Appendix A
Study Approach and Methods
In response to a request by the Office of the Assistant Secretary for Preparedness and Response, the National Institute of Allergy and Infectious Disease, and the Food and Drug Administration of the U.S. Department of Health and Human Services, the National Academies of Sciences, Engineering, and Medicine’s Committee on Clinical Trials During the 2014–2015 Ebola Outbreak was charged with exploring the scientific and ethical issues related to clinical trials conducted in Guinea, Liberia, and Sierra Leone between 2014 and 2015. The committee’s final report will inform guidelines and best practices for the design, conduct, and reporting of clinical trials in response to a future outbreak.
COMMITTEE EXPERTISE
The National Academies formed a committee of 16 experts to conduct an 18-month study to deliberate and respond to the statement of task. The committee was composed of individuals with expertise in clinical trial investigations and ethics review committees experience, international health law, regulatory and health systems oversight, public engagement and local/ community and cultural perspectives, biostatistics and clinical trial design, clinical infectious disease science and case management, crisis management, and emergency preparedness and response. Representation included U.S., European, and African participants as well as a consultant on clinical trial methodology, Janet Darbyshire.
MEETINGS AND INFORMATION-GATHERING ACTIVITIES
The committee deliberated from January to December 2016, during the course of which it held six in-person meetings (February, March, June, August, September, and November). The February, March, June, and August meetings included portions open to the public, and the open session agendas for those sessions appear below. The committee meetings in September and November were held only in closed session.
To inform its deliberations the committee gathered information through a variety of mechanisms: (1) three 3-day workshops with open public sessions; (2) one 2-hour webinar in May with international regulators; (3) one open public comment session during its June meeting; (4) systematic literature reviews of the scientific, ethical, social, and anthropological issues and other pertinent background research; (5) solicitation and consideration of written statements from stakeholders and members of the public through the committee’s Current Projects System website and committee e-mail; and (6) personal communication between committee members and staff and individuals who have been directly involved in or have special knowledge of the issues under consideration.
IDENTIFYING WEST AFRICAN EXPERTS FOR A LOCAL PERSPECTIVE
The committee held a 2-day public workshop in August 2016 in Monrovia, Liberia, where it spoke with local experts from Guinea, Liberia, and Sierra Leone knowledgeable about scientific research, ethical review and pharmaceutical regulations, Ebola clinical care, survivors of Ebola, and social mobilization and gathered their input on a wide range of topics related to the committee’s charge, including (1) the clinical trials conducted during the Ebola outbreak, (2) ethical and social implications of clinical trials being conducted in the three countries, (3) the role of the community in implementing clinical trials, and (4) inter-epidemic planning. Participants for this public workshop were identified through conversations with committee members, anthropologists who worked in country, suggestions from trial sponsors, and published news and literature discussing pertinent players during the Ebola outbreak. This meeting included an open public comment session during which input was invited from any interested parties.
TRIAL ANALYSIS
As part of the statement of task, the committee was asked to assess the scientific validity of the information that arose as a result of the clinical trials conducted during the 2014–2015 Ebola outbreak. While numerous
attempts to study investigational agents occurred in West Africa during this time including through compassionate use, observational studies, and other investigations of therapies that lacked sufficient detail on protocol or results—the trials assessed by the committee were chosen based on the trial location (Guinea, Liberia, or Sierra Leone) and on whether or not a formal clinical trial was conducted. The committee reviewed the trials based on available trial results in the literature as well as on other publications or presentations that addressed the scientific, ethical, and logistical considerations of each trial team.
LITERATURE AND PRESS REVIEW
The committee and staff conducted a literature search that was concentrated on journals found in the following databases: Medline, Embase, PubMed, Scopus, Web of Science, Anthropology Plus, Proquest, African Journals Online, African Index Medicus, ClinicalTrials.gov, and Northern Light. Broad search terms were used to cast as wide a net as possible. The articles obtained by use of the search terms were reviewed for their relevance to the committee’s charge. Other targeted literature reviews were conducted throughout the committee’s deliberations as novel issues arose.
Clinical Trial Design and Conduct
Search Parameters:
- Date range: all years
- International, English only
Databases:
- Scopus
- Web of Science
- Embase and Medline
- Proquest
- Northern Light
Search Strategy:
Adaptive Clinical Trials
- TITLE-ABS (“clinical trial” AND (“adaptive randomized trial” OR “adaptive trial” OR “platform trial*” OR “new Bayesian” OR “Bayesian adaptive” OR “Bayesian meta-analysis”))
Historical Controls
- TITLE ((“historical”) AND (“randomized clinical trial” OR “randomized trial” OR rct OR “clinical trial”))
Clinical Trials During Outbreaks
- TITLE-ABS((“infectious disease” or ebola or cholera or AIDS or HIV or “avian flu” or “avian influenza” or MERS or “Middle East respiratory syndrome” or “Marburg virus” or “viral haemorrhagic fever” or Legionnaires or “meningococcal disease” or “acute haemorrhagic fever syndrome” or SARS or “severe acute respiratory syndrome”)) w/10 outbreak and “clinical trial*”)
Ethics of Randomization
- TITLE ((ethics OR ethical) AND randomization) OR ABS ((ethics OR ethical) AND randomization) AND TITLE-ABS-KEY (“high risk” OR “infectious disease” OR “high mortality”))
Informed Consent
- (informed consent or consent or informed decision).mp. AND (understanding or comprehension or retention or knowledge or awareness or recall).mp. AND (biomedical research or clinical research or clinical trials or randomi*ed controlled clinical trials or random allocation trials or intervention trials).mp. AND Africa/ OR (lowincome countr* or developing countr* or vulnerable populations or disadvantaged populations or underserved populations).mp.
Clinical Trials in Developing Countries
- randomization and ethics and (Asia or Africa or Thailand or “developing countr*”)
Anthropology
Search Parameters:
- Date range: all years;
- International, English only
Databases:
- PubMed
- Anthropology Plus
- AnthroSource
- ClinicalTrials.gov
Search Strategy:
Compassionate Use
- Search terms: compassionate use, undue inducement, standard of care Ebola, community engagement, informed consent
Community Acceptance of Clinical Trials
- Search terms: Ebola, therapeutic misconception, consent, community engagement, clinical trial, Ebola treatment unit, vaccination, consent, surveillance, quarantine
PUBLIC COMMITTEE MEETING AGENDAS
Meeting 1: Washington, DC; February 22–23
Public Workshop of the Committee on Clinical Trials During the 2014–2015 Ebola Outbreak
First Committee Meeting
February 22–23, 2016
Keck Center: 500 Fifth Street, NW
Washington, DC 20001
Room 100
Day 1
Monday, February 22
CLOSED COMMITTEE SESSION
8:00 a.m.–4:00 p.m.
OPEN SESSION
4:00 p.m. | Opening Remarks to Public Audience |
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4:05 p.m. | Delivery of Study Charge and Q&A/Discussion with Committee |
Objectives:
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Moderators: Gerald Keusch and Keith McAdam, Committee Co-Chairs | |
Sponsor Panelists:
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5:00 p.m. | ADJOURN Open Session |
Day 2 Tuesday, February 23 |
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OPEN SESSION | |
9:00 a.m. | Opening Remarks to Public Audience |
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9:05 a.m. | Delivery of Study Charge and Q&A/Discussion with Committee |
Objectives:
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Moderators: Gerald Keusch and Keith McAdam, Committee Co-Chairs |
Sponsor Panelists:
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10:00 a.m. | ADJOURN Open Session |
CLOSED COMMITTEE SESSION | |
10:00 a.m. – 4:00 p.m. |
Meeting 2: London, UK; March 22–24
Public Workshop of the Committee on Clinical Trials During the 2014–2015 Ebola Outbreak
Second Committee Meeting
March 22–24, 2016
British Medical Association
BMA House
Tavistock Square
London WC1H 9JP
United Kingdom
Day 1
Tuesday, March 22, 2016
Meeting Objectives: | |
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9:45 a.m. |
Welcome by Committee Co-Chairs
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10:00 a.m. | Opening Presentation: Presentation and Q&A |
Bridging the Divide: Connecting Clinician, Patient, and Researcher | |
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SESSION I – PERSPECTIVES ON THE COMMUNICATION OF CLINICAL RESEARCH DURING AN EMERGENCY | |
(60 min; 10-min panelist presentations followed by 30-min discussion and Q&A) | |
10:30 a.m. | Objectives: |
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Moderator: Sheila Davis, Chief Nursing Officer, Partners In Health | |
Panelists: | |
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SESSION II – CLINICAL TRIAL DESIGN AND IMPLEMENTATION: REFLECTIONS ON THE CLINICAL TRIALS CONDUCTED DURING THE 2014–2015 EBOLA OUTBREAK | |
(Session II will consist of three panels and extend after lunch; speakers are encouraged to stay throughout the entire session) | |
Objectives: | |
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Moderators: Janet Darbyshire, Emeritus Professor of Epidemiology, University College London; and Abdel Babiker, Professor of Epidemiology and Medical Statistics, Medical Research Council Clinical Trials Unit, University College London | |
11:30 a.m. | Overview Presentation (20 mins): |
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11:50 a.m. | Panel 2A. Vaccine Trials Conducted During the Ebola Outbreak |
(60 min; 10-min panelist presentations followed by 40-min discussion and Q&A) | |
Panelists: | |
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12:50 p.m. | LUNCH |
1:50 p.m. | Panel 2B. Therapeutic Trials Conducted During the Ebola Outbreak |
(85 min; 10-min panelist presentations followed by 45-min discussion and Q&A) | |
Panelists: | |
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3:15 p.m. | BREAK |
3:30 p.m. | Panel 2C. Panel Reflections and Considerations for the Design of Clinical Trials |
(60 min; 10-min panelist presentations followed by 40-min discussion and Q&A) | |
Objectives: | |
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Panelists: | |
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SESSION III – PUBLIC HEALTH CONTEXT | |
(30 min; 10-min panelist presentation followed by 20-min discussion and Q&A) | |
4:30 p.m. |
Objectives:
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Moderator: David Peters, Professor, Johns Hopkins Bloomberg School of Public Health | |
Panelist: | |
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5:00 p.m. | ADJOURN |
Day 2
Wednesday, March 23, 2016
SESSION IV – ETHICAL CONSIDERATIONS IN THE CONDUCT OF CLINICAL TRIALS DURING AN EMERGENCY
(60 min; 10-min presentations followed by 40-min discussion)
10:00 a.m. | Objectives: |
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Moderator: Olayemi Omotade, Professor of Pediatrics and Child Health, University of Ibadan | |
Panelists: | |
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CLOSED SESSION – COMMITTEE ONLY | |
11:15 a.m.–1:25 p.m. | |
SESSION V – PREPARING FOR AND FINANCING CLINICAL TRIALS | |
(60 min; 10-min panelist presentations followed by 40-min discussion and Q&A) | |
1:30 p.m. |
Objectives:
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Panelists: | |
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CLOSED SESSION – COMMITTEE ONLY | |
2:35 p.m.–3:15 p.m. | |
OPEN SESSION | |
3:30 p.m. | Q&A with Jeremy Farrar, Director, Wellcome Trust |
4:00 p.m. | ADJOURN |
Day 3
Thursday, March 24, 2016
SESSION VI – ETHICAL AND SCIENTIFIC CONSIDERATIONS FOR PRIORITIZING RESEARCH DURING OUTBREAKS
(60 min; 10-min panelist presentations followed by 40-min Q&A)
10:00 a.m. | Objectives: |
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Moderator: Alex John London, Professor, Carnegie Mellon University | |
Panelists: | |
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11:00 a.m. | ADJOURN |
Meeting 3: Webinar; May 19
Public Webinar of the Committee on Clinical Trials During the 2014–2015 Ebola Outbreak
May WebEx Session: 2-Hour Webinar
May 19, 2016
REGULATORY CONSIDERATIONS
Meeting Objectives: | |
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Panelists:
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Hour 1: | Welcome by Moderator and Speaker Introductions (5 min) |
Moderator: Michelle Mello, Professor of Law and Professor of Health Research and Policy, Stanford University | |
Discussion: Standards of Evidence (45 min)
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Hour 2: |
Discussion: Prioritization and Collaboration (45 min)
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Open Discussion and Q&A with Committee (25 mins) | |
ADJOURN |
Meeting 4: Washington, DC; June 13–15
Public Workshop of the Committee on Clinical Trials During the 2014–2015 Ebola Outbreak
Third Committee Meeting
June 13–15, 2016
Keck Center: 500 Fifth Street NW
Washington, DC 20001
Room 208
Day 1
Monday, June 13, 2016
Meeting Objectives: | |
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SESSION I – FOSTERING INTERNATIONAL COORDINATION AND COLLABORATION | |
Objectives:
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for emergency response while still maintaining their autonomy. |
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8:30 a.m. |
Welcome by Committee Co-Chairs
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8:45 a.m. | Opening Presentation: (15- to 20-min presentation followed by Q&A) |
Lessons from Past Epidemics
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9:15 a.m. | Moderator: Kathryn M. Edwards, Vanderbilt University School of Medicine |
Panelists:
(90 min; 10-min opening remarks by each panelist, followed by discussion and Q&A)
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10:45 a.m. | BREAK |
SESSION II – THE FEASIBILITY OF CLINICAL RESEARCH DURING HUMANITARIAN EMERGENCIES | |
Objectives:
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11:00 a.m. | Moderator: Janice Cooper, Liberia Mental Health initiative |
Panelists:
(90 min; 10-min opening remarks by each panelist, followed by discussion and Q&A)
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12:30 p.m. | LUNCH |
SESSION III – THE ECONOMIC IMPLICATIONS OF OUTBREAKS | |
1:00 p.m. |
Objectives:
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Moderator: Gerald Keusch, Committee Co-Chair, Boston University Schools of Medicine and Public Health | |
Panelists: | |
(60 min; 10-min opening remarks by each panelist, followed by discussion and Q&A)
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Day 2
Tuesday, June 14, 2016
SESSION IV – CLINICAL TRIALS CONDUCTED DURING THE 2014–2015 OUTBREAK
Objectives:
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8:30 a.m. |
Welcome by Committee Co-Chairs
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8:45 a.m. |
Opening Presentation:
(15- to 20-min presentation followed by Q&A) |
Looking Forward: Principles for Conducting Research during Emergencies, Lessons Learned through the Liberia–U.S. Joint Clinical Research Partnership
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9:15 a.m. | Moderator: Jens Lundgren, University of Copenhagen |
Panel 1: Vaccine Trials Conducted During the Ebola Outbreak | |
(90 min; 10-min opening remarks by each trial team followed by discussion and Q&A) | |
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10:45 a.m. | BREAK |
11:00 a.m. | Moderator: Roger J. Lewis, Harbor–UCLA Medical Center |
Panel 2: Therapeutic Trials Conducted During the Ebola Outbreak | |
(90 min; 10-min opening remarks followed by discussion and Q&A) | |
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12:30 p.m. |
Closing Presentation
(15- to 20-min presentation followed by Q&A) |
Fostering International Cooperation and Collaboration
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1:00 p.m. | ADJOURN Public Session Day 2 |
Day 3
Wednesday, June 15, 2016
SESSION V – DECISION MAKING DURING EMERGENCIES
Objectives:
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8:30 a.m. |
Welcome by Committee Co-Chairs
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8:45 a.m. |
Opening Presentation:
(15- to 20-min presentation followed by Q&A) |
Aligning Regulatory, Public Health, and Clinical Care Goals During an Epidemic Crisis | |
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9:15 a.m. | Moderator: Charles D. Wells, Sanofi |
Panelists: | |
(90 min; 10-min opening remarks by each panelist, followed by discussion and Q&A) | |
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10:45 a.m. | BREAK |
SESSION VI – MANAGING GROUP DYNAMICS DURING CRISES | |
11:00 a.m. |
Objectives:
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Moderator: Keith McAdam, Committee Co-Chair, Emeritus Professor of Clinical and Tropical Medicine, London School of Hygiene & Tropical Medicine | |
Panelists: | |
(90 min; 10-min opening remarks by each panelist followed by discussion and Q&A) | |
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SESSION VII – PUBLIC COMMENT | |
12:30 p.m. |
Open Public Comment (30 min)
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1:00 p.m. | ADJOURN Public Session |
Meeting 5: Monrovia, Liberia; August 14–17
Public Workshop of the Committee on Clinical Trials During the 2014–2015 Ebola Outbreak
Fourth Committee Meeting
August 15–16, 2016
Bella Casa Hotel
2nd Street Sinkor Tubman Blvd.
Monrovia, Liberia
Day 1
Monday, August 15, 2016
SETTING RESEARCH PRIORITIES DURING EMERGENCY INFECTIOUS DISEASE EVENTS
Day 1 Meeting Objective: | |
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8:30 a.m. | Meeting Registration |
9:00 a.m. | Welcome by Committee Co-Chairs |
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Welcome and Perspectives from the Ministries of Health | |
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Co-Moderators: Janice Cooper, Carter Center Liberia M. Bailor Barrie, Wellbody Alliance | |
Speakers (10-min prepared remarks each, followed by Q&A): | |
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10:00 a.m. | BREAK |
10:15 a.m. |
Panel 1: Prioritizing Research in Outbreak Response
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Co-Moderators: Janice Cooper, Carter Center Liberia M. Bailor Barrie, Wellbody Alliance | |
Panelists (10-min prepared remarks each):
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Respondents (5 min each, reaction to panelists):
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Moderated Discussion with Committee and Participants | |
11:45 a.m. | LUNCH |
12:45 p.m. | Panel 2: Perspectives from the Research and Training Community |
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Moderator: Fred Wabwire Mangen, Makerere University–Uganda | |
Panelists (10-min prepared remarks each):
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Respondents (5 min each, reaction to panelists):
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Moderated Discussion with Committee and Participants | |
2:45 p.m. | BREAK |
3:00 p.m. |
Panel 3: Perspectives from Regulatory Authorities
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Moderator: Susan Ellenberg, University of Pennsylvania | |
Panelists (10-min prepared remarks each): | |
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Respondent (5 min, reaction to panelists):
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Moderated Discussion with Committee and Participants | |
4:00 p.m. |
Panel 4: Perspectives from the Ethics Review Board (ERB)
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Moderator: Olayemi Omotade, University of Ibadan | |
Panelists (10-min prepared remarks each):
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Respondents (5 min each, reaction to panelists):
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Moderated Discussion with Committee and Participants | |
5:30 p.m. | ADJOURN |
6:15 p.m. |
Wine Reception and Dinner at the Bella Casa Restaurant “Suave”
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Day 2
Tuesday, August 16, 2016
ENGAGING COMMUNITIES IN RESEARCH DESIGN AND IMPLEMENTATION DURING OUTBREAKS
Day 2 Meeting Objective: | |
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8:30 a.m. | Meeting Registration |
9:00 a.m. |
Welcome by Committee Co-Chairs
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Panel 5: Community Mobilizers’ Perspectives
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Moderator: Charles Wells, Sanofi | |
Panelists (10-min prepared remarks each):
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Respondents (5 min each, reaction to panelists):
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Moderated Discussion with Committee and Participants | |
10:30 a.m. | BREAK |
10:45 a.m. |
Panel 6: Patient and Clinician Perspectives
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Moderator: David Peters, Johns Hopkins University | |
Panelists (10-min prepared remarks each):
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Moderated Discussion with Committee and Participants | |
12:15 p.m. | LUNCH |
1:15 p.m. |
Panel 7: Perspectives from Civil Society
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Moderator: Abdel G. Babiker, Medical Research Council Clinical Trials Unit, UCL | |
Panelists (10-min prepared remarks each):
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Moderated Discussion with Committee and Participants | |
2:30 p.m. | BREAK |
2:45 p.m. |
Breakout Groups with Facilitated Discussion
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3:45 p.m. |
Reconvene in Plenary Session
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4:15 p.m. |
Panel 8: Building Local Research Capacity to Meet Community Needs
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Panelists and Group Leads (10 minutes prepared remarks followed by breakout groups with facilitated discussion): | |
Moderator: Roger Lewis, Harbor–UCLA Medical Center | |
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Moderated Discussion with Committee and Participants | |
5:15 p.m. |
Open Comment Period and Workshop Wrap-Up
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5:30 p.m. | ADJOURN |
Day 3
Wednesday, August 17, 2016
LIBERIA SITE VISITS
1:00 p.m. |
Committee Liberia site visits
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