SARS-CoV 19: Administering experimental medicines in a pandemic
Dear Editor
The SARS -CoV-2 (COV) pandemic is currently being managed primarily through Non-Pharmaceutical Interventions (NPIs) due to the lack of any approved therapies or a vaccine against COV. This has led to the repositioning of some existing medications, many of which have limited direct relationship to the causality, pathophysiology or clinical course of COV. These medications, at most, have minimal evidence, usually from in-vitro studies or inadequately powered clinical studies [1] on the benefit-risk in COV patients and should therefore be considered as “experimental” therapies demonstrating only equipoise (neither benefit nor harm). There is therefore an urgent need to collect clinical data that will facilitate or prevent their continued use in COV patients.
The conduct of clinical trials on experimental medicines during a pandemic requires pragmatism when emotions run high and preserving public health and saving lives remain paramount. When the workload and stress levels are high amongst HCPs [2], it will be unfair to impose an additional workload through the conduct of poorly designed trials. Implementing simple and well-designed trials in real time during a pandemic allows society to rapidly access medicines of “potential value”, whilst at the same time enabling the collection of data to make appropriate scientific assessments of the “real value” of the medicine(s) for use in the current and future COV epidemics. Emotions should not be allowed to override the science. Lessons from the experience of the Ebola epidemic and the report of the WHO panel convened to look at the ethics of providing experimental medicines during epidemics [3] could be helpful.
The usual ethical considerations such as informed consent and ethical committee approvals should continue to apply even in pandemics, but these could be implemented using simple pragmatic processes. The ethical use of control arms with available standard of care (SoC) needs careful consideration. In a disease such as COV, which has significantly variable outcomes across the population, it is essential to have a control group of patients to compare the effect of the experimental medicines. However, patients , investigators and indeed ethics committees could reject participation in trials with a control arm when some healthcare systems allow the use of some of the medications perceived to be “safe” to patients with COV. The recent FDA approval of Hydroxyquinoline for hospitalized COV patients, though only for patients where access to clinical trials are unavailable, will further complicate the recruitment into control arms. Every effort should be made to educate the scientific community, ethics committees and the public at large on the need for a control arm. It will be a shame to end up in a situation where meaningful conclusions cannot be made on the benefit-risk profile or the value of these medications for future COV recurrences.
Most of the ongoing and planned trials have rightly focused on hospitalized COV patients where the need for effective therapies remains critical. However, the PRINCIPLE trial that is currently being launched to study the effect of Hydroxyquinoline in older patients with mild symptoms in a primary care setting will provide useful data that will facilitate the early use of the drug to contain the disease in future flareups.
Several clinical endpoints are being assessed in many of the trials. The use of mortality as the primary end point in the SOLIDARITY AND RECOVERY trials should be welcomed, as it is not only the most medically relevant patient centric endpoint but as a hard and robust measurement, it is easy to register in any resource restrained environment, including pandemics. The thousands of patients required to provide an acceptable power to the trials will require the participation of many sites from the non-High-Income countries which in addition will allow the data to be globally relevant. Global pandemics will need global solutions. It will also be helpful to have an internationally accepted definition of what constitutes “death directly attributed to COV”. In many instances COV acts only to “precipitate” a downward course in many patients who already have compromised organ function [4]. Perhaps restricting the mortality endpoint only to patients with the characteristic radiological and/or hypoxic features of a “COV lung” may be a possibility. A consensus view on “Covid Deaths” is overdue not only to facilitate the power calculations for the conduct of clinical trials but also to meaningfully compare case fatality rates across various countries during the pandemic and understand the overall course and prognosis of COV.
When resources are limited, the ethical principles of Justice and Societal utility should also come into play in the allocation of limited supplies of diagnostics and therapeutics to the population. Health Care
Professionals and Carers, especially those working in highly exposed environments, should have been given priority in the allocation of the limited supplies of the diagnostic test for COV in UK. It is hoped that when similar situations develop in the future, priority will be given to frontline essential workers in the distribution of any limited supplies of proven therapies and/or vaccines based on the ethical principle of reciprocity”.
REFERENCES:
1. Gautret P et al, Hydroxychloroquine and azithromycin as a treatment of COVID -19 : results of an open label non-randomized clinical trial, International J of Anti-Microbial agents 2020 online, 105949. https://doi.org/10.1016/j.ijantimicag.2020.105949
2. Brooks SK, Webster RK, Smith LE, Woodland L, Wessely S, Greenberg N et al. The psychological impact of quarantine and how to reduce it: rapid review of the evidence. Lancet 2020; 395: 912-920.
3. Report of the Ebola Interim Assessment Panel – July 2015. https://www.who.int/csr/resources/publications/ebola/ebola-panel-report/en/
4. Zunyou Wu & McGoogan JM, Characteristics of and important lessons from the Coronavirus Disease 2019 (Covid 19) Outbreak in China, JAMA 2020 online. doi:10.1001/jama.2020.2648
Competing interests:
No competing interests
02 April 2020
Nadarajah Sreeharan
Visiting Professor
Kings College, London, UK & University of Jaffna, Sri Lanka
Rapid Response:
SARS-CoV 19: Administering experimental medicines in a pandemic
Dear Editor
The SARS -CoV-2 (COV) pandemic is currently being managed primarily through Non-Pharmaceutical Interventions (NPIs) due to the lack of any approved therapies or a vaccine against COV. This has led to the repositioning of some existing medications, many of which have limited direct relationship to the causality, pathophysiology or clinical course of COV. These medications, at most, have minimal evidence, usually from in-vitro studies or inadequately powered clinical studies [1] on the benefit-risk in COV patients and should therefore be considered as “experimental” therapies demonstrating only equipoise (neither benefit nor harm). There is therefore an urgent need to collect clinical data that will facilitate or prevent their continued use in COV patients.
The conduct of clinical trials on experimental medicines during a pandemic requires pragmatism when emotions run high and preserving public health and saving lives remain paramount. When the workload and stress levels are high amongst HCPs [2], it will be unfair to impose an additional workload through the conduct of poorly designed trials. Implementing simple and well-designed trials in real time during a pandemic allows society to rapidly access medicines of “potential value”, whilst at the same time enabling the collection of data to make appropriate scientific assessments of the “real value” of the medicine(s) for use in the current and future COV epidemics. Emotions should not be allowed to override the science. Lessons from the experience of the Ebola epidemic and the report of the WHO panel convened to look at the ethics of providing experimental medicines during epidemics [3] could be helpful.
The usual ethical considerations such as informed consent and ethical committee approvals should continue to apply even in pandemics, but these could be implemented using simple pragmatic processes. The ethical use of control arms with available standard of care (SoC) needs careful consideration. In a disease such as COV, which has significantly variable outcomes across the population, it is essential to have a control group of patients to compare the effect of the experimental medicines. However, patients , investigators and indeed ethics committees could reject participation in trials with a control arm when some healthcare systems allow the use of some of the medications perceived to be “safe” to patients with COV. The recent FDA approval of Hydroxyquinoline for hospitalized COV patients, though only for patients where access to clinical trials are unavailable, will further complicate the recruitment into control arms. Every effort should be made to educate the scientific community, ethics committees and the public at large on the need for a control arm. It will be a shame to end up in a situation where meaningful conclusions cannot be made on the benefit-risk profile or the value of these medications for future COV recurrences.
Most of the ongoing and planned trials have rightly focused on hospitalized COV patients where the need for effective therapies remains critical. However, the PRINCIPLE trial that is currently being launched to study the effect of Hydroxyquinoline in older patients with mild symptoms in a primary care setting will provide useful data that will facilitate the early use of the drug to contain the disease in future flareups.
Several clinical endpoints are being assessed in many of the trials. The use of mortality as the primary end point in the SOLIDARITY AND RECOVERY trials should be welcomed, as it is not only the most medically relevant patient centric endpoint but as a hard and robust measurement, it is easy to register in any resource restrained environment, including pandemics. The thousands of patients required to provide an acceptable power to the trials will require the participation of many sites from the non-High-Income countries which in addition will allow the data to be globally relevant. Global pandemics will need global solutions. It will also be helpful to have an internationally accepted definition of what constitutes “death directly attributed to COV”. In many instances COV acts only to “precipitate” a downward course in many patients who already have compromised organ function [4]. Perhaps restricting the mortality endpoint only to patients with the characteristic radiological and/or hypoxic features of a “COV lung” may be a possibility. A consensus view on “Covid Deaths” is overdue not only to facilitate the power calculations for the conduct of clinical trials but also to meaningfully compare case fatality rates across various countries during the pandemic and understand the overall course and prognosis of COV.
When resources are limited, the ethical principles of Justice and Societal utility should also come into play in the allocation of limited supplies of diagnostics and therapeutics to the population. Health Care
Professionals and Carers, especially those working in highly exposed environments, should have been given priority in the allocation of the limited supplies of the diagnostic test for COV in UK. It is hoped that when similar situations develop in the future, priority will be given to frontline essential workers in the distribution of any limited supplies of proven therapies and/or vaccines based on the ethical principle of reciprocity”.
REFERENCES:
1. Gautret P et al, Hydroxychloroquine and azithromycin as a treatment of COVID -19 : results of an open label non-randomized clinical trial, International J of Anti-Microbial agents 2020 online, 105949.
https://doi.org/10.1016/j.ijantimicag.2020.105949
2. Brooks SK, Webster RK, Smith LE, Woodland L, Wessely S, Greenberg N et al. The psychological impact of quarantine and how to reduce it: rapid review of the evidence. Lancet 2020; 395: 912-920.
3. Report of the Ebola Interim Assessment Panel – July 2015. https://www.who.int/csr/resources/publications/ebola/ebola-panel-report/en/
4. Zunyou Wu & McGoogan JM, Characteristics of and important lessons from the Coronavirus Disease 2019 (Covid 19) Outbreak in China, JAMA 2020 online. doi:10.1001/jama.2020.2648
Competing interests: No competing interests