NHS Galleri Clinical Trial Communications via NHS DigiTrials request

GRAIL Bio UK Ltd and Queen Mary University of London (QMUL), as joint data controllers, are requesting vital status information for a consented cohort of participants who have been recruited to a clinical trial called ‘NHS-Galleri’. The vital status checks for a trial participant's most up-to-date address. It also checks if any participants have died, so that the trial can update the cohort and remove these participants from any mailings.

Note that all members of the team running the trial are based at the Cancer Prevention Trials Unit (CPTU) at QMUL. For the sake of consistency, and as QMUL is listed as a data controller, when referring to QMUL throughout the application, this encompasses the team at CPTU.

Background, Purpose and Rationale behind NHS-Galleri:

A new Multi-Cancer Early Detection (MCED) test has been developed that can detect many types of cancer from a single blood sample. This test is called Galleri (Registered Trademark). This trial aims to find out whether it is better at discovering cancer early, compared to other tests that the NHS currently uses. The purpose of NHS-Galleri is to demonstrate the clinical utility of the MCED blood test for individuals in a general screening population in a real world NHS setting. The rationale behind this trial is that MCED is a novel screening paradigm, and assessment of the use and impact of test results is necessary to enable integration into clinical practice. This will be the first randomised, double blind, controlled trial statistically powered to assess clinical utility of a MCED test.

Recruitment to the trial was aided by NHS Englands Digi-Trials team via a sister application, DARS-NIC-456778-J0G3H, and took place from August 2021 to July 2022 with a recruitment target of 140,000 people. Different areas were targeted for recruitment, beginning with North-west England. Recruitment in a particular area lasted for 4 – 6 weeks, before moving on to another area. Recruitment was managed through mobile units on scheduled routes around a particular area. Batches of invitations were constructed to target whatever area the mobile units were in at the time of writing out to potential participants. Potential participants were only contacted once and there were no follow-ups sent after the original invitation letter.

Objectives of the Trial

• Primary Objective:

- For cancers that are routinely staged, determine whether there is a statistically significant reduction in the absolute numbers of stage III and IV cancers diagnosed in the intervention arm as compared to the control arm following three annual test and an average of 16-18 months follow-up after the third test, using a fixed-sequence strategy as below:

a. For a prespecified group of cancer types, including lung, head and neck, colorectal, pancreas, myeloma/plasma cell neoplasm, liver / bile duct, stomach, oesophagus, anus, lymphoma, ovary and bladder.

b. For all cancer types, excluding prostate cancer.

c. For all cancer types.

• Secondary Objectives:

1) For cancers that are routinely staged, determine whether there is a statistically significant reduction in the absolute numbers of advanced cancers (defined as a cancer diagnosed at stage III or IV or one that results in a cancer-specific death) in the intervention arm as compared to the control arm following three annual tests and an average of 16-18 months follow-up after the third test, using a fixed-sequence strategy as below:

a) First, evaluate for a statistically significant difference in a prespecified group of primary cancer types: lung, head & neck, colorectal, pancreas, myeloma/plasma cell neoplasm, liver/bile duct, stomach, oesophagus, anus, lymphoma, ovary, and bladder.

b) If a statistically significant reduction in absolute numbers is found, continue by evaluating for a difference in all cancer types excluding prostate cancer.

c) If the above evaluations are both significant, evaluate for a difference in all cancer types.

2) For cancers that are routinely staged, determine whether there is a difference in the proportion of stage I and II cancers between the two arms of the study in the third testing round (i.e. for cancers diagnosed with an average 16-18 months of follow-up after the third test).

3) Evaluate the performance (overall sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and cancer signal origin accuracy) of the MCED test in the intervention arm after each annual round of testing and in aggregate across the three intervals of testing.

4) Evaluate the safety, including harms, of the testing pathway in the intervention arm among individuals with positive MCED test results.

a) Assess participant-reported anxiety among those receiving a positive MCED test result following the initial blood draw at various time points.

b) Examine the radiation exposure by participants associated with follow-up diagnostic procedures following a positive MCED test result

c) Describe the number and type of invasive procedures performed, and number of complications and deaths associated with follow-up diagnostic procedures.

5) Determine whether there is a statistically significant reduction in the absolute numbers of stage IV cancers diagnosed in the intervention arm compared to the control arm, following the initial screening round and 12 months of follow-up (excluding cancers identified by the test performed at the 12-month visit)

a) For a prespecified group of cancer types: lung, head & neck, colorectal, pancreas, myeloma/plasma cell neoplasm, liver/bile duct, stomach, oesophagus, anus, lymphoma, ovary, and bladder;

b) For all cancer types excluding prostate cancer;

c) For all cancer types.

6) Determine whether there is a reduction in the absolute numbers of stage IV cancers diagnosed in the intervention arm compared to the control arm, following three annual tests and an average of 16-18 months follow-up after the third test

a) For a prespecified group of cancer types: lung, head & neck, colorectal, pancreas, myeloma/plasma cell neoplasm, liver/bile duct, stomach, oesophagus, anus, lymphoma, ovary, and bladder;

b) For all cancer types excluding prostate cancer

c) For all cancer types.

7) Determine whether there is a statistically significant difference in cancer detection rates in the two arms of the study with 12 months follow-up after the first test.

8) Model the expected differences in cancer-specific mortality at 7 years post-randomisation based on cancers diagnosed within an average of 40-42 months of randomisation.

9) Summarize stage distribution per cancer type for the two arms, and compare the absolute numbers of stage IV alone as well as stage III and IV cancers, following the third screening and an average 16-18* months of follow-up.

10) Determine whether there is a reduction in the absolute numbers of stage III and IV cancers, excluding breast, cervical, and colorectal (i.e., those without a standard of care screening modality) as compared to the control arm following the third annual screening and an average 16-18 months of follow-up.

11) Assess the impact on cancer-specific mortality:

a. (Endpoint powered) Assess the potential for avoidance/postponement of cancer death by comparing the rates of death from cancer with-specific mortality rates among individuals receiving a positive MCED test at any of the 3 screening rounds in the intervention arm with that among individuals retrospectively testing positive at any of the 3 screening rounds in the control arm, at 3 years after the last study visit (retrospectively testing all samples from cancer deaths in the control arm).

b. (Endpoint not powered) Compare cancer-specific mortality in the intervention and control arms for all cancer types at a) 3 years and b) 6 years after the last study visit.

12) Compare the absolute numbers of stage IV cancers following the second blood draw and 12 months of follow-up, with prevalent cases excluded.

13) Compare the absolute numbers of stage III and IV cancers following the third blood draw and an average 16-18 months of follow-up, with cases from the first and second screenings excluded.

14) Assess the impact of use of the MCED test across three annual timepoints on healthcare resource utilization for cancer diagnosis and treatment.

15) Assess the potential impact of overdiagnosis by comparing the cumulative incidence (Kaplan-Meier curves) of cancers diagnosed after a positive baseline MCED test up to 36-48 months after randomization between the intervention and control arms (retrospectively testing baseline samples from all participants diagnosed with cancer in the control arm).

Patient and Public Involvement and Engagement (PPI&E):

Patients and members of the public have played a key role in determining the most appropriate study procedures, including the use of personal data, and continue to feed into the trial decision-making process with the support of a behavioural scientist embedded in the Cancer Prevention Trials Unit. Two PPI contributors have reviewed all study materials and sit on the Trial Steering Committee to feed into trial decisions. The trial team periodically consults additional advisory groups of members of the public to inform participant procedures and key messaging. In terms of data sharing and management, PPI contributors have provided important input on the acceptability of sharing pseudonymised data with GRAIL Inc. Prior to the start of the trial, PPI contributors were asked to consider whether it was appropriate to share and obtain personal data of consented trial participants with NHS England to receive updated vital status and home address and have not raised concerns. They have also checked the clarity of wording in the patient information sheet to ensure that participants could make an informed decision.

Transparency / Communication with Participants:

The Health Research Authority (HRA) details in their Research Transparency Strategy that ‘Informing Participants’ is one of the four elements of research transparency, stating that it is a good practice requirement that people who have taken part in a research project are thanked for their contribution and told about what it helped the researchers to find out, where appropriate. Furthermore, the UK Policy Framework for Health and Social Care Research says: “Information about the findings of the research [should be] available, in a suitable format and timely manner, to those who took part in it, unless otherwise justified.”

The NHS Galleri trial team are looking to send an invitation letter to participants to book their follow up appointments and a ‘Thank You’ Communication letter to all participants enrolled on the NHS-Galleri Trial following completion of trial appointments, and therefore need to know if any have changed their address. Additionally, this service will help to identify any participants known to have died so that the trial team can avoid sending these communications to participants. This agreement is therefore being put in place with NHS England to facilitate this.

In order to ensure that the NHS-Galleri trial contains the most accurate and up to date participant details, study participants have consented for NHS England to provide the study with updated contact details, using the NHS DigiTrials Communication Service.

Vital Status check via the NHS DigiTrial's Communication's Service:

QMUL will provide NHS England with participant information (Study ID, NHS Number, Date of Birth, Family Name, Given Name and Postcode) via Secure Electronic File Transfer (SEFT)

NHS England will perform a vital status check and identify any participants known to have sadly died. NHS England will then retrieve the address for the remaining participants and return this to QMUL. The file will also contain details of validation failures, no known addresses and a list of unique references of individuals who have sadly died.

Continu-forms Holdings (CFH) DocMail Ltd will perform the mailing as instructed by GRAIL Bio UK Ltd.

Organisations involved in this agreement, and their roles:

• GRAIL Bio UK Ltd are a joint Data Controller and Lead for this agreement, who also process the data. It is responsible for sponsoring and funding the trial, as well as the building and maintenance of the Clinical Records Management System.

• QMUL are a joint Data Controller who also process the data and are responsible for implementing the trial and for primary objective analysis.

• NHS England are responsible for running the cohort of participants via a vital status check as part of the NHS DigiTrials communications service.

• CFH Docmail are acting as a data processor on behalf of GRAIL Bio UK Ltd and QMUL and are responsible distribution of mailing as instructed by GRAIL Bio UK Ltd

• Amazon Web Services (AWS UK) supply IT infrastructure for GRAIL Bio UK Ltd and are therefore listed as data processors.

• Arrow Business Communications Limited (ARO) supply IT infrastructure for QMUL's Trusted Research Environment and are therefore listed as data processors.

NHS England are listed as a strategic partner in relation to NHS-Galleri, but have no input into how the trial is run or determining the outcome. NHS England therefore do not consider them to be a Data Controller. Cancer Research UK appear on trial-related documentation by virtue of the fact that QMUL's Cancer Prevention Trials Unit are a Cancer Research UK Trials Unit. Cancer Research UK as an organisation in their own right have no involvement in the running of the trial, nor are they funding any of the trial activities. NHS England therefore do not consider them to be a Data Controller or Data processor on this agreement.

GDPR Legal Basis for the Processing of Personal Data:

GRAIL Bio UK Ltd, as joint Data Controller, is using Article 6(1)(f) "processing is necessary for the purposes of the legitimate interests pursued by the controller or by a third party except where such interests are overridden by the interests or fundamental rights and freedoms of the data subject which require protection of personal data, in particular where the data subject is a child." Processing personal data is necessary for GRAIL Bio UK Ltd’s legitimate interests which are described in this application. The data to which access is requested are proportionate and necessary to achieve those interests. GRAIL Bio UK Ltd has completed a legitimate interests assessment (LIA) and NHS England are satisfied that the interests of the data subjects do not override their legitimate interests; that they would reasonably expect the processing and it would not cause unjustified harm. The data subjects interests and fundamental rights are protected through appropriate minimisation of fields and patient records being processed; protection of the data in a secure environment, and guaranteeing secure destruction at any stage at the request of NHS England or after a defined period on completion of the project.

Additionally (as health data is a special category of Personal Data), GRAIL Bio UK Ltd is using Article 9:2(j): Special category data used for “Archiving in the public interest, scientific or historical research or statistical purposes”, with a basis in law.

QMUL, as joint Data Controller, is using Article 6:1(e): Specific task in the ‘public interest’ or task that has a clear basis in law, and additionally (as health data is a special category of Personal Data) Article 9:2(j): Special category data used for “Archiving in the public interest, scientific or historical research or statistical purposes”, with a basis in law.

Commercial Benefit:

In the future, GRAIL Bio UK Ltd may receive commercial benefit (including intangible or indirect commercial benefits such as positive publicity) from the successful outcomes of the trial. GRAIL Bio UK Ltd and the NHS have entered into a partnership whereby the Galleri test will be piloted in clinical trials within the NHS in England. If the test is shown to work as intended in these clinical trials, the NHS may purchase the test from GRAIL and make the test routinely available in the future to benefit patient.

All organisations party to this agreement must comply with the Data Sharing Framework Contract requirements, including those regarding the use (and purposes of that use) by “Personnel” (as defined within the Data Sharing Framework Contract i.e: employees, agents and contractors of the Data Recipient who may have access to that data).

STORAGE AND PROCESSING LOCATIONS

Amazon Web Services (AWS UK) supply IT infrastructure for GRAIL Bio UK Ltd and are therefore listed as data processors. They supply support to the system, but do not access data. Therefore, any access to the data held under this agreement would be considered a breach of the agreement.

This includes granting of access to the database[s] containing the data. AWS UK use only UK data centres and provides a private cloud platform which hosts the Clinical Records Management System (“CRMS”) which was developed and is managed by GRAIL Bio UK Ltd. Enrolled participants consent to the transfer and storage of their data to GRAIL Bio UK Ltd and the CPTU (located at QMUL) for the purposes of this agreement.

ARO supply IT infrastructure for QMUL's Trusted Research Environment and are therefore listed as data processors. They supply a managed system, but do not access data. Therefore, any access to the data held under this agreement would be considered a breach of the agreement. They manage access to the file system with instruction from QMUL. Enrolled participants consent to the transfer and storage of their identifiable data to the CPTU (located at QMUL) for the purposes of updating their vital status information which includes updated address and status of death (if applicable).

PROPOSED METHODOLOGY

Cohort:

1.      A consented cohort is submitted by QMUL to NHS England via Secure Electronic File Transfer (SEFT)

2.      The cohort is validated using an automated pipeline to check for errors.

3a.    If the file has more than 2% errors, the file is sent back from NHS England to QMUL via SEFT to be reviewed and corrected.

3b.    If the file has less than 2% errors, this will be accepted by NHS England and processed using an automated pipeline to check for vital status and addresses.

Data Returned:

A file containing the following information will be returned to QMUL from NHS England via SEFT:

a. Participant records that didn’t meet the validation criteria and couldn’t be processed (e.g. mandatory fields were missing)

b. Updated participant details so that the study can enrich their cohort with any new addresses or fact of death

c. Unique references for deceased records

d. Unique references for records with insufficient information to facilitate contact (e.g. no address on file)

Mailing:

QMUL will share the demographics file securely with GRAIL Bio UK Ltd.

Letters are triggered via an Application Programming Interface (API) by the Clinical Research Management System (CRMS) managed by GRAIL Bio UK. Updated address data is ingested into CRMS to update study records. CFH DocMail Ltd will then perform the mailing as instructed by GRAIL Bio UK Ltd.

The NHS England identifiable record-level data from the demographics dataset will be accessible only to those substantive employees with appropriate and authorized access at (i) QMUL, (ii) GRAIL Bio UK Ltd, and (iii) CFH Docmail Ltd. This Record level identifiable data will be stored in the secure AWS S3 folders (for GRAIL Bio UK Ltd) and ARO TRE (for QMUL) and CFH Docmail Ltd.

Processing will be carried out on organisation-owned and managed devices, either directly in person or remotely. To remotely access the devices requires a secure 2-factor authenticator (Virtual Private Network (VPN) and users are then able to securely access the server on the organisation's cloud platform. All data processing will be conducted within the confines of the organisation's cloud platform, and will not be downloaded to remote devices for storage or processing.

As the study has a large cohort of over 140,000 participants , the vital status check will take place in the full list as the first extract, then small batches every 2 weeks over the period of 2 years until the end of the active trial period. Invitations to participants are being staggered and so the study needs regular (2 weekly) updates on any changes in participant addresses and deaths. Further rounds of vital status checks will be undertaken fortnightly for a period of 2 years, with a one month break in July/August 2023, when the study is not taking appointments. A full cohort check is to be completed prior to the ’Thank You’ communication scheduled for all active trial participants.

Handling follow up queries

After receiving the vital status check from NHS England, GRAIL Bio UK Ltd will securely process participant name and address details to update their records. This information will then be used to send letters to participants as part of the trial.

A 'return to sender' address will need to be included on the letters - this will be to QMUL's Cancer Prevention Trials Unit.

Participants were contacted prior to their 12-month and 24-month study visits to schedule their appointment. If a participant did not respond to the contact, reasonable attempts were made to contact the participant by the study team to ask the participant to schedule their study visit. This vital status check will primarily be used to contact participants to schedule their appointments however may also be used to communicate key trial information following completion of the 24-month study visits. Long-term outcomes data from health records will continue to be collected and samples from these participants can be used in analyses. Return to sender letters will be managed on an ad-hoc basis to contact the participants.

Option to withdraw

On all participant communications, participants are given information that taking part is voluntary and they can choose to leave the trial (withdraw) for any reason, at any time.

The key immediate output will be a file of updated participant vital status check, and names and addresses of participants which would be passed from NHS England to QMUL who will securely share with GRAIL Bio UK Ltd. GRAIL Bio UK Ltd will then instruct CFH Docmail Ltd to generate the mailings.

The ultimate output of this data processing will be participants being mailed a letter to invite them to book their follow-up appointments in order to maintain retention of participants in the trial as well as to Thank them for their participation in the trial. This data processing is for this single element of the much larger NHS-Galleri trial so other outputs such as results presentations and publications would not be expected as a result of this specific process.

The NHS-Galleri trial has a separate DSA for other data that are being processed that would generate these more traditional outputs. However, the process of securely sending the study results to trial participants described in this application will be an exemplar of good practice, which will encourage other researchers to provide similar information to their trial participants.

Keeping participants informed of results of trials they are involved with is a high priority according to the Health Research Authority and is best practice.

NHS-Galleri will has been using this process for approximately 2 years, for invitation letters on the trial to help with trial retention. The trial team are looking to send one more mass ‘Thank You’ communication out to all trial participants in early October 2024. GRAIL Bio UK Ltd hopes that by communicating with participants via this mailout, it will keep the participants informed about the status of the trial, and provides an opportunity to remind participants that information about how their data is handled is available on the trial website.

This service will also prevent the team sending this mailing to participants that have died.

TBC