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Concept note: Implementation of Cohort Event Monitoring protocol for molnupiravir 1 Background and problem statement Molnupiravir has been newly introduced as an oral medicine for the treatment of non-severe COVID-19. WHO has provided a conditional recommendation for molnupiravir for those at highest risk of hospitalization. The conditional recommendation reflects the concern for widespread treatment with molnupiravir before more safety data become available, and risk mitigation strategies include undertaking active pharmacovigilance surveillance. Currently there are clinical trials taking place in high income countries (HICs) such as the UK, which is collecting safety information in their population. Such activities are missing or limited in low- and middle-income countries (LMICs) consisting of populations with different risk factors and less vaccine coverage. There is a strong interest to closely monitor the safety profile of newly introduced COVID-19 therapeutics to quickly identify and address any safety concerns. Cohort Event Monitoring is an active surveillance method that can be used to follow-up early users of molnupiravir to ensure timely collection of post-market safety data. These data can then be taken into consideration by national regulatory authorities (NRAs) at the time of granting full-market authorization or making other regulatory decisions. In addition these data can be used by the WHO Clinical Guideline Development Group (GDG) to update current recommendations on molnupiravir. WHO has published a protocol for Cohort Event Monitoring of molnupiravir, and intends to support implementation of the protocol in at least six countries. 2 Proposed plan 2.1 Study design Multi-country Cohort Event Monitoring: prospective, observational, single-arm cohort study design. 2.2 Outcome Objectives Primary objective 1. to characterize and estimate the incidence of all adverse events (AEs, including serious adverse events (SAEs), medication errors, off-label use and misuse) occurring in enrolled patients. Secondary objectives 1. to characterize and estimate the incidence of maternal and perinatal outcomes in women inadvertently exposed to molnupiravir during pregnancy and neonate/infant/child exposed during breastfeeding; 2. to detect signals of drug-drug interactions and interactions with traditional medicines; 3. to estimate the incidence of severe COVID-19 disease following treatment with molnupiravir, to detect possible lack of adherence to treatment or lack of effect. 2.3 Study Population Participants will be recruited among patients who are prescribed molnupiravir for treatment of non- severe COVID-19 disease at sites participating in this study. Study participation will be strictly voluntary. 2.4 Sample size The target study size is 30 000 patients treated with molnupiravir for COVID-19 disease. This study size can rule out events occurring with a frequency of at least 1 per 10 000 with at least 95% confidence. The aim is to recruit patients from multiple sites in several countries to reach a cohort size of 30 000 as quickly as possible in order to confirm the safety of molnupiravir as early as possible. Since the pandemic situation and the number of COVID-19 cases can vary in different countries at different times, this may result in some countries recruiting more patients than others. 2.5 Participating countries Countries will initially be prioritized after considering 1) supply of molnupiravir; and 2) expression of interest. Further selection of countries will be done if required, and the following factors will be taken into consideration: population size, vaccine coverage, country experience using active safety surveillance methods, and ACT-A allocation of molnupiravir. 2.6 Tools for data collection, management and analysis A combination of different tools will be used to collect, manage and analyse data. Data collection Initial baseline data will be collected by study staff at health facilities where molnupiravir is dispensed. Data will be collected and via the WHO data tools provided, or countries’ own tools with a data bridge to transfer the data. For follow-up data collection through self-reporting, a questionnaire via a mobile app (via existing apps or a reporting app, weblink via text message or WhatsApp), or email is proposed. Some sites may choose to have study staff fill in follow-up questionnaires following home visits or phone calls. Data management The WHO xMart system is proposed as the data repository. The xMart platform is a data harmonization and warehousing solution used by the World Health Organization (WHO) for health data. This tool contains a collection of features to help WHO data managers standardize, integrate and store in a format that is ready for analysis. More information: https://extranet.who.int/xmart4/docs/general/Overview.html Data analysis For descriptive and basic rate calculations the Xmart is proposed. For more sophisticated analysis programming in R connected to Xmart is suggested. 2.7 Study monitoring, visits and data validation Centralized monitoring will be performed during the data collection. This will allow the identification of outliers or trends that may need attention from the research team to identify and mitigate problems during the study period. Details of centralized monitoring will be outlined in the data management plan. Each site will be visited at least once during the study period to check compliance with study procedures and ethical requirements. Validation of data collected will be done via cross checks of randomly selected data samples. Ambiguous data may will also be checked during the site visits for clarification. These visits might be conducted by WCO or regional office staff, potential implementing partners or representative from the Ministry of Health. During the course of the study, for-cause on-site monitoring visits may be made, to check adherence to the protocol and quality of data collection. These visits will be organized for those sites for which performance issues are identified. Appropriate tools will be developed to facilitate the conduct of these site monitoring visits. 3 Collaborations, roles and responsibilities The overall running and coordination of the project will be the responsibility of the WHO Pharmacovigilance (PVG) team. WHO HQ will work closely and rely on the support from regional and country office colleagues for site selection, implementation and sensitization. WHO HQ PVG will collaborate with the WHO Health information system strengthening team to develop digital solutions for data collection and management. WHO HQ, regions and countries will work with countries to develop study protocols and submit to WHO ethic review committee submissions. Training materials will be prepared and made available on the OpenWHO.org platform by WHO HQ. The national study team will consist of researchers at participating study sites, or members of the national PV centre or a mixture of both. The study team will consist of the principle investigator and other study staff that will be responsible for recruiting patients and collecting signed informed consent forms, obtaining baseline information as per protocol, follow up patients (through home visits (phone calls (sending follow up forms via electronic tools). The study staff will also perform country specific analysis and alert national authorities of any signals of concern. A WHO signal detection team will be formed and will consist of a member of the study team, a member of the national PV centre from each participating country and the WHO Collaborating Centre for International Drug Monitoring, UMC. This team will review the pooled data for signals, validate signals and perform an in-depth review. Quality assurance and monitoring of will be performed by implementing partners. This project will be run in close collaboration with the MoH of participating countries (national PV center) to ensure alignment and coordination with the national pharmacovigilance system and capacity development. 4 Deliverables • Country selection As mentioned in section 2.5, a mapping of supply of molnupiravir and expression of interest from countries will be conducted, and participating countries will be selected. WHO regional and country offices will help with this mapping. • Country and site-specific protocol development, data management plan and statistical analysis plan The WHO CEM template protocol will be adapted to countries and study sites in collaboration with participating country officials, and will be completed with a description of the data collection/management tools and study specific procedures . A data management and statistical analysis plan will be developed. • Application for ethics approval The final country specific protocol will be submitted national/institutional review board for clearance then to WHO ERC for approval. • Data collection, data management and data analysis tools development A collaboration with the digital innovation department is planned for the data management component. • Training at site selection The OpenWHO.org platform will be used to train at participating health facilities. • Study subject recruitment A target of 30,000 participants will be recruited. This will be 2500-5000 participants in each country. It is expected that some sites will recruit more than others depending on the supply, availability of alternatives and COVID-19 epidemiology and the total number of participants per country can be outside the 2500-5000 target. • Data collection Various data collection tools will be utilized to gain maximum response rate possible.  • Data analysis WHO HQ will be responsible for statistical calculation of the data (rates and descriptive), through a consulting group. Any safety issues will be raised with the WHO Advisory Committee on Safety of Medicinal Products sub-committee. • Data dissemination Interim reports of findings will be expected monthly. A final report is expected at the end of the study. Findings will be shared globally and published in a scientific peer-review journal (open access). 5 Funding WHO will support six countries to implement the protocol. Others partners such as Global Fund and UNITAID will provide financial support to additional countries to implement the protocol in collaboration with WHO. 6 Overall workplan and timelines A high level workplan is proposed below with key tasks listed . Task Q1 Q2 Q3 Q4 Y2Q1 Y2Q2 Y2 Q3 ERC approval of master protocol Country selection Ethic site specific protocol Tool and data management tools developed Training Statistical analysis plan Recruitment of participants Data collection Interim analysis Close study Final analysis Please note the timeline is for six countries, and will be extended if more countries participate. WORLD HEALTH ORGANIZATION ORGANISATION MONDIALE DE LA SANTÉ WELTGESUNDHEITSORGANISATION Date: 29 April 2022 ВСЕМИРНАЯ ОРГАНИЗАЦИЯ ЗДРАВООХРАНЕНИЯ REGIONAL OFFICE FOR EUROPE Ms Elen Ohov BUREAU RÉGIONAL DE L’EUROPE REGIONALBÜRO FÜR EUROPA Adviser ЕВРОПЕЙСКОЕ РЕГИОНАЛЬНОЕ БЮРО European Union Affairs and International Co- Head office: operation Department UN City, Marmorvej 51, Ministry of Social Affairs DK-2100 Copenhagen Ø, Denmark Suur-Ameerika 1 Tel.: +45 45 33 70 00; Fax: +45 45 33 70 01 Email: [email protected] 10122 Tallinn Website: http://www.euro.who.int Estonia Our reference: Your reference: Notre référence: Votre référence: Unser Zeichen: Ihr Zeichen: См. наш номер: На Ваш номер: Dear Ms Ohov, REQUEST TO PARTICIPATE IN ACTIVE SAFETY SURVEILLANCE USING COHORT EVENT MONITORING FOR MOLNUPIRAVIR The Pharmacovigilance Team within the Regulation and Safety Unit under the Department of Regulation and Prequalification (RPQ/REG/PVG) is inviting Member States to express their interest in participating in the WHO study on safety monitoring of molnupiravir for treatment of mild to moderate COVID-19 infection using cohort event monitoring. In March 2022, WHO published a Cohort Event Monitoring (CEM) protocol for the active safety surveillance of molnupiravir, to compliment the conditional recommendations for use of molnupiravir issued in the WHO Therapeutics and COVID-19: living guideline. A concept note is attached for your information. WHO will provide support to at least six low- and middle- income countries to implement this protocol. The selection of countries will be based on the following: • Country supply of molnupiravir • Expression of interest to participate We would appreciate if you could please inform us by 10 May 2022 on whether the Ministry of Health or Health Insurance currently provides molnupiravir for patients with mild to moderate Covid -19 and whether your country would be interested in participating in this project on active safety surveillance using cohort event monitoring for molnupiravir. We look forward to your response, which can be addressed directly to Dorina Pirgari ([email protected]), Access to medicines and Health Products (AMP), WHO Regional Office for Europe. Sincerely yours, Dr Natasha Azzopardi Muscat Director, Division of Country Health Policies and Systems UN City, Marmorvej 51 Tel.: +45 45 33 70 00 Email: [email protected] DK-2100 Copenhagen Ø Fax: +45 45 33 70 01 Website: http://www.euro.who.int Denmark Encls: Concept note: Implementation of Cohort Event Monitoring protocol for molnupiravir Copy for information to: Ms Triin Uusberg, Head, European and International Coordination Department, Ministry of Social Affairs, Suur-Ameerika 1, 10129 Tallinn, Estonia H.E. Ms Katrin Saarsalu-Layachi, Ambassador Extraordinary and Plenipotentiary, Permanent Representative, Permanent Mission of the Republic of Estonia to the United Nations Office and other international organizations in Geneva, Chemin du Petit-Saconnex 28A, CH-1209 Genève, Switzerland H.E. Mr William Mart Laanemäe, Ambassador Extraordinary and Plenipotentiary, Embassy of the Republic of Estonia, Frederiksgade 19, 4th floor, 1265 Copenhagen K, Denmark Ms Kristina Köhler, Liaison Officer, WHO Country Office, Estonia, Paldiski Road 81, 10617 Tallinn, Estonia –2– Saatja: PANAGIOTAKI, Katerina <[email protected]> Saadetud: 03.05.2022 16:56 Adressaat: Elen Ohov <[email protected]> Koopia: Triin Uusberg <[email protected]>; SM Info <[email protected]>; <[email protected]>; <[email protected]>; <[email protected]>; <[email protected]>; KÖHLER, Kristina <[email protected]>; LINDHARDT, Lisbeth Sjaelborg <[email protected]>; PIRGARI, Dorina <[email protected]> Teema: Request to participate in active safety surveillance using cohort event monitoring for molnupiravir Please see the attached correspondence sent from the World Health Organization, Regional Office for Europe. One or more attachments may be included.Veuillez vous r¨¦f¨¦rer ¨¤ la correspondance ci-jointe du Bureau r¨¦gional de l'Europe de l'Organisation mondiale de la sant¨¦. Une ou plusieurs annexes peuvent ¨ºtre jointes.Mit der Bitte um Kenntnisnahme der beiliegenden Korrespondenz (eine oder mehrere Anlagen), Weltgesundheitsorganisation, Regionalb¨¹ro f¨¹r Europa. §³§Þ. §á§â§Ú§Ü§â§Ö§á§Ý§Ö§ß§ß§à§Ö §á§Ú§ã§î§Þ§à §à§ä §¦§Ó§â§à§á§Ö§Û§ã§Ü§à§Ô§à §â§Ö§Ô§Ú§à§ß§Ñ§Ý§î§ß§à§Ô§à §Ò§ð§â§à §£§ã§Ö§Þ§Ú§â§ß§à§Û §à§â§Ô§Ñ§ß§Ú§Ù§Ñ§è§Ú§Ú §Ù§Õ§â§Ñ§Ó§à§à§ç§â§Ñ§ß§Ö§ß§Ú§ñ (§à§Õ§Ú§ß §Ú§Ý§Ú §ß§Ö§ã§Ü§à§Ý§î§Ü§à §á§â§Ú§Ü§â§Ö§á§Ý§Ö§ß§ß§í§ç §æ§Ñ§Û§Ý§à§Ó). Katerina PanagiotakiAccess to Medicines and Health Products (AMP)WHO Regional Office for EuropeCopenhagen, DenmarkOffice: 3.3.11Web: Follow WHO on | | |