NHS Digital Data Release Register - reformatted

Grail Bio Uk Ltd projects

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


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

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

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

Purposes: (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.