Ethical Innovation for Global Health:Pandemic, Democracy and Ethics in Research
December 4 (Mon), 6 (Wed), 2023

Authors ---- no conflict of interest
Placebo, Access

Kurihara C, Greco D, Dhai A, editors/authors

Placebo

Saio T, M.D.

Tsubaki H, Statistician

Acknowledgment, for the oversea travel of authors for the meeting directly related to the topic

Shimoda K
Watanabe H
40th meeting President Past President
Japanese Society of Clinical Pharmacology and Therapeutics
23rd Annual Conference ofthe Japanese Society of Transcultural Psychiatry

Varvara Baroutsou President, International
Federation of Association of Pharmaceutical
Physicians and Pharmaceutical Medicine (IFAPP)

Ethical Innovation for Global Health:Pandemic, Democracy and Ethics in Research
December 4 (Mon), 6 (Wed), 2023

Historical analysis/Conflicting points
DoH (1964 first ver.) 1975-2000
Physician should provide
best-proven intervention in the world
even in comparative study

Historical analysis/Conflicting points
DoH (1964 first ver.) 1975-2000
Physician should provide
best-proven intervention in the world
even in comparative study
Goal of research never precedent to patientinterest/benefit (§8) : Declaration of Geneva
 International Code of Medical Ethics

Historical analysis/Conflicting points
DoH (1964 first ver.) 1975-2000
Physician should provide
best-proven intervention in the world
even in comparative study
Goal of research never precedent to patientinterest/benefit (§8) : Declaration of Geneva
 International Code of Medical Ethics

Best proven intervention in the world
Global standard (universalism, deontologist)
Best available intervention in the local settings
Local standard (pluralism, utilitarian)

Historical analysis/Conflicting points
DoH (1964 first ver.) 1975-2000
Physician should provide
best-proven intervention in the world
even in comparative study
Goal of research never precedent to patientinterest/benefit (§8) : Declaration of Geneva
 International Code of Medical Ethics

Best proven intervention in the world
Global standard (universalism, deontologist)
Best available intervention in the local settings
Local standard (pluralism, utilitarian)
Biostatisticians/EBM advocators
Condition of comparative study:
Clinical Equipoise, uncertainty
NIH Bioethicists
Clinical equipoise is “deceptive”

Historical analysis/Conflicting points
DoH (1964 first ver.) 1975-2000
Physician should provide
best-proven intervention in the world
even in comparative study
Goal of research never precedent to patientinterest/benefit (§8) : Declaration of Geneva
 International Code of Medical Ethics

DoH 2002-now*
When proven intervention exists,
placebo can be permitted whenno additional risk of serious or irreversible harm

Best proven intervention in the world
Global standard (universalism, deontologist)
Best available intervention in the local settings
Local standard (pluralism, utilitarian)
Biostatisticians/EBM advocators
Condition of comparative study:
Clinical Equipoise, uncertainty
NIH Bioethicists
Clinical equipoise is “deceptive”*To be accurately, there is difference between 2002 and 2008

Historical analysis/Conflicting points
DoH (1964 first ver.) 1975-2000
Physician should provide
best-proven intervention in the world
even in comparative study
Goal of research never precedent to patientinterest/benefit (§8) : Declaration of Geneva
 International Code of Medical Ethics

DoH 2002-now*
When proven intervention exists,
placebo can be permitted whenno additional risk of serious or irreversible harm
CIOMS 2002, before 2016 revision

Best proven intervention in the world
Global standard (universalism, deontologist)
Best available intervention in the local settings
Local standard (pluralism, utilitarian)
Biostatisticians/EBM advocators
Condition of comparative study:
Clinical Equipoise, uncertainty
NIH Bioethicists
Clinical equipoise is “deceptive”
ICH E10 2000
No additional risk of serious or
irreversible harm
*To be accurately, there is difference between 2002 and 2008

Historical analysis/Conflicting points
DoH (1964 first ver.) 1975-2000
Physician should provide
best-proven intervention in the world
even in comparative study
Goal of research never precedent to patientinterest/benefit (§8) : Declaration of Geneva
 International Code of Medical Ethics

DoH 2002-now*When proven intervention exists,
placebo can be permitted whenno additional risk of serious or irreversible harm
CIOMS 2002, before 2016 revision
CIOMS 2016
When proven intervention exists,
placebo can be permitted whenminor increase above minimal risk

Best proven intervention in the world
Global standard (universalism, deontologist)
Best available intervention in the local settings
Local standard (pluralism, utilitarian)
Biostatisticians/EBM advocators
Condition of comparative study:
Clinical Equipoise, uncertainty
NIH Bioethicists
Clinical equipoise is “deceptive”
ICH E10 2000
No additional risk of serious orirreversible harm
*To be accurately, there is difference between 2002 and 2008

Typical case of establishment of “best proventherapy in the world” (not locally available)
Mother-to-childe transmission HIV prevention• Cons: Placebo trial in developing countries ≒ Tuskegee study• Pros: Placebo trial in developing countries for their health needs

Typical case of establishment of “best proventherapy in the world” (not locally available)
Mother-to-childe transmission HIV prevention• Cons: Placebo trial in developing countries ≒ Tuskegee study• Pros: Placebo trial in developing countries for their health needs

Twist and turns/Declining authority• US FDA abandoned DoH (2000)
Because DoH does not permit placebo when proven intervention exists.
• Brazil / Latin America rejected DoH (2002*～)
Because DoH permits placebo when proven intervention exists with highthreshold of risk of harm.
*To be accurately, there is difference between 2002 and 2008

Debates in various disease areas
Exclusion from “best proven intervention”• Populations excluded from efficacy trials (pregnant, children,elderly, some intrinsic/extrinsic factors, ..)• “best proven” becoming uncertain (“assay sensitivity”)• “best proven” for surrogate endpoint but not for true endpoint• Changes of the strain of virus

Debates in various disease areas
Exclusion from “best proven intervention”• Populations excluded from efficacy trials (pregnant, children,elderly, some intrinsic/extrinsic factors, ..)• “best proven” becoming uncertain (“assay sensitivity”)• “best proven” for surrogate endpoint but not for true endpoint• Changes of the strain of virus

No justification of placebo when proven intervention exists.

Debates in various disease areas
Exclusion from “best proven intervention”• Populations excluded from efficacy trials (pregnant, children,elderly, some intrinsic/extrinsic factors, ..)• “best proven” becoming uncertain (“assay sensitivity”)• “best proven” for surrogate endpoint but not for true endpoint• Changes of the strain of virus

No justification of placebo when proven intervention exists.

Case of Ebola outbreak• Pros and Cons on placebo study when No Proven Intervention:WHO’s recommendation for emergency use of Unproven
Intervention (MEURI).

Case of COVID-19• End of 2020 to early 2021: global vaccine roll-out started
based on emergency use authorization (EUA).
• WHO Ad Hoc Expert Group on the Next Steps for COVID19 Vaccine Evaluation:“Countries with limited or no access to a known effective
vaccine could thus ethically permit placebo-controlled
trials of vaccines of potential relevance to them even if
effective vaccines were already being marketed
elsewhere.”Case of COVID-19• End of 2020 to early 2021: global vaccine roll-out started
based on emergency use authorization (EUA).
• WHO Ad Hoc Expert Group on the Next Steps for COVID19 Vaccine Evaluation:“Countries with limited or no access to a known effective
vaccine could thus ethically permit placebo-controlled
trials of vaccines of potential relevance to them even if
effective vaccines were already being marketed
elsewhere.”
Strongly criticized by several ethicists;
Against the DoH: “best proven intervention (in the world)”

Conclusion
1. The meaning of “best proven intervention” must be
clarified to be “intervention proven in the world to bethe best”.
2. Policy for risk of placebo-controlled study when shouldbe risk minimization (based on the wording in the2016 CIOMS) and “clinical equipoise” or“uncertainty” should be the condition of comparative
study, being rephrased in wording understood by andshared with physicians, patients, and the public.

Ethical Innovation for Global Health:Pandemic, Democracy and Ethics in Research
December 4 (Mon), 6 (Wed), 2023

Post-trial access• Right of access of study participants to the intervention provento be effective (and safe): the norm first agreed in the DoH 2000.
• Downgraded in 2004, 2008, 2013, to be the item in a protocol
reviewed by the ethics committee and informed consent form forcandidate participants.
• COVID-19 has revealed the inequality in the distribution of theresult of science, typically the availability of vaccines.

Post-trial access• Right of access of study participants to the intervention provento be effective (and safe): the norm first agreed in the DoH 2000.
• Downgraded in 2004, 2008, 2013, to be the item in a protocol
reviewed by the ethics committee and informed consent form forcandidate participants.
• COVID-19 has revealed the inequality in the distribution of theresult of science, typically the availability of vaccines.

Our conclusion• Post-trial access must be assured not only for trial participants,
but for those who most in need in the world.

Challenges to be overcome• Patent monopoly and insufficient technology transfer: criticalpart of the obstacles to post-trial access for all.
• TRIPS Doha Declaration in times of HIV/AIDS pandemic and
COVAX and TRIPS waiver in COVID-19
along with expanding production capacity in MICs and LMICs
are “Good Start”, but not yet solution.
• Ethical norm of “post-trial access” must be described as a goal
to be shared and achieved in a global society.