PANORAMIC: Platform Adaptive trial of NOvel antiviRals for eArly treatMent of covid-19 In the Community

Despite high uptake of vaccination against COVID-19, the disease remains prevalent in the UK and in many countries around the world, with many patients continuing to require hospital admission. Early treatment with antiviral agents may prevent progression to the later phase of COVID-19. Therefore, there is an urgent need to identify treatments for COVID-19 for use in the community early on in the illness that prevent the need for hospital admission and improves time to recovery. It is therefore vital that the University of Oxford use this opportunity to accelerate enrolment into COVID-19 therapeutics trials.

The PANORAMIC (Platform Adaptive trial of NOvel antiviRals for eArly treatMent of covid-19 In the Community) trial is the only national priority clinical trial evaluating potential novel antivirals for COVID-19 in the primary care setting, endorsed by the Chief Medical Officers (CMOs) of all four devolved nations. The primary aim is to determine the effectiveness of selected antiviral agents in preventing hospitalisation and/or death in higher-risk patients with a confirmed positive SARS-CoV-2 PCR test result. The PANORAMIC trail is run by the Nuffield Department of Primary Care Health Sciences at the University of Oxford. For the purposes of this data sharing agreement, the Nuffield Department of Primary Care Health Sciences will be referred to as the 'University of Oxford' in this agreement.

An update for version 1 of this agreement was regarding positive SARS-CoV-2 Lateral Flow Test (LTF) was added. Originally, the study team required a positive Polymerase Chain Reaction (PCR) test for inclusion in the main analysis. UK guidelines have reduced the amount of PCR testing that is recommended. In a context of high prevalence, false positive results from Lateral Flow Tests (LFTs) are minimal, and LFTs are now considered to be giving a truer reflection of infection status in some cases. In line with the changing policy and science, the study team now allow eligibility based on a positive SARS-CoV-2LFT without the requirement for a confirmatory PCR test for inclusion in the main analysis.

A further update for version 3 of this agreement was regarding the continuation of recruitment into 2023. The PANORAMIC trial is ongoing into 2022-2023 despite restrictions being lifted in the UK and free PCR and LTF testing being discontinued on 30 March 2022. Based on the study team's previous year's experience, the Covid-19 infection rate dropped between June and October 2021 and slowly picked up again from November and peaked in December 2021/January 2022, therefore the study is continuing over the forthcoming year to continue investigating new treatment arms. The study team would like to continue recruitment of participants to PANORAMIC because the long term effect of vaccine is still not known and the uncertainty of the future trend of infection. In addition, the study team are continuing recruitment of participants to the ‘Paxlovid arm’, which is a new treatment that was added to PANORAMIC in Spring 2022. With regards to testing of Covid-19, participants are currently recruited from PANORAMIC hubs only. Only those that qualify for tests under government schemes can participate due to the requirement for a positive test.

*** New for Version 4 of this agreement ***

This current renewal for version 4 of this agreement is regarding the renewal of the data requested for a further 12 months. The study team would like to continue recruitment of participants to PANORAMIC because the long term effect of vaccine is still not known and the uncertainty of the future trend of infection.

PANORAMIC continues with a more complex novel antiviral agent, Paxlovid. There are some who consider that the threshold for using Paxlovid should be lowered, whereas others consider that this drug is unlikely ever to be cost-effective, given its many interactions and exclusions, and that the population is now highly vaccinated. All agree that findings from the drug company trial that was conducted in an unvaccinated population before Omicron began to circulate cannot be extrapolated to apply to the current situation in the UK. Furthermore, critically important information is missing about virology outcomes, cost effectiveness and impact of the use of this drug on illness and potential viral resistance. The PANORAMIC trial is addressing a critically important question, as well as generating novel information that will be applied to millions of clinical decisions worldwide.

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Recruitment into the current arm (Paxlovid) of the trial is challenging; awareness of participation in COVID clinical trials has diminished as the public’s focus has shifted away from COVID. However, despite vaccination, people continue to become seriously ill with COVID and this is likely to increase in the Autumn and over the coming winter. As the PANORAMIC trial has not met its target recruitment figure, they are planning to extend the recruitment period until March 2024, to allow for seasonal variance and a likely higher recruitment rate over Autumn and over the coming Winter 2023. The trial team will need to extend the agreement alongside this so that they can continue to collect important outcome data on the trial participants so that follow-up can be completed.

PANORAMIC is:

• Recruiting across the whole UK* - anyone age 18** or over who match the participant criteria can participate, regardless of location (aged 50 or over, or 18-49 with a pre-existing condition),

• For both recruiters and patients it is a simple process to complete enrolment to the trial via a secured online platform.

• Obtaining consent /consultee advice, checking eligibility, issuing study medication and materials, and follow-up is managed remotely through a central facility at the University of Oxford or delegate. Contracts would be in place with delegates and vendors carrying out these tasks. (Under an update for version 1 of this agreement it was clarified that University of Oxford utilise the services of Integrated Pharmaceutical Services (IPS) Pharma to distribute the drug to trial participants. The personal data required for distribution is collected directly from the participant at the time of consent and IPS Pharma do not have any access to any NHS England record level data. IPS Pharma do not make any decisions about the means by which any personal data is being processed for this study nor the methodology by which the study is conducted. For these reasons, IPS Pharma are not considered as a Data Controller or Processor).

*** Update for Version 4 for agreement *** The Trial Team have informed NHS England they are planning to end their contract with IPS. Their CTU now has an in-house pharmacy so for cost-saving, they will be using this instead of IPS. This will go live in the last week of June 2023. ***

* PLEASE NOTE - The University of Oxford is obtaining data from NHS England related to residents in England only.

** PLEASE NOTE - The first treatments included in the PANORAMIC trial have conditional licensing for adults and therefore the study team are unable to include children at this stage. Depending on the advice from the Antiviral Taskforce regarding future treatment arms, and their licensing conditions, the inclusion criteria may be amended in future to include under 18’s.

Primary objective -

To determine whether antiviral treatment in the community safely reduces non-elective hospitalisations/deaths in higher risk, symptomatic patients with confirmed COVID-19

Secondary objectives - To explore whether trial treatment reduces:

1) Time to recovery (defined as the first instance that a participant report of feeling recovered from the illness)

2) Participant reported illness severity, reported by daily rating of how well participant feels, enabling identification of sustained recovery.

3) Duration of severe symptoms and symptom recurrence

4) Contacts with the health services

5) New infections in household

6) To investigate the safety of antiviral agents

7) Longer term effects

8) Cost effectiveness

The study team are requesting the Covid-19 UK Non-hospital Antigen Testing Results (pillar 2) dataset in order to identify and successfully recruit potential patients into the trial, early on in their stage of COVID-19 disease. A positive PCR test is essential for inclusion into the trial. The positive PCR test result will be participant reported prior to randomisation, and confirmation of the positive result will be sought at a later date via the Pillar 2 dataset.

The University of Oxford would like to receive names and contact details (including preferably a telephone number and email address) of people who have received a positive COVID-19 swab result from the Pillar 2 testing system. The trial team, based at the University of Oxford, will then contact these potential participants, inform them about the trial and if they are happy, go on to screen and consent them into the PANORAMIC trial. Daily, the trial team would like to receive identifiable record-level data on a random cohort (up to 500) of people aged 18+.

The trial already has a centre set up and operating remotely at the University of Oxford to manage this recruitment in a timely manner. Management of the recruitment to the trial will be undertaken by substantive employees of the University of Oxford who have been appropriately trained in data protection and confidentiality.

The question of whether ‘cold calling’ is appropriate has been considered for this application. As time is of the essence for recruitment into PANORAMIC, the telephone is the most efficient and quickest means to ensure direct contact with the individual, who can answer questions instantly over a call. The study team would also like to use the Short Messaging Service (SMS) and email option for invitation, for those patients who they cannot reach via telephone or those who require follow-up information. During the calls, clear explanation will be given to individual about how the trial has been able to contact them and what to do if they do not wish to be contacted again (i.e. registering a National Data Opt-out). The trial team will respect the wishes of those signed up to the Telephone Preference Service (TPS). The team will ensure that customers flagged on the TPS are not contacted for this trial. The trial team will also ensure the required comorbidities are discussed early on in the calls so as to not to get the individual’s hopes up if they are not in fact eligible for the trial.

*** Update for Version 4 for agreement *** The study team have informed NHS England that it is now likely they will send the potential participants a text message only as the study team don’t have capacity to make calls. The study team now have approved text message templates for this, which include the web link for patients to self-register. ***

Other considerations that have been taken into account in relation to contacting individuals:

• The data relating to positive COVID-19 tests is sent to NHS England at the same time that it is sent to the Business Services Authority, the latter process triggering the SMS to the individual informing them of their result. It then takes around four hours for the Covid-19 UK Non-hospital Antigen Testing Results (Pillar 2) dataset within NHS England to be updated with this information. Given that this information then needs to be extracted from the dataset at some point in the next 24 hours, then used by the trial team to make contact with the individual, the risk of the individual being informed of their test result by the trial team before they have read their SMS is small. However, the trial team should have a suitable script prepared to deal with this slim possibility.

• The chances of people having multiple positive COVID-19 test results are rare, and rarer still is the likelihood that they will be one of the 500 people extracted from the thousands of daily test results to be sent to the trial team on more than one occasion. Therefore, the risk of an individual being contacted twice for recruitment into PANORAMIC is extremely low.

• NHS England recognises that there are likely to be more requests of this nature in future and therefore, if multiple trial require extracts of people to contact, suitable controls need to be in place within the extract process to ensure that individuals are not getting contacted for recruitment into trials more than is reasonably expected.

• The study team at the University of Oxford are aware the recent governmental change in policy over COVID-19 testing that will have a significant impact upon the way testing records will be collected, and how the results should be interpreted. Therefore, the study team will inevitably have to actively incorporate this measure in their study design, which will be reflected in future versions of the study Protocol, processing methodology and outcome analyses.

Patient and Public Involvement & Engagement (PPIE)

The PANORAMIC trial has had extensive PPIE engagement to support development of trial materials and processes and to discuss the plans for efficient and safe use of patient data and has plans for significant engagement throughout the period of the study.

The main study PPIE group includes members of five different cultural and faith communities and representatives of those with learning disabilities. They have had three meetings prior to this application, focussing on acceptability of trial processes and optimising patient-facing materials including redesigning the Pictorial Patient Information Sheet (PIS) and co-developing a summary front page for this document. They have reviewed the online trial interface and instructions for participants. This group will continue to meet at least every month when the trial commences recruitment.

The study team have begun to convene additional PPIE groups in Scotland, Northern Ireland and Wales to focus on nation-specific recruitment and dissemination issues and will work with individual cultural and community leaders to ensure inclusion of the most diverse range of participants possible.

*** Update for Version 4 for agreement *** PPIE representatives continue to attend the PANORAMIC Trial Steering Committee meetings where their input is greatly appreciated. The study team still has reps on the Trial Steering Committee, and the trial team have a consultant who does PPIE work and outreach to faith communities. ***

Request to use SCR for consented / consultee advised participants:

The PANORAMIC trial team are requesting to access the Summary Care Record (SCR) for patients recruited into the trial for the purposes of ensuring timely prescribing and safe patient care. SCR access will be essential to successfully recruit participants in the very restrictive timeframe of five days since symptom onset. For the first treatment arm, the trial is run remotely, therefore removing the need for participants to be near to a GP practice. Screening and contact with the trial team is all completed online. The trial team are requesting access to Summary Care Records as part of this application as it will not be possible within the five day window of recruitment from symptom onset, for the trial team to request such information regarding safe prescribing from the participant’s GP.

The PANORAMIC trial team therefore seek permission for the clinical trial team, a group of dedicated doctors and nurses who are fully qualified, study-trained, accredited and registered, to review consenting / consultee advised patients’ Summary Care Records, in order to be able to confirm key information obtained from the patient relevant to safe patient care in the trial. Only nurses and doctors who are registered and accredited with the General Medical Council of the UK or the Nursing and Midwifery Council of the UK who are clinical members of the PANORAMIC study team would review the Summary Care Record for information relevant to safe prescribing and participant care.

The Summary Care Record will be used as a timely, second check regarding medication, allergy, and co-morbidities information to support reconciliation, to ensure safe prescribing. These are all elements of a patient’s SCR with additional information which is a subset of their wider GP record. This access provides an immediate available information source to meet the need to support safe prescribing in a proportionate and timely way. In addition, the Summary Care Record will provide a further safety check, in that access to it will facilitate the opportunity for double-checking participants’ NHS Number and GP practice.

There is a five-day window from symptom onset to enrolment into the trial and so SCR access is critical to confirm eligibility within this very limited time-period.

Access is sought only for those people who have screened eligible to be part of the trial, and who have already signed informed consent / consultee advice for participation in the study and for the trial to access their clinical records. All potential participants are asked specifically for permission for the trial team to access their medical records and have the opportunity to decline this access. In addition, they will be asked specifically and separately for permission about access to their Summary Care Record. For a patient who has provided consent / consultee advice to join the trial and for their SCR to be accessed, the data will be accessed by a clinician to support safe prescribing decisions prior to randomisation in the trial and prescribing medications. A Summary Care Record will only ever be accessed for each individual participant to confirm eligibility for central recruitment, to confirm participant safety and to confirm contact details or hospitalisations.

Access to SCR is required for the period that the trial is recruiting - currently this is December 2021 until March 2024.

This request for SCR access for PANORAMIC, along with the similar request for the sisters trial, PRINCIPLE, together form a first-of-type access request and as an interim position it is included in the Data Sharing Agreement. This is a holding position whilst considerations are undertaken to agree whether to offer this as a service more widely to clinical trials for patient safety purposes. This allows time for an appropriate access and approval process to be developed in future, but in the meantime ensures that SCR access is recognised within the research data access process alongside the normal direct care process for access to SCR.

PARTICIPANT CONSENT / CONSULTEE ADVICE

Under the Common-law Duty of Confidentiality, from the start of recruitment, participants were asked to sign a consent form. Within care home settings only, if the participant did not have the capacity to consent, a friend/relative or nominated consultee advice was sought under the Mental Capacity Act, and a personal / professional legal representative letter was obtained. These patients who were recruited into PANORMIC following declaration by a personal or professional consultee (to date, May 2023) were all confirmed with conditions which mean they are unlikely to regain capacity (such as Dementia), however the University of Oxford do have a re-consenting process in place should this be required for any future participants recruited under personal / professional consultee advice. People who lack capacity to consent for themselves will only be recruited from care homes: adults who lack capacity to consent living elsewhere will not be recruited. If the recruiting health and social care professional deems that a patient in a care home lacks capacity to provide consent for themselves, then a personal or professional legal representative (England and Wales only) will be asked to provide consent.

This Clinical Trial is registered as a clinical trials of investigational medicinal products (CTIMPs). Under Section 30 of the Mental Capacity Act 2005, CTIMPS are specifically excluded from the research provisions of the Act. This is because separate provision is made for including adults lacking capacity in CTIMPs in Schedule 1 of the Medicines for Human Use (Clinical Trials) Regulations 2004. Therefore, for this agreement the National Data Opt Out will not be applied to the data requested, with the exception of Summary Care Record and Pillar 2 data, which has been granted access by the Confidentiality Advisory Group (CAG) via Section 251 of the National Health Service Act 2006 and its current Regulations, the Health Service (Control of Patient Information) Regulations 2002.

FOLLOW UP DATA:

The trial follows up all participants for 28 days and then at three and six months following randomisation.

In this agreement, the University of Oxford are requesting access to record-level data from the following data sets in order to receive follow up data on trial participants:

> Hospital Episode Statistics (HES) Admitted Patient Care (APC)

> HES Critical Care (CC)

> Civil Registration (Deaths) data set

> Medicines dispensed in Primary Care (NHSBSA data)

> Uncurated Low Latency HES APC Dataset

> Uncurated Low Latency HES CC Dataset

> HES Outpatients (OP)

> HES Emergency Care Dataset (ECDS)

These NHS England datasets will be essential to collect the primary outcome, which relates to all-cause hospitalisation/death.

Under an amendment to version 1 of this agreement it was clarified that there was a request to add Low Latency Hospital Episode Statistics (HES) Admitted Patient Care (APC) and Low Latency HES Critical Care (CC) datasets to the existing 28 day follow up data.

Previously (v0 of this agreement), the University of Oxford requested access to HES APC and HES CC datasets. However, due to NHS England’s cleaning and Data Quality procedures, HES datasets are released under data sharing agreements two months in arrears. This has meant that the University of Oxford are delayed in receiving crucial data for analysis. A number of NHS Trusts now submit routine hospital data as part of the Commissioning Data Set (CDS) more frequently such as weekly or even sometimes daily. This subset of more frequently reported management data is reported in Secondary Use Service (SUS). This SUS data is used to create additional uncurated data sets including Low Latency HES APC and Low Latency HES CC which offer access to more current data. Though less complete and quality assured, this data provides the opportunity for more immediate analysis and additional insights compared to that which might be available in delayed HES data. These Low Latency datasets will provide the study team with more immediate access to data required to begin interim analysis more swiftly. However, the study team have confirmed that they will continue to access the regular HES APC and CC datasets to allow for data checking, quality and completeness. All final study reports and outcomes analysis will be based on regular HES dataset information.

Request to add HES Out Patient (OP) and Emergency Care dataset (EDCS) datasets to the existing 28 day follow up data

The University of Oxford have requested access to HES OP and ECDS datasets as part of this agreement.

The request for the addition of HES OP and ECDS datasets are for the purpose of the health economic evaluation, which is embedded within the trial design. This data will be used by the study team to assess the cost effectiveness of each antiviral from an NHS perspective.

Request to add additional data fields to existing Hospital Episode Statistics (HES) Admitted Patient Care (APC) and HES Critical Care (CC) datasets

the University of Oxford have requested additional data fields to be included in the existing HES APC and HES CC datasets for which they are already in receipt as part of the existing 28 day follow up data.

The request for the additional fields within HES APC and HES CC are also for the purpose of the health economic evaluation, which is embedded within the trial design. These fields will enable the study team to assess the cost effectiveness of each antiviral from an NHS perspective.

These additional dataflows will support those already received to follow up consented/consultee advice patients for 28 day follow up data. As per the previous amendment for 28 follow up data, the existing consent/consultee advice covers the provision of these extra datasets/ data fields and it will only be accessed by the team at University of Oxford, and no other organisations will process or store it.

Due to the high rate of recruitment, the Data Safety Monitoring Committee (DSMC) review the trial data weekly and can ask for recruitment into a trial arm to be stopped immediately. Therefore, trial data needs to be made available as soon as possible so that the team can quickly issue a press statement and publication of results if required to do so. There is a need to capture the required data in a more timely and efficient manner via monthly extracts from NHS England. The DSMC is an independent committee with remits to monitor the progress of the study, review of safety data and also the unblinded interim analysis. The DSMC give recommendation, based on the information they receive from the trial statistician, to the Trial Steering Committee (TSC) with regards to the terminating a treatment arm due to treatment effect or treatment failure. The remit of the TSC is to monitor the progress of the study and provide the trial management committee recommendation based on recommendation from the DSMC. Members of both committees are independent from the trial and their memberships have been approved by National Institute of Health research (NIHR) as the funder for this study. The DSMC and TSC do not make any decisions determining the purposes and means of the processing of data or the study purpose and methodology, and are therefore not considered a Data Controller. Additionally, the DSMC and TSC will not have access to any NHS England record level data and will only view aggregated data with small numbers suppressed and are therefore not considered a Data Processor.

The PANORAMIC trial is funded by the NIHR, but do not make any decisions determining the purposes and means of the processing of data or the study purpose and methodology, and are therefore not considered a Data Controller. Additionally, the NIHR will not have access to any NHS England record level data and are therefore not considered a Data Processor.

LEGAL BASIS FOR COMMON LAW DUTY OF CONFIDENTIALITY

For versions 0 through to version 2 of this agreement the Common Law was met by:

The lawful basis for the release and use of the confidential data for Covid-19 UK Non-hospital Antigen Testing Results (Pillar 2) data and access to Summary Care Record (SCR) being shared under this version of the agreement is Regulation 3(4) of the National Health Service (Control of Patient Information Regulations) 2002 (COPI) to require NHS England to share confidential patient information with organisations entitled to process this under COPI for COVID-19 purposes. The only permitted activities under this Data Sharing Agreement (DSA) are for COVID-19 purposes and within bounds of Reg 3(2) COPI. Reg 3 (2) COPI states that: "2) For the purposes of this regulation, “processing” includes any operations, or set of operations set out in regulation 2(2) which are undertaken for the purposes set out in paragraph (1)." The research relates to the monitoring and managing of COVID-19 and would therefore be covered by Reg 3(1)(d) of COPI.

For version 3 of this agreement the Common Law was met by the following after 30/06/2022:

University of Oxford rely on the COPI notice for the statutory sharing of information by NHS England for COVID-19 purposes. When the COPI notice expires, full support and approval for section 251 from the Confidentiality Advisory Group has been received and will supersede the COPI notice for the release and use of the confidential data (Covid-19 UK Non-hospital Antigen Testing Results (pillar 2)) under this agreement.

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Under version 4 of this agreement the Common Law continues to be met by Section 251 from the Confidentiality Advisory Group, who are reviewing this on a yearly basis.

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Consent / Consultee Advice is in place to allow the dissemination of pseudonymised follow-up data to be provided to the study team from NHS England. Details of the trial and expected data flows are explained on the latest version of Patient Information Sheet which will be hosted on the trial website:

https://www.panoramictrial.org/

Only the study team at the University of Oxford will access the requested data. No other organisations are involved in the processing or storage of NHS England record level data. NHS England Record level data will not leave the UK.

LEGAL BASIS FOR PROCESSING DATA

The University of Oxford, as the Data Controller who is also processing the data will process Personal data under GDPR Article 6 (1) (e) - Processing is necessary for the performance of a task carried out in the public interest or in the exercise of official authority vested in the controller. As a higher education establishment, the University conduct research to improve health care and service and the data requested is necessary for the performance of a task carried out in the public interest.

Additionally, under GDPR Article 9(2)(j) processing of Special Category Personal Data (of which Health data is one) is necessary for archiving for research purposes. Data minimisation process is being followed and only data that is required specifically for the purposes of this study has been requested, to protect the rights of the data subjects.

Article 9(2)(h) is additionally being used to cover the processing of SCR specifically: ‘processing is necessary for the purposes of preventive or occupational medicine, for the assessment of the working capacity of the employee, medical diagnosis, the provision of health or social care or treatment or the management of health or social care systems and services’ as it is being used as a timely, second check regarding medication, allergy, and co-morbidities information to support reconciliation, to ensure safe prescribing.

A collaborator agreement is in place between University of Oxford and the institutions listed on the protocol for this clinical trial. The study team have confirmed that the institutions listed within the protocol will not have access to NHS England record level data; nor do they make any decisions determining the purposes and means of the processing of data or the study purpose and methodology - therefore, in line with NHS England’s Data Access Request Service (DARS) standards, NHS England does not consider these other institutions as a joint Controller or Processor for this agreement.

*** New for Version 4 of this agreement ***

For the purposes of Transparency, it is noted here that Paxlovid is manufactured by Pfizer; there could be commercial benefit if this trial proves that Paxlovid should be used in this patient population, however it could also show that it shouldn’t be used. PANORAMIC's aim is to show whether it is effective or not, regardless of any commercial sensitivities. Paxlovid is supplied to the study for no cost by Pfizer. Trial results are reported independently from Pfizer, who will have no involvement in the academic coordination and conduct of the study and will have no ability to suppress or otherwise limit the publication of findings. However, it is acknowledged that if the results of the trial proves that Paxlovid should be used in this patient population then Pfizer may indirectly benefit financially.

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All outputs will be aggregated with small number suppression applied as per the HES analysis guide.

The PANORAMIC trial was able to recruit to the original target much quicker than using conventional methods by receipt of the requested NHS England identifiable data (The Covid-19 UK Non-hospital Antigen Testing Results (pillar 2)). This has in turn enabled the study to extend its recruitment target and begin recruitment to the next arm of trial treatment.

An update on the Treatment Arms was provided for version 4 of this agreement:

As of 27th April 2022, recruitment to the first treatment arm (Molnupiravir) concluded and the second treatment arm (Paxlovid) commenced on 21st April 2022. Paxlovid continues to recruit, with an extension of recruitment planned until March 2024. Current recruitment to the Paxlovid vs. Usual Care arm = 1475, with a target number of around 3000 required.

The study team have approval for gaining access to data in Wales, Scotland and Northern Ireland. The results of the molnupiravir arm of the trial were published in The Lancet in January 2023: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)02597-1/fulltext

The trial team intends to disseminate results via media channels: pre-prints/publications in peer-reviewed journals such as the New England Journal of Medicine (NEJM); press releases in local and national newspapers; BBC news coverage; Department of Health and Social Care (DHSC) press briefings; DHSC Social media updates; via the Antiviral Taskforce webpage; Twitter and Facebook University of Oxford accounts. Results will be disseminated to trial participants via the trial website, supported by the University of Oxford. The study team have been providing regular updates to the NIHR Evaluation, Trials and Studies Coordinating Centre. A protocol paper has been accepted by BMJ Open and is currently undergoing peer review.

Since first participant was randomised into the PANORAMIC trial in December 2021, the Data and Safety monitoring Committee have been reviewing the safety data on a weekly basis. Due to the fast recruitment and lower than expected event rate, the Trial Management Group, with agreement from the Trial Steering Committee, took the decision not to conduct an interim analysis on the basis of preserving the Type I error rate for the current treatment. However, the trial will continue recruitment until the new proposed sample size is met and to evaluate whether the initial antiviral agent is effective in treating COVID-19. Should the recruitment become slower when the new agent is added to the platform, an interim analysis could be triggered before the final analysis. As recruitment is currently slow, the frequency of data review by the DSMC has reduced in line with this.

The study team will update participants by signposting them from their ‘end of trial letter’ to the trial website for the latest results and information. Due to the limited resources of the study trial team and the potential number of study participants involved, the study trial team have made the decision that distributing newsletters or email updates would be difficult to manage at such a scale. The study trial team believe that signposting to the website also ensures that the most up to date information is always available to participants, as newsletters can soon become outdated due to the fast-paced and evolving nature of this platform trial. The study team are also considering the use of video/audio updates and other formats to the website depending on capacity.

***New for version 4***

The trial is of national and international relevance.

The trial continues with a more complex novel antiviral agent, Paxlovid. There are some who consider that the threshold for using Paxlovid should be lowered, whereas others consider that this drug is unlikely ever to be cost-effective, given its many interactions and exclusions, and that the population is now highly vaccinated. All agree that findings from the drug company trial that was conducted in an unvaccinated population before Omicron began to circulate cannot be extrapolated to apply to the current situation in the UK. Furthermore, critically important information is missing about virology outcomes, cost effectiveness and impact of the use of this drug on illness and potential viral resistance. The PANORAMIC trial is addressing a critically important question, as well as generating novel information that will be applied to millions of clinical decisions worldwide. Recruitment into this arm of the trial is challenging; awareness of participation in COVID clinical trials has diminished as the public’s focus has shifted away from COVID. However, despite vaccination, people continue to become seriously ill with COVID and this is likely to increase in the Autumn and over the coming winter. The study team just don’t know how best to use this drug in the UK under the current circumstances, and PANORAMIC can give them the answers.

By mid May 2022, the PANORAMIC trial has recruited over 25,800 participants over 65 sites across England. This record-breaking UK platform trial is believed to be the world’s largest study of community-based treatments for acute COVID-19, in addition to the UK’s fastest ever recruiting interventional trial delivered.

This nationwide trial launched in December 2021 to rapidly generate evidence on which of the people affected with COVID-19 at home and in the community are helped the most by new antiviral treatments - without needing to be treated in hospital. The first antiviral drug, which is currently being assessed through the platform trial is molnupiravir, which has been shown to be safe and effective through smaller-scale trials. The study team aim to build on the existing evidence base by continuing to receive NHS England data for the participants who have taken part in this arm of the trial. The study is expected to show how well molnupiravir works in a predominantly vaccinated population, as well as its cost effectiveness. Despite this significant milestone being reached, recruitment to the molnupiravir arm continues in earnest , due to the lower than expected event rate in the primary outcome, with the researchers aiming to enrol thousands more participants into this trial arm in order to achieve the expected treatment effect with more certainty. The PANORAMIC trial also intends to investigate a range of other potentially ground-breaking oral antiviral drugs, which can be safely taken at home by people in at-risk groups in the early stages of infection.

Since 21st April 2022, Paxlovid has been added to PANORAMIC. Paxlovid is a novel antiviral that has recently been issued a conditional license by the MHRA and has been approved for use in the PANORAMIC trial by the Antiviral Task Force. Paxlovid can be an alternative treatment to molnupiavir if demonstrated to be effective, especially would be beneficial to those who are unable to take molnupiravir.

The data received from NHS England will continue to enhance trial recruitment. The Covid-19 UK Non-hospital Antigen Testing Results (Pillar 2) data should continue to help to identify a more targeted cohort of potential participants who will give a conversion rate from screening to randomisation. The current conversion rate in PANORAMIC is around 70% of those who responded to the calls and screened were randomised.

*** Update for Version 4 for agreement ***

The study team say the conversion rate in PANORAMIC is now closer to 30% and therefore the continued use of Pillar 2 data will help with this.

The Summary Care Record (SCR) data should help to assess eligibility of participants, by the clinical team with the information available, within the symptom duration window. Access to SCR will continue to occur during eligibility stage, after participant consent / consultee advice, prior to randomisation within the trial. Currently 71% of participants randomised within 3 days from symptom starts. The Hospital Episode Statistics datasets requested in this agreement aim to verify the primary outcome data, and with the additional data for health economic evaluation, the study team is aiming to reduce patients and hospital burden in data collection of resource data.

Despite high uptake of vaccination against COVID-19, the disease remains prevalent in the UK and in many countries around the world, with many patients continuing to require hospital admission. Early treatment with antiviral agents may prevent progression to the later phase of COVID-19. Therefore, there is an urgent need to identify treatments for COVID-19 for use in the community early on in the illness that prevent the need for hospital admission and improves time to recovery. It is therefore vital that the University of Oxford use this opportunity to accelerate enrolment into COVID-19 therapeutics trials.

The PANORAMIC (Platform Adaptive trial of NOvel antiviRals for eArly treatMent of covid-19 In the Community) trial is the only national priority clinical trial evaluating potential novel antivirals for COVID-19 in the primary care setting, endorsed by the Chief Medical Officers (CMOs) of all four devolved nations. The primary aim is to determine the effectiveness of selected antiviral agents in preventing hospitalisation and/or death in higher-risk patients with a confirmed positive SARS-CoV-2 PCR test result. The PANORAMIC trail is run by the Nuffield Department of Primary Care Health Sciences at the University of Oxford. For the purposes of this data sharing agreement, the Nuffield Department of Primary Care Health Sciences will be referred to as the 'University of Oxford' in this agreement.

Update for version 1 regarding positive SARS-CoV-2 Lateral Flow Test (LTF) (MARCH 2022)

Originally, the study team required a positive Polymerase Chain Reaction (PCR) test for inclusion in the main analysis. UK guidelines have reduced the amount of PCR testing that is recommended. In a context of high prevalence, false positive results from Lateral Flow Tests (LFTs) are minimal, and LFTs are now considered to be giving a truer reflection of infection status in some cases. In line with the changing policy and science, the study team now allow eligibility based on a positive SARS-CoV-2LFT without the requirement for a confirmatory PCR test for inclusion in the main analysis.

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Update for version 3 (JULY 2022)

The PANORAMIC trial is ongoing into 2022-2023 despite restrictions being lifted in the UK and free PCR and LTF testing being discontinued on 30.03.2022. Based on the study team's previous year's experience, the Covid-19 infection rate dropped between June and October 2021 and slowly picked up again from November and peaked in December 2021/January 2022, therefore the study is continuing over the forthcoming year to continue investigating new treatment arms. The study team would like to continue recruitment of participants to PANORAMIC because the long term effect of vaccine is still not known and the uncertainty of the future trend of infection. In addition, the study team are continuing recruitment of participants to the ‘Paxlovid arm’, which is a new treatment that was added to PANORAMIC in Spring 2022. With regards to testing of Covid-19, participants are currently recruited from PANORAMIC hubs only. Only those that qualify for tests under government schemes can participate due to the requirement for a positive test.

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PANORAMIC is:

• Recruiting across the whole UK* - anyone age 18** or over who match the participant criteria can participate, regardless of location (aged 50 or over, or 18-49 with a pre-existing condition),

• For both recruiters and patients it is a simple process to complete enrolment to the trial via a secured online platform.

• Obtaining consent /consultee advice, checking eligibility, issuing study medication and materials, and follow-up is managed remotely through a central facility at the University of Oxford or delegate. Contracts would be in place with delegates and vendors carrying out these tasks. (**Update for version 1: University of Oxford utilise the services of Integrated Pharmaceutical Services (IPS) Pharma to distribute the drug to trial participants. The personal data required for distribution is collected directly from the participant at the time of consent and IPS Pharma do not have any access to any NHS Digital Record level data. IPS Pharma do not make any decisions about the means by which any personal data is being processed for this study nor the methodology by which the study is conducted. For these reasons, IPS Pharma are not considered as a Data Controller or Processor**)

*PLEASE NOTE - The University of Oxford is obtaining data from NHS Digital related to residents in England only.

** PLEASE NOTE - The first treatments included in the PANORAMIC trial have conditional licensing for adults and therefore the study team are unable to include children at this stage. Depending on the advice from the Antiviral Taskforce regarding future treatment arms, and their licensing conditions, the inclusion criteria may be amended in future to include under 18’s.

Primary objective -

To determine whether antiviral treatment in the community safely reduces non-elective hospitalisations/deaths in higher risk, symptomatic patients with confirmed COVID-19

Secondary objectives - To explore whether trial treatment reduces:

1) Time to recovery (defined as the first instance that a participant report of feeling recovered from the illness)

2) Participant reported illness severity, reported by daily rating of how well participant feels, enabling identification of sustained recovery.

3) Duration of severe symptoms and symptom recurrence

4) Contacts with the health services

5) New infections in household

6) To investigate the safety of antiviral agents

7) Longer term effects

8) Cost effectiveness

The study team are requesting the Covid-19 UK Non-hospital Antigen Testing Results (pillar 2) dataset in order to identify and successfully recruit potential patients into the trial, early on in their stage of COVID-19 disease. A positive PCR test is essential for inclusion into the trial. The positive PCR test result will be participant reported prior to randomisation, and confirmation of the positive result will be sought at a later date via the Pillar 2 dataset.

The University of Oxford would like to receive names and contact details (including preferably a telephone number and email address) of people who have received a positive COVID-19 swab result from the Pillar 2 testing system. The trial team, based at the University of Oxford, will then contact these potential participants, inform them about the trial and if they are happy, go on to screen and consent them into the PANORAMIC trial. Daily, the trial team would like to receive identifiable record-level data on a random cohort (up to 500) of people aged 18+.

The trial already has a centre set up and operating remotely at the University of Oxford to manage this recruitment in a timely manner. Management of the recruitment to the trial will be undertaken by substantive employees of the University of Oxford who have been appropriately trained in data protection and confidentiality.

The question of whether ‘cold calling’ is appropriate has been considered for this application. As time is of the essence for recruitment into PANORAMIC, the telephone is the most efficient and quickest means to ensure direct contact with the individual, who can answer questions instantly over a call. The study team would also like to use the Short Messaging Service (SMS) and email option for invitation, for those patients who they cannot reach via telephone or those who require follow-up information. During the calls, clear explanation will be given to individual about how the trial has been able to contact them and what to do if they do not wish to be contacted again (i.e. registering a National Data Opt-out). The trial team will respect the wishes of those signed up to the Telephone Preference Service (TPS). The team will ensure that customers flagged on the TPS are not contacted for this trial. The trial team will also ensure the required comorbidities are discussed early on in the calls so as to not to get the individual’s hopes up if they are not in fact eligible for the trial.

Other considerations that have been taken into account in relation to contacting individuals:

• The data relating to positive COVID-19 tests is sent to NHS Digital at the same time that it is sent to the Business Services Authority, the latter process triggering the SMS to the individual informing them of their result. It then takes around four hours for the Covid-19 UK Non-hospital Antigen Testing Results (Pillar 2) dataset within NHS Digital to be updated with this information. Given that this information then needs to be extracted from the dataset at some point in the next 24 hours, then used by the trial team to make contact with the individual, the risk of the individual being informed of their test result by the trial team before they have read their SMS is small. However, the trial team should have a suitable script prepared to deal with this slim possibility.

• The chances of people having multiple positive COVID-19 test results are rare, and rarer still is the likelihood that they will be one of the 500 people extracted from the thousands of daily test results to be sent to the trial team on more than one occasion. Therefore, the risk of an individual being contacted twice for recruitment into PANORAMIC is extremely low.

• NHS Digital recognises that there are likely to be more requests of this nature in future and therefore, if multiple trial require extracts of people to contact, suitable controls need to be in place within the extract process to ensure that individuals are not getting contacted for recruitment into trials more than is reasonably expected.

• The study team at the University of Oxford are aware the recent governmental change in policy over COVID-19 testing that will have a significant impact upon the way testing records will be collected, and how the results should be interpreted. Therefore, the study team will inevitably have to actively incorporate this measure in their study design, which will be reflected in future versions of the study Protocol, processing methodology and outcome analyses.

Patient and Public Involvement & Engagement (PPIE)

The PANORAMIC trial has had extensive PPIE engagement to support development of trial materials and processes and to discuss the plans for efficient and safe use of patient data and has plans for significant engagement throughout the period of the study.

The main study PPIE group includes members of five different cultural and faith communities and representatives of those with learning disabilities. They have had three meetings prior to this application, focussing on acceptability of trial processes and optimising patient-facing materials including redesigning the Pictorial Patient Information Sheet (PIS) and co-developing a summary front page for this document. They have reviewed the online trial interface and instructions for participants. This group will continue to meet at least every month when the trial commences recruitment.

The study team have begun to convene additional PPIE groups in Scotland, Northern Ireland and Wales to focus on nation-specific recruitment and dissemination issues and will work with individual cultural and community leaders to ensure inclusion of the most diverse range of participants possible.

Request to use SCR for consented / consultee advised participants:

The PANORAMIC trial team are requesting to access the Summary Care Record (SCR) for patients recruited into the trial for the purposes of ensuring timely prescribing and safe patient care. SCR access will be essential to successfully recruit participants in the very restrictive timeframe of five days since symptom onset. For the first treatment arm, the trial is run remotely, therefore removing the need for participants to be near to a GP practice. Screening and contact with the trial team is all completed online. The trial team are requesting access to Summary Care Records as part of this application as it will not be possible within the five day window of recruitment from symptom onset, for the trial team to request such information regarding safe prescribing from the participant’s GP.

The PANORAMIC trial team therefore seek permission for the clinical trial team, a group of dedicated doctors and nurses who are fully qualified, study-trained, accredited and registered, to review consenting / consultee advised patients’ Summary Care Records, in order to be able to confirm key information obtained from the patient relevant to safe patient care in the trial. Only nurses and doctors who are registered and accredited with the General Medical Council of the UK or the Nursing and Midwifery Council of the UK who are clinical members of the PANORAMIC study team would review the Summary Care Record for information relevant to safe prescribing and participant care.

The Summary Care Record will be used as a timely, second check regarding medication, allergy, and co-morbidities information to support reconciliation, to ensure safe prescribing. These are all elements of a patient’s SCR with additional information which is a subset of their wider GP record. This access provides an immediate available information source to meet the need to support safe prescribing in a proportionate and timely way. In addition, the Summary Care Record will provide a further safety check, in that access to it will facilitate the opportunity for double-checking participants’ NHS Number and GP practice.

There is a five-day window from symptom onset to enrolment into the trial and so SCR access is critical to confirm eligibility within this very limited time-period.

Access is sought only for those people who have screened eligible to be part of the trial, and who have already signed informed consent / consultee advice for participation in the study and for the trial to access their clinical records. All potential participants are asked specifically for permission for the trial team to access their medical records and have the opportunity to decline this access. In addition, they will be asked specifically and separately for permission about access to their Summary Care Record. For a patient who has provided consent / consultee advice to join the trial and for their SCR to be accessed, the data will be accessed by a clinician to support safe prescribing decisions prior to randomisation in the trial and prescribing medications. A Summary Care Record will only ever be accessed on one occasion for each individual participant.

Access to SCR is required for the period that the trial is recruiting - currently this is December 2021 until Sept 2023.

This request for SCR access for PANORAMIC, along with the similar request for the sisters trial, PRINCIPLE, together form a first-of-type access request and as an interim position it is included in the Data Sharing Agreement. This is a holding position whilst considerations are undertaken to agree whether to offer this as a service more widely to clinical trials for patient safety purposes. This allows time for an appropriate access and approval process to be developed in future, but in the meantime ensures that SCR access is recognised within the research data access process alongside the normal direct care process for access to SCR.

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PARTICIPANT CONSENT / CONSULTEE ADVICE

Under the Common-law Duty of Confidentiality, from the start of recruitment, participants were asked to sign a consent form. Within care home settings only, if the participant did not have the capacity to consent, a friend/relative or nominated consultee advice was sought under the Mental Capacity Act, and a personal / professional legal representative letter was obtained. These patients who were recruited into PANORMIC following declaration by a personal or professional consultee (to date, July 2022) were all confirmed with conditions which mean they are unlikely to regain capacity (such as Dementia), however the University of Oxford do have a re-consenting process in place should this be required for any future participants recruited under personal / professional consultee advice.

As consultee advice cannot override the rights of an individual’s National data opt-out request, any participants recruited under personal / professional consultee advice will have National Data Opt-Outs applied.

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FOLLOW UP DATA:

The trial follows up all participants for 28 days and then at three and six months following randomisation.

In this agreement, the University of Oxford are requesting access to record-level data from the following data sets in order to receive follow up data on trial participants:

> Hospital Episode Statistics (HES) Admitted Patient Care (APC)

> HES Critical Care (CC)

> Civil Registration (Deaths) data set

> Medicines dispensed in Primary Care (NHSBSA data)

> Uncurated Low Latency HES APC Dataset

> Uncurated Low Latency HES CC Dataset

> HES Outpatients (OP)

> HES Emergency Care Dataset (ECDS)

These NHS Digital datasets will be essential to collect the primary outcome, which relates to all-cause hospitalisation/death.

Data requests for version 1 (v1) of this agreement (MARCH 2022):

Request to add Low Latency Hospital Episode Statistics (HES) Admitted Patient Care (APC) and Low Latency HES Critical Care (CC) datasets to the existing 28 day follow up data (v1)***

Previously (v0 of this agreement), the University of Oxford requested access to HES APC and HES CC datasets. However, due to NHS Digital’s cleaning and Data Quality procedures, HES datasets are released under data sharing agreements two months in arrears. This has meant that the University of Oxford are delayed in receiving crucial data for analysis. A number of NHS Trusts now submit routine hospital data as part of the Commissioning Data Set (CDS) more frequently such as weekly or even sometimes daily. This subset of more frequently reported management data is reported in Secondary Use Service (SUS). This SUS data is used to create additional uncurated data sets including Low Latency HES APC and Low Latency HES CC which offer access to more current data. Though less complete and quality assured, this data provides the opportunity for more immediate analysis and additional insights compared to that which might be available in delayed HES data. These Low Latency datasets will provide the study team with more immediate access to data required to begin interim analysis more swiftly. However, the study team have confirmed that they will continue to access the regular HES APC and CC datasets to allow for data checking, quality and completeness. All final study reports and outcomes analysis will be based on regular HES dataset information.

Request to add HES Out Patient (OP) and Emergency Care Dataset (EDCS) datasets to the existing 28 day follow up data (v1)

The University of Oxford have requested access to HES OP and ECDS datasets as part of this agreement.

The request for the addition of HES OP and ECDS datasets are for the purpose of the health economic evaluation, which is embedded within the trial design. This data will be used by the study team to assess the cost effectiveness of each antiviral from an NHS perspective.

Request to add additional data fields to existing Hospital Episode Statistics (HES) Admitted Patient Care (APC) and HES Critical Care (CC) Datasets (v1)

the University of Oxford have requested additional data fields to be included in the existing HES APC and HES CC datasets for which they are already in receipt as part of the existing 28 day follow up data.

The request for the additional fields within HES APC and HES CC are also for the purpose of the health economic evaluation, which is embedded within the trial design. These fields will enable the study team to assess the cost effectiveness of each antiviral from an NHS perspective.

These additional dataflows will support those already received to follow up consented/consultee advice patients for 28 day follow up data. As per the previous amendment for 28 follow up data, the existing consent/consultee advice covers the provision of these extra datasets/ data fields and it will only be accessed by the team at University of Oxford, and no other organisations will process or store it.

Due to the high rate of recruitment, the Data Safety Monitoring Committee (DSMC) review the trial data weekly and can ask for recruitment into a trial arm to be stopped immediately. Therefore, trial data needs to be made available as soon as possible so that the team can quickly issue a press statement and publication of results if required to do so. There is a need to capture the required data in a more timely and efficient manner via monthly extracts from NHS Digital. The DSMC is an independent committee with remits to monitor the progress of the study, review of safety data and also the unblinded interim analysis. The DSMC give recommendation, based on the information they receive from the trial statistician, to the Trial Steering Committee (TSC) with regards to the terminating a treatment arm due to treatment effect or treatment failure. The remit of the TSC is to monitor the progress of the study and provide the trial management committee recommendation based on recommendation from the DSMC. Members of both committees are independent from the trial and their memberships have been approved by National Institute of Health research (NIHR) as the funder for this study. The DSMC and TSC do not make any decisions determining the purposes and means of the processing of data or the study purpose and methodology, and are therefore not considered a Data Controller. Additionally, the DSMC and TSC will not have access to any NHS Digital record level data and will only view aggregated data with small numbers suppressed and are therefore not considered a Data Processor.

The PANORAMIC trial is funded by the NIHR, but do not make any decisions determining the purposes and means of the processing of data or the study purpose and methodology, and are therefore not considered a Data Controller. Additionally, the NIHR will not have access to any NHS Digital record level data and are therefore not considered a Data Processor.

LEGAL BASIS FOR COMMON LAW DUTY OF CONFIDENTIALITY

The lawful basis for the release and use of the confidential data for Covid-19 UK Non-hospital Antigen Testing Results (Pillar 2) data and access to Summary Care Record (SCR) being shared under this version of the agreement is Regulation 3(4) of the National Health Service (Control of Patient Information Regulations) 2002 (COPI) to require NHS Digital to share confidential patient information with organisations entitled to process this under COPI for COVID-19 purposes. The only permitted activities under this Data Sharing Agreement (DSA) are for COVID-19 purposes and within bounds of Reg 3(2) COPI. Reg 3 (2) COPI states that: "2) For the purposes of this regulation, “processing” includes any operations, or set of operations set out in regulation 2(2) which are undertaken for the purposes set out in paragraph (1)." The research relates to the monitoring and managing of COVID-19 and would therefore be covered by Reg 3(1)(d) of COPI.

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UPDATE for Version 3: LEGAL BASIS AFTER 30/06/2022:

University of Oxford rely on the COPI notice for the statutory sharing of information by NHS Digital for COVID-19 purposes. When the COPI notice expires, full support and approval for section 251 from the Confidentiality Advisory Group has been received and will supersede the COPI notice for the release and use of the confidential data (Covid-19 UK Non-hospital Antigen Testing Results (pillar 2)) under this agreement.

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Consent / Consultee Advice is in place to allow the dissemination of pseudonymised follow-up data to be provided to the study team from NHS Digital. Details of the trial and expected data flows are explained on the latest version of Patient Information Sheet which will be hosted on the trial website:

https://www.panoramictrial.org/

Only the study team at the University of Oxford will access the requested data. No other organisations are involved in the processing or storage of NHS Digital record level data. NHS Digital Record level data will not leave the UK.

LEGAL BASIS FOR PROCESSING DATA

The University of Oxford, as the Data Controller who is also processing the data will process Personal data under GDPR Article 6 (1) (e) - Processing is necessary for the performance of a task carried out in the public interest or in the exercise of official authority vested in the controller. As a higher education establishment, the University conduct research to improve health care and service and the data requested is necessary for the performance of a task carried out in the public interest.

Additionally, under GDPR Article 9(2)(j) processing of Special Category Personal Data (of which Health data is one) is necessary for archiving for research purposes. Data minimisation process is being followed and only data that is required specifically for the purposes of this study has been requested, to protect the rights of the data subjects.

Article 9(2)(h) is additionally being used to cover the processing of SCR specifically: ‘processing is necessary for the purposes of preventive or occupational medicine, for the assessment of the working capacity of the employee, medical diagnosis, the provision of health or social care or treatment or the management of health or social care systems and services’ as it is being used as a timely, second check regarding medication, allergy, and co-morbidities information to support reconciliation, to ensure safe prescribing.

A collaborator agreement is in place between University of Oxford and the institutions listed on the protocol for this clinical trial. The study team have confirmed that the institutions listed within the protocol will not have access to NHS Digital record level data; nor do they make any decisions determining the purposes and means of the processing of data or the study purpose and methodology - therefore, in line with NHS Digital’s DARS standards, NHS Digital does not consider these other institutions as a joint Data Controller or Data Processor for this agreement.

All outputs will be aggregated with small number suppression applied as per the HES analysis guide.

The PANORAMIC trial was able to recruit to the original target much quicker than using conventional methods by receipt of the requested NHS Digital identifiable data (The Covid-19 UK Non-hospital Antigen Testing Results (pillar 2)). This has in turn enabled the study to extend its recruitment target and begin recruitment to the next arm of trial treatment.

*** Update for version 3 (JULY 2022) ***

As of 27th April 2022, recruitment to the first treatment arm (Molnupiravir) concluded and the second treatment arm (Paxlovid) commenced on 21st April 2022

The study team have also gained approval to access Secure Anonymised Information Linkage (SAIL) Wales data. Application to Scotland and also data access from Northern Ireland are underway . The statistical analysis team have also started the coding process and preliminary analysis of the primary outcome will take place as soon as all the data are received.

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The trial team intends to disseminate results via media channels: pre-prints/publications in peer-reviewed journals such as the New England Journal of Medicine (NEJM); press releases in local and national newspapers; BBC news coverage; Department of Health and Social Care (DHSC) press briefings; DHSC Social media updates; via the Antiviral Taskforce webpage; Twitter and Facebook University of Oxford accounts. Results will be disseminated to trial participants via the trial website, supported by the University of Oxford. The study team have been providing regular updates to the NIHR Evaluation, Trials and Studies Coordinating Centre.

Since first participant was randomised into the PANORAMIC trial in December 2021, the Data and Safety monitoring Committee have been reviewing the safety data on a weekly basis. Due to the fast recruitment and lower than expected event rate, the Trial Management Group, with agreement from the Trial Steering Committee, took the decision not to conduct an interim analysis on the basis of preserving the Type I error rate for the current treatment. However, the trial will continue recruitment until the new proposed sample size is met and to evaluate whether the initial antiviral agent is effective in treating COVID-19. Should the recruitment become slower when the new agent is added to the platform, an interim analysis could be triggered before the final analysis.

The study team will update participants by signposting them from their ‘end of trial letter’ to the trial website for the latest results and information. Due to the limited resources of the study trial team and the potential number of study participants involved, the study trial team have made the decision that distributing newsletters or email updates would be difficult to manage at such a scale. The study trial team believe that signposting to the website also ensures that the most up to date information is always available to participants, as newsletters can soon become outdated due to the fast-paced and evolving nature of this platform trial. The study team are also considering the use of video/audio updates and other formats to the website depending on capacity.

The trial is of national and international relevance during this pandemic.

By mid May 2022, the PANORAMIC trial has recruited over 25,800 participants over 65 sites across England. This record-breaking UK platform trial is believed to be the world’s largest study of community-based treatments for acute COVID-19, in addition to the UK’s fastest ever recruiting interventional trial delivered.

This nationwide trial launched in December 2021 to rapidly generate evidence on which of the people affected with COVID-19 at home and in the community are helped the most by new antiviral treatments - without needing to be treated in hospital. The first antiviral drug, which is currently being assessed through the platform trial is molnupiravir, which has been shown to be safe and effective through smaller-scale trials. The study team aim to build on the existing evidence base by continuing to receive NHS Digital data for the participants who have taken part in this arm of the trial. The study is expected to show how well molnupiravir works in a predominantly vaccinated population, as well as its cost effectiveness. Despite this significant milestone being reached, recruitment to the molnupiravir arm continues in earnest , due to the lower than expected event rate in the primary outcome, with the researchers aiming to enrol thousands more participants into this trial arm in order to achieve the expected treatment effect with more certainty. The PANORAMIC trial also intends to investigate a range of other potentially ground-breaking oral antiviral drugs, which can be safely taken at home by people in at-risk groups in the early stages of infection.

Since 21st April 2022, Paxlovid has been added to PANORAMIC. Paxlovid is a novel antiviral that has recently been issued a conditional license by the MHRA and has been approved for use in the PANORAMIC trial by the Antiviral Task Force. Paxlovid can be an alternative treatment to molnupiavir if demonstrated to be effective, especially would be beneficial to those who are unable to take molnupiravir.

The data received from NHS Digital will continue to enhance trial recruitment. The Covid-19 UK Non-hospital Antigen Testing Results (Pillar 2) data should continue to help to identify a more targeted cohort of potential participants who will give a conversion rate from screening to randomisation. The current conversion rate in PANORAMIC is around 70% of those who responded to the calls and screened were randomised. The Summary Care Record (SCR) data should help to assess eligibility of participants, by the clinical team with the information available, within the symptom duration window. Access to SCR will continue to occur during eligibility stage, after participant consent / consultee advice, prior to randomisation within the trial. Participants SCR record will not be accessed after the participant has been randomised to a treatment arm. Currently 71% of participants randomised within 3 days from symptom starts. The Hospital Episode Statistics datasets requested in this agreement aim to verify the primary outcome data, and with the additional data for health economic evaluation, the study team is aiming to reduce patients and hospital burden in data collection of resource data.

Despite high uptake of vaccination against COVID-19, the disease remains prevalent in the UK and in many countries around the world, with many patients continuing to require hospital admission. Early treatment with antiviral agents may prevent progression to the later phase of COVID-19. Therefore, there is an urgent need to identify treatments for COVID-19 for use in the community early on in the illness that prevent the need for hospital admission and improves time to recovery. It is therefore vital that the University of Oxford use this opportunity to accelerate enrolment into COVID-19 therapeutics trials.

The PANORAMIC (Platform Adaptive trial of NOvel antiviRals for eArly treatMent of covid-19 In the Community) trial is the only national priority clinical trial evaluating potential novel antivirals for COVID-19 in the primary care setting, endorsed by the Chief Medical Officers (CMOs) of all four devolved nations. The primary aim is to determine the effectiveness of selected antiviral agents in preventing hospitalisation and/or death in higher-risk patients with a confirmed positive SARS-CoV-2 PCR test result. The PANORAMIC trail is run by the Nuffield Department of Primary Care Health Sciences at the University of Oxford. For the purposes of this data sharing agreement, the Nuffield Department of Primary Care Health Sciences will be referred to as the 'University of Oxford' in this agreement.

**Update for version 1 regarding positive SARS-CoV-2 Lateral Flow Test (LTF)***

Originally, the study team required a positive PCR test for inclusion in the main analysis. UK guidelines have reduced the amount of PCR testing that is recommended. In a context of high prevalence, false positive results from Lateral Flow Tests (LFTs) are minimal, and LFTs are now considered to be giving a truer reflection of infection status in some cases. In line with the changing policy and science, the study team now allow eligibility based on a positive SARS-CoV-2LFT without the requirement for a confirmatory PCR test for inclusion in the main analysis.

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PANORAMIC is:

• Recruiting across the whole UK* - anyone age 18** or over who match the participant criteria can participate, regardless of location (aged 50 or over, or 18-49 with a pre-existing condition),

• For both recruiters and patients it is a simple process to complete enrolment to the trial via a secured online platform.

• Obtaining consent, checking eligibility, issuing study medication and materials, and follow-up is managed remotely through a central facility at the University of Oxford or delegate. Contracts would be in place with delegates and vendors carrying out these tasks. (**Update for version 1: University of Oxford utilise the services of Integrated Pharmaceutical Services (IPS) Pharma to distribute the drug to trial participants. The personal data required for distribution is collected directly from the participant at the time of consent and IPS Pharma do not have any access to any NHS Digital Record level data. IPS Pharma do not make any decisions about the means by which any personal data is being processed for this study nor the methodology by which the study is conducted. For these reasons, IPS Pharma are not considered as a Data Controller or Processor**)

*PLEASE NOTE - The University of Oxford is obtaining data from NHS Digital related to residents in England only.

** PLEASE NOTE - The first treatment included in the PANORAMIC trial has conditional licensing for adults and therefore the study team are unable to include under children at this stage. Depending on the advice from the Antiviral Taskforce regarding future treatment arms, and their licensing conditions, the inclusion criteria may be amended in future to include under 18’s.

Primary objective -

To determine whether antiviral treatment in the community safely reduces non-elective hospitalisations/deaths in higher risk, symptomatic patients with confirmed COVID-19

Secondary objectives - To explore whether trial treatment reduces:

1) Time to recovery (defined as the first instance that a participant report of feeling recovered from the illness)

2) Participant reported illness severity, reported by daily rating of how well participant feels, enabling identification of sustained recovery.

3) Duration of severe symptoms and symptom recurrence

4) Contacts with the health services

5) New infections in household

6) To investigate the safety of antiviral agents

7) Longer term effects

8) Cost effectiveness

The study team are requesting the Covid-19 UK Non-hospital Antigen Testing Results (pillar 2) dataset in order to identify and successfully recruit potential patients into the trial, early on in their stage of COVID-19 disease. A positive PCR test is essential for inclusion into the trial. The positive PCR test result will be participant reported prior to randomisation, and confirmation of the positive result will be sought at a later date via the Pillar 2 dataset.

The University of Oxford would like to receive names and contact details (including preferably a telephone number and email address) of people who have received a positive COVID-19 swab result from the Pillar 2 testing system. The trial team, based at the University of Oxford, will then contact these potential participants, inform them about the trial and if they are happy, go on to screen and consent them into the PANORAMIC trial. Daily, the trial team would like to receive identifiable record-level data on a random cohort (up to 500) of people aged 18+.

The trial already has a centre set up and operating remotely at the University of Oxford to manage this recruitment in a timely manner. Management of the recruitment to the trial will be undertaken by substantive employees of the University of Oxford who have been appropriately trained in data protection and confidentiality.

The question of whether ‘cold calling’ is appropriate has been considered for this application. As time is of the essence for recruitment into PANORAMIC, the telephone is the most efficient and quickest means to ensure direct contact with the individual, who can answer questions instantly over a call. The study team would also like to use the Short Messaging Service (SMS) and email option for invitation, for those patients who they cannot reach via telephone or those who require follow-up information. During the calls, clear explanation will be given to individual about how the trial has been able to contact them and what to do if they do not wish to be contacted again (i.e. registering a National Data Opt-out). The trial team will respect the wishes of those signed up to the Telephone Preference Service (TPS). The team will ensure that customers flagged on the TPS are not contacted for this trial. The trial team will also ensure the required comorbidities are discussed early on in the calls so as to not to get the individual’s hopes up if they are not in fact eligible for the trial.

Other considerations that have been taken into account in relation to contacting individuals:

• The data relating to positive COVID-19 tests is sent to NHS Digital at the same time that it is sent to the Business Services Authority, the latter process triggering the SMS to the individual informing them of their result. It then takes around four hours for the Covid-19 UK Non-hospital Antigen Testing Results (Pillar 2) dataset within NHS Digital to be updated with this information. Given that this information then needs to be extracted from the dataset at some point in the next 24 hours, then used by the trial team to make contact with the individual, the risk of the individual being informed of their test result by the trial team before they have read their SMS is small. However, the trial team should have a suitable script prepared to deal with this slim possibility.

• The chances of people having multiple positive COVID-19 test results are rare, and rarer still is the likelihood that they will be one of the 500 people extracted from the thousands of daily test results to be sent to the trial team on more than one occasion. Therefore, the risk of an individual being contacted twice for recruitment into PANORAMIC is extremely low.

• NHS Digital recognises that there are likely to be more requests of this nature in future and therefore, if multiple trial require extracts of people to contact, suitable controls need to be in place within the extract process to ensure that individuals are not getting contacted for recruitment into trials more than is reasonably expected.

• The study team at the University of Oxford are aware the recent governmental change in policy over COVID-19 testing that will have a significant impact upon the way testing records will be collected, and how the results should be interpreted. Therefore, the study team will inevitably have to actively incorporate this measure in their study design, which will be reflected in future versions of the study Protocol, processing methodology and outcome analyses.

Patient and Public Involvement & Engagement (PPIE)

The PANORAMIC trial has had extensive PPIE engagement to support development of trial materials and processes and to discuss the plans for efficient and safe use of patient data and has plans for significant engagement throughout the period of the study.

The main study PPIE group includes members of five different cultural and faith communities and representatives of those with learning disabilities. They have had three meetings prior to this application, focussing on acceptability of trial processes and optimising patient-facing materials including redesigning the Pictorial Patient Information Sheet (PIS) and co-developing a summary front page for this document. They have reviewed the online trial interface and instructions for participants. This group will continue to meet at least every month when the trial commences recruitment.

The study team have begun to convene additional PPIE groups in Scotland, Northern Ireland and Wales to focus on nation-specific recruitment and dissemination issues and will work with individual cultural and community leaders to ensure inclusion of the most diverse range of participants possible.

Request to use SCR for consented participants:

The PANORAMIC trial team are requesting to access the Summary Care Record (SCR) for patients recruited into the trial for the purposes of ensuring timely prescribing and safe patient care. SCR access will be essential to successfully recruit participants in the very restrictive timeframe of five days since symptom onset. For the first treatment arm, the trial is run remotely, therefore removing the need for participants to be near to a GP practice. Screening and contact with the trial team is all completed online. The trial team are requesting access to Summary Care Records as part of this application as it will not be possible within the five day window of recruitment from symptom onset, for the trial team to request such information regarding safe prescribing from the participant’s GP.

The PANORAMIC trial team therefore seek permission for the clinical trial team, a group of dedicated doctors and nurses who are fully qualified, study-trained, accredited and registered, to review consenting patients’ Summary Care Records, in order to be able to confirm key information obtained from the patient relevant to safe patient care in the trial. Only nurses and doctors who are registered and accredited with the General Medical Council of the UK or the Nursing and Midwifery Council of the UK who are clinical members of the PANORAMIC study team would review the Summary Care Record for information relevant to safe prescribing and participant care.

The Summary Care Record will be used as a timely, second check regarding medication, allergy, and co-morbidities information to support reconciliation, to ensure safe prescribing. These are all elements of a patient’s SCR with additional information which is a subset of their wider GP record. This access provides an immediate available information source to meet the need to support safe prescribing in a proportionate and timely way. In addition, the Summary Care Record will provide a further safety check, in that access to it will facilitate the opportunity for double-checking participants’ NHS Number and GP practice.

There is a five-day window from symptom onset to enrolment into the trial and so SCR access is critical to confirm eligibility within this very limited time-period.

Access is sought only for those people who have screened eligible to be part of the trial, and who have already signed informed consent for participation in the study and for the trial to access their clinical records. All potential participants are asked specifically for permission for the trial team to access their medical records and have the opportunity to decline this access. In addition, they will be asked specifically and separately for permission about access to their Summary Care Record. For a patient who has provided consent to join the trial and for their SCR to be accessed, the data will be accessed by a clinician to support safe prescribing decisions prior to randomisation in the trial and prescribing medications. A Summary Care Record will only ever be accessed on one occasion for each individual participant.

Access to SCR is required for the period that the trial is recruiting - currently this is December 2021 until Sept 2023.

This request for SCR access for PANORAMIC, along with the similar request for the sisters trial, PRINCIPLE, together form a first-of-type access request and as an interim position it is included in the Data Sharing Agreement. This is a holding position whilst considerations are undertaken to agree whether to offer this as a service more widely to clinical trials for patient safety purposes. This allows time for an appropriate access and approval process to be developed in future, but in the meantime ensures that SCR access is recognised within the research data access process alongside the normal direct care process for access to SCR.

FOLLOW UP DATA:

The trial follows up all consented participants for 28 days and then at three and six months following randomisation.

In this agreement, the University of Oxford are requesting access to record-level data from the following data sets in order to receive follow up data on trial participants:

> Hospital Episode Statistics (HES) Admitted Patient Care (APC)

> HES Critical Care (CC)

> Civil Registration (Deaths) data set

> Medicines dispensed in Primary Care (NHSBSA data)

***New for v1 of this agreement:

> Uncurated Low Latency HES APC Dataset

> Uncurated Low Latency HES CC Dataset

> HES Outpatients (OP)

> HES Emergency Care Dataset (ECDS)

***

These NHS Digital datasets will be essential to collect the primary outcome, which relates to all-cause hospitalisation/death.

New requests for version 1 (v1) of this agreement (MARCH 2022):

*** Request to add Low Latency Hospital Episode Statistics (HES) Admitted Patient Care (APC) and Low Latency HES Critical Care (CC) datasets to the existing 28 day follow up data (v1)***

Previously (v0 of this agreement), the University of Oxford requested access to HES APC and HES CC datasets. However, due to NHS Digital’s cleaning and Data Quality procedures, HES datasets are released under data sharing agreements two months in arrears. This has meant that the University of Oxford are delayed in receiving crucial data for analysis. A number of NHS Trusts now submit routine hospital data as part of the Commissioning Data Set (CDS) more frequently such as weekly or even sometimes daily. This subset of more frequently reported management data is reported in Secondary Use Service (SUS). This SUS data is used to create additional uncurated data sets including Low Latency HES APC and Low Latency HES CC which offer access to more current data. Though less complete and quality assured, this data provides the opportunity for more immediate analysis and additional insights compared to that which might be available in delayed HES data. These Low Latency datasets will provide the study team with more immediate access to data required to begin interim analysis more swiftly. However, the study team have confirmed that they will continue to access the regular HES APC and CC datasets to allow for data checking, quality and completeness. All final study reports and outcomes analysis will be based on regular HES dataset information.

*** Request to add HES Out Patient (OP) and Emergency Care Dataset (EDCS) datasets to the existing 28 day follow up data (v1)***

The University of Oxford have requested access to HES OP and ECDS datasets as part of this agreement.

The request for the addition of HES OP and ECDS datasets are for the purpose of the health economic evaluation, which is embedded within the trial design. This data will be used by the study team to assess the cost effectiveness of each antiviral from an NHS perspective.

***Request to add additional data fields to existing Hospital Episode Statistics (HES) Admitted Patient Care (APC) and HES Critical Care (CC) Datasets (v1)***

the University of Oxford have requested additional data fields to be included in the existing HES APC and HES CC datasets for which they are already in receipt as part of the existing 28 day follow up data.

The request for the additional fields within HES APC and HES CC are also for the purpose of the health economic evaluation, which is embedded within the trial design. These fields will enable the study team to assess the cost effectiveness of each antiviral from an NHS perspective.

These additional dataflows will support those already received to follow up consented patients for 28 day follow up data. As per the previous amendment for 28 follow up data, the existing consent covers the provision of these extra datasets/ data fields and it will only be accessed by the team at University of Oxford, and no other organisations will process or store it.

******

Due to the high rate of recruitment, the Data Safety Monitoring Committee (DSMC) review the trial data weekly and can ask for recruitment into a trial arm to be stopped immediately. Therefore, trial data needs to be made available as soon as possible so that the team can quickly issue a press statement and publication of results if required to do so. There is a need to capture the required data in a more timely and efficient manner via monthly extracts from NHS Digital. The DSMC is an independent committee with remits to monitor the progress of the study, review of safety data and also the unblinded interim analysis. The DSMC give recommendation, based on the information they receive from the trial statistician, to the Trial Steering Committee (TSC) with regards to the terminating a treatment arm due to treatment effect or treatment failure. The remit of the TSC is to monitor the progress of the study and provide the trial management committee recommendation based on recommendation from the DSMC. Members of both committees are independent from the trial and their memberships have been approved by National Institute of Health research (NIHR) as the funder for this study. The DSMC and TSC do not make any decisions determining the purposes and means of the processing of data or the study purpose and methodology, and are therefore not considered a Data Controller. Additionally, the DSMC and TSC will not have access to any NHS Digital record level data and will only view aggregated data with small numbers suppressed and are therefore not considered a Data Processor.

The PANORAMIC trial is funded by the NIHR, but do not make any decisions determining the purposes and means of the processing of data or the study purpose and methodology, and are therefore not considered a Data Controller. Additionally, the NIHR will not have access to any NHS Digital record level data and are therefore not considered a Data Processor.

LEGAL BASIS FOR COMMON LAW DUTY OF CONFIDENTIALITY

The lawful basis for the release and use of the confidential data for Covid-19 UK Non-hospital Antigen Testing Results (Pillar 2) data and access to Summary Care Record (SCR) being shared under this version of the agreement is Regulation 3(4) of the National Health Service (Control of Patient Information Regulations) 2002 (COPI) to require NHS Digital to share confidential patient information with organisations entitled to process this under COPI for COVID-19 purposes. The only permitted activities under this Data Sharing Agreement (DSA) are for COVID-19 purposes and within bounds of Reg 3(2) COPI. Reg 3 (2) COPI states that: "2) For the purposes of this regulation, “processing” includes any operations, or set of operations set out in regulation 2(2) which are undertaken for the purposes set out in paragraph (1)." The research relates to the monitoring and managing of COVID-19 and would therefore be covered by Reg 3(1)(d) of COPI.

Consent is in place to allow the dissemination of pseudonymised follow-up data to be provided to the study team from NHS Digital. Details of the trial and expected data flows are explained on the latest version of Patient Information Sheet which will be hosted on the trial website:

https://www.panoramictrial.org/

Only the study team at the University of Oxford will access the requested data. No other organisations are involved in the processing or storage of NHS Digital record level data. NHS Digital Record level data will not leave the UK.

LEGAL BASIS FOR PROCESSING DATA

The University of Oxford, as the Data Controller who is also processing the data will process Personal data under GDPR Article 6 (1) (e) - Processing is necessary for the performance of a task carried out in the public interest or in the exercise of official authority vested in the controller. As a higher education establishment, the University conduct research to improve health care and service and the data requested is necessary for the performance of a task carried out in the public interest.

Additionally, under GDPR Article 9(2)(j) processing of Special Category Personal Data (of which Health data is one) is necessary for archiving for research purposes. Data minimisation process is being followed and only data that is required specifically for the purposes of this study has been requested, to protect the rights of the data subjects.

Article 9(2)(h) is additionally being used to cover the processing of SCR specifically: ‘processing is necessary for the purposes of preventive or occupational medicine, for the assessment of the working capacity of the employee, medical diagnosis, the provision of health or social care or treatment or the management of health or social care systems and services’ as it is being used as a timely, second check regarding medication, allergy, and co-morbidities information to support reconciliation, to ensure safe prescribing.

A collaborator agreement is in place between University of Oxford and the institutions listed on the protocol for this clinical trial. The study team have confirmed that the institutions listed within the protocol will not have access to NHS Digital record level data; nor do they make any decisions determining the purposes and means of the processing of data or the study purpose and methodology - therefore, in line with NHS Digital’s DARS standards, NHS Digital does not consider these other institutions as a joint Data Controller or Data Processor for this agreement.

All outputs will be aggregated with small number suppression applied as per the HES analysis guide.

The PANORAMIC trial was able to recruit to the original target much quicker than using conventional methods by receipt of the requested NHS Digital identifiable data (The Covid-19 UK Non-hospital Antigen Testing Results (pillar 2)). This has in turn enabled the study to extend its recruitment target and begin planning the next arm of trial treatment. The statistical analysis team aim to receive follow up data in a more timely manner, therefore answering the COVID-19 treatment in the community question more quickly with the aim of preventing COVID-19 patients being hospitalised so in turn reducing NHS burden.

The trial team intends to disseminate results via media channels: pre-prints/publications in peer-reviewed journals such as the New England Journal of Medicine (NEJM); press releases in local and national newspapers; BBC news coverage; Department of Health and Social Care (DHSC) press briefings; DHSC Social media updates; via the Antiviral Taskforce webpage; Twitter and Facebook University of Oxford accounts. Results will be disseminated to trial participants via the trial website, supported by the University of Oxford. The study team have been providing regular updates to the NIHR Evaluation, Trials and Studies Coordinating Centre.

Since first participant was randomised into the PANORAMIC trial in December 2021, the Data and Safety monitoring Committee have been reviewing the safety data on a weekly basis. Due to the fast recruitment and lower than expected event rate, the Trial Management Group, with agreement from the Trial Steering Committee, took the decision not to conduct an interim analysis on the basis of preserving the Type I error rate for the current treatment. However, the trial will continue recruitment until the new proposed sample size is met and to evaluate whether the initial antiviral agent is effective in treating COVID-19. Should the recruitment become slower when the new agent is added to the platform, an interim analysis could be triggered before the final analysis.

The study team will update participants by signposting them from their ‘end of trial letter’ to the trial website for the latest results and information. Due to the limited resources of the study trial team and the potential number of study participants involved, the study trial team have made the decision that distributing newsletters or email updates would be difficult to manage at such a scale. The study trial team believe that signposting to the website also ensures that the most up to date information is always available to participants, as newsletters can soon become outdated due to the fast-paced and evolving nature of this platform trial. The study team are also considering the use of video/audio updates and other formats to the website depending on capacity.

The trial is of national and international relevance during this pandemic.

By the end of March 2022, the PANORAMIC trial has recruited over 19,000 participants over 64 sites across England. This record-breaking UK platform trial is believed to be the world’s largest study of community-based treatments for acute COVID-19, in addition to the UK’s fastest ever recruiting interventional trial delivered.

This nationwide trial launched in December 2021 to rapidly generate evidence on which of the people affected with COVID-19 at home and in the community are helped the most by new antiviral treatments - without needing to be treated in hospital. The first antiviral drug, which is currently being assessed through the platform trial is molnupiravir, which has been shown to be safe and effective through smaller-scale trials. The study team aim to build on the existing evidence base by continuing to receive NHS Digital data for the participants who have taken part in this arm of the trial. The study is expected to show how well molnupiravir works in a predominantly vaccinated population, as well as its cost effectiveness. Despite this significant milestone being reached, recruitment to the molnupiravir arm continues in earnest , due to the lower than expected event rate in the primary outcome, with the researchers aiming to enrol thousands more participants into this trial arm in order to achieve the expected treatment effect with more certainty. The PANORAMIC trial also intends to investigate a range of other potentially ground-breaking oral antiviral drugs, which can be safely taken at home by people in at-risk groups in the early stages of infection.

The data received from NHS Digital will continue to enhance trial recruitment. The Covid-19 UK Non-hospital Antigen Testing Results (Pillar 2) data should continue to help to identify a more targeted cohort of potential participants who will give a conversion rate from screening to randomisation. The current conversion rate in PANORAMIC is around 70% of those who responded to the calls and screened were randomised. The Summary Care Record (SCR) data should help to assess eligibility of participants, by the clinical team with the information available, within the symptom duration window. Access to SCR will continue to occur during eligibility stage, after participant consent, prior to randomisation within the trial. Participants SCR record will not be accessed after the participant has been randomised to a treatment arm. Currently 71% of participants randomised within 3 days from symptom starts. The Hospital Episode Statistics datasets requested in this agreement aim to verify the primary outcome data, and with the additional data for health economic evaluation, the study team is aiming to reduce patients and hospital burden in data collection of resource data.

Despite high uptake of vaccination against COVID-19, the disease remains prevalent in the UK and in many countries around the world, with many patients continuing to require hospital admission. Early treatment with antiviral agents may prevent progression to the later phase of COVID-19. Therefore, there is an urgent need to identify treatments for COVID-19 for use in the community early on in the illness that prevent the need for hospital admission and improves time to recovery. It is therefore vital that the University of Oxford use this opportunity to accelerate enrolment into COVID-19 therapeutics trials.

The PANORAMIC (Platform Adaptive trial of NOvel antiviRals for eArly treatMent of covid-19 In the Community) trial is the only national priority clinical trial evaluating potential novel antivirals for COVID-19 in the primary care setting, endorsed by the Chief Medical Officers (CMOs) of all four devolved nations. The primary aim is to determine the effectiveness of selected antiviral agents in preventing hospitalisation and/or death in higher-risk patients with a confirmed positive SARS-CoV-2 PCR test result. The PANORAMIC trail is run by the Nuffield Department of Primary Care Health Sciences at the University of Oxford. For the purposes of this data sharing agreement, the Nuffield Department of Primary Care Health Sciences will be referred to as the 'University of Oxford' in this agreement.

**Update for version 1 regarding positive SARS-CoV-2 Lateral Flow Test (LTF)***

Originally, the study team required a positive PCR test for inclusion in the main analysis. UK guidelines have reduced the amount of PCR testing that is recommended. In a context of high prevalence, false positive results from Lateral Flow Tests (LFTs) are minimal, and LFTs are now considered to be giving a truer reflection of infection status in some cases. In line with the changing policy and science, the study team now allow eligibility based on a positive SARS-CoV-2LFT without the requirement for a confirmatory PCR test for inclusion in the main analysis.

******

PANORAMIC is:

• Recruiting across the whole UK* - anyone age 18** or over who match the participant criteria can participate, regardless of location (aged 50 or over, or 18-49 with a pre-existing condition),

• For both recruiters and patients it is a simple process to complete enrolment to the trial via a secured online platform.

• Obtaining consent, checking eligibility, issuing study medication and materials, and follow-up is managed remotely through a central facility at the University of Oxford or delegate. Contracts would be in place with delegates and vendors carrying out these tasks. (**Update for version 1: University of Oxford utilise the services of Integrated Pharmaceutical Services (IPS) Pharma to distribute the drug to trial participants. The personal data required for distribution is collected directly from the participant at the time of consent and IPS Pharma do not have any access to any NHS Digital Record level data. IPS Pharma do not make any decisions about the means by which any personal data is being processed for this study nor the methodology by which the study is conducted. For these reasons, IPS Pharma are not considered as a Data Controller or Processor**)

*PLEASE NOTE - The University of Oxford is obtaining data from NHS Digital related to residents in England only.

** PLEASE NOTE - The first treatment included in the PANORAMIC trial has conditional licensing for adults and therefore the study team are unable to include under children at this stage. Depending on the advice from the Antiviral Taskforce regarding future treatment arms, and their licensing conditions, the inclusion criteria may be amended in future to include under 18’s.

Primary objective -

To determine whether antiviral treatment in the community safely reduces non-elective hospitalisations/deaths in higher risk, symptomatic patients with confirmed COVID-19

Secondary objectives - To explore whether trial treatment reduces:

1) Time to recovery (defined as the first instance that a participant report of feeling recovered from the illness)

2) Participant reported illness severity, reported by daily rating of how well participant feels, enabling identification of sustained recovery.

3) Duration of severe symptoms and symptom recurrence

4) Contacts with the health services

5) New infections in household

6) To investigate the safety of antiviral agents

7) Longer term effects

8) Cost effectiveness

The study team are requesting the Covid-19 UK Non-hospital Antigen Testing Results (pillar 2) dataset in order to identify and successfully recruit potential patients into the trial, early on in their stage of COVID-19 disease. A positive PCR test is essential for inclusion into the trial. The positive PCR test result will be participant reported prior to randomisation, and confirmation of the positive result will be sought at a later date via the Pillar 2 dataset.

The University of Oxford would like to receive names and contact details (including preferably a telephone number and email address) of people who have received a positive COVID-19 swab result from the Pillar 2 testing system. The trial team, based at the University of Oxford, will then contact these potential participants, inform them about the trial and if they are happy, go on to screen and consent them into the PANORAMIC trial. Daily, the trial team would like to receive identifiable record-level data on a random cohort (up to 500) of people aged 18+.

The trial already has a centre set up and operating remotely at the University of Oxford to manage this recruitment in a timely manner. Management of the recruitment to the trial will be undertaken by substantive employees of the University of Oxford who have been appropriately trained in data protection and confidentiality.

The question of whether ‘cold calling’ is appropriate has been considered for this application. As time is of the essence for recruitment into PANORAMIC, the telephone is the most efficient and quickest means to ensure direct contact with the individual, who can answer questions instantly over a call. The study team would also like to use the Short Messaging Service (SMS) and email option for invitation, for those patients who they cannot reach via telephone or those who require follow-up information. During the calls, clear explanation will be given to individual about how the trial has been able to contact them and what to do if they do not wish to be contacted again (i.e. registering a National Data Opt-out). The trial team will respect the wishes of those signed up to the Telephone Preference Service (TPS). The team will ensure that customers flagged on the TPS are not contacted for this trial. The trial team will also ensure the required comorbidities are discussed early on in the calls so as to not to get the individual’s hopes up if they are not in fact eligible for the trial.

Other considerations that have been taken into account in relation to contacting individuals:

• The data relating to positive COVID-19 tests is sent to NHS Digital at the same time that it is sent to the Business Services Authority, the latter process triggering the SMS to the individual informing them of their result. It then takes around four hours for the Covid-19 UK Non-hospital Antigen Testing Results (Pillar 2) dataset within NHS Digital to be updated with this information. Given that this information then needs to be extracted from the dataset at some point in the next 24 hours, then used by the trial team to make contact with the individual, the risk of the individual being informed of their test result by the trial team before they have read their SMS is small. However, the trial team should have a suitable script prepared to deal with this slim possibility.

• The chances of people having multiple positive COVID-19 test results are rare, and rarer still is the likelihood that they will be one of the 500 people extracted from the thousands of daily test results to be sent to the trial team on more than one occasion. Therefore, the risk of an individual being contacted twice for recruitment into PANORAMIC is extremely low.

• NHS Digital recognises that there are likely to be more requests of this nature in future and therefore, if multiple trial require extracts of people to contact, suitable controls need to be in place within the extract process to ensure that individuals are not getting contacted for recruitment into trials more than is reasonably expected.

• The study team at the University of Oxford are aware the recent governmental change in policy over COVID-19 testing that will have a significant impact upon the way testing records will be collected, and how the results should be interpreted. Therefore, the study team will inevitably have to actively incorporate this measure in their study design, which will be reflected in future versions of the study Protocol, processing methodology and outcome analyses.

Patient and Public Involvement & Engagement (PPIE)

The PANORAMIC trial has had extensive PPIE engagement to support development of trial materials and processes and to discuss the plans for efficient and safe use of patient data and has plans for significant engagement throughout the period of the study.

The main study PPIE group includes members of five different cultural and faith communities and representatives of those with learning disabilities. They have had three meetings prior to this application, focussing on acceptability of trial processes and optimising patient-facing materials including redesigning the Pictorial Patient Information Sheet (PIS) and co-developing a summary front page for this document. They have reviewed the online trial interface and instructions for participants. This group will continue to meet at least every month when the trial commences recruitment.

The study team have begun to convene additional PPIE groups in Scotland, Northern Ireland and Wales to focus on nation-specific recruitment and dissemination issues and will work with individual cultural and community leaders to ensure inclusion of the most diverse range of participants possible.

Request to use SCR for consented participants:

The PANORAMIC trial team are requesting to access the Summary Care Record (SCR) for patients recruited into the trial for the purposes of ensuring timely prescribing and safe patient care. SCR access will be essential to successfully recruit participants in the very restrictive timeframe of five days since symptom onset. For the first treatment arm, the trial is run remotely, therefore removing the need for participants to be near to a GP practice. Screening and contact with the trial team is all completed online. The trial team are requesting access to Summary Care Records as part of this application as it will not be possible within the five day window of recruitment from symptom onset, for the trial team to request such information regarding safe prescribing from the participant’s GP.

The PANORAMIC trial team therefore seek permission for the clinical trial team, a group of dedicated doctors and nurses who are fully qualified, study-trained, accredited and registered, to review consenting patients’ Summary Care Records, in order to be able to confirm key information obtained from the patient relevant to safe patient care in the trial. Only nurses and doctors who are registered and accredited with the General Medical Council of the UK or the Nursing and Midwifery Council of the UK who are clinical members of the PANORAMIC study team would review the Summary Care Record for information relevant to safe prescribing and participant care.

The Summary Care Record will be used as a timely, second check regarding medication, allergy, and co-morbidities information to support reconciliation, to ensure safe prescribing. These are all elements of a patient’s SCR with additional information which is a subset of their wider GP record. This access provides an immediate available information source to meet the need to support safe prescribing in a proportionate and timely way. In addition, the Summary Care Record will provide a further safety check, in that access to it will facilitate the opportunity for double-checking participants’ NHS Number and GP practice.

There is a five-day window from symptom onset to enrolment into the trial and so SCR access is critical to confirm eligibility within this very limited time-period.

Access is sought only for those people who have screened eligible to be part of the trial, and who have already signed informed consent for participation in the study and for the trial to access their clinical records. All potential participants are asked specifically for permission for the trial team to access their medical records and have the opportunity to decline this access. In addition, they will be asked specifically and separately for permission about access to their Summary Care Record. For a patient who has provided consent to join the trial and for their SCR to be accessed, the data will be accessed by a clinician to support safe prescribing decisions prior to randomisation in the trial and prescribing medications. A Summary Care Record will only ever be accessed on one occasion for each individual participant.

Access to SCR is required for the period that the trial is recruiting - currently this is December 2021 until Sept 2023.

This request for SCR access for PANORAMIC, along with the similar request for the sisters trial, PRINCIPLE, together form a first-of-type access request and as an interim position it is included in the Data Sharing Agreement. This is a holding position whilst considerations are undertaken to agree whether to offer this as a service more widely to clinical trials for patient safety purposes. This allows time for an appropriate access and approval process to be developed in future, but in the meantime ensures that SCR access is recognised within the research data access process alongside the normal direct care process for access to SCR.

FOLLOW UP DATA:

The trial follows up all consented participants for 28 days and then at three and six months following randomisation.

In this agreement, the University of Oxford are requesting access to record-level data from the following data sets in order to receive follow up data on trial participants:

> Hospital Episode Statistics (HES) Admitted Patient Care (APC)

> HES Critical Care (CC)

> Civil Registration (Deaths) data set

> Medicines dispensed in Primary Care (NHSBSA data)

***New for v1 of this agreement:

> Uncurated Low Latency HES APC Dataset

> Uncurated Low Latency HES CC Dataset

> HES Outpatients (OP)

> HES Emergency Care Dataset (ECDS)

***

These NHS Digital datasets will be essential to collect the primary outcome, which relates to all-cause hospitalisation/death.

New requests for version 1 (v1) of this agreement (MARCH 2022):

*** Request to add Low Latency Hospital Episode Statistics (HES) Admitted Patient Care (APC) and Low Latency HES Critical Care (CC) datasets to the existing 28 day follow up data (v1)***

Previously (v0 of this agreement), the University of Oxford requested access to HES APC and HES CC datasets. However, due to NHS Digital’s cleaning and Data Quality procedures, HES datasets are released under data sharing agreements two months in arrears. This has meant that the University of Oxford are delayed in receiving crucial data for analysis. A number of NHS Trusts now submit routine hospital data as part of the Commissioning Data Set (CDS) more frequently such as weekly or even sometimes daily. This subset of more frequently reported management data is reported in Secondary Use Service (SUS). This SUS data is used to create additional uncurated data sets including Low Latency HES APC and Low Latency HES CC which offer access to more current data. Though less complete and quality assured, this data provides the opportunity for more immediate analysis and additional insights compared to that which might be available in delayed HES data. These Low Latency datasets will provide the study team with more immediate access to data required to begin interim analysis more swiftly. However, the study team have confirmed that they will continue to access the regular HES APC and CC datasets to allow for data checking, quality and completeness. All final study reports and outcomes analysis will be based on regular HES dataset information.

*** Request to add HES Out Patient (OP) and Emergency Care Dataset (EDCS) datasets to the existing 28 day follow up data (v1)***

The University of Oxford have requested access to HES OP and ECDS datasets as part of this agreement.

The request for the addition of HES OP and ECDS datasets are for the purpose of the health economic evaluation, which is embedded within the trial design. This data will be used by the study team to assess the cost effectiveness of each antiviral from an NHS perspective.

***Request to add additional data fields to existing Hospital Episode Statistics (HES) Admitted Patient Care (APC) and HES Critical Care (CC) Datasets (v1)***

the University of Oxford have requested additional data fields to be included in the existing HES APC and HES CC datasets for which they are already in receipt as part of the existing 28 day follow up data.

The request for the additional fields within HES APC and HES CC are also for the purpose of the health economic evaluation, which is embedded within the trial design. These fields will enable the study team to assess the cost effectiveness of each antiviral from an NHS perspective.

These additional dataflows will support those already received to follow up consented patients for 28 day follow up data. As per the previous amendment for 28 follow up data, the existing consent covers the provision of these extra datasets/ data fields and it will only be accessed by the team at University of Oxford, and no other organisations will process or store it.

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Due to the high rate of recruitment, the Data Safety Monitoring Committee (DSMC) review the trial data weekly and can ask for recruitment into a trial arm to be stopped immediately. Therefore, trial data needs to be made available as soon as possible so that the team can quickly issue a press statement and publication of results if required to do so. There is a need to capture the required data in a more timely and efficient manner via monthly extracts from NHS Digital. The DSMC is an independent committee with remits to monitor the progress of the study, review of safety data and also the unblinded interim analysis. The DSMC give recommendation, based on the information they receive from the trial statistician, to the Trial Steering Committee (TSC) with regards to the terminating a treatment arm due to treatment effect or treatment failure. The remit of the TSC is to monitor the progress of the study and provide the trial management committee recommendation based on recommendation from the DSMC. Members of both committees are independent from the trial and their memberships have been approved by National Institute of Health research (NIHR) as the funder for this study. The DSMC and TSC do not make any decisions determining the purposes and means of the processing of data or the study purpose and methodology, and are therefore not considered a Data Controller. Additionally, the DSMC and TSC will not have access to any NHS Digital record level data and will only view aggregated data with small numbers suppressed and are therefore not considered a Data Processor.

The PANORAMIC trial is funded by the NIHR, but do not make any decisions determining the purposes and means of the processing of data or the study purpose and methodology, and are therefore not considered a Data Controller. Additionally, the NIHR will not have access to any NHS Digital record level data and are therefore not considered a Data Processor.

LEGAL BASIS FOR COMMON LAW DUTY OF CONFIDENTIALITY

The lawful basis for the release and use of the confidential data for Covid-19 UK Non-hospital Antigen Testing Results (Pillar 2) data and access to Summary Care Record (SCR) being shared under this version of the agreement is Regulation 3(4) of the National Health Service (Control of Patient Information Regulations) 2002 (COPI) to require NHS Digital to share confidential patient information with organisations entitled to process this under COPI for COVID-19 purposes. The only permitted activities under this Data Sharing Agreement (DSA) are for COVID-19 purposes and within bounds of Reg 3(2) COPI. Reg 3 (2) COPI states that: "2) For the purposes of this regulation, “processing” includes any operations, or set of operations set out in regulation 2(2) which are undertaken for the purposes set out in paragraph (1)." The research relates to the monitoring and managing of COVID-19 and would therefore be covered by Reg 3(1)(d) of COPI.

Consent is in place to allow the dissemination of pseudonymised follow-up data to be provided to the study team from NHS Digital. Details of the trial and expected data flows are explained on the latest version of Patient Information Sheet which will be hosted on the trial website:

https://www.panoramictrial.org/

Only the study team at the University of Oxford will access the requested data. No other organisations are involved in the processing or storage of NHS Digital record level data. NHS Digital Record level data will not leave the UK.

LEGAL BASIS FOR PROCESSING DATA

The University of Oxford, as the Data Controller who is also processing the data will process Personal data under GDPR Article 6 (1) (e) - Processing is necessary for the performance of a task carried out in the public interest or in the exercise of official authority vested in the controller. As a higher education establishment, the University conduct research to improve health care and service and the data requested is necessary for the performance of a task carried out in the public interest.

Additionally, under GDPR Article 9(2)(j) processing of Special Category Personal Data (of which Health data is one) is necessary for archiving for research purposes. Data minimisation process is being followed and only data that is required specifically for the purposes of this study has been requested, to protect the rights of the data subjects.

Article 9(2)(h) is additionally being used to cover the processing of SCR specifically: ‘processing is necessary for the purposes of preventive or occupational medicine, for the assessment of the working capacity of the employee, medical diagnosis, the provision of health or social care or treatment or the management of health or social care systems and services’ as it is being used as a timely, second check regarding medication, allergy, and co-morbidities information to support reconciliation, to ensure safe prescribing.

A collaborator agreement is in place between University of Oxford and the institutions listed on the protocol for this clinical trial. The study team have confirmed that the institutions listed within the protocol will not have access to NHS Digital record level data; nor do they make any decisions determining the purposes and means of the processing of data or the study purpose and methodology - therefore, in line with NHS Digital’s DARS standards, NHS Digital does not consider these other institutions as a joint Data Controller or Data Processor for this agreement.

All outputs will be aggregated with small number suppression applied as per the HES analysis guide.

The PANORAMIC trial was able to recruit to the original target much quicker than using conventional methods by receipt of the requested NHS Digital identifiable data (The Covid-19 UK Non-hospital Antigen Testing Results (pillar 2)). This has in turn enabled the study to extend its recruitment target and begin planning the next arm of trial treatment. The statistical analysis team aim to receive follow up data in a more timely manner, therefore answering the COVID-19 treatment in the community question more quickly with the aim of preventing COVID-19 patients being hospitalised so in turn reducing NHS burden.

The trial team intends to disseminate results via media channels: pre-prints/publications in peer-reviewed journals such as the New England Journal of Medicine (NEJM); press releases in local and national newspapers; BBC news coverage; Department of Health and Social Care (DHSC) press briefings; DHSC Social media updates; via the Antiviral Taskforce webpage; Twitter and Facebook University of Oxford accounts. Results will be disseminated to trial participants via the trial website, supported by the University of Oxford. The study team have been providing regular updates to the NIHR Evaluation, Trials and Studies Coordinating Centre.

Since first participant was randomised into the PANORAMIC trial in December 2021, the Data and Safety monitoring Committee have been reviewing the safety data on a weekly basis. Due to the fast recruitment and lower than expected event rate, the Trial Management Group, with agreement from the Trial Steering Committee, took the decision not to conduct an interim analysis on the basis of preserving the Type I error rate for the current treatment. However, the trial will continue recruitment until the new proposed sample size is met and to evaluate whether the initial antiviral agent is effective in treating COVID-19. Should the recruitment become slower when the new agent is added to the platform, an interim analysis could be triggered before the final analysis.

The study team will update participants by signposting them from their ‘end of trial letter’ to the trial website for the latest results and information. Due to the limited resources of the study trial team and the potential number of study participants involved, the study trial team have made the decision that distributing newsletters or email updates would be difficult to manage at such a scale. The study trial team believe that signposting to the website also ensures that the most up to date information is always available to participants, as newsletters can soon become outdated due to the fast-paced and evolving nature of this platform trial. The study team are also considering the use of video/audio updates and other formats to the website depending on capacity.

The trial is of national and international relevance during this pandemic.

By the end of March 2022, the PANORAMIC trial has recruited over 19,000 participants over 64 sites across England. This record-breaking UK platform trial is believed to be the world’s largest study of community-based treatments for acute COVID-19, in addition to the UK’s fastest ever recruiting interventional trial delivered.

This nationwide trial launched in December 2021 to rapidly generate evidence on which of the people affected with COVID-19 at home and in the community are helped the most by new antiviral treatments - without needing to be treated in hospital. The first antiviral drug, which is currently being assessed through the platform trial is molnupiravir, which has been shown to be safe and effective through smaller-scale trials. The study team aim to build on the existing evidence base by continuing to receive NHS Digital data for the participants who have taken part in this arm of the trial. The study is expected to show how well molnupiravir works in a predominantly vaccinated population, as well as its cost effectiveness. Despite this significant milestone being reached, recruitment to the molnupiravir arm continues in earnest , due to the lower than expected event rate in the primary outcome, with the researchers aiming to enrol thousands more participants into this trial arm in order to achieve the expected treatment effect with more certainty. The PANORAMIC trial also intends to investigate a range of other potentially ground-breaking oral antiviral drugs, which can be safely taken at home by people in at-risk groups in the early stages of infection.

The data received from NHS Digital will continue to enhance trial recruitment. The Covid-19 UK Non-hospital Antigen Testing Results (Pillar 2) data should continue to help to identify a more targeted cohort of potential participants who will give a conversion rate from screening to randomisation. The current conversion rate in PANORAMIC is around 70% of those who responded to the calls and screened were randomised. The Summary Care Record (SCR) data should help to assess eligibility of participants, by the clinical team with the information available, within the symptom duration window. Access to SCR will continue to occur during eligibility stage, after participant consent, prior to randomisation within the trial. Participants SCR record will not be accessed after the participant has been randomised to a treatment arm. Currently 71% of participants randomised within 3 days from symptom starts. The Hospital Episode Statistics datasets requested in this agreement aim to verify the primary outcome data, and with the additional data for health economic evaluation, the study team is aiming to reduce patients and hospital burden in data collection of resource data.

Despite high uptake of vaccination against COVID-19, the disease remains prevalent in the UK and in many countries around the world, with many patients continuing to require hospital admission. Early treatment with antiviral agents may prevent progression to the later phase of COVID-19. Therefore, there is an urgent need to identify treatments for COVID-19 for use in the community early on in the illness that prevent the need for hospital admission and improves time to recovery. It is therefore vital that the University of Oxford use this opportunity to accelerate enrolment into COVID-19 therapeutics trials.

The PANORAMIC (Platform Adaptive trial of NOvel antiviRals for eArly treatMent of covid-19 In the Community) trial is the only national priority clinical trial evaluating potential novel antivirals for COVID-19 in the primary care setting, endorsed by the Chief Medical Officers (CMOs) of all four devolved nations. The primary aim is to determine the effectiveness of selected antiviral agents in preventing hospitalisation and/or death in higher-risk patients with a confirmed positive SARS-CoV-2 PCR test result.

PANORAMIC is:

• Recruiting across the whole UK* - anyone age 18** or over who match the participant criteria can participate, regardless of location.

• For both recruiters and patients it is a simple process to complete enrolment on to the trial.

• Obtaining consent, checking eligibility, issuing study medication and materials, and follow-up is managed remotely through a central facility at the University of Oxford.

*PLEASE NOTE - The University of Oxford is obtaining data from NHS Digital related to residents in England only.

** PLEASE NOTE - The first treatment included in the PANORAMIC trial has conditional licensing for adults and therefore the study team are unable to include under children at this stage. Depending on the advice from the Antiviral Taskforce regarding future treatment arms, and their licensing conditions, the inclusion criteria may be amended in future to include under 18’s.

Primary objective -

To determine whether antiviral treatment in the community safely reduces non-elective hospitalisations/deaths in higher risk, symptomatic patients with confirmed COVID-19

Secondary objectives - To explore whether trial treatment reduces:

1) Time to recovery (defined as the first instance that a participant report of feeling recovered from the illness)

2) Participant reported illness severity, reported by daily rating of how well participant feels, enabling identification of sustained recovery.

3) Duration of severe symptoms and symptom recurrence

4) Contacts with the health services

5) New infections in household

6) To investigate the safety of antiviral agents

7) Longer term effects

8) Cost effectiveness

The study team are requesting the Covid-19 UK Non-hospital Antigen Testing Results (pillar 2) dataset in order to identify and successfully recruit potential patients into the trial, early on in their stage of COVID-19 disease. A positive PCR test is essential for inclusion into the trial. The positive PCR test result will be participant reported prior to randomisation, and confirmation of the positive result will be sought at a later date via the Pillar 2 dataset.

The University of Oxford would like to receive names and contact details (including preferably a telephone number and email address) of people who have received a positive COVID-19 swab result from the Pillar 2 testing system. The trial team, based at the University of Oxford, will then contact these potential participants, inform them about the trial and if they are happy, go on to screen and consent them into the PANORAMIC trial. Daily, the trial team would like to receive identifiable record-level data on a random cohort (up to 500) of people aged 18+.

The trial already has a centre set up and operating remotely at the University of Oxford to manage this recruitment in a timely manner. Management of the recruitment to the trial will be undertaken by substantive employees of the University of Oxford who have been appropriately trained in data protection and confidentiality.

The question of whether ‘cold calling’ is appropriate has been considered for this application. As time is of the essence for recruitment into PANORAMIC, the telephone is the most efficient and quickest means to ensure direct contact with the individual, who can answer questions instantly over a call. The study team would also like to use the Short Messaging Service (SMS) and email option for invitation, for those patients who they cannot reach via telephone or those who require a follow-up information. During the calls, clear explanation will be given to individual about how the trial has been able to contact them and what to do if they do not wish to be contacted again (i.e. registering a National Data Opt-out). The trial team will apply the Telephone Preference Service. The trial team will also ensure the required comorbidities are discussed early on in the calls so as to not to get the individual’s hopes up if they are not in fact eligible for the trial.

Other considerations that have been taken into account in relation to contacting individuals:

• The data relating to positive COVID-19 tests is sent to NHS Digital at the same time that it is sent to the Business Services Authority, the latter process triggering the SMS to the individual informing them of their result. It then takes around four hours for the Covid-19 UK Non-hospital Antigen Testing Results (pillar 2) dataset within NHS Digital to be updated with this information. Given that this information then needs to be extracted from the dataset at some point in the next 24 hours, then used by the trial team to make contact with the individual, the risk of the individual being informed of their test result by the trial team before they have read their SMS is small. However, the trial team should have a suitable script prepared to deal with this slim possibility.

• The chances of people having multiple positive COVID-19 test results are rare, and rarer still is the likelihood that they will be one of the 500 people extracted from the thousands of daily test results to be sent to the trial team on more than one occasion. Therefore, the risk of an individual being contacted twice for recruitment into PANORAMIC is extremely low.

• NHS Digital recognises that there are likely to be more requests of this nature in future and therefore, if multiple trial require extracts of people to contact, suitable controls need to be in place within the extract process to ensure that individuals are not getting contacted for recruitment into trials more than is reasonably expected.

Patient and Public Involvement & Engagement (PPIE)

The Panoramic trial has had extensive PPIE engagement to support development of trial materials and processes and to discuss the plans for efficient and safe use of patient data and has plans for significant engagement throughout the period of the study.

The main study PPIE group includes members of five different cultural and faith communities and representatives of those with learning disabilities. They have had three meetings prior to this application, focussing on acceptability of trial processes and optimising patient-facing materials including redesigning the Pictorial Patient Information Sheet (PIS) and co-developing a summary front page for this document. They have reviewed the online trial interface and instructions for participants. This group will continue to meet at least every month when the trial commences recruitment.

The study team have begun to convene additional PPIE groups in Scotland, Northern Ireland and Wales to focus on nation-specific recruitment and dissemination issues and will work with individual cultural and community leaders to ensure inclusion of the most diverse range of participants possible.

Request to use SCR for consented participants:

The PANORAMIC trial team are requesting to access the Summary Care Record (SCR) for patients recruited into the trial for the purposes of ensuring timely prescribing and safe patient care. SCR access will be essential to successfully recruit participants in the very restrictive timeframe of five days since symptom onset. For the first treatment arm, the trial is run remotely, therefore removing the need for participants to be near to a GP practice. Screening and contact with the trial team is all completed online. The trial team are requesting access to Summary Care Records as part of this application as it will not be possible within the five day window of recruitment from symptom onset, for the trial team to request such information regarding safe prescribing from the participant’s GP.

The PANORAMIC trial team therefore to seek permission for the clinical trial team, a group of dedicated doctors and nurses who are fully qualified, study-trained, accredited and registered, to review consenting patients’ Summary Care Records, in order to be able to confirm key information obtained from the patient relevant to safe patient care in the trial. Only nurses and doctors who are registered and accredited with the General Medical Council of the UK or the Nursing and Midwifery Council of the UK who are clinical members of the PANORAMIC study team would review the Summary Care Record for information relevant to safe prescribing and participant care.

The Summary Care Record will be used as a timely, second check regarding medication, allergy, and co-morbidities information to support reconciliation, to ensure safe prescribing. These are all elements of a patient’s SCR with additional information which is a subset of their wider GP record. This access provides an immediate available information source to meet the need to support safe prescribing in a proportionate and timely way. In addition, the Summary Care Record will provide a further safety check, in that access to it will facilitate the opportunity for double-checking participants’ NHS Number and GP practice.

There is a five-day window from symptom onset to enrolment into the trial and so SCR access is critical to confirm eligibility within this very limited time-period.

Access is sought only for those people who have screened eligible to be part of the trial, and who have already signed informed consent for participation in the study and for the trial to access their clinical records. All potential participants are asked specifically for permission for the trial team to access their medical records and have the opportunity to decline this access. In addition, they will be asked specifically and separately for permission about access to their Summary Care Record. For a patient who has provided consent to join the trial and for their SCR to be accessed, the data will be accessed by a clinician to support safe prescribing decisions immediately prior to prescribing medications. A Summary Care Record will only ever be accessed on one occasion for each individual participant/

Access to SCR is required for the period that the trial is recruiting - currently this is December 2021 until Sept 2023.

This request for SCR access for PANORAMIC, along with the similar request for the sisters trial, PRINCIPLE, together form a first-of-type access request and as an interim position it is included in the Data Sharing Agreement. This is a holding position whilst considerations are undertaken to agree whether to offer this as a service more widely to clinical trials for patient safety purposes. This allows time for an appropriate access and approval process to be developed in future, but in the meantime ensures that SCR access is recognised within the research data access process alongside the normal direct care process for access to SCR.

FOLLOW UP DATA:

In this agreement, the University of Oxford are requesting access to record-level data from the following data sets in order to receive follow up data on trial participants:

> Hospital Episode Statistics (HES) Admitted Patient Care (APC)

>HES Critical Care (CC)

> Civil Registration (Deaths) data set

> Medicines dispensed in Primary Care (NHSBSA data)

The trial follows up all consented participants for 28 days and then at three and six months following randomisation.

Due to the high rate of recruitment, the Data Safety Monitoring Committee review the trial data weekly and can ask for recruitment into a trial arm to be stopped immediately. Therefore trial data needs to be made available as soon as possible so that the team can quickly issue a press statement and publication of results if required to do so. There is a need to capture the required data in a more timely and efficient manner via monthly extracts from NHS Digital.

HES APC, HES Critical Care, and Civil Registration of Deaths datasets will be essential to collect the primary outcome, which relates to all-cause hospitalisation/death.

LEGAL BASIS FOR COMMON LAW DUTY OF CONFIDENTIALITY

The lawful basis for the release and use of the confidential data (Covid-19 UK Non-hospital Antigen Testing Results (pillar 2) and Summary Care Record (SCR)) being shared under this version of the agreement is Regulation 3(4) of the National Health Service (Control of Patient Information Regulations) 2002 (COPI) to require NHS Digital to share confidential patient information with organisations entitled to process this under COPI for COVID-19 purposes. The only permitted activities under this Data Sharing Agreement (DSA) are for COVID-19 purposes and within bounds of Reg 3(2) COPI. Reg 3 (2) COPI states that: "2) For the purposes of this regulation, “processing” includes any operations, or set of operations set out in regulation 2(2) which are undertaken for the purposes set out in paragraph (1)." The research relates to the monitoring and managing of COVID-19 and would therefore be covered by Reg 3(1)(d) of COPI.

Consent is in place to allow the pseudonymised follow-up data to be provided to the study team from NHS Digital and details of the trial and expected data flows are explained on the latest version of Patient Information Sheet which will be hosted on the trial website: https://www.panoramictrial.org/ (currently in development).

Only the study team at the University of Oxford will access the requested data. No other organisations are involved in the processing or storage of NHS Digital record level data. NHS Digital Record level data will not leave the UK.

LEGAL BASIS FOR PROCESSING DATA

The University of Oxford, as the Data Controller who is also processing the data will process Personal data under GDPR Article 6 (1) (e) - Processing is necessary for the performance of a task carried out in the public interest or in the exercise of official authority vested in the controller. As a higher education establishment, the University conduct research to improve health care and service and the data requested is necessary for the performance of a task carried out in the public interest.

Additionally, under GDPR Article 9(2)(j) processing of Special Category Personal Data (of which Health data is one) is necessary for archiving for research purposes. Data minimisation process is being followed and only data that is required specifically for the purposes of this study has been requested, to protect the rights of the data subjects.

Article 9(2)(h) is additionally being used to cover the processing of SCR specifically: ‘processing is necessary for the purposes of preventive or occupational medicine, for the assessment of the working capacity of the employee, medical diagnosis, the provision of health or social care or treatment or the management of health or social care systems and services’ as it is being used as a timely, second check regarding medication, allergy, and co-morbidities information to support reconciliation, to ensure safe prescribing.

The PANORAMIC trial is funded by the National Institute of Health Research (NIHR), but do not make any decisions determining the purposes and means of the processing of data or the study purpose and methodology, and are therefore not considered a Data Controller. Additionally, the NIHR will not have access to any NHS Digital record level data and are therefore not considered a Data Processor.

A collaborator agreement is in place between University of Oxford and the institutions listed on the protocol for this clinical trial. The study team have confirmed that the institutions listed within the protocol will not have access to NHS Digital record level data and therefore, in line with NHS Digital’s DARS standards, does not consider these other institutions as a joint Data Controller or Data Processor for this agreement.

All outputs will be aggregated with small number suppression applied as per the HES analysis guide.

The PANORAMIC trial will recruit to target much quicker than using current methods if the team can receive the requested NHS Digital identifiable data. The statistical analysis team aim to receive follow up data in a more timely manner, therefore answering the COVID-19 treatment in the community question more quickly with the aim of preventing COVID-19 patients being hospitalised so in turn reducing NHS burden.

The trial team intends to disseminate results via media channels: pre-prints/publications in peer-reviewed journals such as the New England Journal of Medicine (NEJM); press releases in local and national newspapers; BBC news coverage; Department of Health and Social Care (DHSC) press briefings; DHSC Social media updates; via the Antiviral Taskforce webpage; Twitter and Facebook University of Oxford accounts. Results will be disseminated to trial participants via the trial website, supported by the University of Oxford. The study team will provide regular updates to the NIHR Evaluation, Trials and Studies Coordinating Centre.

From the start of the trial (beginning of December 2021), the data will be reviewed on a weekly basis to determine whether the antiviral treatment arms meet the superiority/futility criteria. The trial aims to recruit participants within 4 months (by the middle of April 2022) to identify whether the initial antiviral agent is effective in treating COVID-19. The first interim analysis is scheduled for the start of January 2022, after 1,000 study participants have been randomised in the trial.

The study team will update participants by signposting them from their ‘end of trial letter’ to the trial website for the latest results and information. Due to the limited resources of the study trial team and the potential number of study participants involved, the study trial team have made the decision that distributing newsletters or email updates would be difficult to manage at such a scale. The study trial team believe that signposting to the website also ensures that the most up to date information is always available to participants, as newsletters can soon become outdated due to the fast-paced and evolving nature of this platform trial. The study team are also considering the use of video/audio updates and other formats to the website depending on capacity.

The trial is of national and international relevance during this pandemic.

Yielded Benefits is not a requirement for new applications.