This guidance must be read in conjunction with the CPRD research application form which can be downloaded from the landing page of the CPRD electronic research application portal (www.erap.cprd.com) under 'Related resources'.
Please note that all applications must be completed and submitted via the CPRD electronic Research Applications Portal (eRAP) www.erap.cprd.com
Part 1: Application Form
GENERAL INFORMATION ABOUT THE PROPOSED RESEARCH STUDY |
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Question 1: Study Title (Max. 255 characters including spaces)It is important to ensure that the title of the study is clear, concise, easy to understand, and accurately reflects the main purpose/focus of the study. |
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Question 2: Research AreaSpecify the research area of the proposed study. Applicants must select at least one box. |
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Question 3: Purely Observational ResearchApproval from an NHS Research Ethics Committee (REC) may be required if the proposed study is not purely observational. It is the Chief Investigator’s responsibility to determine whether additional REC approval is required. Please consult latest version of GafREC Research Ethics Committee – Standard Operating Procedures for more guidance. |
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Question 4: Patient or GP questionnaires or patient contactQuestionnaires for healthcare professionals or patients must be reviewed and approved via the CPRD RDG process before being used. If available, any questionnaire should be included as an appendix to the application, otherwise the protocol should state that it will be submitted for approval prior to use. The questionnaire must be provided as it is intended to be presented to the recipients, together with any covering letter or guidance on completion which will be provided with the questionnaire. All questionnaires must be accompanied by an appropriate explanation of the purpose of the study for the recipient. |
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Question 5: Chief InvestigatorThe Chief Investigator will take responsibility for ensuring that the research is undertaken with full adherence to CPRD RDG guidelines, and any CPRD Contracts and Terms and Conditions. |
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Question 6: The Corresponding ApplicantThe Corresponding Applicant is the direct point of contact for the RDG Secretariat, and authorised to submit the application on behalf of the Chief Investigator. It is acceptable for the Chief Investigator to be the corresponding applicant. |
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Question 7: Other investigators/collaboratorsAnyone who will have access to CPRD data must be named in the CPRD RDG protocol. All investigators or collaborators must have an authorised eRAP account for a protocol to be submitted. |
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ACCESS TO THE DATA |
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Question 8: Sponsor of the studyThe sponsor for the study is a company, institution, organisation, or group of organisations that takes on responsibility for initiation, management and financing (or arranging the financing) of the proposed research. |
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Question 9: Funding source for the studySpecify the primary funding source for the study. Any organisation, or group of organisations, providing funding for the research project should be listed, including any grants and the awarding bodies. Funding sources must have completed the "New funder request for access to CPRD data form" available from here. Applicants are advised to check with CPRD whether a funding source is approved, otherwise this may slow down protocol approval. |
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Question 10: Institution conducting the researchApplicants must specify the name and address for the institution that will be conducting the research using CPRD data where this is not the sponsor organisation. |
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Question 11: Data Access ArrangementsState the method that will be used to access the data for this study - a study-specific dataset agreement or an institutional multi-study licence. If a licence is to be used, please indicate the licensing institution name and address. |
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Question 12: Data Processor(s)We require information on any organisation that will be processing, accessing, or storing the data requested by the applicant. |
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INFORMATION ON DATA |
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Primary care data collected by the CPRD can be linked to a number of other patient level datasets, (including Hospital Episode Statistics, Office of National Statistic mortality data, Cancer Registry etc...) and is only available for English practices that have consented to participate in the linkage scheme. If you have any questions about accessing linked data, please contact CPRD Enquiries (enquiries@cprd.com). |
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Question 13: Primary Care dataVision and EMIS are different clinical software systems used by general practices in the United Kingdom primary care setting. CPRD has historically collected data from Vision primary care practices, which is referred to as the GOLD primary care data. More recently, CPRD has been able to release data collected via the EMIS software system under the CPRD Aurum primary care data. |
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Question 14: Requests to access linked dataFor all linked data requests, applicants must outline under the protocol section on “Planned use of linked data (if applicable), including the public health benefits to patients in England & Wales” how the main outputs of the proposed study will benefit patients in England and Wales. You may base your justification on how the study findings would improve patient care either directly or indirectly by informing clinical practice guidelines or public health policy.
Applicants seeking access to NCRAS data must also complete a Cancer Dataset Agreement Form (available from CPRD on request) and submit this via the CPRD RDG process as an appendix to the protocol. Applicants must also provide consent for publication of their study title and study institution on the UK Cancer Registry website. As a risk minimisation measure, CPRD routinely provides only one practice and/or one patient level area linkage per study. If you require more than one practice or patient level area linkage (i.e. practice level IMD and Rural-Urban classification), this will need to be discussed with a member of the CPRD Research Team (enquiries@cprd.com), before submitting a CPRD RDG application. Applicants must include the enquiry reference number in the application to evidence the discussion with CPRD about the study requirements. |
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Question 15: Requesting non-standard data linkageInvestigators wishing to link to a dataset not listed under Question 14 of the CPRD research application form must receive CPRD approval for the respective linkage, prior to submitting a CPRD RDG protocol. Applicants must provide the Non-Standard Linkage (NSL) reference number for the CPRD approved linkage as part of their research application. Please contact the CPRD Research Team (enquiries@cprd.com) for more information on accessing data as a non-standard linkage. |
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Question 16: Patient identifiersInvestigators must state whether any person named in the study has access to the data in a patient identifiable form, or any associated identifiable patient index. |
Part 2: Protocol Information
Study TitleReviewer Assessment CriteriaIn this section, reviewers will assess whether the study title clearly describes the main focus and purpose of the proposed research. Application RequirementsIt is important to ensure that the title of the study is clear, concise, easy to understand, and accurately reflects the main purpose/focus of the study. |
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Lay Summary (Max. 250 words)Reviewer Assessment CriteriaIn this section, reviewers will assess whether the proposed research could be easily understood, as a standalone summary, by non-scientific readers. The importance, relevance, and implications of the research to patients, clinical practice or the health care system will also be assessed. Application RequirementsPlease provide a succinct overview of your proposed research in non-technical language. The lay summary should provide an overview of the research without the need to refer to the technical summary. |
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Technical Summary (Max. 300 words)Reviewer Assessment CriteriaTechnical summaries will be evaluated for transparency in communicating the purpose, methods, and benefits of the proposed research to scientific readers as a standalone summary. A high level assessment of the relevance/feasibility of the stated methods and analytical approaches will also be undertaken. Reviewers will also assess whether the benefits of the proposed methods to achieve the objectives of the research outweigh potential risks, including information governance risks such as patient or practice confidentiality issues. Application RequirementsThe technical summary is written primarily for other researchers and clinicians who may be interested in your research. This should include enough technical details to provide a clear idea of your study aim and methods. Your technical summary should be presented as 1-2 paragraphs providing a succinct overview of your research and include details on the following: |
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Outcomes to be MeasuredReviewer Assessment CriteriaIn this section, whether the choice of primary and key secondary outcomes will achieve the intended benefits of the research will be evaluated. An assessment of the feasibility of ascertaining the outcome(s) in CPRD may also be reviewed in this section. Application RequirementsThis section should clearly list the primary and key secondary outcomes of interest in a concise list, separated by semicolons, e.g.: |
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Specific Aims, Objectives, and RationaleReviewer Assessment CriteriaIn this section, reviewers will evaluate the clarity, scope, feasibility, and benefits that may be achieved through the study aim(s) and objectives. Protocols should include details to enable reviewers to evaluate the public health benefits of the research, assess the methods for implementing the stated objectives, determine whether inherent public health risk(s) may arise during the conduct of the research or whether there may be risks to patient/practice confidentiality and/or privacy. Application RequirementsA general aim should normally be provided, followed by one or more specific and related objectives. Studies with many objectives often fail to describe all objectives in sufficient detail in the protocol and may be considered too extensive for a single protocol. |
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Study BackgroundReviewer Assessment CriteriaIn this section, reviewers will assess whether the study background highlights the importance, relevance, and public health value of the research. This should be linked to relevant published literature. Application RequirementsApplicants should explain the reason for the research aim and objectives and support this with relevant information from the scientific or other literature. This should highlight key issues that are currently unanswered or in dispute in the field. Background information may refer to previous or similar studies conducted in GPRD, CPRD or other data sources. All supporting statements should be duly referenced in this section with the full reference included in the “Reference” section of the protocol. |
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Study TypeReviewer Assessment CriteriaIn this section, reviewers will assess whether the study type(s), as described below, are appropriate to address the stated aims and objectives of the research and to achieve the intended public health benefits. Application RequirementsSpecify whether the study will be primarily descriptive, hypothesis generating, hypothesis testing, or a methodological piece of research. We recognise that a single research study may comprise one or more of the following study types:
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Study DesignReviewer Assessment CriteriaIn this section, reviewers will assess whether the study design(s), as described below, are appropriate and can be reliably implemented in CPRD to achieve the intended benefit of the research. Feasibility of the design may also require an assessment of the methods - numbers expected in CPRD (feasibility counts), sample size considerations, data sources to be used, study exposures and outcomes or proposed data analysis. Application RequirementsApplicants should briefly state the overall research design, strategy, and reasons for choosing the proposed study design. |
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Feasibility countsReviewer Assessment CriteriaIn this section, reviewers will assess the feasibility of the research, that is, whether there is likely to be “adequate” number of patients in CPRD to address the main objectives of the proposed research. Where numbers may be low, reviewers will also consider the sample size calculation, study design, and data analysis sections of the protocol to assess whether the research may present patient and/or practice re-identification risks. Applicants should include a risk mitigation plan in their protocol where there may be potential re-identification risks. Application RequirementsApplicants must provide an estimate of the expected number of patients available in the CPRD and/or linked data sets for the proposed study. Applicants may refer to relevant publications using CPRD data to gauge study feasibility or support their application with feasibility counts based on CPRD data. In some cases, feasibility counts can be requested from CPRD and for more information applicants should contact enquiries@cprd.com.
If options to increase your study population are not feasible, please outline mitigation approaches to minimise the risk of inadvertently identifying patients or practices during the conduct and/or publication of the study. |
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Sample size considerationsReviewer Assessment CriteriaIn this section, reviewers will assess whether a sample size calculation is needed and if so, whether the samplesize/power of the study will be sufficient to address the primary hypothesis of the research. Where numbers may be low, reviewers will consider your study design and proposed data analysis to assess whether your research may present potential patient and/or practice re-identification risks. Applicants should include a risk mitigation plan in their protocol where there may be potential re-identification risks. Application RequirementsAll protocols must include some consideration of whether the sample-size (and study power for hypothesis testing studies) will be sufficient to meet the primary outcome of the research.
If applicants wish to make a case that it is worth proceeding with a study even though the expected numbers are lower than desired – for example, in studies of extremely rare conditions – then this should be identified and clearly acknowledged as a limitation in the research protocol and addressed in a risk mitigation plan. |
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Planned use of linked data (if applicable), including the public health benefits to patients in England & WalesReviewer Assessment CriteriaWhere applicable, reviewers will assess whether the linked data sources requested are relevant and feasible (can support cohort/comparison identification, exposure definition, outcome ascertainment or covariate definition) to address the study aims and objectives. An explicit review of how the outputs of the proposed study using linked data will benefit patients in England & Wales will also be evaluated. Application RequirementsAny proposed use of linked data sets must be appropriate to the research. This will be assessed against statements made on the CPRD RDG application form and any other relevant information documented in the protocol. For proposals to use data sources routinely linked to CPRD data, for example, Hospital Episode Statistics (HES), Office of National Statistics (ONS) Mortality data, Cancer Registry data, practice/patient area-level data, please describe why the linkage data is necessary for the study and how it will be used. |
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Definition of the Study populationReviewer Assessment CriteriaIn this section, reviewers will assess whether the study population is clearly described and relevant in the context of the research; whether restricting/excluding certain patient groups from the research may disadvantage such patient groups and limit the benefits of the research; whether research to combine data from CPRD with other external non-CPRD data sources may present potential patient and/or practice re-identification risks or other information governance risks. Application RequirementsIt is important to ensure that the protocol clearly defines the study population. The following areas listed below should be addressed in all research protocols: |
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Selection of comparison group(s) or controlsReviewer Assessment CriteriaIn this section, reviewers will assess whether the selection of comparison groups or controls are clearly described, relevant and appropriate, and can be operationalised using the data sources and variables available in CPRD. Whether selection approaches will introduce biases that may limit the benefits of the research will also be evaluated. Application RequirementsWhere controls or comparison groups are needed to support a research question, please describe the following in the research protocol: a) How controls group differs from the main study population. |
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Exposures, Outcomes and CovariatesReviewer Assessment CriteriaIn this section, reviewers will assess whether the exposures, outcomes and covariates of interest are clearly described, relevant in the context of the proposed research and can be operationalised in CPRD using the data sources requested. Reviewers will also assess whether there may be oversights in the selection of covariates or outcomes that may limit the public health value of the research. Potential risks to patient/practice confidentiality and/or privacy arising from the use of specific data variables or sensitive concepts will also be assessed. Application Requirements
A clear description of the exposures and health outcomes of interest to the study should be provided. Operational definitions of these should also be provided to enable an assessment of feasibility. An operational definition is one that can be implemented independently using the data available in the proposed study. For example, "asthma episode" is not an operational definition; a better description would be “record of a Read code for asthma, as listed in Appendix A, and documented in the patient clinical or referral record”. If it is not possible at the time of the CPRD RDG application to provide operational definitions of exposures and/or outcomes because these will be elucidated during the course of the study, an acceptable alternative is to describe the process by which these definitions will be reached.
Applicants should also describe the data sources, where applicable, for determining the main exposures and health outcomes relevant to the study. Data sources might include, for example, primary care clinical records, prescription drug files, test records, administrative linked exposure/disease registries and GP questionnaires. Steps to validate exposure and outcomes are encouraged and may be suggested for diseases not previously studied in the database or for which there is commonly diagnostic uncertainty.
A list of covariates to be included in baseline tables and statistical models as potential confounding variables and effect modifiers should be stated, including the data source/s from which these will be derived. This would suggest that reasonable steps to control for confounding will be taken.
Applicants should provide preliminary code lists for the main exposures and outcomes in order to demonstrate that they have an awareness of the practical issues involved in defining these, where appropriate. Code lists should be provided as appendices and not included in the body of the protocol. Where relevant codes lists are absent, the procedure for developing them has not been described, or the use of codes from a previous study has not been proposed, protocols will be regarded as deficient in this respect. Given the nature of the medical coding system in use in UK primary care, it is advised that, where possible, a named clinician with experience of UK primary care is involved in the process of code list development. |
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Data/ Statistical AnalysisReviewer Assessment CriteriaIn this section, reviewers will assess whether the analysis proposed are aligned with the research objectives, are broadly appropriate for the proposed research from an epidemiological and statistical point of view, and minimise potential risks of patient and/or practices re-identification or other information governance risks. For example, reviewers will assess whether analytical/statistical methods may ‘single out’ patients through investigation of outliers, case review by clinicians, or by conducting stratified analyses. Application RequirementsAll data management and data analysis to be performed should be covered in this section.
Measures of central tendency (mean, median), variation, and correlation are often reported in these types of studies. Trend analysis is an important tool in descriptive studies.
Descriptive statistics to provide useful summaries about the sample and the outcome measures. Together with simple graphics analysis, descriptive statistics form the basis of virtually all quantitative analyses. Hypothesis generating analyses may include measures of disease frequency such as prevalence and incidence and time trend analyses.
Descriptive statistics to provide useful summaries about the sample and the outcome measures; measures of association to be derived and statistical tests to be conducted; pre-specified sub-group analyses including how the analysis will control for potential confounding. Where appropriate, specify the statistical modelling techniques to be used, giving some indication as to how models will be specified.
Applicants are advised to consider the implications of multiple testing as the interpretation of p-values <0.05 (5%) as “statistically significant” may be threatened when many tests are carried out in a single study (Bland, 1995). Approaches for handling missing data may include: |
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Plan for addressing confoundingReviewer Assessment CriteriaIn this section, reviewers will assess whether methods for addressing confounding have been considered, and where needed, are relevant given the study aims and objectives, study type, design and analyses proposed. Reviewers will also assess whether methods to consider confounding may increase the risk of patient and/or practice re-identification or other information governance risks during the conduct and/or publication of research findings. For example, reviewers will assess whether analytical/statistical methods may result in strata with <5 patients or ‘single out’ patients through other investigations. Application RequirementsPurely descriptive studies are exempt from this requirement and can list ‘Not applicable’ in this section. All other studies should here provide some discussion of what will be done in the design and/or analysis to control for confounding. |
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Plans for addressing missing dataReviewer Assessment CriteriaIn this section and where applicable, reviewers will evaluate how missing data will be handled in the research and whether this may lead to spurious findings or incorrect conclusions that may undermine the benefits of the research. Application RequirementsThe potential for missing data is present in most studies and needs to be identified and addressed in this section of the protocol. In practice, missing data is most commonly of concern in relation to covariates, such as BMI and smoking, but would be of bigger concern if the relevant variable is an outcome or exposure. |
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Patient or user group involvementReviewer Assessment CriteriaIn this section, reviewers will evaluate whether patient or user group involvement have been considered during different stages of the research. Application RequirementsIt is expected that many studies will benefit from the involvement of patient or user groups in their planning and refinement stages, and/or in the interpretation of results, in their dissemination, and in informing plans for further work. This is particularly, but not exclusively, true of studies in which patients are to be contacted, and studies with interests in the impact on quality of life. Applicants should indicate whether patient/user groups will be engaged in any way and, if not, explain why patient/user groups will not be engaged. Applications which simply state ‘Not applicable’ will be returned as invalid. |
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Plans for disseminating and communicating study resultsReviewer Assessment CriteriaIn this section, reviewers will evaluate whether there are any restrictions on publication of the research findings that may impact its public health value. For instance, whether the funder have a role in writing up the research or in deciding to submit the paper for publication. An assessment of whether there are potential risks of inadvertently re-identifying patients or practices during publication and dissemination of the outputs of the research will also be considered. Application RequirementsThere is an ethical obligation to disseminate findings of potential scientific or public health importance (e.g., results pertaining to the safety of a marketed medication). Authorship should follow guidelines established by the International Committee of Medical Journal Editors.
When reporting, applicants are advised to follow the principles outlined in the Strengthening the Reporting of Observational studies in Epidemiology (STROBE) and any other relevant guidelines in the Enhancing the Quality and Transparency of health research (EQUATOR) network. The Consolidated Standards of Reporting Trials (CONSORT) statement refers to randomised studies, but also provides useful guidance, the principles of which may be applicable to observational hypothesis-testing studies |
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Conflict of interest statementReviewer Assessment CriteriaIn this section, reviewers will evaluate applicants’ conflict of interest statements to determine whether these may influence publication and/or communication of the research findings. Application RequirementsEach applicant must provide a conflict of interest statement. The statement should be transparent about any sources of funding not already listed on the application including relevant financial interests of investigators/collaborators, and any relevant paid or unpaid positions held by investigators/collaborators. |
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Limitations of the study design, data sources, and analytic methodsReviewer Assessment CriteriaIn this section, reviewers will evaluate whether there are important limitations of the study that have not been considered or adequately considered and which may affect the conclusions drawn from the research. Application RequirementsLimitations of the study such as issues relating to bias and confounding, misclassification, random error and generalisability etc... should be considered. Specific consideration of the potential impact on findings should be provided. For example, primary care databases contain little, if any, information about over the counter drug (OTC) usage. Applicants studying a class of drugs for which some products are available OTC should recognise which drug exposures are likely to be underestimated and discuss the expected impact on the findings. |
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ReferencesReviewer Assessment CriteriaIn this section, reviewers will assess whether the supporting evidence about the research e.g. study background and methods, are linked to published scientific or other literature. Application RequirementsPlease provide a numbered list of references at the end of the protocol. The reference list should include the titles of the papers, but it is not necessary to include all the authors. A minimum of three authors is sufficient, and the Vancouver format for referencing is preferred. |
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List of AppendicesReviewer Assessment CriteriaIn this section, reviewers will inspect preliminary code lists for the main study exposure(s) and outcome(s) to assess their relevance and feasibility for conducting the research in CPRD data sources. Other documentation referred to in the application will also be assessed, where needed. Application RequirementsPlease provide all appendices related to this research protocol as separate documents. |
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Grant ID (optional)Please provide a grand ID reference where this is applicable. |
Other information
Data deletion
CPRD Dataset Agreement Terms and Conditions state that applicants will need to provide evidence that any received datasets have been deleted no later than 12 months following receipt. Applicants are required to keep a register of any copies made and will be asked to provide data destruction certificates for all copies or backups.
Applicants may apply for extensions to the 12 month period which must be approved by CPRD.
Confidentiality of research protocols
All research applications to the CPRD RDG process are held securely and confidentially at the CPRD. No information about study applicants or protocol content are released to third parties, other than in accordance with CPRD’s Transparency Policy, without first seeking the agreement of the Chief Investigator of the study. Only applicants named on the research protocol can make enquiries about the protocol.
Ethical review of protocols
CPRD has obtained ethical approval from a National Research Ethics Service Committee (NRES), for all purely observational research using anonymised CPRD data; namely, studies which do not include patient involvement (which is the vast majority of CPRD studies). CPRD RDG committees review protocols for feasibility, public health benefits/risks and information governance risks, but may recommend that study-specific ethical approval is sought if ethical issues arise in relation to an individual study. Separate ethical approval will be required for any study which includes any form of direct patient involvement.
It is the Chief Investigator’s responsibility to determine whether additional REC approval is required. Please consult latest version of GafREC Research Ethics Committee – Standard Operating Procedures for more guidance.
Voluntary registration of CPRD RDG approved protocols
Epidemiological studies are increasingly being included in registries of research around the world, including those primarily set up for clinical trials. To increase awareness amongst researchers of ongoing research, CPRD encourages voluntary registration of epidemiological research conducted using MHRA databases. This will not replace information on CPRD RDG -approved protocols that may be published on the CPRD website. It is for the applicant to determine the most appropriate registry for their study. Applicants should inform the RDG Secretariat on registering a protocol and provide the location.
Reporting findings
When reporting the findings of a CPRD RDG-approved protocol, authors are encouraged to indicate that the study was approved and should provide information on any deviations from the original protocol. For protocols approved from 01 April 2014 onwards, applicants are required to include the ISAC or RDG protocol number in journal submissions, with a statement in the manuscript declaring approval by the ISAC or RDG process, where applicable. If the protocol was subject to any amendments, the last amended version should be the one submitted.
Applicants are required to submit a copy of all peer-reviewed publications based on CPRD data to CPRD. Applicants should inform the CPRD of the publication outcome/s and, where appropriate, to send a copy or link of publications or a copy of funder’s report summarising the research. These can be sent to CPRD enquiries (enquiries@cprd.com).
Please note that the CPRD reserves the right to audit the concordance between approved study protocols and published research.
It is essential that consideration is given to preserving confidentiality at the reporting stage. The possibility of unintentional (deductive) disclosure arises when cells with small numbers of patients are quoted. Applicants should note that, when reporting the data, CPRD policy is that no cell should contain <5 events.