Vulnerable populations in research ethics

Pmc3601707vulnerable population and methods for their safeguardpreethi shivayogichairperson, lifeline ethics committee, bangalore, indiaaddress for correspondence: dr. E-mail: @pauthor information ► copyright and license information ►copyright : © perspectives in clinical researchthis is an open-access article distributed under the terms of the creative commons attribution-noncommercial-share alike 3. Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly article has been cited by other articles in uctionthe inherited skepticism of disregard and contempt for human rights from the past has left powerful influences, making autonomy, justice and safety the citadels for current ethical research practices. Civil rights violations from the infamous nazi and tuskegee to radiation human experimentations have promoted sustained maturation and augmentation of clinical bioethical research environments. The lack of informed consent (ic), or coercive, guileful, forceful influences and methods that were used to obtain consent from potential participants; this associated with impaired risk-benefit scales, unjustified research population selections have prompted international regulations to stand firm on principles advocating conscientious clinical and ethical research systems. Following marketing approvals, medicinal products are conventionally utilized by pharmaceutical organizations, medical practitioners and allied bodies across a wide range of age groups, genders, special populations, nationalities and races, who unfortunately had not been satisfactorily represented in pertinent clinical studies resulting in deficient evidence-based health able populationthere are several definitions available for the term “vulnerable population”, the words simply imply the disadvantaged sub-segment of the community[1] requiring utmost care, specific ancillary considerations and augmented protections in research. The vulnerable individuals’ freedom and capability to protect one-self from intended or inherent risks is variably abbreviated, from decreased freewill to inability to make informed choices. Vulnerable communities need assiduous attention during designing studies with unique recruitment considerations and quality scrutiny measurements of overall safety and efficacy strategies ensuing research. Ethical dilemmas are widely prevalent in research involving these populations with regard to communications, data privacy and therapeutic deliberations. Non-therapeutic research participation is granted if the envisaged risks are minimal[2] and well-being of this community is not compromised. Research with this sub-segment of population is validated if reasonable direct benefits are foreseen, in compliance with local legal regulations. 1,3] the vulnerable populations refers to but not limited to children, minors, pregnant women, fetuses, human in vitro fertilization, prisoners, employees, military persons and students in hierarchical organizations, terminally ill, comatose, physically and intellectually challenged individuals, institutionalized, elderly individuals, visual or hearing impaired, ethnic minorities, refugees, international research, economically and educationally disabled and healthy volunteers. 3]there is an aggrandized awareness with pressing needs to include potential participants from heterogeneous demographics and variegated vulnerable backgrounds, both from the regulatory and patient groups. 5]the cornerstones of vulnerable participant safeguard ubiquitously comprises of comprehensive ic process, authorized substitute decision makers, addressing privacy and confidentiality concerns, justified benefit versus risk assessments, equitable justice and methods of subject selection. 2,6]discussion on methods for safeguardchanges in benefit to risk ratios, either aggravated risks than those assumed and or a decrease in direct benefits presaged to the vulnerable participant should deter fresh enrolment and stagger or discontinue further participation up till the issue is appropriately corrected. The interim analyses of research may be made available in public domain to apprise the scientific community of the integrity of the study and initiate public pment of comprehensive safety monitoring plans with data safety monitoring committee (dsmc) supervision and wherever applicable with observational study monitoring boards are crucial. Their role may be optimized by involving them in both, early and late trial phases[7] soliciting vulnerable subjects, to contribute recommendations to the scientific caliber, integrity, safety, lucidity, timeliness, and quality of data and documentation. Compliance to advocated norms and sustained monitoring by ethical review boards (erbs),[8] governmental agencies and independent dsmc is form of willful violations to good clinical practices (gcp) with connotations to autonomy, voluntariness, distributive justice, other parameters of safeguards are to be imperatively scrutinized and those involved to be appropriately penalized by applicable tion of rights, well-being, safety with measurements of risk-benefit scales, privacy and confidentiality of vulnerable subjects and ascertaining appended safeguards[4] are prerogatives of erbs. Infringement of methodologies in data collection and dissemination could bring individuals into disrepute, especially in research involving socially sensitive issues associated with stigma, as with hiv, mental illnesses, genetic[4] or of epidemiological natures. Therefore, establishment of updated security mechanisms of human research data protections is of paramount priority to industry, erbs and supervising trial documents require meeting the expectations of erbs, especially with reference to vulnerable subjects’ protection. 9] competent and trained erbs overseeing sensitive studies should observe full-scheduled reviews[4] and may have representatives from specific populations during deliberations. The concerned erbs prior to decision making may establish site research conditions, example a prison site[10] with relevance to participant rights, safety and well-being. The erbs’ standard practices should include continued review for compliance whilst monitoring these tly due to disparate factors, there is neither uniformity nor equitable standards in the understanding and grading of risks globally for these populations with relevance to extent of acceptability and evaluation of quantum of risks to establish consistent safeguards in biomedical research aiding of regulatory in biomedical and behavioral research is maximal in providing scientific direction to industry and unambiguous thought-through instructions. International collaborations of regulatory organizations can establish scientific and regulatory policies to positively impact global safeguards for vulnerable ent reporting guidelines should be followed by industry in maintaining validated databases for safety data dissemination highlighted for this community, with risks being regularly interpreted by expert clinical evaluators, steering committees and timely recommendations shared between stakeholders. There is a continual need to federate and be vigilant to develop strategies for establishing appropriate advancements in monitoring plans according to trends scrutinized from quality of ic process has an impressive influence on the tenets of research with direct implications to comprehension of proposed study particularly in vulnerable subjects. 9] language and literacy capabilities of the potential vulnerable participants are to be assessed by the research site personnel. 16]the philosophy involved in including pregnant women is based on the principle that information gleaned from good research leads to augmented standards of maternal and fetal healthcare. 5] this population may inadvertently be exposed to high risks of unintentional detrimental effects as a result of their conditions as noted in post marketing research practices. Should the exclusion of this sub-segment be planned, a viable justification needs to be elucidated in the relevant research documents. Programs and registries for follow up evaluations subsequent to pregnancy research for fetus and child are prerequisites. 18]research in intellectually challenged individuals is an arduous, daunting task for investigators as cognition of the subject forms a major determinant in establishing adequate comprehension justifying communication to secure transfer of information. 3] the decisional capacity of prospective vulnerable subjects is a direct determinant to their enrolment eligibility. 19] if the anticipated discomforts for the proposed research are higher than minimal with no foreseen direct benefits to the subject, nonetheless, research is authenticated if sufficient targeted scientific information may be garnered. Pediatric studies are prone to sensitive issues and risks, needing periodic reassessments by the concerned ethics, scientific review boards with public concurrence. In non-therapeutic research, declination to participate by the child requires to be abided by the investigator. 10] mostly, research conducted on prisoners pertains to health and social issues with potential direct benefits, confined to their environmental conditions. 3] the discerning witness without conflicts of interest comprehends the information and conveys to the probable subject, establishing a robustuous consent process and transfers knowledge and responsibilities involved in proposed ch in the terminally ill and in conditions of emergency medicine,[3] in these circumstances subjects are potentially very vulnerable as waiver from consent may be inevitable despite several social, legal and ethical debates. Further in this form of research, befitting statistical designs and inferences are to be ch in hierarchical organizations as in the armed forces, institutions or hospital groups, here employees or students by nature of adjacency of work or association with investigators, may acquiesce to participate in anticipation of favoritism, consternation, retribution or compelling socioeconomic backgrounds. Declination to participate should not affect their careers and the protocol sample study population incorporates the vulnerable subset of patients, rationale for their representation, scientific significance and contributions are to be discussed. The pillars of vulnerable participant safeguards are to be specifically expounded in the protocol and icd.

The higher the severity of risks encountered in this sample population, the more aggressive the sioninvestigators require factual guidance from regulatory with reference to practical difficulties confronted during conduct of these forms of research. The need of the day is responsible, experienced, sensitive researchers[21] guiding conscientious teams to treat vulnerable communities with concern, patience, respect, equitably, allowing free will, ruling out any form of inducement, enticements, insensitivity or goals of clinical research whether privately or publicly funded are to represent the best interests of this community within the framework of the protocol and by adherence to the principles of gcp. In general, accurate definitions of groups of representatives’ example, viable infant or nonviable fetus, and other technical terminologies and special procedures pertinent to sub-populations should clearly be defined without ambiguity[16] which aids both, study personnel and subjects in consent ess through continued education of stakeholders including media and public would result in better attitudes and approach to this form of sensitive research. Watchdog panels overseeing vulnerable participant protection should remain in an open ongoing dialogue with stakeholders, monitoring compliancy to advocated precautions and norms. Enhancing the interaction between the erbs and investigators may expand their ability to comprehend the trends involved and engage in greater understanding of ongoing safeguards of these populations. Compassionate use of therapeutic interventions may be made available to vulnerable subjects following completion of research. Comprehensive mandatory pharmacovigilance and targeted risk management plans during post marketing are science with responsible research provides an authentic groundwork to heighten best practices in medical management of vulnerable populations. Nevertheless, clinical research is metamorphosing and escalating in complexity, blurring the line between potential risks and benefits encumbering the development of comprehensive robust monitoring all walk down this inconstant dynamic path of research. Wma declaration of helsinki-ethical principles for medical research involving human subjects-59th wma general assembly, seoul, korea, october 2008 2. Indian council of medical research ethical guidelines for biomedical research on human participants, new delhi, 2006 5. Us department of health and human services - office of human research protections (ohrp)-irb ohrp, additional protections for children involved as subjects in research, subpart d, code of federal regulations title 45, part 46 protection of human subjects 20. Articles from perspectives in clinical research are provided here courtesy of wolters kluwer -- medknow s:article | pubreader | epub (beta) | printer friendly | l issue: l repatriation: physicians’ and nurses’ responses to a ting vulnerability: informed consent in persons with alzheimer’s ting research with the elderly: ethical concerns for a vulnerable l issues in conducting research with persons with original involvement in functional assessment of problem behaviors related to adhd as a basis for intervention ing postpartum depression and choosing to be a mother. Relationship between baseline self-efficacy and breastfeeding ting research with the elderly: ethical concerns for a vulnerable a. The growth of this group is unprecedented in american history, owing in part to advances in health care research having a positive impact on longevity. Ethical protection becomes a principal concern when a group, such as the elderly, is identified as vulnerable. This article reviews concepts of autonomy, beneficence, and justice in relation to geriatric research and discusses ethical risks with case ds: informed consent, research, ethics, geriatric, vulnerable population, ethical principles, case one of the fastest growing segments of the population, over 70 million american citizens will be considered elderly by 2030. The growth of this group is unprecedented in american history, owing in part to advances in health care research having a positive impact on longevity. The purpose if this paper is to identify and discuss ethical risks unique to this vulnerable population and propose possible solutions with case ting research with the elderly: ethical concerns for a vulnerable increasing number of elderly americans will propel research in multiple disciplines in an effort to describe, understand, and treat problems of aging. Medical research for physical aging, diseases and conditions, and pharmacologic and other interventions alone will consume vast research resources. In addition, psychological research will be conducted on memory, cognition, and personality; and social research will investigate effectiveness of social programs and services. Marketing research will also be conducted to influence the buying decisions of a growing market l principles guiding a person’s participation in research have evolved substantially over the last 50 years, with special considerations for groups identified as vulnerable. The formation of a national bioethics advisory commission3 in 1995 followed a history of examination of moral and ethical behavior in research as a result of the nuremburg trials of world war ii (wwii). The german city of nuremburg was the location where physicians and staff of the nazi military where brought to trial for “murders, brutalities, cruelties, atrocities, and other inhumane acts”4 which were conducted under the guise of medical research. The involvement of physicians, calling what amounted to torture as ‘research’, galvanized the medical community into establishing an ethical code of conduct. The national commission for the protection of human subjects of biomedical and behavioral research was created by act of congress in 1974. The belmont report represented the commission’s work which delineated the boundaries of biomedical and behavioral research, assessing risk/benefit, guidelines for the selection of subjects, and the constitution of informed consent in diverse belmont report laid the cornerstones of bioethical practice with the principles of respect for persons, beneficence, and justice. In biomedical research, this principle extends essentially to deciding whether to participate, free from coercion, in a research study (voluntariness). However, informed consent can only be made if there is provision of adequate information and comprehension of the risks and benefits related to participation in research. Respect for persons also encompasses the right of the individual to have informed, voluntary participation, protection of his/her person and information when participating in research cence. In addition to allowing the individual the right to choose whether to participate in research, the principle of beneficence ensures well-being while participating in a study9 and maximizes any benefit that potentially accrues as a result of participation. Those who submit to the risks of research should have equal share in the potential benefit. Essentially, the principle of justice states that all people should be treated y as a vulnerable does not intrinsically make one vulnerable. In fact, the nbac3 does not list the elderly as a vulnerable population even though children, the institutionalized, and women are recognized as more open to harm and vulnerable to coercion. Department of health and human services),13 states specifically that a vulnerable population may be at risk due to age, health, functional status, chronic or terminal illness, inability to effectively communicate, or financial circumstances, all of which may apply to the elderly. Inequalities in emotional and physical power between the subject and the researcher, a situation that also relates to some elderly, can potentially compromise principles of ethics. Easy fatigability, shortness of breath, and severe pain are examples of factors which contribute to differences in physical power between researchers and potential elderly subjects. High social vulnerability among the frail15 can contribute to differences in emotional nt issues related to research with the cdc defines elderly as greater than 65 years of age. In the following sections, ethical issues related to inclusion of sub-populations of the elderly in research will be related to the independent healthy age alone does not confer vulnerability, there are undeniable aspects of aging that open individuals to risks related to research. Researchers may present complexity in the number of facts given, speed of presentation, length and complexity of sentences, or force of presentation which may result in decreased understanding. 19 while not intentionally coercive, researchers may inadvertently offer more than the risks and benefits outlined in the study by providing the benefit of social contact.

Areas of concern and threats to ethical research will be discussed based on this study. She enjoys her job, but looks forward to the time she can spend with her daughter and her family in a nearby initial telephone contact at home, the lead researcher asked for ms. Snow, the researcher, looks at the detailed pamphlet offered, signs the consent, and completes the survey before returning to the office at the end of the lunch break. Mildred’s participation in the study ends at this point with no further researcher analysis. If the subject wears reading glasses the researcher should ensure their wearing during the study presentation. While the researcher’s forcefulness cannot be gauged, it is not unreasonable to assume that lack of time added urgency and some forcefulness to the presentation. While we do not know if the researcher presented the study with fewer details and straightforward language, unless this was purposefully done, there may not have been comprehension of the ining comprehension is essential, especially with a vulnerable population. To prevent an authoritative look, a young, researcher could make the presentation, dressed casually without references to an organization such as nametags or uniform, or use of titles. Rather than asking for the participant’s work number, the researcher should have identified a mutually agreeable this case study, there may have been coercion by calling the participant at work concerning a study about assisted living. Possibly the participant did not want to be viewed as person who would soon by leaving employment due to infirmity and was uncomfortable having the researcher contact her at her place of work. She may have felt vulnerable to economic stress as she was employed past a point at which most americans retire. It is conceivable that in an effort to avoid stressful contacts with the researcher, she agreed to the study to end further remuneration was offered for study participation, but researchers should be aware that financial incentives may be unfairly compelling for those of moderate, low, or fixed incomes. Mildred, widowed and alone, may have been subject to coercion through the need for companionship rather than the merits of the the elderly, a support system is perhaps the most important factor in creating a vulnerable situation. Participants need time to make informed and autonomous participant’s social and education status were not clearly identified, but gainful employment in a technical job would suggest that the participant is not especially vulnerable related to these factors. Not evident in this case, is the risk of exclusion related to the extra care needed during recruitment and research with the elderly. Mildred, despite the benignity of the situation, was vulnerable in several ways and should have been adequately protected. The research may have been related to the dependent chronically ill (frail) l issues related to recruitment of the healthy independent elderly apply to dependent chronically ill elderly, but there are additional concerns generated by the presence of illness and loss of independence. In this case, the researcher has taken care to allow the participant time to reflect, contact her support system, and present the study clearly without pressure. However, as previously seen, elderly participants are vulnerable to subtle principle of beneficence requires full disclosure of risks and benefits for study participation but risks may be assessed differently between young and old, such as the inconvenience of blood draws. May’s participation in the study created a conflict of interest, even though he was not the researcher. Persons with dementia often agree with the researcher during consent procedures but are not necessarily indicating their willingness to participate. A research study is investigating the use of artificial sunshine to prevent ‘sundown syndrome’ in the elderly in a nursing home. Oscar is not known, and brings the ethics of this study related to beneficence into question. The researchers should have allowed more time for the family to examine the merits of the sion. Circumstances may bring about a change in vulnerable status such as in health, financial, or social position. Physical changes, decreased mobility, chronic illness, loss of support systems, and changes in cognitive ability can interfere with the freedom to es guiding ethical treatment of humans in research in the united states have evolved from historical events and led to development of the seminal belmont report. World research policies have been influenced by the principles of respect for persons (autonomy), beneficence (nonmaleficence), and justice. The irb guidebook published by the office for human research protections (formerly the office of protection from research risks (oprr) has not been updated since 1993. The ethical researcher must independently examine and reflect before undertaking studies with people, especially the vulnerable ir, m. Experienced consent in geriatrics research: a new method to optimize the capacity to consent in frail elderly subjects. Unjustified exclusion of elderly people from studies submitted to research ethics committee for approval: descriptive study. Retrieved july 11, 2007 from cinahl l issue: l repatriation: physicians’ and nurses’ responses to a ting vulnerability: informed consent in persons with alzheimer’s ting research with the elderly: ethical concerns for a vulnerable l issues in conducting research with persons with original involvement in functional assessment of problem behaviors related to adhd as a basis for intervention ing postpartum depression and choosing to be a mother. To this article has been published in health research policy and systems 2017 15: peer review concept of vulnerability has held a central place in research ethics guidance since its introduction in the united states belmont report in 1979. It signals mindfulness for researchers and research ethics boards to the possibility that some participants may be at higher risk of harm or wrong. Despite its important intended purpose and widespread use, there is considerable disagreement in the scholarly literature about the meaning and delineation of vulnerability, stemming from a perceived lack of guidance within research ethics standards. The aim of this study was to assess the concept of vulnerability as it is employed in major national and international research ethics policies and conducted an in-depth analysis of 11 (five national and six international) research ethics policies and guidelines, exploring their discussions of the definition, application, normative justification and implications of policies and guidelines explicitly defined vulnerability, instead relying on implicit assumptions and the delineation of vulnerable groups and sources of vulnerability. On the whole, we found considerable richness in the content on vulnerability across policies, but note that this relies heavily on the structure imposed on the data through our results underscore a need for policymakers to revisit the guidance on vulnerability in research ethics, and we propose that a process of stakeholder engagement would well-support this dsresearch ethicsvulnerable populationsvulnerabilityresearch policyethics policyresearch ound: the function of vulnerability in research ethics guidance and policyresearch on human subjects is thought to be fundamentally ethically challenging, requiring ethics standards to guide researchers as well as approval and oversight of research proposals from independent committees. Society allows researchers to invite individuals to participate in research once certain conditions are met, including a research ethics board’s (reb, also known as institutional review boards, or irbs, or research ethics committees, or recs) determination that risks and benefits are appropriately balanced, that the proposed strategy for subject recruitment is fair, and that voluntary, informed consent will be sought from each potential subject [1]. The concept of vulnerability, which finds it origins in the united states belmont report of 1979 [2], plays a central role in research ethics thinking, drawing attention to situations where these conditions may not be met [1]. Since 1979, the number of legal and non-legal research ethics policies and guidelines has increased tremendously and, with them, the use and scope of the concept of vulnerability or vulnerable populations [2, 3].

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However, there is much scholarly disagreement over the appropriate meaning and application of this concept in research ethics, and policymakers are charged with the challenge of navigating this contentious landscape in the development and refinement of research guidelines and policies [4]. A growing body of literature critiques and aims to advance the way vulnerability is conceptualised and employed in research ethics, with major debates regarding foundational elements of this important ethical concept [5–10]. Debates surrounding the concept of vulnerability in research is widespread agreement that some research participants may be particularly vulnerable and in need of special protections, yet the concept of vulnerability itself has been described as ‘vague’ [11], with a lack of consensus in the scholarly literature regarding the concept’s central features. Contrasting accounts have been proposed regarding the justification of vulnerability and which ethical principles translate into obligations for the special protection of vulnerable research participants. Some accounts propose a justice-based reason for protection, concerned with the fairness of participant recruitment and of the distribution of research burdens and benefits [12, 13]. In research, there are often gaps between the rules intended to govern and the practices at hand, requiring those tasked with the implementation of these rules to interpret and apply them in their specific context [3]. In this context, a better understanding of the justifications of vulnerability becomes a crucial goal of scholarly work in this application of vulnerability and its scope in research has also been a subject of much debate. An overly broad concept captures all research participants, creating conceptual confusion over the meaning of ‘special protections’, while an overly narrow concept may leave some vulnerable participants at risk and without the needed protection [5, 11, 12, 14]. Further, it must provide researchers and research ethics boards with the information necessary to identify those who are vulnerable, as well as what they might be vulnerable to. There are compelling arguments against narrow definitions of vulnerable groups that support the identification of specific factors within the research context and the participants’ personal situation that create possible vulnerabilities [6]. Arguing that vulnerability lacks an organising principle, hurst [5] suggests that vulnerable persons are properly conceived of as those who have “an identifiably increased likelihood of incurring additional or greater wrong”. This account emphasises that both individual and situational factors must be evaluated in defining vulnerability because being overly focused on individual characteristics can obscure features of the research protocol or environment that may harm participants. Luna and vanderpoel [14] describe layers of vulnerability which arise from interactions between an individual’s characteristics and their environment, and which interact with one another to create an inextricably context-dependent our knowledge, an in-depth analysis of the concept of vulnerability as it exists in the policies and guidelines that govern research on human subjects has not been conducted. Without a clear understanding of the conceptualisation and operationalisation of vulnerability in current research ethics, recommendations for its refinement risk being disconnected from the range of policy options. To explore the diversity of options with respect to the enshrinement and application of the concept of vulnerability in research ethics guidelines, we conducted an in-depth analysis of major national and international research ethics policies and ed by previous research ethics policy analyses [3, 15], we compiled a sample of internationally- and nationally-adopted research ethics guidelines and policies, focusing on canada (the authors’ own regulatory context) and regions with similar demographic and legal structures to canada, including australia, the european union, the united kingdom, and the united states [15]. We began our search using a compilation of international human research standards produced by the office for human research protections of the united states department of health and human services [16]. Additionally, we performed secondary searches of the references of any included guidelines and policies for relevant, non-duplicated primary goal was to build a sample of guidelines and policies that discussed or referenced vulnerability in general health research. The nuremberg code) as well as those focused on specific areas of or issues within research (e. Paediatric research, genetic research), put forward by professional organisations, or published as working papers, drafts, commentaries, or otherwise less broadly adopted documents. See table 1 for an overview of our sample and the key characteristics of included characteristics of guideline and policy ation of helsinki2013intldeclaration of helsinkia statement of ethical principles proposing how physicians should act in research; not legally bindingprimarily physicians; others involved in medical research with human subjects are encouraged to adopt its principlesarticles of the declaration itself are intended as guiding ethical principles for researchcouncil for international organizations of medical sciences, international ethical guidelines for biomedical research involving human subjects. Guidance document intended to guide the effective application of the declaration of helsinki’s ethical principles in research, especially in low-resource countries; not legally bindingcioms member bodies, which include international and national biomedical organisations (e. World medical association)cites three guiding ethical principles: respect for persons, beneficence, and justiceunesco universal declaration on bioethics and human rights2005intlunesco declarationa universal framework of principles to guide states in formulating legislation and policies, as well as to guide the actions of individuals, groups, communities, institutions and corporations, public and privateaddressed to states, but also provides guidance for individuals, groups, communities and corporations, public and privatearticles of the unesco declaration itself are intended as guiding bioethical principlesdirective of 4 april 2001 n°2001/20/ec2001eueu clinical trials directivea legislative act that establishes specific provisions for good clinical practice in clinical trials; eu member states must meet these provisions though the directive does not legislate howeu member statesnot explicitly provided; states that “[t]he accepted basis for the conduct of clinical trials in humans is founded in the protection of human rights and the dignity of the human being… as for instance reflected in the 1996 version of the helsinki declaration” [20] regulation of 16 april 2014 n°536/20142014eueu clinical trials regulationa binding legislative act applying to all clinical trials conducted in the eueu member statesnot explicitly providedinternational conference on harmonisation, good clinical practice1996us, eu, jp, aus, caich gcpan ethical and scientific quality standard for designing, conducting, recording, and reporting human subject research trials; serves as a unified standard for ca, the eu, jpn, and us to facilitate the mutual acceptance of clinical data by the regulatory authorities in these jurisdictionstargeted at those involved in the generation of clinical trial data intended to be submitted to regulatory authorities, especially in ca, the eu, jpn, and us; can also be used by others involved in clinical investigations “that may have an impact of the safety and well-being of human subjects” [22] not explicitly provided; states that “clinical trials should be conducted in according with the ethical principles that have their origin in the declaration of helsinki” ([22], art. National statement on ethical conduct in human research2007ausaustralian national statementmust be used to inform the design, ethical review, and conduct of human research funded by or taking place under the auspices of the bodies that have developed the statement (i. National health and medical research council, australian research council, australian vice-chancellors’ committee)researchers, members of ethical review bodies, and those involved in research governance, as well as potential research participantsdescribes four guiding values and principles: research merit and integrity, justice, beneficence, and respecttri-council policy statement, 2nd edition2014catcps2to be eligible to receive and administer research funds from the federal research agencies responsible for this policy (i. Canadian institutes of health research, natural sciences and engineering research council of canada, social sciences and humanities research council), institutions must agree to comply with it; while not required to do so, other organisations and entities are encouraged to adopt this policy to guide the ethical aspects of the design, review and conduct of research involving humansall those involved in the conduct and review of research funded by the federal research agencies, e. Institutions, researchers, ethics review boards, out three core principles: respect for persons, concern for welfare, and justiceresearch governance framework for health and social care, 2nd edition2005ukuk research governance frameworksets out a framework of principles, requirements, and standards for the governance of research in health and social care and applies to all research relating to the responsibilities of the secretary of state for healthintended for all those who design research studies, participate in research, host research in their organisation, fund research proposals or infrastructure, manage research, and undertake researchnot explicitly providedthe belmont report1979usbelmont reporta statement of basic ethical principles and guidelines intended to assist in resolving the ethical problems that surround the conduct of research created by the national commission for the protection of human subjects of biomedical and behavioral research for the department of health, education, and welfarethose involved in the review and conduct of researchlays out three basic ethical principles: respect for persons, beneficence, and justicetitle 45 code of federal regulations, part 461991uscommon ruleserves as a federal policy for human subjects research, and applies to all research conducted or supported by or affiliated with the federal agencies by which is has been adoptedthose involved in the review and conduct of research associated with the federal agencies by which the common rule has been adoptednot explicitly provided, but the regulations were created on the basis of the belmont international, eu european union, aus australia, ca canada, jp japan, uk united kingdom, us united -policy component stage of analysis consisted of an inter-policy analysis, allowing us to capture and explore patterns in the data across our sample. Using this truncated keyword allowed us to identify all uses of the terms ‘vulnerability’ or ‘vulnerable’. We hypothesised, based on the literature (as described in the background section), that research ethics guidance on vulnerability should include at least the following basic content: (1) a definition of vulnerability, (2) a discussion of the sources or circumstances from which vulnerability can arise and/or identification of groups likely to be in those circumstances, (3) an explanation of the ethical justification of the concept to aid in its application. This resulted in the addition of a fourth content category, ‘implications of vulnerability’, which captures responses to vulnerable participants laid out within the guidelines and policies. In their meaning) with one another, and (3) what overall impression a guideline or policy user might have about the concept of vulnerability within the -policy comparative ng policies in our sample reference vulnerability and/or vulnerable subjects, but only three out of eleven explicitly define these terms (table 2). Of these, the council for international organizations of medical sciences (cioms) and the tri-council policy statement: ethical conduct for research involving humans (tcps2) guidelines define vulnerability itself, while the international conference on harmonisation, good clinical practice (ich gcp) instead provides a definition of vulnerable subjects. These definitions share similar structures, all defining vulnerability or vulnerable subjects and identifying paradigmatic sources (or causes) of vulnerability. This reference suggests an important link between vulnerability and autonomy, though this connection is not further t regarding definitions of vulnerability and detailing the use of qualifying  intldeclaration of helsinki–• some groups and individuals are “particularly vulnerable” ([17], art. 8) euclinical trials directive––clinical trials regulation–– us, eu, jp, aus, caich gcpglossary defines vulnerable subjects as “[i]ndividuals whose willingness to volunteer in a clinical trial may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a hierarchy in case of refusal to participate” ([23], art. National ausnational statement–• where “potential participants [in dependent or unequal relationships] are especially vulnerable” special measures may be required ([23], p. 56)• people with a cognitive impairment, intellectual disability, or mental illness have “distinctive vulnerabilities as research participants” and are “more-than-usually vulnerable to various forms of discomfort or stress” ([23], p. 58) catcps2“vulnerability – a diminished ability to fully safeguard one’s own interests in the context of a specific research project. 210)• participants, researchers, and research ethics board members may be rendered “more vulnerable” during publicly declared emergencies ([24], p. 141) ukresearch governance framework–– usbelmont report–• “also, inducements that would ordinarily be acceptable may become undue influences if the subject is especially vulnerable” ([26], part c. Language captures nuances about degrees or types of international, eu european union, aus australia, ca canada, jp japan, uk united kingdom, us united states, cioms council for international organizations of medical sciences, tcps2 tri-council policy statement: ethical conduct for research involving humans, ich gcp international conference on harmonisation, good clinical definition provided by the tcps2 is distinct from the others because it explicitly states that vulnerability is context-dependent, and is experienced “to different degrees and at different times, depending on [an individual’s or group's] circumstances” ([24], p.

The declaration of helsinki, australian national statement, and belmont report, for example, discuss participants who are “particularly vulnerable” [17], “more-than-usually vulnerable” [23], or “especially vulnerable” [26], respectively. Unlike the tcps2, no other guidelines in our sample state explicitly that vulnerability should be thought of as existing on a spectrum, or as a feature that can vary between l justifications for the concept of guidelines and policies (cioms, unesco declaration, declaration of helsinki, australian national statement, tcps2, belmont report) provide explicit ethical argumentation relating to vulnerability and/or vulnerable subjects. In all cases where guiding ethical principles are provided by a policy or guideline, vulnerability-related concerns are discussed in the application of each t on the ethical justification of vulnerability and its normative status in each  intlich gcp–consideration for ethics reviewciomsthe protection of dependent or vulnerable persons and populations is described itself as a principle; additionally, concerns relating to vulnerability are grounded in both the principles of respect for persons and justicefundamental principle/application of other principlesunesco declarationrespect for human vulnerability and personal integrity is itself a fundamental principle in this frameworkfundamental principledeclaration of helsinkiconcerns related to vulnerability are themselves principles in this frameworkfundamental principle euclinical trials directive–consideration for ethics reviewclinical trials regulation–consideration for ethics reviewnational ausaustralian national statementconsiderations related to vulnerability are discussed in relation to the principles of principles of respect for persons, research merit and integrity, justice, and beneficenceapplication of other principles catcps2the principles of respect for persons, justice (fairness and equity), and concern for welfare all entail special obligations regarding vulnerabilityapplication of other principles ukresearch governance framework–consideration for ethics review usbelmont reportthe principles of respect for persons, beneficence, and justice all entail special obligations relating to vulnerabilityapplication of other principlescommon rule–consideration for ethics international, eu european union, aus australia, ca canada, jp japan, uk united kingdom, us united states, cioms council for international organizations of medical sciences, tcps2 tri-council policy statement: ethical conduct for research involving humans, ich gcp international conference on harmonisation, good clinical normative status of the concept of vulnerability is inconsistent across policies and guidelines. In certain cases (cioms, australian national statement, tcps2, belmont report), obligations towards vulnerable research participants arise from the application of other fundamental principles. Specifically, principles 19 and 20 of the declaration of helsinki focus on vulnerability, with 19 stating that “[s]ome groups and individuals are particularly vulnerable and may have an increased likelihood of being wronged or of incurring additional harm” [17]. In the introduction to the cioms guidelines, issues of human rights are described as relating to two principles, one of which is the “protection of dependent or vulnerable persons and populations” ([18], p. 11), while the principle of respect for persons is described as entailing “at least two fundamental ethical considerations”, including “protection of persons with impaired or diminished autonomy, which requires that those who are dependent or vulnerable be afforded security against harm or abuse” ([18], p. The remaining guidelines (ich gcp, eu clinical trials directive, eu clinical trials regulation, united kingdom research governance framework, common rule), vulnerability is not explicitly discussed in relation to any ethical principles, nor is it described as a guiding principle itself. In these cases, concerns relating to vulnerable persons seem to serve the role of consideration for ethics review or ethical research with no explicit ethical fying vulnerable groups and guidelines and policies in the sample provide means through which vulnerability can be identified. Vulnerable groups identified in our sample are captured in table 4, along with the corresponding explanations of why a subject group is considered vulnerable or what they are vulnerable to, when these details are available. Notably, while the eu clinical trials directive and clinical trials regulation, as well as the united kingdom research governance framework, all identify vulnerable subject groups, none of these policies provide any supporting explanation. Further, only four policies (cioms, australian national statement, tcps2, and the common rule) provide any explanations of what certain identified groups are vulnerable able groups identified in our sample, as well as explanations for this designation, where d by social status or situation prisoners (cioms, ich gcp, aus. National statement, tcps2, common rule)vulnerable because: • historically considered vulnerable and “have, at times, been treated unfairly and inequitably in research, or have been excluded from research opportunities”a ([24], p. 8) • explanation unclear [18, 22]vulnerable to: • coercion or undue influence [27] certain ethnic, racial minority, or ethnocultural groups (cioms, ich gcp, tcps2, belmont report)vulnerable because: • historically considered vulnerable and “have, at times, been treated unfairly and inequitably in research, or have been excluded from research opportunities”a ([24], p. 8) • may continually be sought as research subjects due to ready availability and administrative convenience; have a dependent status and, frequently, compromised capacity for free consent; are easy to manipulate as a result of their illness or socioeconomic condition b[26] • explanation unclear [18, 22] patients in emergency settings, prospective participants for emergency research (cioms, clinical trials regulation, ich gcp, tcps2)vulnerable because: • their incapacity to make decisions creates vulnerable circumstances [24] • no explanation [21] • explanation unclear [18, 22] subordinate members of hierarchies or relationshipsc (cioms, ich gcp, aus. National statement)vulnerable because: • voluntary consent may be compromised by expectations of benefit or repercussions from superiors [18, 22] • pre-existing relationships may compromise the voluntariness of consent because they typically involve unequal status, where one party has influence or authority over the other [23]vulnerable to: • being over-researched [18, 23] economically disadvantaged persons (belmont report, common rule)vulnerable because: • dependent status, impaired capacity to consent, easy to manipulate as a result of their illness [26]vulnerable to: • coercion or undue influence [27] homeless persons (cioms, ich gcp) • explanation unclear [18, 22] institutionalized persons (tcps2, belmont report)vulnerable because: • historically considered vulnerable and “have, at times, been treated unfairly and inequitably in research, or have been excluded from research opportunities”a ([24], p. 8) • their ability to fully safeguard their own interests in research may be limited, and their situation may compromise the voluntariness of consent in other ways [24] • may continually be sought as research subjects due to ready availability and administrative convenience; have a dependent status and, frequently, compromised capacity for free consent; are easy to manipulate as a result of their illness or socioeconomic conditionb [26] nomads (cioms, ich gcp) • explanation unclear [18, 22] persons in nursing homes (cioms, ich gcp) • explanation unclear [18, 22] persons lacking political or social power (cioms) • explanation unclear [18] refugees or displaced persons (cioms, ich gcp) • explanation unclear [18, 22] women (cioms, tcps2)vulnerable to: • in some parts of the world, they may be vulnerable to neglect or harm in research “because of their social conditioning to submit to authority, to ask no questions, and to tolerate pain and suffering” ([18], p. 73)vulnerable because:• historically considered vulnerable and “have, at times, been treated unfairly and inequitably in research, or have been excluded from research opportunities”a ([24], p. 8) countries or communities with limited resources (cioms)vulnerable to: • exploitation by sponsors and investigators who are relatively wealthy [18] educationally disadvantaged persons (common rule)vulnerable to: • coercion or undue influence [27] members of communities unfamiliar with modern medical concepts (cioms) • explanation unclear [18] neonates in intensive care (aus. National statement)vulnerable because: • developmental vulnerability (potential for long-range impacts on health and development) [23] patients in terminal care (aus. National statement)vulnerable to: • unrealistic expectations of benefit [23] participants and researchers in research that uncovers illegal activities (aus. National statement)vulnerable because: • vulnerability may arise because of discovery of participants’ illegal activity [23] those with diminished capacity for self-determination (tcps2) • historically vulnerable and “have, at times, been treated unfairly and inequitably in research, or have been excluded from research opportunities”a ([24], p. 8) the least organizationally developed communities (tcps2)vulnerable to: • exploitation [24]grouped by patient/participant condition children, minors, or young people (cioms, clinical trials directive, clinical trials regulation, aus. National statement, tcps2, common rule)vulnerable because: • limited freedom or capacity to consent [18, 24] • vulnerability arising from developmental stage [24] • no explanation [20, 21] • explanation unclear [23]vulnerable to: • coercion or undue influence [27] persons with mental illness or mental health problems (clinical trials regulation, aus. National statement, tcps2, uk research governance framework)vulnerable because: • historically considered vulnerable and “have, at times,  been treated unfairly and inequitably in research, or  have been excluded from research opportunities”a ([24], p. 8) • unclear [21, 25]vulnerable to: • various forms of discomfort and stress [23] elderly persons (cioms, clinical trials regulation, tcps2)vulnerable because: • likely to acquire “vulnerability-defining” traits (e. 65] • historically considered a group in vulnerable circumstances “have, at times, been treated unfairly and inequitably in research, or have been excluded from research opportunities”a ([24], p. 8) • no explanation [21] persons with limited (or no) freedom or capacity to consent (cioms, clinical trials regulation, ich gcp)vulnerable because: • relatively (or absolutely) incapable of protecting their own interests [18] • no explanation [21] • explanation unclear [22]vulnerable to: • exploitation for financial gain by guardians [18] pregnant or breastfeeding women (clinical trials regulation, common rule)vulnerable to: • coercion or undue influence [27] • no explanation [21] adults with learning difficulties (uk research governance framework) • no explanation [25] handicapped persons (common rule) • no explanation [27] mentally disabled persons (common rule)vulnerable to: • coercion or undue influence [27] persons who have serious, potentially disabling or life-threatening diseases (cioms)vulnerable because: • may be treated with drugs or other therapies with unproven safety and efficacy [18] very sick persons (belmont report)vulnerable because: • may continually be sought as research subjects due to ready availability and administrative convenience; have a dependent status and, frequently, compromised capacity for free consent; are easy to manipulate as a result of their illness or socioeconomic conditionb [26] people suffering from multiple chronic conditions (clinical trials regulation) • no explanation [21] persons with a cognitive impairment or intellectual disability (aus. Is not clear whether the tcps2 intends these groups it refers to as having been historically in vulnerable circumstances as still at risk of this. Given that this is mentioned but not negated, we included these groups in our belmont report lists a number of vulnerable groups and a series of explanations of their vulnerability. The australian national statement lists “carers and people with chronic conditions or disabilities, including long-term hospital patients, involuntary patients, or people in residential care or supported acumination; health care professionals and their patients or clients; teachers and their students; prison authorities and prisoners; governmental authorities and refugees; employers or supervisors and employees (including members of the police and defence forces); service-providers (government or private) and especially vulnerable communities to whom the service is provided” ([23], p. Table is grouped by category, and organized by the number of times a group is mentioned in the policies and the sample, a great number of groups are identified as vulnerable. Excluding the examples of subgroups discussed in the footnote to table 4), 32 groups were identified; when these subgroups are included, the total number of groups identified as vulnerable expands to 51. It outlines various scenarios regarding the vulnerability of young people: in some cases, young people may be able to understand information but their “relative immaturity means they remain vulnerable” ([23], p. 50); in other cases they may be “mature enough to understand and consent [though] not vulnerable through immaturity in ways that warrant additional consent” ([23], p. 50); and in yet other cases, young people may be “mature enough to understand the relevant information and to give consent, although vulnerable because of immaturity in other respects” ([23], p. The ‘other respects’ in which immaturity can render young people vulnerable are not made explicit, leaving the designation of vulnerability open to interpretation in this case. Other policies employ similarly open-ended strategies, the cioms guidelines most explicitly by listing vulnerable groups and sources of vulnerability, and adding that “[t]o the extent that these and other classes of people have attributes resembling those of classes identified as vulnerable, the need for special protection of their rights and welfare should be reviewed and applied, where relevant” ([18], p. Is little overlap between the explanations provided by policies and guidelines for other frequently-identified vulnerable groups, and there was a lack of explanation from at least two of them for prisoners, patients in emergency settings, and ethnocultural and racial minorities. The eu clinical trials directive and clinical trials regulation and united kingdom research governance framework provide no explanation or justification for any of the groups they designate as vulnerable, and while the common rule specifies that it is concerned with vulnerability to coercion or undue influence, it does not address 'handicapped persons' in this explanation despite also identifying them as a vulnerable subject group.

The cioms and ich gcp guidelines, on the other hand, provide definitions of vulnerable subjects and explanations for some vulnerable groups. However, both of these policies include categories of 'other vulnerable groups' and fail to provide any connection between these other groups and their overarching definition of vulnerability. As such, it is unclear whether they are designated as vulnerable on some other unstated policies and guidelines identify sources or circumstances of vulnerability independently, i. For example, neither the declaration of helsinki nor the unesco declaration identifies any particular subject groups as vulnerable. It is important to note that, while the tcps2 does identify certain groups as likely to be in vulnerable circumstances, it qualifies any such labels, emphasising that “[i]ndividuals should not automatically be considered vulnerable simply because of assumptions made about the vulnerability of the group to which they belong” ([24], p. S of vulnerability identified independently from vulnerable ation of helsinkian increased likelihood of being wronged or of incurring harmunesco declarationpersons may be rendered vulnerable by disease or disability or other personal, societal or environmental conditionstcps2persons may be in vulnerable circumstances because of social or legal stigmatisation associated with their activity or 2 tri-council policy statement: ethical conduct for research involving ations of vulnerability in policies in our sample identify practical implications of vulnerability in research, i. Responses to vulnerability in the design and review of research and to vulnerable participants themselves. Further, these implications span the research process, from considerations important in the design of research to actions that must be taken when vulnerable persons are participating in research (table 6). Ations of vulnerability, grouped by research is carried out with vulnerable participants it should be responsive to the needs, conditions, or priorities of the vulnerable group involveddeclaration of helsinki;ciomsvulnerable subjects should be involved in research only when it cannot be carried out with less vulnerable subjectsciomsspecial justification is required for involving vulnerable groups in research and appropriateness ought to be demonstratedcioms;belmont reportchildren should not be included in early-phase research until therapeutic effects have been shown in adultsciomsopportunities to participate in and influence research affecting their welfare should not be withheld from vulnerable groupstcps2members of vulnerable groups are entitled to access the benefits of researchciomschildren must be involved in studies of medicinal products likely to be of value to themeu clinical trials directivepeople with a cognitive impairment, intellectual disability, or mental illness are entitled to participate in research, which need not be limited to their particular impairment, disability, or illnessaustralian national statementresearch with communities vulnerable to exploitation should strive to enhance capacity for participationtcps2patients receiving high-risk clinical care should not be inappropriately included in or excluded from researchtcps2risk to vulnerable subjects is justified when it arises from interventions that will provide a direct health benefit, or when it will benefit the subject’s population l protections and duals and groups of special vulnerability should be protectedunesco declaration special ethical obligations exist towards vulnerable subjectstcps2 vulnerable subjects should receive special/specific protectionsdeclaration of helsinki groups or individuals in vulnerable circumstances may need or desire special measures to ensure their safety in a specific research projecttcps2 vulnerable subjects should be afforded security against harm or abusecioms special (or additional) protections for the rights and welfare of vulnerable subjects should be appliedcioms; common ion and l attention should be paid to trials involving vulnerable subjectsich gcp special attention or regard should be paid to vulnerable communities, groups, or personsunesco declaration;tcps2 researchers and rebs should recognise and address changes in participants’ circumstances that may impact their ch ethics board reviewing research with vulnerable subjects should include members with expertise on these populationscommon rule;eu clinical trials regulation community members on rebs ought to reflect participant’s perspectives, particularly important when participants are vulnerable and/or risks are ing harms, risks and those gauging the severity of harm in research, the vulnerability of a population will be relevantaustralian national statement the existence of vulnerable circumstances may require greater effort to minimise risks/maximise benefits to participantstcps2 care must be taken to ensure the risks and burdens of proposed research with persons with a cognitive impairment, intellectual disability, or mental illness are justified by potential benefitsaustralian national tment vulnerability of persons in unequal, dependent relationships must be taken into account when considering recruiting these personsnational s of informed t may need to be re-confirmed in research where participants are vulnerablenational statement the method of consent in qualitative research depends, in part, on the vulnerability of the research participant; the method must be tailored for their protectionnational statement;tcps2 when requirements of free, informed, ongoing consent cannot be met, vulnerable participants ought to be involved in decision-making, i. Obtaining assent, asking about their feelings regarding participationtcps2 clinician-researchers must take care not to overplay the benefits of research participation to vulnerable patients, who may be misled to enter research with false hopetcps2 inducements that may not be excessive or inappropriate for other participants may be undue influences if the subject is especially vulnerablebelmont report care should be taken in the informed consent process to ensure that women vulnerable to coercion have adequate time and a proper environment in which to take decisionscioms care should be taken in the informed consent process for adults with mental health problems or learning difficulties to ensure that information is provided in the appropriate format and that the roles and responsibilities of those involved are clearly explained and understooduk research governance framework additional consent from a parent or guardian may be required for young people who are vulnerable through immaturity in ways that warrant thisnational statement researchers should invite participants in dependent or unequal relationships to discuss their participation with someone who can support them in making their decision; especially vulnerable participants in these circumstances should be offered participant advocatesnational must assess risks and benefits of debriefing participants and whether debriefing plan is appropriate for participants, especially when they are research ethics board, cioms council for international organizations of medical sciences, tcps2 tri-council policy statement: ethical conduct for research involving humans, ich gcp international conference on harmonisation, good clinical practice. Majority of policies and guidelines identify implications relating to restrictions for research with vulnerable groups or individuals, but these entail both negative and positive duties. Overall, these policies and guidelines propose that the involvement of vulnerable groups in research ought to be restricted to some extent; vulnerable persons ought to be involved only when the research cannot be carried out with persons who are less vulnerable and special justification is required for their involvement. However, when these persons are involved in research, additional actions are required, such as the design of research that is responsive to their needs or priorities and the provision of benefits relevant to their group/subject population. Across our sample, a common underlying assumption seems to be that vulnerable groups can and should be involved in research, but that additional measures are required to ensure this involvement occurs in an ethical manner. In fact, several policies (cioms, eu clinical trials directive, australian national statement, and tcps2) assert that vulnerable groups have a right to participate in research and access its benefits, and while the others do not identify such an entitlement, none go so far as to state that the outright exclusion of vulnerable groups from research best serves to protect implications of vulnerability all tend towards careful inclusion rather than outright exclusion of vulnerable groups from research. However, there is more variability regarding the extent to which these protections afford agency to vulnerable subjects. The majority specify considerations and actions for researchers and rebs, with few explicitly identifying the desires of these individuals as relevant in the application of these measures. The tcps2 in particular puts forth numerous measures intended to promote the agency of those in vulnerable circumstances. For example, it is suggested that they should be afforded opportunities to influence research and that research ought to enhance vulnerable persons’ capacity for participation. Furthermore, the tcps2 guidance states more broadly that vulnerable groups may need or desire special measures to ensure their safety, suggesting a role for participants in the design and implementation of their addition to conditions and restrictions for research involvement, the process of informed consent is a major area of focus in the policies and guidelines. Here in particular there is an emphasis on the provision of meaningful support to enable vulnerable persons to offer a fully informed consent to research. Mechanisms of support include ensuring adequate time and an appropriate environment (cioms), as well as ensuring that information is fully explained and understood (united kingdom research governance framework). In their meaning) with one another, and (3) what overall impression a guideline or policy user might have about the concept of vulnerability within the content areas of vulnerability addressed within each policy/ational declaration of helsinki–xxx ciomsxxxx unesco declaration–xxx eu clinical trials directive–x–x eu clinical trials regulation–x–x ich gcpxx–xnational australian national statement–xxx tcps2xxxx uk research governance framework–x–x belmont report–xxx common rule–x– council for international organizations of medical sciences, tcps2 tri-council policy statement: ethical conduct for research involving humans, ich gcp international conference on harmonisation, good clinical ational policies and ation of declaration conveys a harm/wrong-based conceptualisation of vulnerability that is internally coherent due to its broad language. Implications of vulnerability focus on the need for responsive research, special justification for involving vulnerable persons, and to-group benefits, suggesting these harms include the unfair distribution of the risks and benefits of guidelines present an autonomy-based conceptualisation of vulnerability that is comprehensive in scope but lacks internal clarity in its discussion of vulnerable groups. While the provided definition focuses on vulnerability as stemming from an incapacity to protect one’s own interests owing to both individual and environmental features, vulnerability is also explicitly linked to justice-based concerns about the distribution of the risks and benefits of research. The identified implications of vulnerability thus correspond to concerns relating to participants’ ability to provide free and informed consent and relating to the appropriateness of involving vulnerable participants in research. There is a lack of clarity and consistency, however, in the discussion of vulnerable groups. The cioms guidelines distinguishes between three types of vulnerable groups – those who are “conventionally considered vulnerable”, those who are vulnerable due to social pressures (i. Persons in dependent relationship with researchers, such as students or pharmaceutical employees), and “other groups or classes” ([18], p. The declaration identifies respecting the personal integrity of vulnerable groups as a key implication, suggesting that vulnerability may consist, at least in part, of risks to one’s personal integrity. Other implications include a need to perform research with children in which group benefits will be obtained and ensuring the interests of the patient prevail over those of society. As such, in addition to concerns relating to consent, the directive implicitly relates vulnerability to concerns with the distribution of the benefits and burdens of research. The directive does not provide an ethics framework, so interpretation of this guidance cannot be guided by ethical clinical trials clinical trials regulation conveys a mixed concept of vulnerability, concerned both with issues of consent and increased health risks. While vulnerability is not defined and no explanation for the vulnerability of listed groups is provided, they can be grouped by those assumed to face issues of consent in research (people affected by mental health disorders, minors, and incapacitated subjects) and those who may be at greater physical (i. Health) risks in research (frail or older people, people suffering from chronic conditions, and pregnant or breastfeeding women). The implications identified do not fall along this consent/health risk distinction, however, with a need for research to improve treatments a key implication for frail or older people, people with chronic conditions, and people affected by mental health disorders, and the need for special expertise in research ethics review identified as a specific consideration for minors, incapacitated subjects, and pregnant or breastfeeding women. No ethical framework is provided in the regulation to facilitate interpretation of this guidelines present a consent-based concept of vulnerability that lacks internal clarity due to its broad scope of vulnerable groups. Vulnerable subjects are defined as those whose ability to provide voluntary consent may be compromised by social pressures, and the first category of groups listed is clearly linked to this definition. However, it is not clear how the wide range of 'other vulnerable groups' relates to this definition or which characteristics are thought to render them vulnerable. The guidelines do not provide an ethical framework to facilitate interpretation of the concept of al policies and lian national national statement suggests a comprehensive conceptualisation of vulnerability relating to concerns about consent, fair involvement in research, and a balance of risks and benefits to participants.

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However, while persons in pre-existing/dependent relationships with researchers are said to face issues providing voluntary consent, the key implication relating to this group is grounded in the principle of justice (i. Similarly, while persons with terminal illness are said to be vulnerable to unrealistic expectations of benefit (i. May have a compromised ability to consent), the key response to this is to balance the benefits and burdens of research and is grounded in tcps2 presents an autonomy-based conceptualisation of vulnerability that is comprehensive in scope. However, the policy still relies on the identification of groups likely to be vulnerable, as well as the identification of circumstances that can create vulnerability for a participant. While the definition of vulnerability itself is implicitly linked to the principle of autonomy, obligations towards participants in vulnerable circumstances are more comprehensive and are grounded in the principles of respect for persons, concern for welfare and kingdom research governance framework conveys a consent-based conceptualisation of vulnerability that is narrow in scope, labelling adults who may have issues with understanding and decision-making as vulnerable. It is assumed that vulnerable subjects have a “dependent status and frequently compromised capacity for free consent” ([26], part c. Special considerations about vulnerable subjects are discussed in reference to respect for persons (ordinary inducements may be come undue influences for vulnerable populations), beneficence (special justification is required for research with vulnerable subjects) and justice (vulnerable subjects must be protected from over-recruitment to research). A number of groups are identified as vulnerable, including handicapped persons, but while the other groups are said to be vulnerable to coercion or undue influence, no explanation is provided for handicapped persons. Without a definition of vulnerability, it is not clear what special vulnerability handicapped persons may be faced with in sionthe objective of this analysis was to describe the concept of vulnerability in research ethics policies and guidelines, and to assess how it is conceptualised and operationalised. Instead, vulnerability is most frequently discussed in terms of vulnerable groups, with some attention given to the sources of vulnerability, and the implications of conducting research with vulnerable participants. Responding to vulnerability requires caution and special consideration on the part of researchers and rebs but, ultimately, the implications identified in our study suggest that participant vulnerability need not signal a need for exclusion from research. The few explicit definitions in our sample define vulnerability as a deficiency of the participant, as an inability to protect one’s interests in research. We further discuss how our findings relate to (1) previous critiques found in the scholarly literature and (2) the role of stakeholder engagement in the process of refining the concept of vulnerability in research ethics policies and us critiques from the scholarly the scholarly literature several critiques of vulnerability in research ethics guidelines have been voiced. First, concerns have been raised that the manner in which vulnerability is defined and operationalised in research ethics governance stereotypes and reinforces stigma about whole categories of individuals [9, 12, 31]. Our results reinforce these concerns, as the reliance on listing groups of vulnerable persons is rampant. This labelling [6] or sub-population [30] approach does little to bring attention to the importance of context and of assessing the characteristics of individual research participants beyond their membership in a group [5, 6, 9]. It is important to note that research protocols create groups through sampling “regardless of whether the sample is drawn from a naturally occurring community” ([9], p. Furthermore, it seems that the designation of some groups as vulnerable may be based on assumptions not supported by evidence (e. The designation of pregnant women as vulnerable to coercion or undue influence in the common rule). Major concern has been that vulnerability, as conceived of in the guidelines, focuses overwhelmingly on a lack of ability to consent [10], blinding researchers and rebs to other relevant types of vulnerability, relating, for example, to an increased risk of exploitation [32] or a lack of basic rights [33]. Even the tcps2, with its notable emphasis on vulnerability as a context-dependent feature, ultimately defines it as a person’s inability to protect their own interests in research. In contrast, a growing body of scholarly literature converges around the notion that vulnerability is a relational feature, borne of power asymmetries between participants and research staff, investigators and institutions [10, 31, 34]. Adopting such a view in research ethics guidelines may better serve participants, encouraging measures that would empower and promote their agency in the research context [34]. The existence of conflicts of interest) can actively contribute to disempowering research participants/research subjects and thus create the need for remediation that does not necessarily concern the research participant per se [6, 10]. Need for evidence and stakeholder engagement to refine research ethics policies and guidance on ch ethics guidelines and policies typically stress the importance of vulnerability. However, it has been argued that vulnerability is not a substantive ethical concept in itself, serving only as a marker of other research ethics concerns already captured by existing concepts such as harm or consent [35]. This is certainly an important conceptual concern, but what may be of greater relevance in the realm of policy development is the degree to which the concept of vulnerability is a useful, effective tool for those designing, reviewing and conducting research [5, 6]. It may be the case that vulnerability merely serves to signal concerns relating to other pre-existing ethical concepts, but if these concerns would be otherwise missed, the concept would then be proven to have a vital practical function in research ethics. Luna argues that vulnerability, when conceived of as dynamic, flexible and inessential, can serve as “a fine grain tool to analyze, interpret, and evaluate the research situation” ([6], p. Luna’s account of vulnerability thus provides researchers and rebs with a conceptual tool with which to examine a research participant’s circumstances, identify potential vulnerabilities (e. Relating to capacity or social pressure in the consent process), and develop targeted strategies for their spite of these more sophisticated proposals, there is a dearth of empirical evidence on the functioning of research ethics committees and outcomes of research ethics policies and, to our knowledge, few studies have examined the impact or understandings of the concept of vulnerability based on research ethics guidelines and/or more elaborate scholarly accounts. Empirical evidence has shown that an understanding of vulnerability in the context of research cannot be assumed to be universal – in a study with russian and romanian research ethics trainees, loue and loff [36] found that, at the initiation of their training, their existing understanding of vulnerability varied considerably from conceptualisations in the international guidelines. 37] gathered researchers’ perspectives on vulnerability in hiv/aids clinical trials and on the common rule guidance related to vulnerability and found that researchers assessed vulnerability in relation to situational factors that can render participants vulnerable, and that they emphasised the need to assess vulnerability on a case-by-case basis (i. Taken together, these studies underscore the need for policymakers to clearly delineate and define the concerns vulnerability is intended to encompass, and to assess the alignment of these views with those of research stakeholders. Further, there is a need to assess the outcomes of vulnerability-related guidance and policy and to understand whether protections are actually effective and their impact on vulnerable participants themselves. In this endeavour, the perspectives of researchers and rebs, but also of research participants, who seem to have been largely left out of the development of research ethics guidelines, could be sionour in-depth analysis of human research ethics guidelines and policies allowed us to analyse different perspectives on the concept of vulnerability, including the definitions, justifications, sources, and implications of vulnerability for researchers and rebs. This lack of clarity could diminish the usability of the guidance put forth in policies and therefore undermine its impact on research practices. Practically-oriented refinement of vulnerability could be facilitated by engaging research stakeholders and examining the concrete impact of guidance and policy related to ledgementsthe authors would like to thank michael mcdonald for his feedback on an earlier version of this manuscript, as well as the members of the neuroethics research unit for their feedback throughout the conduct of this g for this study was provided by a cihr grant held by eb, er and mem, an frq-s career award held by er, and graduate scholarships from the ircm and mcgill university held by dbr. No funding body played any role in the design of the study or collection, analysis, interpretation of the data, or in the writing of the bility of data and datasets used and/or analysed during the current study are available from the corresponding author on reasonable s’ and er developed the idea of conducting a review of research ethics policies and guidelines. Dbr drafted the final version of the manuscript and all authors agreed on the final authors have no competing interests to t for approval and consent to s’ affiliations(1)neuroethics research unit, institut de recherches cliniques de montréal(2)biomedical ethics unit and division of experimental medicine, mcgill university(3)faculty of dentistry, oral health and society research unit, mcgill university(4)department of medicine and department of social and preventive medicine, université de montréal(5)department of neurology and neurosurgery, mcgill ons & , zotero, reference manager, refworks (.

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