Penicillin allergy status and its effect on antibiotic prescribing, patient outcomes, and antimicrobial resistance.

The University of Leeds requires access to NHS England data for the purpose of the following research project: ALlergy AntiBiotics And Microbial resistance - ALABAMA Study to look at individual patients enrolled in a randomised controlled trial, with a nested-pilot study, of penicillin allergy de-labelling in primary care, the Penicillin allergy status and its effect on antibiotic prescribing, patient outcomes, and antimicrobial resistance (ALABAMA) study.

The following is a summary of the aims of the research project provided by the University of Leeds:

''The primary objective is to determine whether the Penicillin allergy assessment pathway (PAAP) intervention is clinically effective in increasing the proportion of patients prescribed penicillin to treat conditions where a penicillin is the first-line recommended antibiotic.

Half of penicillin allergic patients who have been enrolled in ALABAMA, were randomised to PAAP and the other half were randomised to usual clinical care. Patient outcomes in the PAAP group will be compared with the outcomes of the patients randomised to usual care (up to 12 months after enrolment).

The secondary objectives are to determine whether the PAAP intervention is clinically effective in improving patient health outcomes compared to usual care. Patient outcomes will include total antibiotic prescribing, hospital admissions and length of hospital stays, mortality rates and healthcare costs.

The aim of the ALABAMA study is to find out if people with a penicillin-allergy record in their GP health records have a true allergy by carrying out specialist testing. This will allow ALABAMA to reduce the number of patients wrongly labelled as penicillin allergic and investigate if such testing leads to better use of antibiotics and improved patient outcomes. NHS England Data will be used in the study to address the secondary objectives relating to length and of number of hospitals stays, mortality and cost effectiveness.

The nested pilot trial was used to assess the safety, acceptability, and practicality of delivering the (PAAP)”.

DATA REQUESTED

The following NHS England Data will be accessed:

Hospital Episode Statistics (HES)

- Admitted Patient Care (APC), Critical Care (CC), Outpatients (OP) and Emergency Care Data Set (ECDS) are necessary to derive estimates of costs associated with hospital care and of hospitalisations and number and duration of hospital admissions, and inform the cost-effectiveness evaluation. HES APC will also be used to identify participants who require a secondary care notes review to enable the trial team to identify any prescription of antibiotic medication participants may have received in hospital.

- Civil Registration Deaths is necessary to derive the rate of death and number of years participants are alive from the start of the study to the date of death or end of study follow-up date, whichever occurs first. The number of years participants are alive will be used in the cost effectiveness analysis. The Data provided by NHS England will be verified against any data received from the other sources. In the event of a discrepancy, the Data provided by NHS England will be included in the analysis

- Medicines Dispensed in Primary Care (NHSBSA) – necessary to give a more complete measure of the antibiotic prescribing and be used to inform the effectiveness of the PAAP. These Data will be used to conduct additional cost-effectiveness analysis using dispensed, as opposed to prescribed, antibiotic medications, as dispensed medications may be more relevant measure of NHS resource use. This Data will also provide intelligence about the safety and effectiveness of a penicillin de-labelling process to improve antimicrobial stewardship.

The level of the Data will be identifiable and is necessary to able linkage of data collected from other sources, including the participant themselves and participating sites.

DATA MINIMISATION

The Data will be minimised as follows:

- Limited to a study cohort identified by the University of Leeds for a cohort of participants who are consented to take part in the ALABAMA study.

- Limited to Data from date of randomisation for each individual participant.

- Medicines Dispensed in Primary Care will be limited to antibiotics.

DATA CONTROLLERSHIP

The University of Leeds is the research sponsor and the controller as the organisation responsible for ensuring that the data will only be processed for the purpose described above.

GDPR LEGAL BASIS

The lawful basis for processing personal data under the UK GDPR is:

Article 6 (1)(e): Processing is necessary for the performance of a task carried out in the public interest or in the exercise of official authority vested in the controller.

The lawful basis for processing special category data under the UK GDPR is:

Article 9 (2)(j): Processing is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes in accordance with Article 89(1) based on Union or Member State law which shall be proportionate to the aim pursued, respect the essence of the right to data protection and provide for suitable and specific measures to safeguard the fundamental rights and the interests of the data subject.

This processing is in the public interest because it adheres to the UK Policy Framework for Health and Social Care Research and aims to produce generalisable and publicly available information to inform future decisions over patients’ treatments or care. It also aims to improve public health by providing evidence to help NHS decision-makers identify effective and cost-effective pathways for allergy assessment.

FUNDING

The funding is provided by the National Institute for Health and Care Research (NIHR). The funding is specifically for the ALABAMA study described. Funding is in place until the study end date of 30th April 2024. The funder will have no ability to suppress or otherwise limit the publication of findings.

ORGANISATIONS ACTING AS PROCESSORS

The University of Oxford, Leeds Teaching Hospital NHS Trust will be Data Processors acting under the instructions of the University of Leeds.

The University of Leeds stores Data on the Cloud hosted by Microsoft.

Data will only be accessed by substantive employers of Data Controller or Data Processor, who are authorised by the lead investigator.

ORGANISATIONS INVOLVED IN AN ADVISORY CAPACITY

The independent Trial Steering Committee (TSC) and independent Data Monitoring and Ethics Committee (DMEC) are involved in an advisory capacity. The TSC provides advice, through its chair, to the chief investigator, the trial sponsor, the trial funder, on all appropriate aspects of the trial. The DMEC provides advice to the TSC.

General Practitioners (GPs), Practice Managers and Research Nurses are involved in an advisory capacity through membership of the "GP Practice Study Advisory Group" to provide advice on the implementation of the study.

TPP (The Phoenix Partnership) had an advisory role in knowledge transfer of implementing SystmOne functionality into study processes. This included the development of the ‘ALABAMA Unit’, similar to a GP practice unit within SystmOne. GPs participating in the study complete an electronic referral within SystmOne to the study team ALABAMA Unit for each consented participant. Consented participants primary care electronic health records’ can then only be accessed by authorised members of the study team within the secure NHS Health and Social Care Network (HSCN) computer network.

PATIENT AND PUBLIC INVOLVEMENT

A Public and Patient Involvement and Engagement (PPIE) group was convened to help refine the purpose of the research. The group supported the collection of the data for the purposes described above. This included working with four PPIE contributors from early design and will continue through to dissemination, implementation, and NHS adoption.

The PPIE involvement has provided a unique perspective on penicillin allergy and has helped to define the research question to ensure it is relevant to the patient population. Specific examples of their ongoing involvement include providing a PPIE perspective on draft publications, topic guides for interviews to develop educational material and other trial materials submitted for ethics approval. They also have ensured that the inclusion criteria is broad and included patient groups that are high antimicrobial users.

COMMERCIAL INVOLVEMENT

The Phoenix Partnership (TPP) is a not-for-profit industrial collaborator in the project and there is a contract in place with the University of Leeds. TPP provide an advisory role to the study team and support the implementation of the reports used to identify participants for the ALABAMA study and have set up the "ALABAMA Unit" in SystmOne to support delivery of the study. There is a potential commercial benefit to TPP which operates SystmOne, an electronic medical record system whose functionality is used in the study. This potential benefit could stem from positive publicity linked to their involvement in the study. It could inform NICE guideline development and potentially influence the choice of clinical computer system chosen by primary care providers. TPP have agreed to knowledge transfer with their competitors (free of charge) regarding how SystmOne functionality has been used.

TPP will be involved in publications and outputs relating to aspects of the research methodology pertaining to the study team’s use of SystmOne.

Leeds Teaching Hospital NHS Trust will transfer data to NHS England. The data will consist of identifying details specifically NHS number, Date of Birth, Name, and a unique study ID for each participant in the cohort to be linked with NHS England Data. A randomisation date will also be provided for each participant when they enrolled onto study.

NHS England will provide the relevant records Data from the HES APC, OP, CC, ECDS, Medicines Dispensed in Primary Care and Civil Registration Deaths to the University of Leeds. The Data will be sent securely and contain no direct identifying data items but will contain a unique study ID which can be used to link the Data with other record level data already held by the recipient and University of Oxford and LTHT. The University of Leeds stores Data on the Cloud provided by Microsoft.

The University of Leeds will extract a sub-set of the Data containing unique study ID, date of death, date of hospital admissions, length of time in hospital, and will securely transfer this to the University of Oxford. The Data will be stored at on secure servers at the Nuffield Department of Primary Care Health Sciences, University of Oxford.

The University of Leeds will extract a sub-set of the Data including unique study ID and date of hospital admissions and will share this will securely transfer to the with LTHT via secure transfer.

Where accessed at LTHT, the Data will be stored on secure servers at LTHT and accessed onsite at premises of LTHT.

The Data will not be backed up at any other location than LTHT, University of Leeds and University of Oxford.

Where accessed at LTHT, the Data will be stored on servers at LTHT and accessed onsite at premises of LTHT.

Where accessed at UoL and UoO, the Data will be stored on servers at UoO and UoL. The Data will be accessed remotely only by authorised members of the research team at the UoL and the UoO.

The Controller(s) must confirm and provide evidence upon audit by NHS England that access via any remote device complies with the data security obligations within this DSA and the Data Sharing Framework Contract.

For Remote access:

- Remote access will only be from secure locations situated within the territory of use (as further restricted elsewhere within the DSA if so done) stated within this DSA;

- Access controls granting users the minimum level of access required are in place;

- Remote access is only via secure connections (e.g., VPNs or secure protocols) to protect data;

- Multifactor authentication (MFA) is required for remote access;

- Device security, including up-to-date software and operating systems, antivirus software, and enabled firewalls are utilised for the remote access;

- All remote access is undertaken within the scope of the organisation’s DSPT (or other security arrangements as per this DSA) and complies with the organisation’s remote access policy

The above applies in addition to any condition set out elsewhere within the DSA (e.g. who may carry out processing, and for what purpose).

The data will not be backed up at another location in any of the three organisations storing the Data under this DSA.

The Data will not leave England at any time.

Access at the University of Leeds is restricted to substantive employees of the University of Leeds who have authorisation from the Chief Investigators.

Access at the University of Oxford is restricted to substantive employees of Nuffield Department of Primary Care Health Services at the University of Oxford who have authorisation from the Chief Investigators.

Access at the LTHT is restricted to substantive employees who have authorisation from the Chief Investigators

All personnel accessing the data have been appropriately trained in data protection and confidentiality.

The identifying details will be stored in a separate database to the linked dataset used for analysis at University of Leeds, LTHT, and University of Oxford. All analyses will use the pseudonymised dataset. There will be no requirement and no attempt to reidentify individuals when using the pseudonymised dataset.

The expected outputs of the processing will be:

• A final report of findings to NIHR is expected to be published in the NIHR Journal Library before the end of 2024.

• Submissions to peer reviewed journals, including separate publications for the main health impact of the intervention, target journal, Journal of Antimicrobial Therapy, a second will report the cost-effectiveness analysis of PAAP, target journal is Value in Health. Both are expected to be published before the end of 2024.

• Presentations at the National Health Economics Study Group meeting and International European Association for Clinical Pharmacology and Therapeutics conferences in Public Health and Health Economics, over the years 2024 and 2025.

• The production of electronic GP database patient identification reports and ''pop up'' -alerts relating to pen-allergy testing. This will enable development and refinement of the SystmOne/RESEARCHOne GP eHR (Electronic health records) systems that TPP provides for the purposes of identifying patients who may benefit from PAAP.

The patient identification reports patient "tagging" processes and electronic alert processes that the ALABAMA team has developed in collaboration with TPP (provider of SystmOne) will use existing features of TPP’s clinical information system software and will be made freely available to users of any clinical system, so they can be developed into new or existing products in use across the NHS.

In addition, information on the PAAP, describing step by step how to manage patients who may be identified by the patient identification reports in eHR systems, will be made publicly available, for use by the NHS, Charities and Academia with the aim of its being adapted and implemented as a new service in routine practice.

The outputs will not contain NHS England Data and will only contain aggregated information with small numbers suppressed as appropriate in line with the relevant disclosure rules for the dataset(s) from which the information was derived.

The outputs will be communicated to relevant recipients through the following dissemination channels within 12 months after the study end, and beyond this timepoint with professional and guideline setting organisations (e.g. the National Institute for Health and Care Excellence [NICE]):

1. Peer reviewed journals, Journal of Antimicrobial Therapy and Value in Health.

2. Dissemination event for patients/ the public, key stakeholders, Trial Steering Committee and Data Monitoring Committee and participating sites to include wider NHS implementation/adoption guidance.

3. Study Summary Reports prepared with Allergy UK, British Society for Allergy and Clinical Immunology (BACSI), commissioners and GP Electronic Health Records (eHR) system providers.

4. Fact sheets summarising study findings to inform NHS immunology/allergy service-Drug Allergy testing for dissemination among NHS specialist Allergy Services.

i. GPs and the Royal College of General Practitioners (RCGP) to transfer knowledge about PAAP and NHS England, Department of Health and professional associations with antimicrobial stewardship policy and practice.

5. Knowledge transfer of the PAAP antimicrobial-allergy testing eHR coding/alerts updates to Health Informatics and GP eHR Providers.

This will take place at two consultation/dissemination events.

6. NICE collaborators working as NICE Guidelines Advisors on Drug allergy and as member of the NICE antimicrobial stewardship committee.

7. Final dissemination event to report research finding to key stakeholders (e.g.-patients/national patient advocates, clinicians, NHS England-commissioners, platform providers participating practices/participants).

8. Plain English summaries for dissemination to wider lay audiences working in collaboration with our PPIE Co-investigator from the Allergy UK National Allergy Strategy Group (NASG) which is an alliance of the professional organisation BSACI (British Society of Allergy and Clinical Immunology), the patient charities, Allergy UK and Anaphylaxis UK.

Expected Benefits relating to Health/or Social Care.

The findings of this study are expected to contribute to more selective use of second line antibiotics throughout the NHS, thereby limiting opportunities for resistance to these treatments to develop and thus safeguarding the effectiveness of what is a limited resource.

Expected Benefits to patients.

Previous studies indicate that most of patients with a penicillin allergy label (90% or more) are not truly allergic and therefore receive unnecessary complex, expensive second-line antibiotics associated with inferior health outcomes. Since second line antibiotics are associated with more complications, including the occurrence of Clostridium difficile, higher risk of treatment failure and need for additional antibiotics than penicillin, most patients with penicillin allergy labels are expected benefit directly from our proposed use of the data.

ALABAMA propose to use the data to measure the effects of PAAP, a ’one-stop’-efficient allergy testing service that seeks to fill the gap left by lack of current allergy service capacity to meet demands of patients for allergy-testing but have currently not service to turn to on an elective basis.

Current eHR labelling assumes an allergy persists for life and there is a lack of adequate coding to consistently revert the exclusion of penicillin's in those tested and found to have a false label. The ALABAMA study will deliver solutions for these shortfalls. The timescale to onset of these benefits is Year 1-3 post-programme end in April 2024.

How outputs will lead to Public Benefits.

These benefits will be achieved by first, demonstrating how PAAP testing can be done to identify patients who despite having a record of penicillin allergy can safely be treated with penicillin. Second by providing practices with an electronic search algorithm to identify those most likely to benefit from PAAP in electronic health records free of charge, thus facilitating rollout of PAAP testing across NHS primary care. Third, through generating evidence suitable for NICE and other organisations to produce guideline for testing of penicillin allergy labels among primary care patients.

Targeting pre-emptive pen-allergy testing, only to those most likely to benefit (by having high antimicrobial use) equates to 0.87% of the UK population aged over 18 years (about 425,000 adults), but wider testing is plausible and has potential to benefit all adults with an unsubstantiated penicillin allergy label (~4.6 million).

The algorithms generated by SystmOne will not involve use of any data from NHS England, which is being used to evaluate outcomes in the study and will be excluded from any products generated by the project. Any outputs or evidence of effectiveness using data from NHS England or otherwise will be disseminated in aggregate form, suppressing aggregate data involving small numbers.

Yielded Benefits is not a requirement for new applications.