Covid

17th WHO Regulatory Update on COVID-19

28 August 2020

Key Messages

The unprecedented rapid development of multiple candidate diagnostics, therapeutics and vaccines against COVID-19 more than ever requires regulators of the world to work together collaboratively. Strong engagement through regulatory networks is key to make this happen efficiently and quickly.

Highlights and main issues

• WHO has recently received two Emergency Use Listing (EUL) submissions for antigen detection RDTs. WHO is currently screening and assessing the information submitted by both manufacturers; the assessment outcomes will be shared as soon as available.

• Since the last regulatory update, there has been a major increase in number of adverse drug reaction reports with remdesivir in the WHO Global Database of Individual Case Safety Reports, VigiBase.

• COVAX, a global initiative aimed at working with vaccine manufacturers to provide countries worldwide equitable access to safe and effective vaccines once they are approved, currently has the world’s largest and most diverse COVID-19 vaccine portfolio – including nine candidate vaccines, with a further nine under evaluation and conversations underway with other major producers.

• Updated WHO Guidelines on DNA vaccines were adopted by an extraordinary meeting of the WHO Expert Committee on Biological Standardization (ECBS) and provide guidance to National Regulatory Authorities and to product developers on international expectations for the quality, safety and efficacy of DNA vaccines.

• The ECBS also advised that a number of unique attributes of mRNA vaccines require specific guidance. WHO is developing a Points to Consider document on evaluation of the quality, safety and efficacy RNA vaccines to address this need.

• The U.S. Food and Drug Administration (FDA) issued an emergency use authorization (EUA) for investigational convalescent plasma for the treatment of COVID-19 in hospitalized patients on 23 August 2020. WHO agrees with FDA that adequate and well-controlled randomized trials remain necessary for a definitive demonstration of convalescent plasma efficacy and to determine the optimal product attributes and appropriate patient populations for its use.

• The International Narcotics Control Board, WHO and the United Nations Office on Drugs and Crime have issued a call to governments to ensure that the procurement and supply of controlled medicines in countries meet the needs of patients, both those who have COVID-19 and those who require internationally controlled medicines for other medical conditions.
© World Health Organization 2020. All rights reserved.
This document is intended for national regulatory authorities, regulatory networks and associated stakeholders. It may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or in whole, in any form or by any means without the permission of the World Health Organization

17th WHO Regulatory Update on COVID-19

Contents
Key Messages……………………………………………………………………………………………………………………………………1 Highlights and main issues ………………………………………………………………………………………………………………….1 Update on the ACT-Accelerator……………………………………………………………………………………………………………2 In vitro diagnostics………………………………………………………………………………………………………………………………3

WHO EUL and listing update …………………………………………………………………………………………………………… 3 Antigen detection rapid diagnostic tests ……………………………………………………………………………………………. 4 IVDs at the core of the ACT-Accelerator……………………………………………………………………………………………. 4 IVDs listed by National Regulatory Authorities in IMDRF jurisdictions……………………………………………………4

Therapeutics……………………………………………………………………………………………………………………………………… 4

Update on the WHO Solidarity trial …………………………………………………………………………………………………… 4

Research mapping of candidate therapeutics……………………………………………………………………………………..5

Adverse drug reactions ………………………………………………………………………………………………………………………. 5 Vaccines …………………………………………………………………………………………………………………………………………… 5 COVAX and the COVAX Facility……………………………………………………………………………………………………….5 Update on WHO Solidarity Vaccine Trial …………………………………………………………………………………………… 6 WHO Guidelines for DNA vaccines……………………………………………………………………………………………………6 WHO Points to Consider on RNA vaccines ……………………………………………………………………………………….. 7 Landscape of candidate vaccines……………………………………………………………………………………………………..7 Convalescent plasma………………………………………………………………………………………………………………………….7 Donors acceptance criteria for COVID-19 convalescent plasma ………………………………………………………….. 7 Research protocols, assays and reference standards ……………………………………………………………………………. 8 WHO Working Group: Assays and reference preparations…………………………………………………………………..8 WHO Working Group: Animal models ………………………………………………………………………………………………. 9 Supply Chain …………………………………………………………………………………………………………………………………….. 9 INCB, WHO and UNODC statement on access to internationally controlled medicines ……………………………… 9 Medical Devices ………………………………………………………………………………………………………………………………… 9 WHO Medical devices newsletter …………………………………………………………………………………………………….. 9

Update on the ACT-Accelerator

To coordinate rapid allocation, deployment and scale up of recommended and quality assured therapeutics to support the COVID-19 response in LMIC, the therapeutics partnership of the ACT-Accelerator has launched a workstream on procurement and deployment. Workstreams on rapid evidence assessment and on market preparedness for therapeutics are already operational. Both small molecules and monoclonal antibodies are being considered by the therapeutics partnership. Monoclonal antibodies require delivery to the patient in complex care settings. Allocation across all countries would require technical cooperation to increase capacity and to monitor absorption capacity including the cold chain. Regulatory cooperation will also be essential.

17th WHO Regulatory Update on COVID-19

In vitro diagnostics WHO EUL and listing update

The WHO Prequalification Unit is assessing products for Emergency Use Listing (EUL) for candidate in vitro diagnostics (IVDs) to detect SARS-CoV-2. The following IVDs are eligible for EUL submission:

• Assays for the detection of SARS-CoV-2 nucleic acid;

• Rapid diagnostic tests and enzyme immunoassays for the detection of IgM/IgG to SARS-CoV-2;
and

• Rapid diagnostic tests for the detection of SARS-CoV-2 antigens.
Manufacturers interested in the EUL submission are invited to contact WHO at diagnostics@who.int and schedule a pre-submission call.
Applicants are asked to submit their applications for assessment based on WHO instructions and requirements for NAT and Ag detection RDTs and IVDs detecting antibodies to SARS-CoV-2 virus.
50 expressions of interest for NAT assays, 22 for antibody detection assays and 2 for antigen detection RDTs have been received so far.
The status of each application: update (25 August 2020)
17 products have been listed as eligible for WHO procurement based on their compliance with WHO
EUL requirements.
‐‐‐

Date Listed

Product name Product code(s) Manufacturer

14 Aug 2020

TaqPathTM COVID 19 CE IVD RT PCR Kit A48067 Thermo Fisher Scientific

14 Aug 2020

Wantai SARS-CoV-2 RT-PCR WS-1248

Beijing Wantai Biological Pharmacy Enterprise Co., Ltd

09 July 2020

COVID-19 Coronavirus Real Time PCR Kit JC10223-1NW-50T

Jiangsu Bioperfectus Technologies Co., Ltd

06 July 2020

Simplexa COVID-19 Direct and Simplexa COVID-19 Positive control Pack

MOL4150, MOL4160 DiaSorin

23 June 2020

Xpert® Xpress SARS-CoV-2 XPRSARS-COV2-10 Cepheid AB

15 June 2020

COVID-19 Real-Time PCR Kit HBRT-COVID-19

Chaozhaou Hybribio Biochemistry Ltd.

11 June 2020

Novel Coronavirus 2019-nCoV Nucleic Acid Detection Kit

(Real Time PCR) GZ-D2RM25 Co., Ltd

Shanghai GeneoDx Biotechnology

5 June 2020

SARS-CoV-2 Nucleic Acid Test (Real-time PCR) KH-G-M-574-48

Shanghai Kehua Bio-engineering Co., Ltd

22 May 2020

Novel Coronavirus (SARS-CoV-2) Real Time Multiplex RT- PCR Kit

RR-0485-02 Shanghai ZJ Bio-Tech Co., Ltd

21 May 2020

FTD SARS-CoV-2 11416300

Fast Track Diagnostics Luxembourg S.à.r.l.

19 May 2020

Multiple Real-Time PCR Kit for Detection of 2019-CoV CT8233-48T

Technologies Co., Ltd.

Beijing Applied Biological

14 May 2020

Detection Kit for 2019 Novel Coronavirus (2019-nCoV) RNA, DA0930, DA0931 and DA0932 Da An Gene Co., Ltd. Of Sun Yat- (PCR- Fluorescence Probing) sen University

07 May 2020

Real-time fluorescent RT-PCR kit for detecting 2019-nCoV MFG030010 BGI Europe A/S

24 April 2020

PerkinElmer® SARS-CoV-2 Real-time RT-PCR Assay SY580 SYM-BIO LiveScience Co., Ltd

09 April 2020

Abbott Realtime SARS-CoV-2 09N77-090 and 09N77-080 Abbott Molecular Inc.

07 April 2020

Primerdesign Ltd COVID-19 genesig Real-Time PCR assay Z-Path-COVID-19-CE Primerdesign Ltd.

17th WHO Regulatory Update on COVID-19

03 April 2020

cobas SARS-CoV-2 Qualitative assay for use on the cobas 6800/8800 Systems

09175431190 and 09175440190

Roche Molecular Systems, Inc.

Antigen detection rapid diagnostic tests

WHO has recently received two EUL submissions for antigen detection RDTs. The Panbio COVID-19 Ag Rapid Test Device (Nasopharyngeal) manufactured by Abbott Rapid Diagnostics Jena GmbH and the STANDARD Q COVID-19 Ag Test manufactured by SD Biosensor, Inc. are rapid, visually-read antigen detection assays, which do not require a specialized reader for result interpretation. Both products are intended for the qualitative detection of SARS-CoV-2 antigen (Ag) in human nasopharyngeal swab specimens. WHO is currently screening and assessing the information submitted by both manufacturers; the assessment outcomes will be shared as soon as available.

IVDs at the core of the ACT-Accelerator

Launched at the end of April 2020, the Access to COVID-19 Tools (ACT)-Accelerator is organized into four pillars of work.

The diagnostics pillar focuses on four areas of work which are critical for speeding up an end to the pandemic; R&D, market readiness, supply and country preparedness. The WHO EUL assessments and support to in-country authorization or listing of IVDs for COVID-19 are at the core of WHO’s support to market readiness and come to complement partners’ efforts towards equal and adequate access to diagnostic tools.

An investment of US$6 billion is required to harness innovation and secure access to vital diagnostic tests over the next 12 months for low- and middle-income countries.

Diagnostics pillar of the ACT-Accelerator: investment case
IVDs listed by National Regulatory Authorities in IMDRF jurisdictions

To help countries, WHO publishes links to emergency lists, together with contact details, on IVDs authorized for use in the International Medical Device Regulators Forum (IMDRF) jurisdictions along with other useful information on policies and guidance.

The most recent update (24 Aug 2020)
Note: WHO does not endorse any of the lists provided by NRAs. The information is

provided exclusively to assist stakeholders with identifying the links to the various lists.

Therapeutics

Update on the WHO Solidarity trial

Solidarity is the second-largest clinical trial in the world, with 24 countries actively enrolling, over 9,000 patients recruited in 400 hospitals (as of 17 August). It is also the largest trial of remdesivir with 3,000 randomized patients and is expected to provide a definitive answer on the impact of remdesivir on mortality and clinical progression.

WHO is actively engaging manufacturers for inclusion in the next stage of the trial the use of anti- inflammatory drugs in hospitalized moderate to severely ill patients, as well as monoclonal antibodies for treatment. In the coming weeks, data from the ongoing studies will be ready for dissemination and WHO will announce what the next stage of the Solidarity therapeutics trial will include.

17th WHO Regulatory Update on COVID-19

Research mapping of candidate therapeutics

A living research mapping of candidate COVID-19 therapeutics, displaying studies per country, showing study design, disease severity in study participants, and type of treatment being studied, as well as network maps of these studies, has been made available at: https://www.covid-nma.com/dataviz/

Living synthesis of Covid-19 study results

A list of treatment comparisons, a summary of the evidence for that comparison, and a detailed description of primary studies, including a risk of bias assessment is at: https://covid- nma.com/living_data/index.php

Adverse drug reactions

Since the last regulatory update, there has been a major increase in number of adverse drug reaction (ADR) reports with remdesivir in the WHO Global Database of Individual Case Safety Reports, VigiBase. With regard to other Solidarity Trial drugs, the ADR-patterns are consistent with those described in earlier reports and mostly within the labelling for the respective drugs.

Reports have been received from all WHO regions, with the largest number now originating in the WHO region of the Americas with 45% of the shared reports.

A descriptive analysis of the new reports (26 Aug 2020) Vaccines

COVAX and the COVAX Facility

• Nine CEPI-supported candidate vaccines are part of the COVAX initiative, with a further nine candidates under evaluation, and procurement conversations on-going with additional producers not currently receiving research and development funding through COVAX – giving COVAX the largest and most diverse COVID-19 vaccine portfolio in the world

• 80 potentially self-financing countries have submitted non-binding expressions of interest to the Gavi-coordinated COVAX Facility, joining 92 low- and middle-income economies that are eligible to be supported by the COVAX Advance Market Commitment (AMC)

• Goal of bringing the pandemic under control via equitable access to COVID-19 vaccines needs urgent, broadscale commitment and investment from countries
172 countries are now engaged in discussions to potentially participate in COVAX, a global initiative aimed at working with vaccine manufacturers to provide countries worldwide equitable access to safe and effective vaccines, once they are approved.
COVAX currently has the world’s largest and most diverse COVID-19 vaccine portfolio – including nine candidate vaccines, with a further nine under evaluation and conversations underway with other major producers.
The full list of candidate vaccines is as follows:

• Inovio, United States of America (Phase I/II)

• Moderna, United States of America (Phase III)

• CureVac, Germany (Phase I)

17th WHO Regulatory Update on COVID-19

• Institut Pasteur/Merck/Themis, France/ United States of America /Austria (Preclinical)

• AstraZeneca/University of Oxford, United Kingdom (Phase III)

• University of Hong Kong, China (Preclinical)

• Novavax, United States of America (Phase I/II)

• Clover Biopharmaceuticals, China (Phase I)

• University of Queensland/CSL, Australia (Phase I)
The nine candidate vaccines that are currently being evaluated for inclusion in the COVAX Facility include two from China, two from the United States of America, one from Republic of Korea, one from the United Kingdom and one global, multi-manufacture partnership. Two of these are in Phase I trials, two are technology transfers and the remainder are at the discovery stage.
The goal of COVAX is by the end of 2021 to deliver two billion doses of safe, effective vaccines that have passed regulatory approval and/or WHO prequalification. These vaccines will be offered equally to all participating countries, proportional to their populations, initially prioritising healthcare workers then expanding to cover vulnerable groups, such as the elderly and those with pre-existing conditions. Further doses will then be made available based on country need, vulnerability and COVID-19 threat. The COVAX Facility will also maintain a buffer of doses for emergency and humanitarian use, including dealing with severe outbreaks before they spiral out of control.
COVAX, the vaccines pillar of the Access to COVID-19 Tools (ACT)-Accelerator, is co-led by the Coalition for Epidemic Preparedness Innovations (CEPI), Gavi, the Vaccine Alliance, and WHO – working in partnership with developed and developing country vaccine manufacturers.
It is the only global initiative that is working with governments and manufacturers to ensure COVID-19 vaccines are available worldwide to both higher-income and lower-income countries.
Update on WHO Solidarity Vaccine Trial
A commentary published on 27 August in The Lancet, including authors from WHO’s Solidarity Vaccines Trial, states that successful vaccines should demonstrate an estimated risk reduction of at least 50% to be considered efficacious. Compared with individual vaccine trials, global multi-vaccine, multi-locality trials, like WHO’s Solidarity Vaccines Trials, with a shared control group can provide powerful, rapid and reliable results on both efficacy and safety of COVID-19 vaccines.
Deployment of a weakly effective vaccine could worsen the COVID-19 pandemic if it is wrongly assumed to substantially reduce risk, or if vaccinated individuals wrongly believe they are immune, thereby reducing implementation of other COVID-19 control measures. It could also interfere with the evaluation of other vaccines by necessitating non-inferiority trials.
in The Lancet: COVID-19 vaccine trials should seek worthwhile efficacy (27 Aug 2020) WHO Guidelines for DNA vaccines
There are 4 candidate DNA vaccines against COVID-19 that are currently in clinical trials and other candidates at an earlier stage of development. An extraordinary meeting of the WHO Expert Committee on Biological Standardization (ECBS), meeting from 24-28 August 2020, adopted updated WHO Guidelines on DNA vaccines. The Guideline covers a broad range of DNA vaccines against infectious diseases and provides guidance to National Regulatory Authorities and to product developers on international expectations for the quality, safety and efficacy of DNA vaccines.
The updated Guideline will be made available shortly at https://www.who.int/biologicals/vaccines/en/ 6

17th WHO Regulatory Update on COVID-19

WHO Points to Consider on RNA vaccines

The extraordinary meeting of the ECBS recommended that WHO develop, as quickly as possible, a Points to Consider (PtC) document on evaluation of the quality, safety and efficacy RNA vaccines. mRNA vaccines have been in early phase clinical trials and recently entered Phase III trials, but no mRNA vaccines have been licensed yet. The ECBS advised that a number of unique attributes of mRNA vaccines require specific guidance.

Currently 6 RNA-based vaccines against COVID-19 are in clinical trial, and whilst the document would cover preventative vaccines against infectious diseases, it would be especially useful to guide evaluation of the candidate COVID-19 RNA vaccines. Self-amplifying constructs that are comprised of only mRNA would be included in the scope of the document.

The text of the PtC will be posted when available at: https://www.who.int/biologicals/vaccines/en/

Landscape of candidate vaccines

A landscape analysis of candidate SARS-CoV-2 vaccines is regularly published by WHO. Landscape of COVID-19 candidate vaccines (25 August 2020)

Convalescent plasma

The decision was based on review of four lines of evidence to support that CCP may be effective in the treatment of hospitalized patients with COVID-19: 1) History of convalescent plasma for respiratory coronaviruses; 2) Evidence of preclinical safety and efficacy in animal models; 3) Published studies of the safety and efficacy of CCP; and 4) Data on safety and efficacy from the US National Expanded Access Treatment Protocol sponsored by the Mayo Clinic.

Current data suggest the largest clinical benefit is associated with high-titer units of CCP administered early in the course of disease. Adequate and well-controlled randomized trials remain necessary for a definitive demonstration of CCP efficacy and to determine the optimal product attributes and appropriate patient populations for its use.

FDA News release on EUA for CCP (23 Aug 2020)
Donors acceptance criteria for COVID-19 convalescent plasma

Common criteria for acceptance of donors of COVID-19 convalescent plasma include establishment of the minimum neutralizing antibody titre required for plasma to be suitable for use CCP. Potential donors may also be tested for presence of antibodies to SARS-CoV-2 in antigen binding assays (e.g. ELISA) although correlation with antibody neutralization titres is uncertain.

The extraordinary meeting of the ECBS (24-28 August 2020) recommended that statements on acceptability criteria for acceptance of donors of convalescent plasma, and of potency statements for convalescent plasma products, are made in terms of relative potency. Once a WHO international Standard for antibodies of SARS-CoV-2 is established, such statements should be made in International Units. This is because, based on experience with antibody assays against a wide range of pathogens, expression of results of antibody assays as titres can result in high inter-laboratory variation. Such

The U.S. Food and Drug Administration (FDA) issued an emergency use authorization (EUA) for

investigational convalescent plasma (CCP) for the treatment of COVID-19 in hospitalized patients on 23

August 2020. The FDA concluded this product may be effective in treating COVID-19 and that the

known and potential benefits of the product outweigh the known and potential risks of the product.

17th WHO Regulatory Update on COVID-19

variation can be reduced by several measures including expression of results relative to a reference preparation.

Research protocols, assays and reference standards

WHO Working Group: Assays and reference preparations

19 August 2020

A longitudinal serology study of neutralizing antibodies in COVID-19 convalescent individuals was presented. Using a pseudotype virus neutralization assay and testing samples taken during a 2-4 month period following recovery, about 20% of convalescents were found to have low titres of neutralizing antibodies whilst about 10% had high titres. Individuals who had a severe course of disease had higher titres than those with mild courses, and males had higher titres than females. The titres of neutralizing antibodies declined, relative to the first sample from each individual, during the 3 months of study, with a half-life of about 5 weeks. Binding antibodies on the other hand, which were also assayed in the study, were maintained at a titre similar to the intial sample throughout. This suggests that assays for binding antibodies are not necessarily good predictors of neutralizing antibodies, especially as time from infection increases.

Another study evaluated the T-cell response in COVID-19 exposed and non-exposed individuals. The researchers used peptide “megapools” designed to stimulate the entirety of the T cell response to SARS-CoV-2 (221 peptides to assay the CD4 and 628 peptides to assay the CD8 response) with a small (5-10ml) blood sample. A cohort of convalescent individuals recovered from mild COVID-19 were compared with stored samples obtained in 2015-2018. The data showed that the spike protein is the dominant antigen that generates T cell responses (both CD4 and CD8). Other SARS-CoV-2 structural, and some non-structural, proteins are also recognized by T cells. Longitudinal studies showed that the CD4 and CD8 responses were maintained at a stable level for the 3 months following infection, the maximum period studied. Some T cell reactivity was seen in samples collected prior to SARS-CoV-2 emerging in the human population. This was shown to be due to prior exposure to endemic human coronaviruses. Whether this pre-existing reactivity influences immunity to SARS-CoV-2 is not known.

26 August 2020

Data to support a claim of an acute episode of reinfection of an individual in Hong Kong were presented. Viruses from the first and second episodes are phylogenetically distinct; virus from the first episode clustering with viruses circulating in the population in March 2020, and virus from the second episode clustering with viruses circulating in the population in August 2020. The time interval between episodes was 142 days and IgG seroconversion was demonstrated after the second episode. The researchers considered these findings to be indicative of reinfection rather than prolonged shedding after the first episode. Further studies are in progress to better understand this finding and confirm the conclusion.

A second presentation described polymorphisms detected in virus stocks prepared for animal model studies. The biological relevance of such heterogeneity is not known. However, in order to reduce this issue as a variable, factors which influence the emergence of virus sub-populations during laboratory manipulations, such as expansion of virus stocks prior to animal challenge studies, were evaluated and described. Conditions to enable production of large volume stocks of virus that are as close as possible to the starting material were identified. WHO intends to collate this information, and experience from other laboratories also working on this issue, into guidance for users of virus stocks.

17th WHO Regulatory Update on COVID-19

WHO Working Group: Animal models

Data on an investigational double monoclonal antibody (mAb) mixture were presented at the 20 August meeting. A double mAb mixture is claimed to reduce the risk of virus escape mutants. In vitro and in vivo data were presented including animal models. The course of COVID-19 disease is shorter in animals than in humans and so are imperfect models. Nevertheless, successful treatment of COVID-19 with the double mAb mixture was demonstrated in a hamster model which supports further studies in human clinical trials.

Supply Chain

INCB, WHO and UNODC statement on access to internationally controlled medicines

The International Narcotics Control Board (INCB), WHO and the United Nations Office on Drugs and Crime (UNODC) call on governments to ensure that the procurement and supply of controlled medicines in countries during the COVID-19 pandemic meet the needs of patients, both those who have COVID-19 and those who require internationally controlled medicines for other medical conditions.

There is a need to ensure access to controlled medicines such as sedatives and analgesics for intubation protocols for the treatment of patients with COVID-19. Non-COVID patients continue to require controlled medicines for the management of pain and palliative care, surgical care and anesthesia, mental health and neurological conditions, and for the treatment of drug use disorders.

Governments should ensure that sufficient quantities of internationally controlled medicines, of assured quality, are available and affordable to people under medical care. Governments are reminded that in acute emergencies, it is possible under the International Drug Control Conventions to utilize simplified control procedures for the export, transportation and supply of medicinal products containing controlled substances, especially in those cases where the competent authorities in the importing countries may not be operating at full capacity. Competent national authorities may permit the export of medicines containing narcotic drugs and/or psychotropic substances to affected areas even in the absence of the corresponding import authorizations and/or estimates.

INCB, WHO and UNODC statement (14 Aug 2020) Medical Devices

WHO Medical devices newsletter

The Newsletter provides updated information on medical devices and related topics, including policies and regulations, quality and safety, health technology assessment, health technology management, priority medical devices, innovation, and global collaborations.

WHO Medical Devices Newsletter

Based on the WHO technical specifications of @ 50 priority medical devices for COVID, found here purchases have been done in WHO, through the supply portal for 13,000 oxygen concentrators, 10,000 pulse oxymeters; 3,000 patient monitors; 5,000 infrared thermometers, 680 ventilators. Most of the medical equipment packages include accessories and consumables and warranties. Training modules are being developed.

For requests and questions, contact Adriana Velazquez at COVID-MED-DEVICES@who.int 9