NHS Digital Data Release Register - reformatted

Grail Bio Uk Ltd projects

• NHS Galleri Clinical Trial Communications via NHS DigiTrials request
• GRAIL-009: A randomized, comparator-controlled trial to assess the clinical utility of a multi-cancer early detection (MCED) test for population screening in the United Kingdom (UK) when added to standard of care
• GRAIL's NHS Galleri Clinical Trial Outcomes Data Request
• SYMPLIFY Study Clinical Trial Outcomes Data Request

208 data files in total were disseminated unsafely (information about files used safely is missing for TRE/"system access" projects).

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NHS Galleri Clinical Trial Communications via NHS DigiTrials request — DARS-NIC-651660-J5T6C

Type of data: information not disclosed for TRE projects

Opt outs honoured: Identifiable (Consent (Reasonable Expectation))

Legal basis: Health and Social Care Act 2012 – s261(2)(c)

Purposes: Yes (Commercial)

Sensitive: Non-Sensitive

When:DSA runs 2022-08-12 — 2024-08-11

Access method: One-Off

Data-controller type: GRAIL BIO UK LTD, KING'S COLLEGE LONDON

Sublicensing allowed: No

Datasets:

1. Demographics

Objectives:

GRAIL Bio UK Ltd and King’s College London (KCL), 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 King's College London. For the sake of consistency, and as King's College London is listed as a data controller, when referring to King's College London 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 Digital's 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) Compare cancer-specific mortality in the intervention and control arms following the third screening and an average 16-18 months of follow-up, for a pre-specified group of cancer types: lung, head & neck, colorectal, pancreas, myeloma/plasma cell neoplasm, liver/bile duct, stomach, oesophagus, anus, lymphoma, ovary, and bladder.

12) 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.

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

14) 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.

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

16) 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, LLC. 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 Digital 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 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 an invitation letter to these participants. This agreement is therefore being put in place with NHS Digital 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 Digital 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:
King's College London will provide NHS Digital with participant information (Study ID, NHS Number, Date of Birth, Family Name, Given Name and Postcode) via Secure Electronic File Transfer (SEFT)
NHS Digital will perform a vital status check and identify any participants known to have sadly died. NHS Digital will then retrieve the address for the remaining participants and return this to King's College London. 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.
• King’s College London are a joint Data Controller who also process the data and are responsible for implementing the trial and for primary objective analysis.
• NHS Digital 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 KCL 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.
• AIMES Management Services Limited supply IT infrastructure for King's College London'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 Digital therefore do not consider them to be a Data Controller. Cancer Research UK appear on trial-related documentation by virtue of the fact that King’s College London 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 Digital 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 Digital 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 Digital 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.

King’s College London, 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.

Expected Benefits:

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 use this process for approximately 2 years. GRAIL Bio UK Ltd hopes that by communicating with participants via this mailout, it will help the retention of participants in the trial and to attend their follow-up appointments.

The communications will also provide an opportunity to avoid sending mailing to participants that have died.

The letters will also provide an opportunity to remind participants that information about how their data are handled is available on the trial website.

Outputs:

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 Digital to King's College London 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. 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.

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GRAIL-009: A randomized, comparator-controlled trial to assess the clinical utility of a multi-cancer early detection (MCED) test for population screening in the United Kingdom (UK) when added to standard of care — DARS-NIC-456778-J0G3H

Type of data: information not disclosed for TRE projects

Opt outs honoured: Identifiable (Section 251 NHS Act 2006)

Legal basis: Health and Social Care Act 2012 – s261(7)

Purposes: Yes (Commercial)

Sensitive: Non-Sensitive

When:DSA runs 2021-07-30 — 2022-07-29

Access method: One-Off

Data-controller type: GRAIL BIO UK LTD, KING'S COLLEGE LONDON

Sublicensing allowed: No

Datasets:

1. Demographics

Objectives:

Grail Bio UK Ltd and King’s College London (KCL), as joint data controllers, are requesting to use NHS Digital data to support a clinical trial called ‘NHS-Galleri’. This agreement is specifically to support the recruitment of a cohort for this trial by writing out to individuals who meet the required eligibility criteria, and whose details have been provided under Section 251 support, and inviting them to take part in the trial.

NHS-Galleri is funded by GRAIL Bio UK Ltd and has received a favourable ethical opinion on 8th June 2021.

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

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) Compare cancer-specific mortality in the intervention and control arms following the third screening and an average 16-18 months of follow-up, for a pre-specified group of cancer types: lung, head & neck, colorectal, pancreas, myeloma/plasma cell neoplasm, liver/bile duct, stomach, oesophagus, anus, lymphoma, ovary, and bladder.
12) 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.
13) Compare the absolute numbers of stage IV cancers following the second blood draw and 12 months of follow-up, with prevalent cases excluded.
14) 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.
15) Assess the impact of use of the MCED test across three annual timepoints on healthcare resource utilization for cancer diagnosis and treatment.
16) 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).

The trial will be conducted throughout England and patients will be recruited from eight Cancer Alliances regions. The aim is to recruit around 140,000 patients, with approximately 70,000 per arm.

Inclusion / Exclusion Criteria:

• Participant Inclusion Criteria:
Participants are eligible to be included in the study only if all of the following criteria apply:
• Participants must be at 50-77 years of age, inclusive, at the time of data extraction from NHS datasets used to identify potential participants; and
• Capable of giving signed and legally effective informed consent, which includes compliance with the requirements and restrictions listed in the Informed Consent Form (ICF) and in this protocol. Consent provided by a legally authorized representative is not permitted in this protocol.

• Participant Exclusion Criteria:
Individuals are excluded from the study if any of the following criteria apply:
• Previous or current participation in another GRAIL-sponsored study
• Personal history of invasive cancer or haematologic malignancy, diagnosed within the three years prior to expected enrolment date
o Note: Individuals with a diagnosis of non-melanoma skin cancer and prostate cancer patients whose only treatment is active surveillance are NOT excluded
• Definitive treatment for invasive cancer or haematologic malignancy within the 3 years prior to expected enrolment date, including adjuvant hormone therapy for cancer (e.g. for breast or prostate cancer)
• Currently taking demethylating or cytotoxic agents for any condition
• Undergoing current investigation for suspected cancer, defined as having been referred to a two week wait clinic or undergoing investigations at an RDC or other clinic with a stated suspicion of cancer.
• Currently on a palliative care pathway

Recruitment is expected to begin in August 2021 and take place over 10 – 12 months. Given the recruitment target of 140,000 people, it is estimated that between one and three million people may need to be written out to.

Different areas will be targeted for recruitment, beginning with Northwest England. Recruitment in a particular area will last for 4 – 6 weeks, before moving on to another area. Recruitment will be managed through mobile units on scheduled routes around a particular area. Batches of invitations will be constructed to target whatever area the mobile units will be in at the time of writing out to potential participants. Potential participants will only be contacted once and there will be no follow-ups sent after the original invitation letter.

Requesting Not to Take Part in Trial:
In addition to the National Data Opt-out, members of the public will be able to specifically request not to be contacted for the NHS-Galleri Trial. GRAIL Bio UK Ltd will promote this information via the dedicated trial website (nhs-galleri.org) and NHS Digital will do the same via a dedicated page on its website (https://digital.nhs.uk/services/nhs-digitrials/nhs-galleri-trial). There will also be an option for people to register their request not to take part in NHS-Galleri by telephone. NHS Digital will record these requests not to take part and ensure that anyone who has registered for this will be excluded from the cohort selection and as a result their details will not be on the list passed to APS Group for invitations to be sent.

GDPR:
For GRAIL Bio UK Ltd:
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 are in the process of completing a legitimate interests assessment (LIA) and 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 Digital or after a defined period on completion of the project.

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.

For King’s College London:

Article 6:1(e): Specific task in the ‘public interest’ or task that has a clear basis in law.

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.

Organisations’ roles and responsibilities:

• GRAIL Bio UK Ltd are the lead organisation and joint data controller. They are responsible for sponsoring and funding the trial and overseeing the work carried out to aid recruitment into the trial. They are also provide the core eligibility criteria for participants.

• King’s College London are joint data controller and are responsible for:
1. generating invitation requests and sending these to NHS Digital on a regular basis
2. monitoring uptake by invitees (i.e. numbers of invitees booking appointments)
3. making decisions to send subsequent waves of invitations in a given area
4. monitoring characteristics of the population booking appointments and entering the study
5. adjusting the selection criteria for subsequent invitations to adjust for underrepresentation of target populations taking up the trial.

• NHS Digital are acting as a data processor on behalf of GRAIL Bio UK Ltd and KCL and are responsible for:
1. Applying the criteria from each invitation request to the datasets to generate a list of invitees
2. Feeding back to KCL the number of invitees actually fulfilled out of the total target population
3. Removing objections or opt outs
4. Sending the list of invitees on to their third-party provider (APS Group) for generating the invitation letters and mailing these out
5. Agreeing with KCL key processing timelines, including
a. Time from invitation submission to submission of list of invitees to APS Group
b. Time from submission to APS Group to mailout
c. Daily cut-off times (i.e. after which processing will take place the next day)
d. Time to feedback to KCL the numbers selected
6. Overseeing performance of APS Group and alerting performance issue to Sponsor (GRAIL Bio UK Ltd)
7. Feeding back to KCL performance in relation to KPIs of APS and NHS Digital
8. Where the number of invitees is less than the population available, invoking a system to choose invitees at random
9. Maintaining a record of people invited and ensuring they are excluded from subsequent rounds of invitations.

• APS are acting as a sub-processor of NHS Digital. Their responsibility is to receive the lists of invitees from NHS Digital and mail out to them accordingly.

No other organisations are involved in this trial. 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. Cancer Research UK appear on trial-related documentation by virtue of the fact that King’s College London Cancer Prevention Trials Unit are a Cancer Research UK Centre. 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.

The trial has co-principal investigators (PI’s), one of whom is based at the University of Leeds and the other is based at University College London. For their work on this trial, both PI’s have contracts in place with GRAIL Bio UK Ltd. Neither of these PI’s will come into contact with the data that is provided to APS by NHS Digital. Additionally, both University of Leeds and UCL as organisations have no involvement whatsoever with this trial and therefore are not classed as Data Controllers or Data Processors.

While GRAIL Bio UK Ltd and KCL are joint data controllers for this trial, neither will have access to the patient-level identifiable data provided by NHS Digital to APS Group. KCL are providing a service to GRAIL Bio UK Ltd under a clinical research agreement and as such have no commercial rights or interests in this work.

GRAIL, Inc. are the manufacturers of the MCED test, Galleri™, and has set up a UK subsidiary, GRAIL Bio UK Ltd, which is the sponsor of the NHS-Galleri trial. 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 NHS 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 patients.

Expected Benefits:

Multi-cancer early detection (MCED) testing is a novel screening paradigm, and assessment of the use and impact of the test alongside current standards of care is necessary to establish clinical utility and enable integration into clinical practice. This will be the first randomised controlled trial in the UK statistically powered to assess the test performance and clinical utility, including harms and benefits, of a multi-cancer early detection test when used in population screening. In its Long-Term Plan, published in January 2019, NHS England set an ambition to achieve a significant shift in the proportion of cancers diagnosed at an early stage by 2028 - that 75% of people with cancer will be diagnosed at stage I or II. Patients diagnosed early, at stages I and II, have the best chance of curative treatment and long-term survival. This study will determine whether the MCED test can provide a meaningful contribution towards achieving that ambition, which would have substantial impacts on cancer treatment and the survival of these patients within the NHS.

The results of this study are expected by 2026 and a full health economic assessment will accompany the trial. Urgent measures need to be put in place to ramp up cancer screening programmes and innovative technologies such as MCED testing may provide a meaningful contribution towards earlier detection of cancers for the UK population. The magnitude of the impact of this invitation strategy will be measured by the success of participant recruitment into the NHS-Galleri trial. It is hoped that the success of participant recruitment and knowledge gathered during this trial will inform the future implementation of the test in the NHS for early cancer detection.

Outputs:

The expected output of the data processing is a report of individuals within the geographic areas of eight Cancer Alliances in England who potentially meet the eligibility criteria for the NHS-Galleri trial, sponsored and funded by GRAIL Bio UK Ltd., in partnership with NHS England and King’s College London.

The results of the NHS-Galleri trial outputs will be published in peer-reviewed publications, presented at conferences, and used by NHS England in their decisions around implementation of the test within the NHS. The interim analysis, which will include analysis of a key secondary objective, is expected by the end of 2023 or beginning of 2024. The primary objective readout is expected by the end of 2025 or beginning of 2026. Planned dissemination activities will aim to enable the engagement with the scientific and policy making communities to ensure that knowledge developed by this research can benefit these communities to help the NHS detect cancer early, when it is easier to treat.

Processing:

As joint data controller, GRAIL Bio UK Ltd provide the core eligibility criteria for those potential participants who will receive invitations. KCL, as joint data controller, refine the population that receive these invitations based on GP practice (as a proxy for location), making adjustments as required to ensure adequate representation of target populations.

NHS Digital would be using an established contract with a mailing provider (APS Group) to fulfil the communications. The APS Group are also used by NHS England and NHS Improvement as a marketing service group that is a recognised and trusted provider of NHS Services. They are used frequently to co-ordinate mail outs for NHS Bodies. APS Group have the REC-approved template invitation letters and would add address details onto the letters prior to mailing it out. All identifiable data provided to APS Group by NHS Digital will be done so under the legal basis of Section 251 support as provided by the Confidentiality Advisory Group (CAG) for this particular trial.

The detailed processing activities are as follows:

COHORT SPECIFICATION:
• KCL are accountable for providing the specification to NHS Digital for each mail out. These specifications will be based on a combination of multiple GP practice codes, age limits and gender balances for potential participants. The information they will provide to NHS Digital on each occasion is:
o An ID for each request.
o A selection of GP practice codes.
o Lower and upper age limits (within the maximum and minimum ages as per the inclusion criteria).
o Male / female percentage split, if required.
o A selection of postcodes, if required.
o The number of invitations required for each request.
• The geographical specifications are based on the locations of the mobile clinics where potential participants will be invited to take part in the trial.
• At a pre-determined point, KCL will transfer details of the specification to NHS Digital via SEFT. This will be on a flexible adhoc basis, determined by the number of responses received for each request.

COHORT IDENTIFICATION:
• Using the inclusion criteria as specified by GRAIL Bio UK Ltd, NHS Digital will interrogate the PDS dataset and extract all those potential participants who meet the inclusion criteria within the latest specification as provided by KCL.
• NHS Digital will then run that extract against the National Cancer Registration and Analysis (NCRAS) dataset and remove any records that meet the exclusion criteria as specified by GRAIL Bio UK Ltd.
• NHS Digital will then remove any records where an opt-out has been registered, either:
• An NHS-Galleri trial-specific right to object.
• A National Data Opt-out.
• The remaining records will have their relevant contact details (Forename, Surname, Address, Postcode, Date of Birth) extracted for despatch to APS Group, as well as NHS Number to be included within an encrypted StudyID (also known as an ‘Invitation Code’).

COHORT DISSEMINATION AND MAILOUT:
• Each time NHS Digital create and disseminate an extract, the records will be added to a mailing list cohort dataset. Every time a fresh extract is produced, it will be checked to ensure that any records appearing in this mailing list dataset are removed in order to prevent potential participants receiving multiple invitations. This mailing list dataset will be maintained for six months after the invitation process is complete in case required for analysis purposes by KCL. Only aggregated data would be used for such analysis.
• NHS Digital will provide APS Group with Forename, Surname, Address, Postcode, Month and Year of Birth, and StudyID / Invitation Code via SEFT.
• APS will then mail out to individuals as required. Note that month and year of birth is required to distinguish between people within a household who may have the same name.
• All potential participants will receive an invitation letter containing their Name, Address and Postcode, and Invitation Code. When the recipient goes to register for an appointment for screening (either online or by telephone) they will be asked to provide an Invitation Code. GRAIL Bio UK Ltd will be able to decrypt this Invitation Code to determine the NHS Number of the individual. Upon arriving for their screening, the individual will be asked to bring their independently sourced NHS Number with them and GRAIL Bio UK Ltd will compare to ensure they have matching NHS Numbers.
• APS will destroy all data in each batch received from NHS Digital one week after mailing out for that batch as instructed by NHS Digital.

COHORT ANALYSIS:
• After each request for invitation, NHS Digital will provide KCL with a summary report containing non-identifiable information relating to how that request was met, for example, number of invitations requested versus number of invitations actually sent. This will aid planning for subsequent invitation requests.

The permitted territory of use for data provided by NHS Digital for this agreement is England and Wales. However, as part of the trial, non-NHS Digital pseudonymised data will be sent to the USA for further analysis as per the trial protocol.

GRAIL Bio UK Ltd. is the Sponsor and funder of the NHS-Galleri trial, in partnership with NHS England and King’s College London. The data processing by the NHS Digital team that will result in the identification and invitation of a cohort of individuals potentially eligible for the trial, is a key component of the trial plan. Without this identification and invitation strategy, a trial of this size and speed with which the study is planned to be enrolled, would not be feasible.

The original requirements for this mailing out included additional clinical criteria based on GP data, such as being part of the gold standards framework, or undergoing palliative care. Due to the current unavailability of this dataset within NHS Digital, this will not be implemented at study launch and requirements will be updated at a later time when it is feasible to implement these criteria.

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GRAIL's NHS Galleri Clinical Trial Outcomes Data Request — DARS-NIC-604847-S4B5L

Type of data: information not disclosed for TRE projects

Opt outs honoured: Identifiable, No (Consent (Reasonable Expectation))

Legal basis: Health and Social Care Act 2012 – s261(2)(c)

Purposes: Yes (Commercial)

Sensitive: Non-Sensitive, and Sensitive

When:DSA runs 2022-02-09 — 2023-02-08 2023.02 — 2024.08.

Access method: Ongoing, One-Off

Data-controller type: GRAIL BIO UK LTD, KING'S COLLEGE LONDON

Sublicensing allowed: No

Datasets:

1. Cancer Registration Data
2. Cancer Waiting Times (CWT) Data Set
3. Diagnostic Imaging Dataset
4. Emergency Care Data Set (ECDS)
5. Hospital Episode Statistics Admitted Patient Care
6. Hospital Episode Statistics Outpatients
7. Radiotherapy Data Set
8. Rapid Cancer Registrations Data Set
9. Systemic Anti-Cancer Therapy Data Set
10. Diagnostic Imaging Data Set (DID)
11. Hospital Episode Statistics Admitted Patient Care (HES APC)
12. Hospital Episode Statistics Outpatients (HES OP)
13. NDRS Cancer Registrations
14. NDRS Linked Cancer Waiting Times (Treatments only)
15. NDRS Linked DIDs
16. NDRS Linked HES APC
17. NDRS Linked HES Outpatient
18. NDRS National Radiotherapy Dataset (RTDS)
19. NDRS Rapid Cancer Registrations
20. NDRS Systemic Anti-Cancer Therapy Dataset (SACT)

Objectives:

GRAIL Bio UK Ltd and King’s College London (KCL), as joint data controllers, are requesting access to pseudonymised record-level data in order to carry out follow-up analysis based on a cohort of patients who are being recruited to a clinical trial called ‘NHS-Galleri’ following being invited to participate if they are found to meet the required eligibility criteria.

Note that all members of the team running the trial are based at the Cancer Prevention Trials Unit (CPTU) at King's College London. For the sake of consistency, and as King's College London is listed as a data controller, when referring to King's College London 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™ and 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 is being aided by NHS Digital's Digi-Trials team via a sister application, DARS-NIC-456778-J0G3H, and is taking place over 10 – 12 months from August 2021 with a recruitment target of 140,000 people. Different areas are being targeted for recruitment, beginning with North-west England. Recruitment in a particular area will last for 4 – 6 weeks, before moving on to another area. Recruitment is being managed through mobile units on scheduled routes around a particular area. Batches of invitations are being constructed to target whatever area the mobile units will be in at the time of writing out to potential participants. Potential participants will only be contacted once and there will be no follow-ups sent after the original invitation letter.

Requesting Not to Take Part in Trial:
In addition to the National Data Opt-out, members of the public are able to specifically request not to be contacted for the NHS-Galleri Trial. GRAIL Bio UK Ltd have promoted this information via the dedicated trial website (nhs-galleri.org) and NHS Digital have done the same via a dedicated page on its website (https://digital.nhs.uk/services/nhs-digitrials/nhs-galleri-trial). There is also an option for people to register their request not to take part in NHS-Galleri by telephone. NHS Digital is recording these requests not to take part and ensuring that anyone who has registered for this will be excluded from the cohort selection and as a result their details will not be on the list for invitations to be sent.

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) Compare cancer-specific mortality in the intervention and control arms following the third screening and an average 16-18 months of follow-up, for a pre-specified group of cancer types: lung, head & neck, colorectal, pancreas, myeloma/plasma cell neoplasm, liver/bile duct, stomach, oesophagus, anus, lymphoma, ovary, and bladder.

12) 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.

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

14) 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.

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

16) 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).

DATA SETS REQUESTED:
> Rapid Registrations Cancer Data Set
> Cancer Registry
> Systemic Anti-Cancer Therapy Data Set (SACT)
> Radiotherapy Data set (RTDS)
> Hospital Episode Statistics (HES) Admitted Patient Care (APC)
> Emergency Care Data Set (ECDS) (released Summer 2022 onwards)
> HES Outpatients (OP)
> Cancer Waiting Times (Treatments and Referrals) (CWT)
> Diagnostic Imaging Dataset (DIDS) (released Summer 2022 onwards)

Patient and Public Involvement and Engagement (PPI&E)
Ongoing PPI&E is conducted throughout the trial. Historical PPI&E was conducted to develop the participant facing materials and on questionnaires, and including specific questions to PPI groups around the sharing of pseudonymised data with GRAIL LLC (US). Ongoing PPI&E includes, for example, PPI&E on new participant facing materials, survey feedback on the participant experience, and questionnaires for follow-up of participants. An embedded behavioural scientist in the Kings College London Cancer
Prevention Trials Unit has been involved in, and will continue to be involved in, analysis of participant communications, and ethical and wellbeing issues within the course of the trail, as well as periodically advise the study organizers and other stakeholder on emerging themes.

In the setting up of the trial, GRAIL has taken seriously, strategies for equity of access and has several plans underway to ensure that under-represented minorities are actively recruited into the trial. Amongst this is the invitation strategy, that will identify and actively send invitations to a greater proportion of individuals from these minorities to take part in the trial. It is hoped that this will positively contribute towards equity of access and inform the provision of cancer services in these areas in the future.

JUSTIFICATION FOR DATA SETS REQUESTED AND DATA MINIMISATION
> Cancer Registry and Rapid Registrations - These central NHS datasets will be the sole source for the data required for primary and secondary objectives analyses in the Study. Will be used to identify Primary endpoints, which are incidence and stage at diagnosis for cancer types that are stage-able (e.g., with available staging systems). Cancer is defined as any of the following cancers:
- Invasive solid cancer, excluding non-melanoma skin cancer
- Haematologic malignancies, including lymphoma, lymphoid leukemia, myeloma/plasma cell neoplasm, myeloid neoplasms (including myelodysplastic and myeloproliferative neoplasms with behaviour code 3 based on ICD-O-3.2*).
[*The International Classification of Diseases for Oncology, Third Edition (ICD-O-3) is the standard classification system for the registration of cancers in the United States (and most areas of the world) and contains widely-accepted histologic categories of brain tumors.]
The Cancer Registry will also be used to identify cohort characteristics/baseline risk - Personal history of cancer assessed using limited set of data fields. Historical cancer data dating back to 1995 will be available.

> Hospital Episode Statistics (HES) Outpatients (OP), Admitted Patient Care (APC) and Emergency Care Data Set (ECDS), Cancer Waiting Times (Treatments and Referrals) (CWT) and Diagnostic Imaging Dataset (DIDS) - Will be used to identify Secondary endpoints (including safety objectives). Among all test positive cases, number of follow-up procedures and number of invasive procedures (including all biopsies, surgical interventions, bronchoscopy, thoracoscopy and endoscopy) to achieve diagnostic resolution (i.e. cancer diagnosis, non-cancer diagnosis, or no diagnosis and discharge from the diagnostic follow-up). Will also identify:
- Number and type of invasive procedures performed in false positive cases;
- Number of complications and deaths resulting from diagnostic procedures;
- Radiation exposure measured in mSv per participant due to test result-directed evaluations

> Systemic Anti-Cancer Therapy Data Set (SACT) and Radiotherapy Data set (RTDS) will also be used (in addition to the above HES, CWT and DIDs data) for health care resource utilization objectives.

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 Digital 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 Digital 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.

King’s College London, 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.

Organisation Roles and Responsibilities:

• 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.
• King’s College London are a joint Data Controller who also process the data and are responsible for implementing the trial and for primary objective analysis.
• GRAIL, Limited Liability Company (LLC). are the manufacturers of the MCED test, Galleri™, and has set up the above UK subsidiary, GRAIL Bio UK Ltd, which is the sponsor of the NHS-Galleri trial. GRAIL, LLC will be receiving pseudonymised record-level NHS Digital data from King’s College London, and are therefore listed as a Data Processor in this agreement.

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 Digital therefore do not consider them to be a Data Controller. Cancer Research UK appear on trial-related documentation by virtue of the fact that King’s College London 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 Digital therefore do not consider them to be a Data Controller.

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.

Yielded Benefits:

-

Expected Benefits:

The use of the datasets referenced herein will be used for the primary and secondary objective analyses of the NHS-Galleri trial. If the trial is successful, it is anticipated that there will be future health benefits to individuals within the NHS

Multi-cancer early detection (MCED) testing is a novel screening paradigm, and assessment of the use and impact of the test alongside current standards of care is necessary to establish clinical utility and enable integration into clinical practice. This will be the first randomised controlled trial in the UK statistically powered to assess the test performance and clinical utility, including harms and benefits, of a multi-cancer early detection test when used in population screening. Due to the scale of this study (expecting approximately 140,000 participants in total to enrol), and the speed with which participants will be enrolled and the results analysed, local data collection for primary and secondary objective analyses is not practical and may overburden already strained NHS hospitals. As such, the study analyses depend entirely on central NHS datasets.

In its Long-Term Plan[a], published in January 2019, NHS England set an ambition to achieve a significant shift in the proportion of cancers diagnosed at an early stage by 2028 - that 75% of people with cancer will be diagnosed at stage I or II. Patients diagnosed early, at stages I and II, have the best chance of curative treatment and long-term survival. This study aims to determine whether the MCED test can provide a meaningful contribution towards achieving that ambition, which would have substantial impacts on cancer treatment and the survival of these patients within the NHS. If the study is successful, it is hoped that the NHS will adopt the test for individuals meeting the test’s intended use (currently, adults with an elevated risk of cancer, such as those aged 50 and older), which could impact the lives of millions of individuals within the NHS.
[a] https://www.longtermplan.nhs.uk/publication/nhs-long-term-plan/

The results of this study are expected by 2026 and a full health economic assessment will accompany the trial. Urgent measures need to be put in place to ramp up cancer screening programmes and innovative technologies such as MCED testing may provide a meaningful contribution towards earlier detection of cancers for the UK population. The magnitude of the impact of this invitation strategy will be measured by the success of participant recruitment into the NHS-Galleri trial. It is expected that the success of participant recruitment and knowledge gathered during this trial will inform the future implementation of the test in the NHS for early cancer detection.

Outputs:

All outputs will be aggregated with small number suppressed as per the HES analysis guide or according to the specific data set's suppression guidance.

The results of the NHS-Galleri trial outputs will be published in peer-reviewed publications, presented at conferences, and used by NHS England in their decisions around implementation of the test within the NHS. The interim analysis, which will include analysis of a key secondary objective, is expected by the end of 2023 or beginning of 2024. The primary objective readout is expected by the end of 2025 or beginning of 2026. Planned dissemination activities will aim to enable the engagement with the scientific and policy making communities to ensure that knowledge developed by this research can benefit these communities to help the NHS detect cancer early, when it is easier to treat.

Processing:

Patient Identifiable Data (PID) referred to in section 5a (above) will be stored in the Clinical Records Management System (“CRMS”) hosted on Amazon Web Service (AWS UK). NHS Digital record-level pseudonymised data referred to in section 5a (above) will be stored in a secure S3 folder (S3 is a type of file storage system in a cloud platform) hosted on Amazon Web Service (AWS UK).

METHODOLOGY
1. The PID referenced in the cohort will be securely transferred from the CRMS as an encrypted dataset (AES 256) to AIMES Management Services Limited's sFTP server. From there, King's College London downloads the cohort into AIMES Trusted Research Environment (TRE) and transfers to NHS Digital via the sFTP portal over Health and Social Care Network (HSCN). Data is stored on the AIMES Trusted Research Environment (for a maximum of 1 week for confirmation of successful receipt by NDRS before being deleted).

2. Kings College London will provide a cohort of approximately 140,000 records (in total), including a pseudo-Study ID, plus the identifiers: NHS Number, Date of Birth, Sex and Post Code along with first recruitment date and withdrawal data (if applicable) to NHS Digital via a Secure Electronic File Transfer Service (SEFT) or other secure, NHS Digital approved file transfer mechanism.

3. An encryption key is sent from the King’s College London team to the CRMS system for encrypting the dataset, allowing for the participants identified in that dataset to be flagged for following by NDRS. Only the King's College London team controls the ability to decrypt the dataset.

4. The NDRS team will use the identifiers to extract record-level pseudonymised data and return the requested data extracts to King's College London via SEFT or other secure, NHS Digital approved file transfer mechanism. All data from NHS Digital will contain only the pseudo-study ID for linkage. All other personal identifiable data will be removed prior to the transfer.

5. The King's College London team will download the resultant record-level pseudonymised data sets into the AIMES Trusted Research Environment and upload to Amazon Web Services S3 (UK Cloud platform) for analysis.

***FREQUENCY - every 6 months beginning March 2022 (Rapid Registrations every 2 months from January 2022). ***
N.B. Diagnostic Imaging Dataset (DIDS) and Emergency Care Data Set (ECDS) will be released from released Summer 2022 onwards.

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. The record-level pseudonymised data extracts referred to in section 5a (above) will be stored in secure S3 folders which are hosted on Amazon Web Service (AWS UK). The PID will be stored separately in the CRMS. Only authorised study team members of GRAIL Bio UK Ltd and King's College London have access to NHS Digital record-level pseudonymised data stored in the secure S3 folders hosted by AWS in the United Kingdom. Enrolled participants consent to the transfer and storage of their health data to GRAIL Bio UK Ltd and King's College London for the purposes of processing the pseudonymised data extracts for this application.

AIMES Management Services Limited supply IT infrastructure for King's College London'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 King’s College London. Enrolled participants consent to the transfer and storage of their identifiable data to King's College London for the purposes of sending identifiers to NHS Digital's NDRS team for data extraction via the sFTP portal over Health and Social Care Network (HSCN). Data is stored on the Trusted Research Environment (for agreed time-limited duration) both PID and pseudonymised and NDRS extract.

Amazon Web Services, Inc (USA) supply IT infrastructure for GRAIL, LLC 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. Enrolled participants also consent, as expressly stated in the consent form and participant information sheet, to the transfer of their pseudonymised health data to GRAIL, LLC in the US for purposes permitted by the study participant consent form. The pseudonymised data will be transferred by GRAIL Bio UK Ltd from the secure S3 folder hosted on Amazon Web Service (AWS UK) to a secure S3 folder hosted on Amazon Web Services, Inc. (USA). The transfer will be undertaken using a secure, encrypted network connection.

The NHS Digital pseudonymised record-level data from the datasets referenced herein will be accessible only to those substantive employees with appropriate and authorized access at (i) King’s College London, (ii) GRAIL Bio UK Ltd, and (iii) GRAIL, LLC, plus one King’s College London study member - who is not substantively employed by King’s College London (see special condition). Record level pseudonymized data will be stored in the secure AWS S3 folders (for GRAIL Bio UK Ltd and GRAIL, LLC) and AIMES TRE (for King’s College London). King’s College London are non-commercial collaborators and in order to provide academic independent analysis for scientific rigor of the study, it is necessary for King’s College London to have an independent copy of the dataset in AIMES TRE. Access to cloud systems where the statistical analysis is performed only from organisation owned/managed devices (whether King’s College London or GRAIL to AIMES or AWS respectively). Statistical data analysis will be carried out on organisation-owned and managed devices, either directly in person or remotely, using an appropriate statistical package. 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 analysis will be conducted within the confines of the organisation's cloud platform, and will not be downloaded to remote devices for storage or processing.

An Independent Data Monitoring Committee (IDMC) will be utilized to assess the progress of the clinical study, the safety data, and key endpoints to provide recommendations to the study Sponsor on whether to continue, modify, or stop the study. The IDMC is intended to provide additional assurance of participant safety and study integrity. Members of the IDMC include a clinician(s) with expertise in relevant clinical specialties, and at least one biostatistician knowledgeable about statistical methods for clinical studies and sequential analysis of study data.

NHS Digital record-level data may not be shared with other organisations or countries outside of those stated in this agreement (i.e. USA and UK). PID will be stored for 10 years following completion of the study and record-level pseudonymised data will be stored for 10 years following completion of the study. All other research data will be stored for a period of 10 years following completion of the study in accordance with regulatory requirements (e.g. UK Policy Framework for Health and Social Care Research), data sharing agreements with NHS bodies, and in line with participant consent. Record-level NHS Digital data may be linked with other datasets held by the Data Processors or Data Controllers on the understanding that the risk of re-identification is minimised and the linkage is undertaken expressly for the purpose of medical research. GRAIL, LLC is not permitted to attempt to re-identify individuals.

HES and ECDS DISCLOSURE CONTROL / SMALL NUMBER SUPPRESSION
In order to protect patient confidentiality, when presenting results calculated from HES record level data, outputs will contain only aggregate level data with small numbers suppressed in line with HES Analysis Guide. When publishing HES data, data processors must make sure that:
· National-level figures only may be presented unrounded, without small number suppression
· cell values from 1 to 7 (inclusive) are suppressed at a sub-national level to prevent possible identification of individuals from small counts within the table.
· Zeros (0) do not need to be suppressed.
· All other counts will be rounded to the nearest 5.
Data will not be made available to any third parties other than those specified except in the form of aggregated outputs with small numbers suppressed in line with the HES Analysis Guide.

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SYMPLIFY Study Clinical Trial Outcomes Data Request — DARS-NIC-604851-W0M3S

Type of data: information not disclosed for TRE projects

Opt outs honoured: Anonymised - ICO Code Compliant, No (Consent (Reasonable Expectation))

Legal basis: Health and Social Care Act 2012 - s261 - 'Other dissemination of information', Health and Social Care Act 2012 – s261(2)(a), Health and Social Care Act 2012 – s261(2)(c)

Purposes: Yes (Commercial)

Sensitive: Non-Sensitive, and Sensitive

When:DSA runs 2022-03-18 — 2023-03-17 2023.01 — 2023.09.

Access method: Ongoing

Data-controller type: GRAIL BIO UK LTD, UNIVERSITY OF OXFORD

Sublicensing allowed: No

Datasets:

1. Cancer Registration Data
2. Cancer Waiting Times (CWT) Data Set
3. Diagnostic Imaging Dataset
4. Emergency Care Data Set (ECDS)
5. Hospital Episode Statistics Admitted Patient Care
6. Hospital Episode Statistics Outpatients
7. Rapid Cancer Registrations Data Set
8. Diagnostic Imaging Data Set (DID)
9. Hospital Episode Statistics Admitted Patient Care (HES APC)
10. Hospital Episode Statistics Outpatients (HES OP)
11. NDRS Cancer Registrations
12. NDRS Linked Cancer Waiting Times (Treatments only)
13. NDRS Linked DIDs
14. NDRS Linked HES APC
15. NDRS Linked HES Outpatient
16. NDRS Rapid Cancer Registrations

Expected Benefits:

Urgent measures need to be put in place to diagnose cancer at earlier stages in the UK and innovative technologies such as MCED testing may provide a meaningful contribution towards earlier detection of cancers for the UK population. The process of diagnosing cancer can often be lengthy and involve expensive imaging or invasive biopsies specific to only one cancer. Often this happens after a patient presents with symptoms and a cancer is more progressed. If the study finds that it is possible to intervene at an earlier stage and detect a cancer using minimally invasive MCED tests, such as GRAIL’s Galleri®™, (which may require subsequent confirmatory testing) GRAIL have the potential to accelerate cancer diagnoses and reduce the number of diagnostic procedures. SYMPLIFY aims to inform best practices for the implementation of multi-cancer detection testing in symptomatic patients referred for cancer investigation.

Galleri®™ could complement the existing 2-Week-Wait (2WW) and RDC pathways by offering a novel approach to patient selection for urgent cancer investigation for people presenting to their GP with symptoms of cancer. This includes patients who might be later diagnosed with cancers with high 5-year mortality that do not currently have a screening programme and some for which workup based on symptoms is not yet standardised.

Initial interim results of the SYMPLIFY study are expected in 2022 and if deemed successful, hopes to lead to the planning and design of another larger trial to evaluate how best to implement the test in NHS primary care to guide decisions about who needs rapid referral to look for a possible cancer and what tests to use following a positive MCED result. At the end of the study, having tested the blood with the MCED test, the team hope to understand more about how well Galleri works in symptomatic people. The full results of this study are expected by the end of 2023.

Outputs:

An early interim analysis will be based on data captured within 3 months after enrolment and a late/complete analysis based on data at 12 months after enrolment to account for delayed diagnoses (including the 9-month and 12-month follow-up data). The output from the interim analysis will include a study report summarizing the results of the primary, secondary and first exploratory objective as noted in the Processing Activities section above.

The key exploratory objective for the study is the analysis of the completeness and quality of cancer diagnostic pathway data gathered from central NHS databases as compared to locally collected data. Datapoints collected locally within 3 months and by 9 months of enrolment will be compared to data collected centrally monthly from 3 through 12 months post enrolment. The completeness, by capture method, and concordance between methods of each data field will be summarized descriptively in the clinical study reports at both interim and end of study timepoint. This will inform the potential to use central data capture for future large-scale studies in the field, as well as identify areas for improvement in central data linkage.

The outputs of data processing at the end of the study aim to include conference abstracts, reports to NHS England and GRAIL, and submissions of SYMPLIFY findings to peer reviewed journal(s). The publications will not contain the data, only the results of its statistical analysis that will be summarized overall, by cancer site, referral pathway. Health economic analyses aims to examine the number of encounters to diagnosis; number and types of tests for diagnosis; comparisons of resource utilisation observed to modelled resource utilisation based on cancer signal detected and CSO.

All outputs will be aggregated with small number suppressed as per the HES analysis guide or according to the specific data set's suppression guidance.

GRAIL may take the results of the SYMPLIFY study to further refine the algorithm of their MCED test that could add commercial value to their product(s). Results of SYMPLIFY may also inform decisions to fund future cancer research in the NHS and/or future decisions to procure a GRAIL test for use in the NHS.

TARGET DATES
The interim analysis is due to be completed by the end of Quarter 2 in 2022. The final 12-month analysis is expected to be complete by the end of 2023.

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