Article

Protecting boundaries
of consent in clinical research:
Implications for improvement
Shirley T Bristol
Loma Linda University, USA
Rodney W Hicks
Western University of Health Sciences, USA
Abstract
Successful clinical research outcomes are essential for improving patient care. Achieving this goal, however,
implies an effective informed consent process for potential research participants. This article traces the
development of ethical and legal requirements of informed consent and examines the effectiveness of
past and current practice. The authors propose the use of innovative monitoring methodologies to
improve outcomes while safeguarding consent relationships and activities. Additional rigorous research
will help direct policy efforts at standardizing quality improvement processes.
Keywords
Clinical research, informed consent, quality improvement
Introduction
The quality of patient care delivery, to a large degree, now depends on Evidence-Based Practice (EBP). As
part of professional responsibilities, many nurses participate in clinical research within institutions to
increase the sufficiency of evidence on which to improve practice.
1
Clinical research studies, including
nursing research studies, may occur in any healthcare setting. When participating in the research process,
nurses, along with other healthcare professionals, need to understand the ethical and legal concerns and
advocate for the protection of potentially vulnerable human research participants.
1,2
Informed consent in clinical research is essential.
3
Informed consent is a legal and ethical prerequisite for
clinical research.
4
The principles of informed consent allow potential research participants to make an
informed and voluntary choice whether to participate, or not. Essentially, informed consent represents
permission to intervene in a persons private sphere.
3
Informed consent serves to promote public confidence
in the integrity of research, critical to processes of research funding and participation, and the resultant new
treatments and interventions.
5
One aspect of ethical research is to clarify how consent providers conduct the informed consent
procedure.
3
Information concerning this process is necessary to determine whether consent providers are
achieving the foundational goals of research oversight.
6
Tensions may arise when regulators endeavor to
Corresponding author: Shirley T Bristol, Loma Linda University, 11262 Campus Street, Loma Linda, CA 92350, USA.
Email: sbristol@llu.edu
Nursing Ethics
2014, Vol. 21(1) 1627
The Author(s) 2013
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balance the interests of the participants with the advancement of science and the support of researcher and
institutional interests.
7
At present, neither research nor regulatory analysis has focused on the practical
problems of protecting the ethical and legal boundaries of vulnerable populations, as a whole, in clinical
research.
4
Therefore, it is essential to assess the outcomes of the researcher-provided informed consent
process, rather than rely on regulator reports of research regulation compliance.
6
Early international development of ethical boundaries
Concepts of moral philosophy and the law underlie informed consent. For many years, principles of moral
conduct were expected to be sufficient to guide ethical, patient care. Physicians were required to use the
highest degree of professional judgment and skills to avoid adverse health outcomes. Neither policymakers
nor researchers attempted regulation of clinical research for centuries. Atrocities committed on civilians and
prisoners during World War II, resulting in the Nuremberg trials, led to the development of the Nuremberg
Code. This code advocated for the use of consent for competent individuals within medical research
protocols.
8
The 1964 World Medical Association Declaration of Helsinki established ethical principles to be applied
worldwide for clinical research involving human subjects, requiring consent to be obtained in writing and
the provision of adequate research information to all potential study participants. Subsequently, additional
international guidelines were developed by the Council for International Organizations of Medical Sciences
(CIOMS), collaborating with the World Health Organization, along with other global and national
guidelines.
8,9
Jurisdictional distinctions within the United States
The concept of protecting individual rights in clinical research is not unique in American society. The
related concepts of individualism and autonomy that underlie todays standards arose from events and
perspectives of early American pioneers.
10
As a result, ethical and legal conduct of clinical research has
been addressed through national regulatory and legal processes.
11
Legal precedents for informed consent lawwere developed in several US and state court cases upholding
the right to self-determination, outlining key informed consent requirements and justifying its purpose.
1114
The US congress enacted the National Research Act in 1974, authorizing the creation of The National
Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. In 1979, the
Commission issued the Belmont Report, an ethical report reemphasizing and interpreting key ethical issues
underlying the informed consent process, and initiating oversight of research activities at local institutions
through Institutional Review Boards (IRBs).
15,16
More recently, the 1996 Health Insurance Portability and
Accountability Act (HIPPA) required additional elements and statements for informed consent disclosure,
for HIPPA-compliant authorizations.
17
From an organizational, legal perspective, the process of informed consent, utilizing standardized
informed consent documents, is considered to function as liability protection. Organizational attorneys
review and approve the forms for use as a contractual agreement between the parties.
18,19
Informed consent has been a difficult issue for the legal community to resolve. The question arises as to
the reality of being able to give decisional authority to participants and, at the same time, to maintain the
authority and discretion of the physician or other healthcare researcher.
20
In a Medical Law Review article,
Jones
21
argued that informed consent is essentially a fairy tale. In his jurisdiction, however, the legal
process could not be reliably enforced through formalized informed consent laws or regulations.
In contrast, research subjects in the United States are granted a formalized legal right to litigate through
the use of state and federal laws. Enforcement also occurs, depending on the type of research, through
Bristol and Hicks 17
17
governmental and accreditation agency regulations. Reducing liability and the potential for federal enforce-
ment penalties is of concern to healthcare lawyers, risk managers, and clinical researchers. Education of the
informed consent process should emphasize that it should not be treated as a bureaucratic process, but as one
requiring expertise in judgment and appropriate use of communication skills to balance the interests of all
parties.
18,19,22,23
Vulnerable research populations need protection
Investigators must protect vulnerable research subjects from potential exploitation, and other forms of
harm, within the design of the research study. All persons are vulnerable, in the broad sense of the term,
since all are susceptible to harm. Vulnerability also encompasses a narrower concept that, at times, and
in certain respects, some individuals or groups of individuals are more vulnerable than others and require
specific safeguards.
24,25
Research participant vulnerability may also be expected where participants have developed relationships
with physicians or other healthcare provider researchers where they may be unduly influenced and denied the
opportunity to control decision making.
26
More recent ethical perspectives of the participant as a consumer
and shared decision maker may render the need for the process to be as legally defensible as possible.
19,27,28
Ethical and legal boundaries of informed consent
The ethical principles of autonomy, beneficence, and justice represent key ethical concerns for human subject
protection in clinical research as identified in The Belmont Report of 1979. Froma procedural perspective, the
process of informed consent seems very straightforward.
11,29
The informed consent process involves meeting
the required legal requirements followed by documentation of a participants consent by a signature. Formal
legal elements of informed consent include appropriate disclosure of information along with individual
decision-making capacity, understanding, and voluntariness. Researchers must understand the intent of each
ethical and legal requirement to appropriately implement the informed consent process.
26
Competing ethical viewpoints for issues under scrutiny
The burden of meeting the requirements of informed consent has raised competing questions as to how best
the elements may be met during the consent process. Research on the effectiveness of the various aspects of
the process has provided some answers, with many questions still remaining.
29,30
Disclosure
Informed consent requires that disclosure is sufficient to allow research participants to make an informed
decision. Sufficient disclosure requires a finding that the potential subject has the capacity to consent and
that there is adequate disclosure of the research purposes, procedures, risks, benefits, and available alterna-
tives. Participants must know their right to withdraw at any time, without penalty. Questions arise as to how
much information should be disclosed, howit should be communicated, and howcomprehension is assured.
The issue of whether intentional nondisclosure is ever acceptable may also arise. Investigators are faced
with the ethical dilemma of howto provide sufficient information for an informed decision versus providing
too much information so that the potential participant feels scared and overwhelmed.
30,31
Courts in the United States have struggled to determine norms for the disclosure of information.
Although other standards have been championed, two competing standards of disclosure have emerged. The
professional practice standard holds that a professional communitys customary practices determine
adequate disclosure. Issues include whether there is a customary standard and whether the majority of
18 Nursing Ethics 21(1)
18
professionals could agree and have the skills to offer the same degree of information to all participants. This
standard is less desirable from an ethical standpoint because it subverts the right of autonomous choice.
31,32
The reasonable person standard is widely utilized in many jurisdictions. This standard requires sufficient
information to be disclosed by reference to a hypothetical reasonable person. Whether information is
pertinent to the discussion is measured by the significance a reasonable person would attach to it.
31,32
Autonomous decision making
The concept of autonomy requires individuals with capacity to be treated with respect as autonomous
agents. Autonomous research participants have the right to hold views, make choices, and take action based
on personal values and beliefs. Conflicting views arise on the acceptable degrees of capacity, understand-
ing, and freedom from constraint that is acceptable for a valid informed consent. Authors who cite the need
for a substantial degree of understanding and freedom from constraint may call into question the definition
of the word substantial.
31
Voluntariness
Researchers and potential participants need to understand that a voluntary decision-making process is
essential during informed consent. Conflicting views exist on the presence of bias, what constitutes mate-
rial or sufficient information to be disclosed, and the degree of influence of emotional appeals, material
offers and rewards or lies may be debated.
29,31
The need for quality improvement
The purpose of protecting the boundaries of the informed consent process is to ensure appropriate
participant decision making. An acceptable quality decision involves sufficient knowledge of key
decision-making information, including options and possible outcome probabilities and clarified percep-
tions of ones values related to the information provided.
33
Informed consent research studies have demon-
strated significant misunderstandings by participants post authorization, despite lengthy and varied
documents and processes. Clinical research professionals have been aware of this problem for a number
of years, admitting the need for an improved consent process.
34
Numerous researchers have attempted the
implementation of new methodologies to improve the issue of misunderstanding, without consistent effects
noted.
34,35
Many organizations do not monitor the practices of their staff in the informed consent process.
As a result, it is often difficult to determine the quality of informed consent processes within the
organization.
7,35
Cook and Hoas
7
described responses to research questions about the assurance of ethically appropriate
consent processes within IRBs in the United States. The IRB respondents emphasized that researchers were
provided with model language and templates, and consent forms were reviewed thoroughly prior to their
use. The frequent complexity and length of consent documents, however, often discouraged research
participants from reading and comprehending them. Most respondents stated that they relied on the
researchers experience and integrity to carry out an appropriate, informed consent process.
Several respondents admitted the ability, theoretically, to monitor the consent process, although they felt
that the logistics would be impractical. In fact, only one respondent stated that routine monitoring of
informed consent was part of their IRB process. Other respondents felt that while IRBs protect participants
fromclinical risks, they are not protecting participants fromcoercion and cultural vulnerability. The authors
recommended further research regarding the effectiveness of research subject protection in a complex
research environment.
7
Bristol and Hicks 19
19
Consent providers compliance with informed consent requirements is a continuing issue for clinical
researchers. According to Sharp,
36
a survey of clinical trial research professionals reported recurring themes
of ethical violations during the process. Additional research also revealed poor disclosure of the research
risks, and a general failure to appropriately obtain informed consent.
37
A growing set of data also shows
consent to be less informed and voluntary. Overall, the research reveals a process with many problems.
3
Previous attempts at quality improvement
A literature review evaluating the effectiveness of informed consent in 26 clinical trials examined patient
perceptions of information disclosure and the impact on decision making. Although patients expressed
satisfaction with the process, the authors noted the failure of the studies to provide evidence regarding the
actual effectiveness of the informed consent process.
38
More recent reviews also agree with the need for
better methods to define, obtain, and evaluate informed consent procedures in clinical research.
3942
The
following discussion will outline overall results of categories of intervention studies aiming to improve the
quality of the informed consent process.
Improved consent forms
Through a systematic review, Flory and Emanuel
43
reviewed intervention studies testing enhanced consent
form interventions. Interventions included the use of condensed forms, a revision of forms using nontech-
nical language and lower reading levels, addition of graphics, and increased font size and italics. Overall,
the findings indicated no significant advantage of one method over another in improving informed consent
comprehension.
Two recent studies have also attempted to investigate possible methods for improving consent forms.
Paris et al.
44
studied the effect of systematic improvement in the readability and/or modification of the con-
sent formby a working group. Findings indicated improved comprehension by individuals reading the mod-
ified and systematic lexicosyntactic improved forms for phase 1 clinical trials. Stunkel et al.
45
investigated
the use of a short, clear consent form versus the standard form for participant satisfaction and comprehen-
sion. Both author teams found no significant difference or preference, based on these scores, for either form.
Although more data are necessary to differentiate effectiveness of short versus longer consent forms,
researchers recommend the use of standardized forms and templates.
Visual aids and multimedia
Twelve early intervention studies evaluated potential multimedia methodologies for the improvement of the
informed consent process in place of, or in addition to, the written consent form. Interventions included the
use of power point presentations, touch-screen presentations, videos, computer presentations, and a narrated
video, followed by postsession testing. Participant comprehension scores between control and intervention
groups for all studies were statistically insignificant with one exception. One study found the use of a
computerized power point presentation statistically significant (p .01), for the testing of comprehension
and recall primarily for a population with mental health problems.
39
Between 2006 and 2008, three
additional studies examined the effect of educational videos and informational aids on the effectiveness
of the informed consent process, with similar results.
4648
Questioning and responsive feedback interventions
Five studies, between 1981 and 2003, using posttests and feedback interventions, measured changes in
understanding outcomes. All five studies used the same questionnaire, regardless of intervention design.
20 Nursing Ethics 21(1)
20
Although overall findings indicated improved participant understanding, the use of the same questionnaire
in the initial questioning and postfeedback sessions was a serious methodological flaw. The possibility of
rote memorization of answers, instead of a confirmed change in comprehension, resulted in a diminished
trustworthiness of the findings.
43
Additional diversified interventions
Flory and Emanuel
43
evaluated five studies between 1997 and 2003, examining additional, diversified
interventions for improving the informed consent process. Two studies did not include new interventions;
instead, investigators used a combination of more common interventions, including the use of basic teach-
ing aids, such as flip charts, computerized presentations, additional pamphlets, educational vignettes, and
decisional aids. Findings indicated that only one of the five studies that included a 1-week protocol tryout,
significantly increased participant understanding.
Coletti et al.
49
used extended discussion, additional pamphlets, and other teaching aids for a simulated
informed consent study aimed at ensuring a competent consent process for future HIVvaccine efficacy trial
participants (N 4572). Researchers provided the selected intervention group with information using the
prototype consent process and invited participants to complete the enhanced educational process. The
participants within the intervention group had a greater baseline understanding score immediately post con-
sent and at all points of follow-up, including at 6-, 12-, and 18-month intervals. Researchers recommended
the use of the enhanced, informed consent prototype not only in future clinical trials but in other clinical
research as well.
Additional educator discussions
Flory and Emanuel
43
examined interventions utilizing extended informed consent discussions in five stud-
ies between 1996 and 2002. Methodologies tested included repetition of informed consent information,
nurseparticipant telephone conversations, and additional meetings with physicians and private educators.
In three of the five studies, extended researcher participant discussions showed statistically significant
increases in comprehension. Cahana and Hurst
3
concur that allowing more time for the participant to
consider information one-on-one with a research professional, including more time to ask questions, is the
most effective intervention investigated.
Implementing quality improvement processes
Several research deaths and other injuries resulted in the temporary closures of research programs by
regulatory agencies at several major US academic institutions in and around the year 1999.
23
Regulators
cited poor compliance with ethical standards in at least some of these cases. One case involved a healthy,
18-year-old patient with a mild form of ornithine transcarbamylase (OTC) deficiency, a rare liver disease,
controlled by drugs and a strict diet.
50
According to the participants father, the patient volunteered to participate in this groundbreaking federal
gene-therapy research study because they were told risks were low, when in fact, researchers knew that the
gene vector injection was toxic in animals at high doses. Four days following the injection, the patient was
pronounced brain dead. Researchers discontinued the study and an investigation ensued, resulting in
government sanctions and civil litigation. In the civil case, the plaintiffs argued a lack of informed consent
related to omission of information regarding previous adverse events with animals and an unknown direct
financial interest of the lead researcher, resulting in an out-of-court settlement.
50
Bristol and Hicks 21
21
The current research mechanisms used to ensure protection of research participants in clinical research
continue to be under scrutiny. Regulatory agencies continue to raise questions concerning a variety of
research issues, including the effectiveness of informed consent. Nevertheless, there is no consensus about
howbest to achieve and assess the quality of informed consent.
40
Quality-monitoring programs often do not
exist, or they consist of file auditors documenting the completion of the consent documents or reviewing
their content. A comprehensive, tested and standardized plan may more effectively influence the informed
consent procedure, resulting in more consistent, quality outcomes.
33,40
Several strategies are relevant in addressing unresolved issues of informed consent in clinical research,
including a collaborative nursing role, the use of consistent evaluation tools, and a consistent monitoring
process through recording and direct observation.
Nursing collaboration in quality improvement
In clinical research, a number of stakeholders perform a variety of roles. Nursing stakeholders may include
nurses functioning in the role of primary investigators (PIs), research nurses or study coordinators or
assistants, informed consent providers, data collectors, and clinical staff. These individuals may work directly
with the research team or through a collaborative effort with other colleagues and students to improve the
research process. Collaboration of nurses with multidisciplinary team members may improve informed
consent processes by influencing the support and development of ongoing quality-monitoring processes.
51,52
Clinical nurse advocacy and informed consent. Nursing advocacy includes the ethical obligation to not only
obtain informed consent but to evaluate and communicate participants understanding of the research study
protocol. Nurses in a variety of roles may also advocate for the participant by ensuring that all the steps of
the process are followed.
53
All nurses must also be clear in defining their nursing role within the research protocol, and in their
understanding of the lawand institutional policies regarding the informed consent process. Nurses with dual
roles as primary caregivers and researchers must be particularly aware of the potential for conflict of interest
between individual participant care and research process needs. Issues such as inappropriate influence may
contribute to the need to limit involvement to prevent the relationship from turning adversarial.
27,53
The independent advocate. The patients interests might best be served by an independent advocate function-
ing as an objective consent provider. The independent advocate would empower the patient to
self-advocate, particularly if outside the control of the healthcare organization and research team. In that
instance, nurses would have no direct contact as a consent provider, but could serve to influence social
justice either individually, in a management position, or on an independent council or multidisciplinary
team from the middle ground.
27
Use of consistent evaluation tools
The protection of clinical research participant rights and interests depends upon the establishment of
effective and efficient means of evaluating the quality of informed consent. This will result in the ability
to monitor and improve the informed consent process.
40
Currently, standardized outcome assessment meth-
ods for evaluating the consent process are nonexistent.
54
Sugarman et al.
40
developed and tested a short
telephone-based assessment, called the Brief Informed Consent Evaluation Protocol (BICEP). Following
the consent process, interviewers surveyed 632 participants in a Veterans Administration (VA) Cooperative
Studies Program clinical trial, utilizing the BICEP survey. Site coordinators and research participants cited
satisfaction with the ease of implementation, the efficiency of questioning, and higher knowledge scores.
22 Nursing Ethics 21(1)
22
This research indicates the largest number of aggregate data reported following testing of a measurement
tool for informed consent in clinical research. The process was highly satisfactory to research participants,
and researchers identified reliability and validity for the study measures. The study authors recommended
testing the BICEP in other settings to see whether it can be adapted for use in monitoring the informed
consent process. Such a modality promises to add an essential element of direct measurement to other
monitoring approaches. Nonetheless, other methods such as intensive interviewing and actual observation
of the informed consent process might indicate a more realistic evaluation.
40
Recording the informed consent process
Because research regulators have not utilized direct methods of informed consent assessment, they cannot
know with certainty that consent providers are presenting clinical research study participants with appro-
priate information and opportunities for autonomous informed consent decision making. It may, therefore,
become necessary to record consent encounters for educational and quality-monitoring purposes.
35
Legal data protection issues of routine recording. Ethical risks inherent in recording potentially jeopardize
participant privacy, trust, and confidentiality. The literature evidences healthcare providers satisfaction
with the effectiveness of recording actual procedures within the clinical setting for the purposes of educa-
tion and quality improvement.
54
In the United States, federal and state privacy laws require authorizations for all photography, with a few
exceptions. For clinical research purposes, informed consent must always be obtained prior to recording. If
the process is also categorized for education and improved patient treatment purposes, the law allows some
variation. In these instances, healthcare organizations have developed policies and procedures to address the
issue of photographic recordings. Informed consent agreements to photograph, for example, have been
placed in the standard admission consent form. If a patient or their guardian does not sign the consent upon
admission, the recording may proceed; however, informed consent must be obtained before the patients
recording may be reviewed.
55
Additionally, anyone who records patient activities must sign an appropriate confidentiality commitment
prior to the taping. Other policy requirements have included secured storage, limited access, and erasing or
destruction of data within a specified time frame. Educational reviews of the photography include an assess-
ment of the procedure recorded, through the use of a specifically developed review form by clinical staff
preapproved to view them.
55
Froma patient perspective, research has shown that cameras in the clinical setting have a minimal impact
on their comfort. Where providers have asked patients to agree to the use of cameras, the overall rate of
approval has been high. Because recordings are potentially permanent and because they may be recorded
out of context or inappropriately edited, duplicated, and transmitted, it is inherent in the process to use
consent forms that meet informed consent requirements.
54
Direct observation
Lavori et al.
56
identified the importance of actual observation of the informed consent process for the
purposes of evaluating its quality. Later, two other researchers also recommended direct observation, stat-
ing that research outcomes would be more persuasive if they viewed real consent processes rather than
simulated or reported encounters. The authors also agreed on the use of direct observation since it is feasible
and ideal, and provides a clearer picture of the encounter.
43,57
Albrecht et al.
57
identified the need for additional research focusing on the actual consent encounter.
Although a number of tools measuring the quality of the informed consent process were available, a
Bristol and Hicks 23
23
standardized quantitative tool to measure the actual consent encounter had not been identified.
58
Past
attempts to examine the consent process have primarily involved indirect measurements.
59,60
Researchers
have recently developed and tested the Process and Quality of Informed Consent (P-QIC) instrument. The
purpose of this instrument is to measure the quality of the informed consent process in clinical research.
42
The tool has also been recommended as a useful tool in educating researchers and other research staff
responsible for obtaining informed consent.
61
Additional research
Research focusing on improving the quality of the informed consent process has, only recently, been
identified as a priority.
3
Quality improvement of the informed consent procedure must include testing
within the clinical research setting, rather than through a speculation of theoretical possibilities.
40,62
Future
studies need to focus not only on consent documents and methodologies but on understanding and improv-
ing the broader process of informed consent. Studies must be designed in a manner that will rigorously test
the proposed interventions to ensure more usable, consistent data upon which to base decision making.
33,56
Summary
Issues regarding the quality and effectiveness of the informed consent process in clinical research continue
to emerge. The overall success of the informed consent process in reaching its mandated goals continues to
be questioned.
34
Many research participants, post consent, continue to show gaps in their knowledge and
understanding of relevant research information. Such gaps suggest less-than-optimal informed consent
outcomes.
34,63
Research has shown that information may often be relayed to research participants through the use of
suboptimal methodologies. Currently, the extent of conformity with recommended practices is unclear.
34,63
Efforts to address these problems, over the past 20 years, have been unsuccessful.
34
Data from intervention
and other studies are unavailable, fragmented, or inconclusive.
34,63
The need to understand the value of
informed consent during the actual consent encounter is crucial since a lack of quality may impact informed
consent decision making and research study recruitment. Researchers should attempt to investigate the use
of newer, more accurate methodologies of quality monitoring so that the informed consent process may be
improved.
63
Additional research data are necessary to determine the best methodologies and communication tech-
niques for conveying research study information. Improved consent processes will enable participants to
make decisions reflective of personal values and preferences.
64
When it comes to ensuring protection of
the rights and interests of clinical research participants, these data are particularly pertinent, obtainable, and
necessary for addressing policy efforts at standardizing and implementing a quality informed consent
process.
40
Declaration of conflicting interests
The authors declare that there is no conflict of interest.
Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-
profit sectors.
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