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Yong Loo Lin School of Medicine Yong Loo Lin School of Medicine

Centre for Biomedical Ethics

Ethical Responsibility to Consider Accessibility of Medicines in Research

Calvin W. L. Ho Assistant Professor, National University of Singapore;

Co-Head, World Health Organization Collaborating Centre for Bioethics;

Member, Ethics Review Board, Médecins Sans Frontières;

Editor-in-Chief, Asian Bioethics Review

[email protected]

mailto:[email protected]



AIMS

1. Access and Vulnerability

a) CIOMS

b) WHO

2. Vulnerability

– Health-related Research

– Infectious Diseases Outbreak

3. Non-Standard & Experimental Interventions

4. Monitored Emergency use of Unproven Interventions outside of Research

5. Justice and Access to Medicines in Research



Case to Consider

• Outbreak of X Disease with average case fatality rate of about 50% depending on viral strain and case management.

• No known treatment but an experimental drug has been validated in non-human primates models only.

• Supportive therapy includes balancing the patient’s fluids and electrolytes, maintaining oxygen status and blood pressure, blood transfusion and replacement of clotting factors.

• Disease has the capacity to cause dramatic outbreaks with high fatality rates.



Case Cont’d

• The incubation period is 2-21 days, and symptom onset is sudden and marked by fever, chills, headache, and myalgia.

• The developer of the drug has obtained an unnamed single patient protocol for emergency use in an individual patient.

• Research proposed to offer lab-confirmed patients with disease X access to a 20-day treatment with the drug under monitored conditions.



Allow the Proposed Research?

• Research could include a patient of any gender or age, as well as pregnant women.

• A patient who intends to participate in the research must be able to provide informed consent.

• However, patients who are determined by the attending clinician to be unlikely to survive due to advance stage of the disease will be excluded from the research.

• As an IRB member, what are some considerations? How will you decide on the protocol?



Vulnerability

• Analytical approaches

– Specification and weighing of risks and benefits (Hurst,

2008); moral interests (2015)

– “Layers of Vulnerability” (Luna and Salles, 2010)

– Inherent, Situational, Pathogenic (Mackenzie, Rogers & Dodds,

2013)

– Distinct characteristics of vulnerability: Incapacitational (or Cognitive), Juridic, Deferential, Social, Situational, Medical, Allocational (Kipnis, 2003)

• By “Subpopulation”

– Children, mentally incapacitated, pregnant women, etc.

– Low-resourced populations (or economic vulnerability)



Vulnerability in Research Ethics

“When vulnerable individuals and groups are considered for recruitment in research, researchers and research ethics committees must ensure that specific protections are in place to safeguard the rights and welfare of these individuals and groups in the context of the research.”

Guideline 15, CIOMS International Ethical Guidelines for Health-related Research Involving Humans, 2016.



CIOMS (Explanation)

“The account of vulnerability in this Guideline seeks to avoid considering members of entire classes of individuals as vulnerable. However, it is useful to look at the specific characteristics that may render individuals vulnerable, as this can aid in identifying the special protections needed for persons who may have an increased likelihood of being wronged or of incurring additional harm as participants in research. Different characteristics may also co-exist, making some individuals more vulnerable than others. This is highly dependent on the context. For example, persons who are illiterate, marginalized by virtue of their social status or behaviour, or living in an authoritarian environment, may have multiple factors that make them vulnerable.”



Situations of Particular Vulnerability

Special attention should be given to ensuring that persons who face heightened susceptibility to harm or injustice during infectious disease outbreaks are able to contribute to decisions about infectious disease outbreak planning and response. Public health officials should recognize that such persons might be distrustful of government and other institutions, and make special efforts to include them in community engagement plans.

Guideline 3, WHO Guidance for Managing Ethical Issues in Infectious Diseases Outbreak, 2016.



Questions to Consider

• Why are some individuals and groups considered particularly vulnerable during infectious disease outbreaks?

• How can vulnerability affect a person’s ability to access services during infectious disease outbreaks?

• How can vulnerability affect a person’s willingness and ability to share and receive information during an infectious disease outbreak?

• Why are stigmatization and discrimination particular risks during infectious disease outbreaks?

• In what ways might vulnerable persons suffer disproportionate burdens from infectious disease response efforts, or have a greater need for resources?



Take into Account

• Difficulty accessing services and resources

• Need for effective alternative communication strategies

• Impact of stigmatization and discrimination

• Disproportionate burdens of outbreak response measures

• Greater need for resources

• Heightened risk of violence



Harm Avoidance / Minimization in PHS “Those responsible for surveillance should identify, evaluate, minimize and disclose risks for harm before surveillance is conducted. Monitoring for harm should be continuous, and, when any is identified, appropriate action should be taken to mitigate it.”

Guideline 8, WHO Guidelines on Ethical Issues in Public Health Surveillance, 2017.



Types of Harm (Potential & Actual)

Harm Result

Physical Public attacks, spouse / partner abuse, domestic violence, delayed or inadequate treatment

Legal Arrest, prosecution, death penalty, expulsion

Social Discrimination, community discrimination, isolation, inability to access care or exclusion from care, refection from the community

Economic Loss of employment or revenue, loss of health care services, loss of insurance, increased insurance premiums, increase health care costs, limited carer options, loss of life resources, forced relocation

Psychological / Emotional

Distress, trauma, stigma



Guideline 8 (Explanation)

• Various moral values and ethical principles should be weighed and balanced against each other and a judgment made about fair distribution of burdens and benefits in different surveillance initiatives or systems in a transparent way (NB Earlier discussion on equity).

• When surveillance entails a predictable risk of harm, additional precautions should be taken to protect the individuals or communities at risk.

• As not all harms can be eliminated, the benefits of surveillance should be proportional to the risk for harm.

• E.g. Sensational representations of statistical facts.



Particular Susceptibility

“Surveillance of individuals or groups who are particularly susceptible to disease, harm or injustice is critical and demands careful scrutiny to avoid the imposition of unnecessary additional burdens.”

Guideline 9, WHO Guidelines on Ethical Issues in Public Health Surveillance, 2017.



Guideline 9 (Explanation)

• Individuals or groups in situations of heightened vulnerability bear an undue proportion of health problems. Responsible authorities should make special efforts to ensure that these populations are included in surveillance in ways that will empower them.

• Public health surveillance and health information systems can provide valuable information to aid the development of health programmes and services to address their health problems and the underlying determinants of health, such as clean water, food security and gender equality.

• To promote equity, surveillance should focus on the specific problems of these vulnerable communities.



Obligations of Healthcare Providers during an Epidemic

There is an ethical imperative to learn as much about the outbreak as possible, as quickly as possible, balancing risks and benefits.

• Duty to do/support research

• Duty to understand research related issues

• Duty to share clinical and medical related data

But there are Additional Obligations …



• Patient care is the priority

• Resources from patient care should not

be diverted to research

• Patients should be informed

• Their confidentiality should be protected

• Community engagement remains

essential

• Trust within the health system is crucial

and must be actively sustained

Crucial to Note



Non-standard Interventions

Often interventions may be ‘experimental’ or ‘exceptional’.

• Interventions should be provided in accord with professional medical standards.

• Those offered medical interventions should be informed about the risks, benefits, and alternatives.

• Presumption: final decision about which medical interventions to accept, if any, belongs to the patient.

• Refusal of intervention might sometimes be rational choice.



Impact on Community Trust

• Overriding refusal of diagnostic, therapeutic or preventative measures can backfire if it leads to distrust among community members.

• Potential benefits of imposing unwanted interventions should be balanced against harm associated with loss of trust.



Equitable Process

• Individual should be given notice and opportunity to raise objections before an impartial decision-maker, such as a court, interdisciplinary review panel, or other entity not involved in the initial decision.

• Burden is on proposer of intervention to show that expected public health benefits justify overriding the individual’s choice.

• Process for resolving objections should be open and transparent.



MEURI

Monitored Emergency use of Unproven Interventions outside of Research



Conditions before MEURI applies

1. No proven effective treatment exists

2. It is not possible to initiate clinical studies immediately

3. Recommendation of scientific advisory committee based on favourable risk-benefit analysis (involving data at least from laboratory or animal studies)

4. Approval of relevant authorities and ethics committee

5. Adequate resources for risk minimization are available

6. Informed consent of patient

7. Emergency use of the intervention is monitored, and results are documented and shared in timely manner



Ethical Basis of MEURI

• Patient Autonomy—right of individuals to make their own decisions based on their own risk-taking strategies.

• Beneficence—providing patients opportunity to improve their condition.

• Not “compassionate use”:

– MEURI requires active monitoring.

– MEURI must satisfy inclusion-exclusion criteria.



Important Ethical Considerations

• Importance of Ethical Oversight

– MEURI is intended to be an exceptional measure for emergency situations—not as a means to circumvent ethical oversight of the use of unproven interventions. MEURI should be subject to ethical oversight.

• Minimizing Risk

– Known risks of intervention should be minimized to the extent reasonably possible (e.g., administration via hygienic conditions).

• Effective Resource Allocation

– MEURI should not preclude or delay initiation of clinical research, and should not divert attention or resources from implementation of effective clinical care and/or public health measures that may be crucial to control an outbreak.



Ethical Considerations: Cont’d

• Collection and Sharing of Meaningful Data

– collect all scientifically relevant data on the safety and efficacy of the intervention, and share transparently and rapidly

• Informed Consent

• Community Engagement

• Fair Distribution

– Who receives intervention in cases of scarcity?

– Is there any possibility of scaling up the intervention?



Conclusion: Who is vulnerable & how do we empower them?

1. Vulnerability as action-enabling, inclusive and empowering

2. Obligations During an Outbreak

– Ethical Considerations

– Equitable Processes

– Engagement and Trust

3. Non-Standard & Experimental Interventions

1. Monitored Emergency use of Unproven Interventions outside of Research

2. What form of access is equitable?



Thank you !

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