Realising the full potential of data-enabled trials in the UK: a call for action

RationaleClinical trials are the gold standard for testing interventions. COVID-19 has further raised their public profile and emphasised the need to deliver better, faster, more efficient trials for patient benefit. Considerable overlap exists between data required for trials and data already collected routinely in electronic healthcare records (EHRs). Opportunities exist to use these in innovative ways to decrease duplication of effort and speed trial recruitment, conduct and follow-up.ApproachThe National Institute of Health Research (NIHR), Health Data Research UK and Clinical Practice Research Datalink co-organised a national workshop to accelerate the agenda for ‘data-enabled clinical trials’. Showcasing successful examples and imagining future possibilities, the plenary talks, panel discussions, group discussions and case studies covered: design/feasibility; recruitment; conduct/follow-up; collecting benefits/harms; and analysis/interpretation.ReflectionSome notable studies have successfully accessed and used EHR to identify potential recruits, support randomised trials, deliver interventions and supplement/replace trial-specific follow-up. Some outcome measures are already reliably collected; others, like safety, need detailed work to meet regulatory reporting requirements. There is a clear need for system interoperability and a ‘route map’ to identify and access the necessary datasets. Researchers running regulatory-facing trials must carefully consider how data quality and integrity would be assessed. An experience-sharing forum could stimulate wider adoption of EHR-based methods in trial design and execution.DiscussionEHR offer opportunities to better plan clinical trials, assess patients and capture data more efficiently, reducing research waste and increasing focus on each trial’s specific challenges. The short-term emphasis should be on facilitating patient recruitment and for postmarketing authorisation trials where research-relevant outcome measures are readily collectable. Sharing of case studies is encouraged. The workshop directly informed NIHR’s funding call for ambitious data-enabled trials at scale. There is the opportunity for the UK to build upon existing data science capabilities to identify, recruit and monitor patients in trials at scale.

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Therapy persistence in newly diagnosed non-valvular atrial fibrillation treated with warfarin or NOAC

Thrombosis and Haemostasis ◽

10.1160/th15-04-0350 ◽

2016 ◽

Vol 115 (01) ◽

pp. 31-39 ◽

Cited By ~ 96

Author(s):

Anja Katholing ◽

Christopher Wallenhorst ◽

Saul Benedict Freedman ◽

Carlos Martinez

Keyword(s):

Atrial Fibrillation ◽

Guideline Adherence ◽

Practice Research ◽

First Year ◽

Clinical Practice Research Datalink ◽

Supplementary Material ◽

One Year ◽

The Uk ◽

Physician Adherence

SummaryEfforts to reduce stroke in atrial fibrillation (AF) have focused on increasing physician adherence to oral anticoagulant (OAC) guidelines, but high early vitamin K antagonist (VKA) discontinuation is a limitation. We compared persistence of non-VKA OAC (NOAC) with VKA treatment in the first year after OAC inception for incident AF in real-world practice. We studied 27,514 anticoagulant-naïve patients with incident non-valvular AF between January 2011 and May 2014 in the UK primary care Clinical Practice Research Datalink, with full medication use linkage: mean age 74.2 ± 12.4, 45.7 % female, mean follow-up 1.9 ± 1.1 years. After treatment initiation and follow-up until 1/2015, the proportion remaining on OAC at one year (persistence) was estimated using competing risk survival analyses. OAC was commenced ≤90 days after incident AF in 13,221 patients (48.1 %): 12,307 VKA and 914 NOAC (apixaban, dabigatran, rivaroxaban). Amongst those treated with OAC, the proportion commencing NOAC increased from zero in 1/2011 to 27.0 % in 5/2014, and OAC prescriptions for CHA2DS2VASc score ≥2 (guideline adherence) increased from 41.2 % to 65.5 %. Persistence with OAC declined over 12 months to 63.6 % for VKA and 79.2 % for NOAC (p< 0.0001). Persistence for those with CHA2DS2VASc ≥2 was significantly greater for NOAC (83.0 %) than VKA (65.3 %, p< 0.0001) at one year and all earlier time points. Comparison of VKA and NOAC cohorts matched on individual CHA2DS2VASc components showed consistent results. In conclusion, persistence was significantly higher with NOAC than VKA, and could alone lead to fewer cardioembolic strokes. Increased guideline adherence following NOAC introduction could further decrease AF stroke burden.Supplementary Material to this article is available online at www.thrombosis-online.com.

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Co-prescription of gabapentinoids and opioids among adults with and without osteoarthritis in the United Kingdom between 1995 and 2017

Rheumatology ◽

10.1093/rheumatology/keaa586 ◽

2020 ◽

Author(s):

Dahai Yu ◽

Tom Appleyard ◽

Elizabeth Cottrell ◽

George Peat

Keyword(s):

Event Rate ◽

Practice Research ◽

Clinical Practice Research Datalink ◽

The United Kingdom ◽

Regional Estimates ◽

Strong Opioids ◽

The Uk ◽

New Diagnosis

Abstract Objectives To produce national and regional estimates and trends for gabapentinoid–opioid co-prescribing rates in patients with OA, both in absolute terms and relative to matched controls without OA. Methods Using the UK Clinical Practice Research Datalink database we first constructed age–sex–practice–date 1:1 matched cohorts of patients aged ≥40 years with and without a new diagnosis of OA between 1995–2017 and estimated the relative incidence of a first gabapentinoid prescription. Incident gabapentinoid users in both cohorts were followed to estimate and compare the event rate of gabapentinoid–opioid co-prescription (prescription from both classes within the same 28-day window). Results The incidence of first gabapentinoid prescription was 3-fold higher in patients with OA than in matched controls [n = 215 357; incidence rate ratio (IRR) 2.93; 95% CI: 2.87, 3.00]. Among incident gabapentinoid users with OA (n = 27 374, median follow-up 3.9 years) the event rate of gabapentinoid–opioid co-prescription was 4.03 (4.02–4.05) per person-year. The rate was higher in OA patients classed as long-term gabapentinoid users (6.24; 6.22–6.26). These rates were significantly higher than in incident gabapentinoid users without OA [adjusted-IRR: 1.29 (1.28–1.30)]. This elevated risk was observed across age, sex, geographic regions, and calendar years, when restricted to strong opioids and to long-term gabapentinoid users, and when co-prescription was defined as within 14 days and same-day prescribing. Conclusions Patients with OA not only have a higher risk of being prescribed a gabapentinoid but, once prescribed a gabapentinoid, are also at greater risk of opioid co-prescription. Strict restriction of gabapentinoid–opioid co-prescription, and improved access to, and uptake of, effective non-pharmacological and surgical alternatives for OA are required.

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Predicting prostate cancer progression: protocol for a retrospective cohort study to identify prognostic factors for prostate cancer outcomes using routine primary care data

BMJ Open ◽

10.1136/bmjopen-2017-019409 ◽

2018 ◽

Vol 8 (1) ◽

pp. e019409 ◽

Cited By ~ 4

Author(s):

Samuel W D Merriel ◽

Margaret T May ◽

Richard M Martin

Keyword(s):

Prostate Cancer ◽

Prognostic Factors ◽

Cancer Progression ◽

Practice Research ◽

Cancer Registration ◽

Clinical Practice Research Datalink ◽

Gleason Grade ◽

Prostate Cancer Progression ◽

The Uk

IntroductionProstate cancer is the most common cancer in men in the UK, with nearly 40 000 diagnosed in 2014; and it is the second most common cause of male cancer-related mortality. The clinical conundrum is that most men live with prostate cancer rather than die from it, while existing treatments have significant associated morbidity. Recent studies have shown very low mortality rates (1% after a median of 10-year follow-up) and no treatment-related reductions in mortality, in men with localised prostate cancer. This study will identify prognostic factors associated with prostate cancer progression to help differentiate aggressive from more indolent tumours in men with localised disease at diagnosis, and so inform the decision to adopt conservative (active surveillance) or radical (surgery or radiotherapy) management strategies.Methods and analysisThe Clinical Practice Research Datalink (CPRD) contains 57 318 men who were diagnosed with prostate cancer between 1 January 1987 and 31 December 2016. These men will be linked to the Office for National Statistics (ONS) and the National Cancer Registration and Analysis Service registry databases for mortality, TNM stage, Gleason grade and treatment data. Men with a diagnosis date prior to 1 January 1987 and men with lymph node or distant metastases at diagnosis will be excluded. A priori determined prognostic factors potentially associated with prostate cancer mortality, the end point of cancer progression, will be measured at baseline, and the participants followed through to development of cancer progression, death or the end of the follow-up period (31 December 2016). Cox proportional hazards regression will be used to estimate crude and mutually adjusted HRs. Mortality risk will be predicted using flexible parametric survival models that can accurately fit the shape of the hazard function.Ethics and disseminationThis study protocol has approval from the Independent Scientific Advisory Committee for the UK Medicines and Healthcare products Regulatory Agency Database Research (protocol 17_041). The findings will be presented in peer-reviewed journals and local CPRD researcher meetings.

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OP0074 MULTIMORBIDITY CLUSTERS, DETERMINANTS AND TRAJECTORIES IN OSTEOARTHRITIS IN THE UK: FINDINGS FROM THE CLINICAL PRACTICE RESEARCH DATALINK

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.1488 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 49.1-50

Author(s):

S. Swain ◽

C. Coupland ◽

V. Strauss ◽

C. Mallen ◽

C. F. Kuo ◽

...

Keyword(s):

Chronic Conditions ◽

Index Date ◽

Latent Class ◽

Rapid Onset ◽

Practice Research ◽

Clinical Practice Research Datalink ◽

Research Support ◽

Gradual Onset ◽

The Uk ◽

Slow Onset

Background:Multimorbidity (≥2 chronic conditions) escalates the risk of adverse health outcomes. However, its burden in people with osteoarthritis (OA) remains largely unknown.Objectives:To identify the clusters of patients with multimorbidity and associated factors in OA and non-OA populations and to estimate the risk of developing multimorbidity clusters after the index date (after diagnosis).Methods:The study used the Clinical Practice Research Datalink – a primary care database from the UK. Firstly, age, sex and practice matched OA and non-OA people aged 20+ were identified to explore patterns and associations of clusters of multimorbidity within each group. Non-OA controls were assigned with same index date as that of matched OA cases. Secondly, multimorbidity trajectories for 20 years after the index date were examined in people without any comorbidities at baseline in both OA and non-OA groups. Latent class analysis was used to identify clusters and latent class growth modelling was used for cluster trajectories. The associations between clusters and age, sex, body mass index (BMI), alcohol use, smoking habits at baseline were quantified through multinomial logistic regression.Results:In total, 47 long-term conditions were studied in 443,822 people (OA- 221922; non-OA- 221900), with a mean age of 62 years (standard deviation ± 13 years), and 58% being women. The prevalence of multimorbidity was 76.6% and 68.9% in the OA and non-OA groups, respectively. In the OA group five clusters were identified including relatively healthy (18%), ‘cardiovascular (CVD) and musculoskeletal (MSK)’ (12.3%), metabolic syndrome (28.2%), ‘pain and psychological (9.1%), and ‘musculoskeletal’ (32.4%). The non-OA group had similar patterns except that the ‘pain+ psychological’ cluster was replaced by ‘thyroid and psychological’. (Figure 1) Among people with OA, ‘CVD+MSK’ and metabolic syndrome clusters were strongly associated with obesity with a relative risk ratio (RRR) of 2.04 (95% CI 1.95-2.13) and 2.10 (95% CI 2.03-2.17), respectively. Women had four times higher risk of being in the ‘pain+ psychological’ cluster than men when compared to the gender ratio in the healthy cluster, (RRR 4.28; 95% CI 4.09-4.48). In the non-OA group, obesity was significantly associated with all the clusters.Figure 1: Posterior probability distribution of chronic conditions across the clusters in Osteoarthritis (OA, n=221922) and Non-Osteoarthritis (Non-OA, n=221900) group. COPD- Chronic Obstructive Pulmonary Disease; CVD- Cardiovascular; MSK- MusculoskeletalOA (n=24139) and non-OA (n=24144) groups had five and four multimorbidity trajectory clusters, respectively. Among the OA population, 2.7% had rapid onset of multimorbidity, 9.5% had gradual onset and 11.6% had slow onset, whereas among the non-OA population, there was no rapid onset cluster, 4.6% had gradual onset and 14.3% had slow onset of multimorbidity. (Figure 2)Figure 2: Clusters of multimorbidity trajectories after index date in OA (n=24139) and Non-OA (n=24144)Conclusion:Distinct identified groups in OA and non-OA suggests further research for possible biological linkage within each cluster. The rapid onset of multimorbidity in OA should be considered for chronic disease management.Supported by:Acknowledgments:We would like to thank the University of Nottingham, UK, Beijing Joint Care Foundation, China and Foundation for Research in Rheumatology (FOREUM) for supporting the study.Disclosure of Interests:Subhashisa Swain: None declared, Carol Coupland: None declared, Victoria Strauss: None declared, Christian Mallen Grant/research support from: My department has received financial grants from BMS for a cardiology trial., Chang-Fu Kuo: None declared, Aliya Sarmanova: None declared, Michael Doherty Grant/research support from: AstraZeneca funded the Nottingham Sons of Gout study, Consultant of: Advisory borads on gout for Grunenthal and Mallinckrodt, Weiya Zhang Consultant of: Grunenthal for advice on gout management, Speakers bureau: Bioiberica as an invited speaker for EULAR 2016 satellite symposium

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Paediatric rotavirus vaccination, coeliac disease and type 1 diabetes in children: a population-based cohort study

BMC Medicine ◽

10.1186/s12916-021-02017-1 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Thomas Inns ◽

Kate M. Fleming ◽

Miren Iturriza-Gomara ◽

Daniel Hungerford

Keyword(s):

Type 1 Diabetes ◽

Cohort Study ◽

Coeliac Disease ◽

Practice Research ◽

Clinical Practice Research Datalink ◽

Rotavirus Vaccine ◽

Rotavirus Vaccination ◽

Increased Risk ◽

The Uk

Abstract Background Rotavirus infection has been proposed as a risk factor for coeliac disease (CD) and type 1 diabetes (T1D). The UK introduced infant rotavirus vaccination in 2013. We have previously shown that rotavirus vaccination can have beneficial off-target effects on syndromes, such as hospitalised seizures. We therefore investigated whether rotavirus vaccination prevents CD and T1D in the UK. Methods A cohort study of children born between 2010 and 2015 was conducted using primary care records from the Clinical Practice Research Datalink. Children were followed up from 6 months to 7 years old, with censoring for outcome, death or leaving the practice. CD was defined as diagnosis of CD or the prescription of gluten-free goods. T1D was defined as a T1D diagnosis. The exposure was rotavirus vaccination, defined as one or more doses. Mixed-effects Cox regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CIs). Models were adjusted for potential confounders and included random intercepts for general practices. Results There were 880,629 children in the cohort (48.8% female). A total of 343,113 (39.0%) participants received rotavirus vaccine; among those born after the introduction of rotavirus vaccination, 93.4% were vaccinated. Study participants contributed 4,388,355 person-years, with median follow-up 5.66 person-years. There were 1657 CD cases, an incidence of 38.0 cases per 100,000 person-years. Compared with unvaccinated children, the adjusted HR for a CD was 1.05 (95% CI 0.86–1.28) for vaccinated children. Females had a 40% higher hazard than males. T1D was recorded for 733 participants, an incidence of 17.1 cases per 100,000 person-years. In adjusted analysis, rotavirus vaccination was not associated with risk of T1D (HR = 0.89, 95% CI 0.68–1.19). Conclusions Rotavirus vaccination has reduced diarrhoeal disease morbidity and mortality substantial since licencing in 2006. Our finding from this large cohort study did not provide evidence that rotavirus vaccination prevents CD or T1D, nor is it associated with increased risk, delivering further evidence of rotavirus vaccine safety.

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Calcium channel blockers and cancer: a risk analysis using the UK Clinical Practice Research Datalink (CPRD)

BMJ Open ◽

10.1136/bmjopen-2015-009147 ◽

2016 ◽

Vol 6 (1) ◽

pp. e009147 ◽

Cited By ~ 25

Author(s):

Lamiae Grimaldi-Bensouda ◽

Olaf Klungel ◽

Xavier Kurz ◽

Mark C H de Groot ◽

Ana S Maciel Afonso ◽

...

Keyword(s):

Clinical Practice ◽

Risk Analysis ◽

Calcium Channel ◽

Calcium Channel Blockers ◽

Practice Research ◽

Clinical Practice Research Datalink ◽

Channel Blockers ◽

The Uk

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Development and validation of prediction models to estimate risk of primary total hip and knee replacements using data from the UK: two prospective open cohorts using the UK Clinical Practice Research Datalink

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2018-213894 ◽

2018 ◽

Vol 78 (1) ◽

pp. 91-99 ◽

Cited By ~ 7

Author(s):

Dahai Yu ◽

Kelvin P Jordan ◽

Kym I E Snell ◽

Richard D Riley ◽

John Bedson ◽

...

Keyword(s):

Clinical Practice ◽

Large Scale ◽

Prediction Models ◽

Cox Proportional Hazards ◽

Practice Research ◽

Clinical Practice Research Datalink ◽

Total Hip ◽

Risk Of Death ◽

Geographical Regions ◽

The Uk

ObjectivesThe ability to efficiently and accurately predict future risk of primary total hip and knee replacement (THR/TKR) in earlier stages of osteoarthritis (OA) has potentially important applications. We aimed to develop and validate two models to estimate an individual’s risk of primary THR and TKR in patients newly presenting to primary care.MethodsWe identified two cohorts of patients aged ≥40 years newly consulting hip pain/OA and knee pain/OA in the Clinical Practice Research Datalink. Candidate predictors were identified by systematic review, novel hypothesis-free ‘Record-Wide Association Study’ with replication, and panel consensus. Cox proportional hazards models accounting for competing risk of death were applied to derive risk algorithms for THR and TKR. Internal–external cross-validation (IECV) was then applied over geographical regions to validate two models.Results45 predictors for THR and 53 for TKR were identified, reviewed and selected by the panel. 301 052 and 416 030 patients newly consulting between 1992 and 2015 were identified in the hip and knee cohorts, respectively (median follow-up 6 years). The resultant model C-statistics is 0.73 (0.72, 0.73) and 0.79 (0.78, 0.79) for THR (with 20 predictors) and TKR model (with 24 predictors), respectively. The IECV C-statistics ranged between 0.70–0.74 (THR model) and 0.76–0.82 (TKR model); the IECV calibration slope ranged between 0.93–1.07 (THR model) and 0.92–1.12 (TKR model).ConclusionsTwo prediction models with good discrimination and calibration that estimate individuals’ risk of THR and TKR have been developed and validated in large-scale, nationally representative data, and are readily automated in electronic patient records.

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Statin use and reduced risk of biliary tract cancers in the UK Clinical Practice Research Datalink

Gut ◽

10.1136/gutjnl-2018-317504 ◽

2018 ◽

Vol 68 (8) ◽

pp. 1458-1464 ◽

Cited By ~ 3

Author(s):

Zhiwei Liu ◽

Rotana Alsaggaf ◽

Katherine A McGlynn ◽

Lesley A Anderson ◽

Huei-Ting Tsai ◽

...

Keyword(s):

Clinical Practice ◽

Biliary Tract ◽

Conditional Logistic Regression ◽

Incidence Density ◽

Practice Research ◽

Clinical Practice Research Datalink ◽

Biliary Tract Cancers ◽

The Uk ◽

Reduced Risk ◽

Statin Use

ObjectiveTo evaluate the association between statin use and risk of biliary tract cancers (BTC).DesignThis is a nested case–control study conducted in the UK Clinical Practice Research Datalink. We included cases diagnosed with incident primary BTCs, including cancers of the gall bladder, bile duct (ie, both intrahepatic and extrahepatic cholangiocarcinoma), ampulla of Vater and mixed type, between 1990 and 2017. For each case, we selected five controls who did not develop BTCs at the time of case diagnosis, matched by sex, year of birth, calendar time and years of enrolment in the general practice using incidence density sampling. Exposures were defined as two or more prescription records of statins 1 year prior to BTC diagnosis or control selection. ORs and 95% CIs for associations between statins and BTC overall and by subtypes were estimated using conditional logistic regression, adjusted for relevant confounders.ResultsWe included 3118 BTC cases and 15 519 cancer-free controls. Current statin use versus non-use was associated with a reduced risk of all BTCs combined (adjusted OR=0.88, 95% CI 0.79 to 0.98). The reduced risks were most pronounced among long-term users, as indicated by increasing number of prescriptions (ptrend=0.016) and cumulative dose of statins (ptrend=0.008). The magnitude of association was similar for statin use and risk of individual types of BTCs. The reduced risk of BTCs associated with a record of current statin use versus non-use was more pronounced among persons with diabetes (adjusted OR=0.72, 95% CI 0.57 to 0.91). Among non-diabetics, the adjusted OR for current statin use versus non-use was 0.91 (95% CI 0.81 to 1.03, pheterogeneity=0.007).ConclusionCompared with non-use of statins, current statin use is associated with 12% lower risk of BTCs; no association found with former statin use. If replicated, particularly in countries with a high incidence of BTCs, our findings could pave the way for evaluating the value of statins for BTC chemoprevention.

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Validation of hip osteoarthritis diagnosis recording in the UK Clinical Practice Research Datalink

Pharmacoepidemiology and Drug Safety ◽

10.1002/pds.4673 ◽

2018 ◽

Vol 28 (2) ◽

pp. 187-193 ◽

Cited By ~ 3

Author(s):

Rory J. Ferguson ◽

Daniel Prieto‐Alhambra ◽

Christine Walker ◽

Dahai Yu ◽

Jose M. Valderas ◽

...

Keyword(s):

Clinical Practice ◽

Hip Osteoarthritis ◽

Practice Research ◽

Clinical Practice Research Datalink ◽

The Uk

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Peptides in COVID-19 Clinical Trials—A Snapshot

Biologics ◽

10.3390/biologics1030018 ◽

2021 ◽

Vol 1 (3) ◽

pp. 300-311

Author(s):

Kai Hilpert

Keyword(s):

Clinical Trials ◽

Antiviral Activity ◽

Russian Federation ◽

Current Situation ◽

Routine Diagnostics ◽

Current Review ◽

The Usa ◽

The Russian Federation ◽

The Uk

Since the beginning of the COVID-19 pandemic, there has been a strong drive and desire to find effective treatments for and protection against the disease. On the webpage ClinicalTrials.gov, a total of 6505 clinical trials currently (September 2021) investigating various aspects of COVID-19 are registered. Of these, 124 studies involving peptides were identified. These 124 were further evaluated, and 88 trials that used peptides only for routine diagnostics were excluded. The remaining 36 trials were classified into 5 different classes according to their function: immunomodulatory (5 trials), regain homeostasis (10 trials), diagnostics/biomarkers (8 trials), vaccination (9 trials), and antiviral activity (4 trials, all overlap with immunomodulatory activities). In the current review, these 36 trials are briefly described and tabularly summarised. According to the estimated finish date, 14 trials have not yet finished. All of the finished trials are yet to report their results. Seven trials were based in the USA, and Egypt, France, the UK, Turkey, and the Russian Federation conducted three trials each. This review aims to present a snapshot of the current situation of peptides in COVID-19 clinical trials and provides a template to follow up on trials of interest; it does not claim to be a complete overview.

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