S5-3_Hilary Marston

Ethical Challenges during COVID-19:
Research with Vulnerable Populations
Hilary D. Marston, MD, MPH
December 1st, 2023
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Disclaimer
• The views and opinions presented here represent those of the speaker
and should not be considered to represent advice or guidance from the
Food and Drug Administration (FDA) or the Department of Health and
Human Services (HHS).
www.fda.gov
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Key Messages
www.fda.gov
• Ethical principles underlying the conduct of clinical research remain the same in a public
health emergency.
• Every effort should be made to maintain Good Clinical Practice standards to assure
human subject protections and data validity.
• Too often, vulnerable populations are inappropriately excluded from trials or trials
specific to these populations are delayed.
• The additional protections afforded these populations under FDA and HHS
regulations are intended to ensure they can be included in clinical research in a way
that assures their protection.
• Excluding these individuals can lead to additional disease burden and uncertainty as
they decide whether to take a treatment that has not been studied in similar
individuals.
• For these reasons, the DOH principles hold true for public health emergencies without
revision.
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Speed is of the essence, so time for debate must be minimized
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“The committee concludes that the
randomized controlled trial (RCT) was an
ethical and appropriate design to use, even in
the context of the Ebola epidemic, stating
that RCTs are the most reliable way to identify
the relative benefits and risks of products
being studied. Except when rare
circumstances are applicable, every effort
should be made to implement RCTs during
epidemics.”
Sound design principles remain in epidemics…
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Though speed is essential,
requirements for participant protection
must also be maintained, including for
vulnerable populations
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What are vulnerable populations?
• The HHS Common Rule does not explicitly define, but offers
examples
• “children, prisoners, individuals with impaired decision-making
capacity, or economically or educationally disadvantaged
persons” (45 CFR 46.107(a))
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Two populations of specific interest in public
health emergencies
• Pediatric populations
• Pregnant people (in US, often not considered vulnerable, but
frequently excluded from research nonetheless)
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Two populations of specific interest in public
health emergencies
• Pediatric populations
• Pregnant people
www.fda.gov Source: cdc.gov, COVIDNET as of 9.24.22
COVID is a larger threat to adults, but pediatric
morbidity and mortality exists
www.fda.gov
In fact, in the US, COVID hospitalizations surpassed influenza
Source: M Delahoy et al. Clin Inf Dis May 20, 2022.
As did COVID deaths
Source: https://insidemedicine.bulletin.com/delta-and-omicron-killed-far-more-children-than-flu-ever-does
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www.fda.gov
July 2020
Moderna
Phase 3 for
adults begins
December 2020
mRNA vaccines
EUA in US for 18+
Dec 2020
Moderna 12-
18 trial begins
June 2022
Moderna EUA
ages 6 mos-17
March 2021
Moderna trial for
ages 6 mos-12
yrs begins
*Moderna dates displayed for illustrative purposes
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www.fda.gov Source: NIH Treatment Guidelines
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Conducting ethical studies in children
• Close review of the consent document (parental permission) to assure it is balanced and
written in plain language
• Children cannot consent for themselves, adequate provisions for soliciting a child’s assent
need to be made when a child is capable of providing assent
www.fda.gov
• Additional risk mitigation efforts in protocol design
• Additional oversight by safety monitors, DMC, IRBs and the FDA
• Novel trial designs such as an adaptive enrollment practices in order
to enroll less vulnerable populations first before broadening the pool
of subjects enrolled
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Additional Protections
• Review of the protocol and recruitment practice to assure that there is a fair selection of subjects.
The scientific goal of the study should be the basis for determining the individuals that will be
enrolled in the research and that the targeted population is not exploited due to their condition
or vulnerability.
• Pre-specified stopping rules
• Consideration of including IRB members knowledgeable about and experienced in working with
populations vulnerable to coercion or undue influence – 21 CFR 56.107(a)
• Community consultation to assess the opinion of those likely to be enrolled (done in emergency
research under 21 CFR 50.24(a)(7)(i))
• Public Disclosure of the research to assure transparency (e.g. ClinicalTrials.gov, and emergency
research under 21 CFR 50.24(a)(7)(ii) and (iii))
www.fda.gov
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Ethical Considerations for Pediatric Clinical Trials
• Children are a vulnerable population who cannot consent for
themselves and who therefore are afforded additional safeguards
when participating in a clinical investigation.
• When finalized, this draft guidance will describe the ethical
framework for protecting children in clinical research, and steps
for considering enrollment.
• The draft guidance provides a detailed description of the
additional human subject protection regulations that are included
in 21 CFR 50, subpart D (Additional Safeguards for Children in
Clinical Investigations).
www.fda.gov Adapted from Melanie E. Bhatnagar
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Two populations of specific interest in public
health emergencies
• Pediatric populations
• Pregnant people
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NIH Zika DNA Vaccine: Phase
2/2b Study Population
•Healthy men and women ages 15-35 years in
areas at risk of Zika infection
–Negative result pregnancy test (hCG)
–Agree to use effective means of birth control to avoid
pregnancy through 12 weeks after last vaccination (all
pregnancies will be followed for outcome)
–Not breastfeeding
•No history of confirmed Zika infection (subject
self-report)
•24 months of follow up
–Scheduled visits every 2 weeks and for any possible Zika symptoms
VRC Clinical Trial Program
Adapted from Karin Bok, NIAID
Zika pandemic impacted pregnancy directly, but pregnant
people were generally excluded from vaccine trials
Risk of COVID in
pregnancy well
known
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N = 30,420
Ages 18 and older
N = 43,548
Ages 16 and older
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Published Jan. 29, 2021
Published Jan. 28, 2021
CDC Recommends, WHO Disagrees
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Ethical Considerations for Pregnant Populations
• Pregnant people need to be able to make informed decisions regarding treatments and
preventive modalities.
• It is important to gather data on the benefits and risks of new therapeutics and vaccines for
pregnant people intentionally and in a systematic way, allowing for appropriate follow up of
diverse outcomes
• Pregnant people and fetus/newborn should also be able to benefit from new vaccine
technologies addressing previously unmet medical needs
• The benefit of vaccination should be balanced against lack of data/theoretical risk of
unknown outcomes
• Pregnant people are unlikely to be included in efficacy trials during a pandemic/emergency
• Developmental & Reproductive Toxicity (DART) study should be conducted expeditiously,
ideally with other toxicology studies
www.fda.gov Adapted from Karin Bok, NIAID
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www.fda.gov
Special considerations for resource poor
environments in emergencies
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Resource Poor Environment as Vulnerability
• Need to assure that the goals of the research are in line with the public health needs of the host
country(ies)
• Efforts are needed to assure prospective subjects are not exploited due to their condition or
environment
• Consideration should be given to building research capacity in the host country(ies) through
collaborative partnership(s)*
• Consideration should be given to facilitating post trial access when appropriate
• The targeting of high-risk population for COVID trials should be done with great care to assure that
the health needs of each individual are addressed
www.fda.gov
* Emanuel EJ et al. What Makes Clinical Research in Developing Countries Ethical? The Benchmarks
of Ethical Research. The Journal of Infectious Diseases, Volume 189, Issue 5, 1 March 2004
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Summary:
• Ethical principles outlined in the Declaration of Helsinki hold true in public health emergencies
• In fact, the urgency of the moment often tests our resolve to maintain protections, making joint
understanding of this imperative all the more important
• Regarding vulnerable populations, excluding them unnecessarily can lead to a paucity of data to
guide practice and care. They can be enrolled, but existing guidance on participant protection
should be consulted
www.fda.gov
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Acknowledgements
• Ann Meeker-O’Connell
• Pablo Morales
• Kevin Prohaska
• Karin Bok
• Melanie E. Bhatnagar
• Dionna Green
• Adam Berger
• Julie Kaneshiro