the consent form and for investigators to take an active role in ensuring that consent is voluntary and informed.
The need for further research and evaluation of the informed consent process became abundantly clear from the committee’s investigation of the literature and from the testimony of experts and research participants. Such research should be funded by federal agencies as well as private research organizations, and institutionally based QI programs should include the
local effectiveness of informed consent processes as part of a comprehensive and iterative evaluation of protection programs (see Chapter 6).
The solicitation of informed consent would be strengthened by the measures urged in this report, including the establishment of an ethically based protection program; the education and certification of all senior personnel involved in studies; the settlement of institutions’ legal concerns in a process distinct from human studies’ approval; the evaluation, disclosure, and management of individual and institutional conflicts of interest; the requirement for in-depth scientific review before Research ERB consideration of human studies issues; and an increase in unaffiliated membership on review boards. However, the central feature of ensuring that the informed consent process occurs and is effective lies in the commitment to this effort of the investigator and every member of the research team.
Heeding the Collective Rights and Interests of Participant Communities
The concept of “community” in the context of research has been discussed for some time and became part of official federal policy when FDA and NIH published new rules for the waiver of consent in emergency research (FDA, 1996; NIH, 1996). The new rules included the protection of consultation with the community, public disclosure of the study design and attendant risks before its commencement, and public disclosure of study results when completed. Other studies, particularly in genetics research and those involving controversial topics (e.g., behavior, violence) have also raised concerns about whether and how communities can be consulted before and during research and, in fact, whether there are any circumstances in which “community consent” can be contemplated or required.
The notion of community consultation increasingly is viewed as beneficial to participants, to investigators, and to the integrity of the study design (Dresser, 2001). It is especially critical when the investigator is not a member of, or is unfamiliar with, the community that is the focus of or the host for the research. However, the idea of “community consent” has been problematic for several reasons, but largely because of the difficulty involved in defining communities. Communities are defined by social and ethnic group boundaries, which are highly permeable and fluid. Individuals rarely reside fully in one group over time and place and often belong to more than one community. In addition, communities are more often socially rather than biologically constructed, and individuals self-define their communities.
Furthermore, identifying the spokesperson(s) for a particular community or ethnic group for the purpose of obtaining a community or group’s
consent to a research study is especially problematic. Although community spokespersons are important, they are also power brokers guarding the interests of their group and may have different perceptions of research than those individuals they attempt to represent. In a 2001 report on the ethical issues involved in international research, NBAC made two recommendations regarding community involvement and consent that are broadly applicable:
Researchers should consult with community representatives to develop innovative and effective means to communicate all necessary information in a manner that is understandable to potential participants. When community representatives will not be involved, the protocol presented to the ethics review committee should justify why such involvement is not possible or relevant…
Where culture or custom requires that permission of a community representative be granted before researchers may approach potential research participants, researchers should be sensitive to such local requirements. However, in no case may permission from a community representative or council replace the requirement of a competent individual’s voluntary informed consent (2001a, p. vi, recommendations 3.5 and 3.7).
The committee endorses the NBAC recommendations. Investigators and Research ERBs have a significant responsibility and great latitude to make adjustments to protect groups or communities as appropriate, but many may not be well equipped to exercise this responsibility. Investigators and Research ERBs can involve individuals and communities in making decisions about relevant protocols and the development of consent forms that are understandable to them. As such, investigators and Research ERBs should be informed, knowledgeable, and sensitive to the research aims of community-based studies and the communities involved in these studies.
Steps to increase researchers’ accountability and responsibility to communities might include requiring them, in their grant proposals, to justify their selection and definition of communities; to demonstrate sensitivity to the possible community implications of their research where appropriate; and to anticipate potential group harms. Research ERBs can make recommendations to investigators regarding actions that could be taken to educate and inform the community about the research and to enlist their support in enrolling individuals into the study. Research ERBs could also suggest ways to communicate research results back to the community. Reciprocally, communities should participate in reviewing such research.
Public advisory groups at NIH and research institutions could play an important role in reviewing applications for research projects involving communities, recommending funding priorities and ensuring appropriate community representation and protection of community rights.
ROLES AND EXPECTATIONS OF RESEARCH PARTICIPANTS
Once a study is approved to begin recruiting participants, the protection system should immediately begin to protect the rights and welfare of potential participants. When individuals agree to participate in a project, they will be faced with a number of new roles and responsibilities. By being more assertive and protective of their own rights, participants can improve protections—not only for themselves, but also for others—and improve the quality of the research to which they are contributing. A more active participant role can help to balance the power between the investigator and toward the participant.
Federal regulations and international guidelines refer to “human subjects” of research rather than to “participants” in research, language that distinguishes the person being studied from the investigator and signals an asymmetry of power. The regulations aim to “protect” the rights and welfare of participants, with the underlying premise that those being studied are vulnerable when their interests conflict with those of science or of the investigators and that when such conflicts arise, the human rights of the participants trump the scientific interests of investigators and their research organizations.
This concept of protection, however, is not entirely consistent with an alternative framework that views research as a good in itself. Advocates of this framework, which include prospective “human subjects,” have come to regard access to research as a right (Batt, 1994; Epstein, 1996; IOM, 1994a, 1999; Love, 1995; Merkatz and Summers, 1997). Thus, the historical and somewhat mythical basis of the investigator/subject relationship in which the individual volunteers out of altruism and despite risks is being supplanted by a new reality in which research participants sometimes demand access to trials, are often backed by an advocacy movement, and are ready to confront the research enterprise when mistakes are made or injustices arise.
The Role of the Individual Research Participant
Research participants are a diverse group of individuals who enter into the research setting for a variety of reasons and who play important roles in the research process. A participant in one study may be a seriously ill patient deciding among experimental treatments under the guidance of a health care professional. In another study, a student of journalism might be interviewing prominent business figures, and the “subject” may be considerably more powerful than the investigator. Those who respond to a survey may have only glancing contact with any investigator. Even within the confines of a phase 1 clinical trial testing dose and toxicity, the person
participating in the trial may truly be the healthy “subject,” or a desperately ill patient who views participation in the trail as a potential means of extending life.
Despite the perceived possibility of serving as a “guinea pig,”12 the public has not lost faith in the goals of biomedical research, nor in researchers; substantial majorities of those questioned in a recent survey of participant attitudes about research favored clinical trial participation in most instances presented to them (Harris Interactive, 2002), and more individuals than ever are currently enrolled in studies. However, research participants do express concerns regarding their ability to fully interpret risks based on the information provided to them. They report uncertainty about whether their access to information about protocols is sufficient to facilitate their independent and informed decision making through the informed consent process. And, they want open access to research that may be relevant to their conditions or interests.
Recommendation 4.2: Decisionally capable participants should understand their potential role in any study in which they enroll, the rationale underlying that study, and importantly, what is required of them to prevent unanticipated harm to themselves and to maintain the scientific integrity of the study.
Comprehension of participant responsibility within a study is essential, because failure to adhere to a protocol may expose the participant to unanticipated harm, invalidate the study, and expose other research participants to unnecessary risks, all of which can undermine a study’s future benefits to others.
Research participants should be assisted in expanding their knowledge about the clinical research process by being offered educational materials and by being encouraged to ask questions of the investigator or other members of the research team. This is particularly important for studies involving greater than minimal risk and those protocols enrolling patients rather than healthy volunteers. Furthermore, participants should be encouraged to read the consent form thoroughly and write down questions for the investigator, if they are able. Participants should be provided the time to take the document home and to discuss the study with family, friends, or their personal physicians. If they do not understand any portion of the consent form, they should be provided the opportunity to request assistance from a representative or advocate in this process or to ask the investigator to further clarify the information. Participants should never sign the consent form unless they believe that they understand its content
and feel comfortable with their decision. The informed consent process may require multiple discussions between the participant and the investigator.
If the study involves an investigational product, efforts must be made to ensure that the participant understands the proper usage, dosage, storage, maintenance (in the case of a device), and disposal of the product before the trial begins. Further, a participant should appreciate that he or she is responsible for following these directions throughout the trial, as well as reporting any change in symptoms or overall health as quickly as possible to an investigator or his or her representative. It should be clearly explained that a participant must inform the investigator if he or she seeks medical care during a study, or if at any time during a study he or she cannot comply with the protocol requirements or does not want to continue participation. Participants have the right to (and should) ask for educational materials regarding the protocol and to ask questions of the investigator, including those relating to findings that result from the study. A list of questions and concerns that individuals might have regarding their potential participation in any research study is provided in Box 4.4.
Individuals who enroll in a research study should fully intend to comply with its requirements as explained to them at the time of enrollment. The decision to enroll in research is a serious commitment and individuals that enter a study with the intent to change treatments if they do not like their treatment assignment, or those that know they are not likely to complete the study should not enroll. In either case, the study and its analysis would be negatively affected, and more significantly, these individuals may cause undue harm to themselves or other participants.
The Need for the Participant Perspective Within the Protection Program
If the research enterprise is to remain relevant to the public, it should incorporate the realities and interests of research consumers, including those of potential research participants and the general public. As the examples of the HIV/AIDS and breast cancer activist initiatives to influence research agendas and policies demonstrate, the mutual education of participant communities and investigators can be a powerful tool in advancing research goals (Dresser, 2001). It has been noted that the perspectives of scientific professionals regarding research participation are likely to differ significantly from those of the general public. Therefore, effective processes are needed to ensure that the perspectives and views of the average individual are part of the research oversight system (Bastian, 1994). Meaningful participation in research does not include tokenism or the appointment to oversight committees only of individuals who are known to be friendly to an institution or to the research system generally. Rather, input to and
Potential Benefits and Harms
Protecting Participant Interests
Study Design and Leadership
Conflict of Interest, Study-related Controversy
regarding the protection program should be sought from those who are prepared to probe and at times challenge conventional research practices (Dresser, 2001). A degree of skepticism regarding such practices serves to stimulate and enhance discussion and is vital to creating a robust and responsive protection program.
The justifications for including public voices within research oversight mechanisms have been delineated in the literature and include principles
also expressed by this committee, such as the need for openness in the system to promote public trust, the need to provide a sufficient level of unaffiliated and nonscientific perspectives in the decision making processes, the need to ensure the ethical implementation of research in a manner consistent with relevant community values, and the need for accountability (Andejeski, 2002; Bastian, 1994; Dresser, 2001; Swankin, 2001). As noted in Preserving Public Trust, “those participating in research are also in the best position to appreciate their wants and needs as a practical matter” (IOM, 2001a, p. 41). The committee further believes that whenever possible, a broad and diverse constituency should inform the perspectives of participant representatives, in order to supplement their individual perspectives with the cumulative experience of the larger group.
The presence of a support structure external to the research organization could be another advantage of the consumer-informed model for participant representation. For instance, public members and consumer representatives on health care licensing boards, governing boards, and advisory bodies have access to objective support from the Citizen Advocacy Center. This nonprofit organization provides research, training, technical support, and networking opportunities “to help public members make their contributions informed, effective, and significant” (CAC, 2002). The establishment of a similar organization for unaffiliated Research ERB members might provide a neutral (i.e., nondisease or research-centered) source for the training and support of participant representatives. In the absence of such an organization, the committee encourages consumer groups to expand their efforts to provide educational programs to their members. Additionally, the committee encourages research organizations to pursue partnerships with local organizations such as patient organizations, religious organizations, and community centers in order to identify individuals with the skills and potential to become effective Research ERB members. Such partnerships should include the development of policies that will encourage and facilitate increased participation in the protection program by unaffiliated members (e.g., holding Research ERB meetings during the evening so that unaffiliated members do not have to miss work to attend) (Rand Reed, 2001).
Basic Research Education Needs
Before enrolling in any research study, potential research participants should be provided with basic information regarding the research process, including the implications of the experimental nature of the individual projects that they may be considering. Several groups have developed materials directed at providing this information to potential participants in biomedical research (Centerwatch, 2001; NCI, 1998; VA, 2002). In the cited examples, a description of the research process is provided using lay termi-
nology (e.g., “What Are Clinical Trials?”), along with a discussion of the review process and oversight structure. A list of questions potential participants should ask investigators, similar to those listed in Box 4.4, is also provided. More in-depth discussions of similar topics recently have been published by both Centerwatch and ECRI (formerly the Emergency Care Research Institute) (ECRI, 2002; Getz and Borfitz, 2002). For clinical trials, the Council for Public Representatives at NIH has recommended that each research site provide a list of “Frequently Asked Questions” for any individual considering participation (NIH COPR, 2001). The committee encourages further expansion and dissemination of these materials through multiple formats (including Web-based tools) in order to facilitate the engaged and meaningful participation of research volunteers.
As discussed in Chapter 3, individuals asked to serve in an oversight capacity within protection programs as a participant or community representative should be provided with the background knowledge and tools to fulfill this role. For example, unaffiliated members of Research ERBs should be provided with educational opportunities regarding the history of research, the need for ethical review, the methodology of research design, the federal regulations governing research, the role of advocacy for participants, and the processes for protocol review, as well as information on how to assess risk and consider possible benefits and the group dynamics pertinent to Research ERB deliberations.
Existing programs may serve as useful models for educating research participants about the research process. For example, Project LEAD, a project of the National Breast Cancer Coalition, includes language and concepts critical to understanding scientific research in clinical medicine, basic science, and epidemiology (Dickersin et al., 2001; Hinestrosa, 2001). Beneficial skills to develop through such programs might include those related to leadership, the critical appraisal of scientific literature, and those involved in understanding how research decisions are made. All of these skills can increase a participant representative’s confidence to ask questions and to share his or her perspective on technical issues (Hinestrosa, 2001).
Although research protocols are developed in many different ways, ultimately, a professional investigator is responsible for the conduct of the research and the relationship with the involved participants. This individual should work within the culture of a protection program that maintains the highest ideals of justice, beneficence, and respect for persons. To discharge his or her responsibility, the investigator should be trained in the methods and values of human research in addition to the technical aspects of a
protocol. The research organization through which he or she is engaged in the project should ensure that only qualified investigators are given the privilege of doing research with human beings.
The voluntary informed consent of research participants is essential for ethically sound research involving humans. In order to ensure that participants provide truly informed consent, the informed consent process should be interactive and ongoing, rather than focused on the signing of a written consent form. Research staff should ensure that participants understand the risks and benefits of the study as well as their responsibilities as participants.
Participants can play useful roles in the generation of new research ideas, in the evaluation of protocols for their impact on patients, and in guaranteeing a participant-focused review, particularly by serving on Research ERBs. In addition, potential research participants should be aware of the responsibilities necessary to maintain compliance with a protocol in order to prevent harm to themselves or the invalidation of the study. In this sense, participants have an important social responsibility that is as critical to the validity of human research as the scientific design itself.