Research during outbreaks Key ethical issues Andreas Reis

Research during outbreaks Key ethical issues Andreas Reis, MD MSc Global Health Ethics Unit Frühjahrsakademie der Studienstiftung, AG 1 Annecy, 17. -24. März 2013

Outline • Introduction • WHO Guidelines & Training Manual • Selected issues: • Community involvement • Informed consent • Study design • Other topics Entebbe, 9 -10 March 2017

Introduction Entebbe, 9 -10 March 2017

Introduction • During an infectious disease outbreak: ethical obligation to learn as much as possible as quickly as possible, in order to inform the ongoing public health response, and to allow for proper scientific evaluation of new interventions being tested. • Carrying out this obligation requires carefully designed and ethically conducted scientific research. Entebbe, 9 -10 March 2017

Introduction • Research conducted during an infectious disease outbreak should be designed and implemented in conjunction with other public health interventions. • Research should not compromise the public health response to an outbreak or the provision of appropriate clinical care. • All clinical trials must be prospectively registered in an appropriate clinical trial registry. Entebbe, 9 -10 March 2017

Introduction International ethical standards of non-outbreak situations apply: • studies are scientifically valid and add social value; • risks are reasonable in relation to anticipated benefits; • participants are selected fairly and participate voluntarily (in most situations following an explicit process of informed consent); • participants’ rights and well being are sufficiently protected; • studies undergo an adequate process of independent review; • All actors in research, have an obligation to ensure that these principles are upheld in outbreak situations. Entebbe, 9 -10 March 2017

WHO Guidelines & Training Manual Entebbe, 9 -10 March 2017

WHO Guidance document (2016) Entebbe, 9 -10 March 2017

WHO Training Manual l November 2015: Publication of WHO training manual l Presentations & case studies l 19 co authors, many reviewers l Materials already used in 8 workshops (Guinea, Sierra Leone, Liberia, South Africa, Tunisia, China, Cambodia) l More workshops planned (2017: Oman, Thailand) Entebbe, 9 -10 March 2017

Core competencies I. RESEARCH AND SURVEILLANCE Core Competency 1: Ability to analyse the boundaries between public health practice (including surveillance) and research, and their ethical implications in public health emergencies. Core Competency 2: Ability to define adequate processes for ethics review in public health interventions, surveillance, and research in the course of public health emergencies. Core Competency 3: Ability to identify tensions between the common good and individual autonomy in the course of epidemic and disaster response: SURVEILLANCE Core Competency 4: Ability to identify tensions between the common good and individual autonomy in the course of epidemic and disaster response: RESEARCH AND CLINICAL TRIALS Core Competency 5: Ability to explain how publication ethics relate to public health surveillance or research in public health emergencies. Entebbe, 9 -10 March 2017

Core competencies II. PATIENT CARE Core Competency 6: Ability to define ethically relevant criteria for triage, resource allocation and standard of care in the course of epidemic and disaster response. Core Competency 7: Ability to discuss the professional duties of health care workers in the conduct of public health surveillance or research in public health emergencies. Entebbe, 9 -10 March 2017

Online training course Entebbe, 9 -10 March 2017

Selected ethical issues Entebbe, 9 -10 March 2017

Public & community engagement Entebbe, 9 -10 March 2017

Community engagement: How NOT to do it Public engagement for testing GGM Source: Guidance framework for testing of GMM. WHO, TDR & FNIH, 2014 Entebbe, 9 -10 March 2017

Public & community engagement: background l Overarching ethical principle: communities Respect for l Trust of communities is key to success! l Ethical obligations broader than activities mandated by administrative laws or policies l Regulatory compliance ≠ ethical & community engagement obligations Entebbe, 9 -10 March 2017

Public & community engagement l Rigorous site ‐selection procedures. l Early initiation of community engagement activities. l Characterize and build knowledge of the community, its diversity and its changing needs. l Provide information about the research and ensure that its purpose is clear. l Establish relationships and commitments to build trust with relevant authorities in the community. l Understand community perceptions and attitudes about the proposed research. Entebbe, 9 -10 March 2017

Public & community engagement l Identify, mobilize and develop relevant community assets and capacity. l Maximize opportunities for stewardship, ownership and shared control by the community. l Ensure adequate opportunities and respect for dissenting opinions. l Secure permission/authorization from the community – not same as informed consent! l Review, evaluate and if necessary, modify engagement strategy. (Source: Lavery et al, 2010) Entebbe, 9 -10 March 2017

Public & community engagement: levels l Within the project team: articulate value and social purpose of research; ethical reflection l With the host community: – obligations to people living within a trial site – Clarify interests at stake and respond to concerns – Reaching agreement on whether trial should proceed l Third parties: Individuals not immediately associated with the trial site (public health or intl. development organizations, general public) – consider and respond to concerns Entebbe, 9 -10 March 2017

Public & community engagement l Adequate communication & engagement plans should be put in place before the start l Importance of scientific team to be involved in community engagement l But: need for specialized skills of social scientists & communication experts l Rumour management: Public opinion can quickly turn Entebbe, 9 -10 March 2017

Informed consent Entebbe, 9 -10 March 2017

Informed consent l Process by which individuals receive adequate information and given an explicit choice about whether or not to accept a particular intervention l Several reasons in favour of respecting one’s autonomy: – Individuals are often in a good position to determine what is in their own best interests – hence facilitates well being – Autonomy is often itself seen as a component of well being – Respect for individuals can be indirectly shown by acknowledging their self sovereignty l Routinely required in clinical practice and research Entebbe, 9 -10 March 2017

Informed consent in emergencies l Informed consent must be carefully managed for research in public health disasters l Special factors of a public health emergency need to be taken into consideration l Populations are vulnerable, desperate, with no other choice of treatment beyond experimental treatment – impacts on voluntariness l May be difficult: language/cultural barriers, traumatic shock, cognitive impairment, logistical and practical difficulties, etc. l Must take consideration of inclusion of vulnerable populations in research Slide reproduced from presentation titled “Ethical issues in conduct of trials in the context of an epidemic – general ethical considerations” by Lisa Schwartz Entebbe, 9 -10 March 2017

Assent l Children and adolescents who are legally minors cannot give legally valid informed consent, but they may be able to give assent. l To give assent means that the child or adolescent is meaningfully engaged in the research discussion in accordance with his or her capacities. l Assent must be considered as a process and is not merely the absence of dissent. (Source: CIOMS 2016) Entebbe, 9 -10 March 2017

Assent l Researchers must involve the child or adolescent in the actual decision making process and use age appropriate information. l The process of obtaining assent must take into account not only the age of children, but also their individual circumstances, life experiences, emotional and psychological maturity, intellectual capabilities and the child’s or adolescent’s family situation. Entebbe, 9 -10 March 2017

Assent l As adolescents near the age of majority, their agreement to participate in research may be ethically (though not legally) equivalent to consent. l In this situation, parental consent is ethically best considered as “co consent” but legally, the adolescent’s agreement remains assent. l If child or adolescent participants reach the legal age of majority according to applicable law and become capable of independent informed consent during the research, their written informed consent to continued participation must be sought. Entebbe, 9 -10 March 2017

Proxy consent l Proxy/ surrogate / third party consent: a substituted judgment by a close relative or friend, based on knowledge of patient's values, preferences, and view of life. l Research should be designed specifically to benefit critically ill patients; no other way of doing the research l Incremental non therapeutic risk must only comprise a minimal risk. Entebbe, 9 -10 March 2017

Deferred consent l Normally: informed consent prior to researcn l But sometimes not possible, e. g. emergencies l Deferred consent: When a patient is enrolled into a study, and consent is taken later, either from a surrogate decision maker or from the patient when he/she is able to provide informed consent. l Ethical justification for using this exceptional informed consent process: based on a balance between risks and benefits. l information and biological materials collected will not be used until the deferred informed consent process can be applied to the patient or to a legal representative Entebbe, 9 -10 March 2017

Study design Entebbe, 9 -10 March 2017

Study design Selecting an appropriate research methodology • Exposing research participants to risk is ethically unacceptable if the study is not designed in a manner capable of providing valid results. • It is therefore imperative that all research be designed and conducted in a methodologically rigorous manner. Entebbe, 9 -10 March 2017

Study design l In clinical trials, the appropriateness of features such as randomization, placebo controls, should be determined on a case by case basis, with attention to both the scientific validity of the data and the acceptability of the methodology to the community l Cluster randomized trials and stepped wedge designs may be more acceptable to communities l In qualitative studies, the potential benefits of using methodologies such as focus groups (in which individual confidentiality cannot be guaranteed) or of interviewing traumatized victims should be balanced against the risks and burdens to the individuals involved. Entebbe, 9 -10 March 2017

Study design l Research participants: – Informed consent remains important ethical requirement – Vulnerable populations (e. g. pregnant women, children, and those with mental incapacities) should not be excluded from trials. l Health care workers and researchers: – Risk of study to personnel through a particular study protocol should be minimized (e. g. multiple blood samples etc. ) – Healthcare workers must be well informed about, and agree to be implementers of, the research; – Adequate protective equipment and training Entebbe, 9 -10 March 2017

Table of Contents Entebbe, 9 -10 March 2017

Guidance point 9: Emergency use of unproven interventions • In an outbreak characterized by high mortality, it can be ethically appropriate to offer experimental interventions outside clinical trials • Conditions: No proven treatment exists; not possible to initiate clinical trials; some data on efficacy and safety available; approved by ethics committee and national authorities; risks are minimized; informed consent; data is rapidly shared. Entebbe, 9 -10 March 2017

Table of Contents Entebbe, 9 -10 March 2017

Rapid data sharing “Researchers, authors, sponsors, editors and publishers all have ethical obligations with regard to the publication and dissemination of the results of research. Researchers have a duty to make publicly available the results of their research on human subjects and are accountable for the completeness and accuracy of their reports. All parties should adhere to accepted guidelines for ethical reporting. Negative and inconclusive as well as positive results must be published or otherwise made publicly available. Sources of funding, institutional affiliations and conflicts of interest must be declared in the publication. Reports of research not in accordance with the principles of this Declaration should not be accepted for publication. ” World Medical Association – 2013 Declaration of Helsinki Entebbe, 9 -10 March 2017

Guidance point 10: Rapid data sharing • • • In an emergency, data on etiological factors, epidemiology, efficacy of vaccines and treatments are crucial for the public health response Ethical obligation to collect and share data as quickly as possible during an infectious disease outbreak Problem: "publish or perish" – some actors are hesitant to share data before publication Entebbe, 9 -10 March 2017

Guidance point 10: Rapid data sharing • Journals should facilitate data sharing by allowing researchers to rapidly disseminate information with immediate implications for public health without losing the opportunity for subsequent consideration for publication in a journal • WHO: "Zika Open" Initiative http: //www. who. int/bulletin/online_first/zika_open/en/ • Statement by journals http: //www. thelancet. com/campaigns/zika/statement "…. dissemination ahead of submission of any paper will not pre empt its publication in these journals. . . " Entebbe, 9 -10 March 2017

Table of Contents Entebbe, 9 -10 March 2017

Guidance point 11: Long-term storage of biological specimen l Biological specimen often collected during research in emergencies l Future use of potential concern to individuals, communities, or countries l Informed consent to participants should include specific information l Community engagement should discuss the storage (& sharing) of specimen l Material transfer agreements should be concluded and specify – specify the purpose of the transfer, – certify the specimen donor's consent as appropriate, – provide for adequate confidentiality protection, – cover the physical security of the specimens, – require that the country of origin is acknowledged in future research reporting, and – guarantee that the benefits of any subsequent use of the specimens will be shared with the communities from which the samples were obtained. Entebbe, 9 -10 March 2017

Adaptations to standard ethical oversight l Centralized emergency ethics committees – National research ethics committees or delegated to international organizations l Pre approval of research protocols – Sharing of best practices for research design already ‘pre screened’ by multiple RECs – Quicker assessment of ethical gaps in emergency context l Rolling ethics approval – Parts of a trial protocol approved while other elements modified in real time – Remain conditional to periodic re approval of REC – Prevent abandonment of rigid protocols upon emergence of new information l Joint approval by different ethics and regulatory bodies l Retrospective ethics review – Limitation: unethical activities may occur prior to completion of review Entebbe, 9 -10 March 2017

Acknowledgments l Abha Saxena, Team Leader, WHO Global Health Ethics l Global Network of WHO Collaborating Centres for Bioethics l Carl Coleman, Consultant Entebbe, 9 -10 March 2017

Many thanks for your attention! reisa@who. int www. who. int/ethics Articulating ethical and evidence-based policy options Entebbe, 9 -10 March 2017