34th International Conference on Pharmacoepidemiology & Therapeutic Risk Management (ICPE), Prague, August 2018

Title

Risk of major and clinically relevant non-major (CRNM) bleeding in patients prescribed rivaroxaban for Stroke Prevention in non-valvular AF (SPAF) and the prevention and/or treatment of Deep Vein Thrombosis and/or Pulmonary Embolism (DVT/PE) in primary care in England.

Dhanda S, Davies M, Roy D, Wise L and Shakir S. Presented by Alison Evans.

Background

Clinical trials and observational studies have reported bleeding risk in patients (pts) taking rivaroxaban. A PASS was carried out as part of the RMP to monitor the safety and use of rivaroxaban using real-world primary (1°) care data in England.

Objectives

To estimate the risk of major and CRNM bleeding in pts prescribed rivaroxaban for SPAF and DVT/PE in 1° care.

Methods

Pts identified from dispensed prescriptions in England (2012-2016). Detailed questionnaires sent to general practitioners (GPs) at ≥3 and ≥12 months of observation collected information on risk factors for bleeding (HAS-BLED) and bleeding outcomes. Summary descriptive statistics and 12-month risk estimates were calculated.

Results

Cohort = 17546 pts: 10225 pts with AF (58.3% of cohort, median age 78 years (yrs) [IQR 70-84], 5253 (51.4%) male); 5959 pts with DVT/PE (34.0 % of cohort, median age 66 yrs [IQR 50-78]; 3197 (53.6%) female). In both groups, the median HAS-BLED score was 1 (IQR 1-2, 0-1, respectively) reflecting a low risk of major bleeding.

AF group: Risk Major + CRNM bleeding 8.3% ([95% CI 7.8, 8.9]; n=825). Risk Major bleed (MB) 2.4% ([95% CI 2.1, 2.7]; n=239), CRNM bleeding 6.0% ([95% CI 5.5, 6.4]; n=592). MB further stratified by site: gastrointestinal (GI) (1.2%; n=117), urogenital (UG) (0.1%; n=13), intracranial (IC) (0.4%; n=42), all other critical organ (excluding IC) (0.3%; n=26) and all non-critical organ sites (0.4%; n=44).

DVT/PE group: Risk Major + CRNM bleeding 4.2% ([95% CI 3.7, 4.7]; n=240). Risk MB 1.4% ([95% CI 1.1, 1.7]; n=82), CRNM bleeding 2.8% ([95% CI 2.4, 3.3]; n=162). MB further stratified by site: GI (0.7%; n=38), UG (0.3%; n=18), IC (0.2%; n=12), all other critical organ (excluding IC) (0.1%; n=4) and all non-critical organ sites (0.2%; n=10).

Conclusion

For the primary outcome of major bleeding, the estimates of risk in the AF and DVT/PE rivaroxaban user populations were overall low and consistent with those estimated from clinical trial data. Differences in methodologies and analysed study populations prevent meaningful comparisons with other studies. This study design has unique strengths, including the collection of timely, granular data directly from prescribing GPs, however selective reporting of outcomes and selection bias might be present, and should be considered when interpreting results.

Title

Multi-level modelling to investigate factors impacting prescribing variability.

Roy D, Wise L and Shakir S

Background

Prescribing guidelines influence treatment choice based on patient (pt) and healthcare system factors. Multi-level modelling (MLM) can provide insight into sources of variability in healthcare, especially where nested hierarchical structures exist. A Specialist Cohort Event Monitoring study investigated the safety and use of rivaroxaban in clinical use, with a warfarin cohort for context.

Objectives

Study to investigate prescribing variability using MLM.

Methods

Data on NHS acute trusts in England/Wales (e.g. population size, trust type) were linked to study pt demographic and drug utilization data, and prescriber details (e.g. degree, specialty).

Using MLM we explored the influence of pt, prescriber and trust characteristics on prescribing variability in 2106 rivaroxaban (59%) vs. 1468 warfarin (41%) adult pt nested in 780 prescribers, nested in 73 trusts. The majority of pt had an indication of DVT/PE (56.4%) or non-valvular AF (AF) (41.2%). The binary outcome was rivaroxaban or warfarin treatment.

Variance components estimate the variability accounted for by each level in the model and are expressed as: Median Odd Ratios (MOR – median relative increase in odds of rivaroxaban treatment if pt changed prescriber (PR) or trust (T)); Proportional Change in Variance (PCV) between models when successively adding fixed effects.

Results

DVT/PE group:

Adjusting for pt factors, MORT=6.9 (PCV=-0.6%); MORPR=2.8 (PCV=3.8%).

Adjusting for pt and prescriber factors, MORT=6.8 (PCV=-2.9%); MORPR=2.6 (PCV=-15.4%).

Adjusting for pt, prescriber and trust factors, MORT=4.9 (PCV=-30.2%); MORPR=2.6 (PCV=3.4%).

Differences between trusts and prescribers (in trusts) are important in treatment choice; trust being more influential. Some pt factors had a relatively large effect on odds of treatment choice although the absolute number of pt impacted was often small. Trust type, was shown to be associated with the odds of treatment choice [Final model: foundation vs acute trusts OR 4.0 (95%CI 1.5, 9.9)].

Data on AF and all indications (combined) will be included in the final presentation.

Conclusion

This study highlights the utility of MLM in exploring pt and non-pt factors in nested hierarchical healthcare settings. Prescribing variability appears dominated by differences between trusts and prescribers (in trusts). Some pt factors were important in treatment choice, but PCV between models suggest that accounting for pt differences does not fully explain the variance between prescribers (in trusts) and between trusts.

Title

Abstract 2500: Utilisation and safety of asenapine in primary care in England: Results from a PASS.

Dhanda S, Coukan F, Wise L and Shakir S

Background

Asenapine is approved in the EU for the treatment of manic episodes associated with bipolar I disorder in adults. A PASS was carried out to monitor the use and safety of asenapine using real-world primary care data in England; targeted safety outcomes were oral hypoaesthesia, oropharyngeal swelling, somnolence and sedation, acute allergic reactions and weight gain (defined as weight (kg) and/or BMI (kg/m2) increase of ≥7% at end of study vs. index).

Objectives

To describe the utilisation and safety of asenapine in primary care in England.

Methods

A cohort study identified patients (pts) from dispensed prescriptions of asenapine in England from Jan 2012-June 2016. Pt characteristics, drug utilisation and outcome data were collected from prescribing general practitioners via questionnaires sent at ≥3, and ≥12 months after the 1st prescription issued for each pt. Summary descriptive statistics were calculated.

Results

The cohort consisted of 122 pts with 3-month data of whom 56 pts had corresponding 12-month data (median age 44 years [IQR 35-55]; 66.4% female). The most frequent indication was bipolar disorder (n=81, 66.4%); for 10 pts (12.3%), the indication was specifically reported as bipolar I disorder. There were also a number of off-label indications e.g., schizophrenia (n=21, 17.2%). Asenapine was prescribed in accordance with the product label for 61 pts (50.0%) who were started on 5mg bd; 19 pts (15.6%) were prescribed 10mg bd.

For the 3-month cohort, incidence of targeted events was; oral hypoaesthesia n=0 (0.0%), oropharyngeal swelling n=1 (0.8%), sedation/somnolence n=5 (4.1%), acute allergic reactions n=0 (0.0%).

For the 12-month cohort, incidence of targeted events was; oral hypoaesthesia n=0 (0.0%), oropharyngeal swelling n=1 (1.8%), sedation/somnolence n=6 (10.7%), acute allergic reactions n=0 (0.0%), weight gain n=10 (17.9%).

In addition to the targeted outcomes other events of interest included four deaths, one of which was a completed suicide, and a case of foetal spina bifida diagnosed in a pregnant patient taking multiple psychiatric medications.

Conclusion

Asenapine was largely prescribed in accordance with prescribing recommendations. Event counts were small and no new safety signals were identified. This study design allowed for the timely collection of drug utilisation and safety data directly from prescribing GPs. However, as a result of the small cohort size, any conclusions from this study should be put into context with results from other post-marketing studies.

Title

Abstract 2508: Utilisation and safety of asenapine in secondary care in the UK: Results from the Observational Safety Evaluation of Asenapine (OBSERVA) study.

Dhanda S, Slade J, Coukan F, Wise L and Shakir S.

Background

The OBSERVA specialist cohort event monitoring (SCEM) study, conducted in secondary care in the UK, formed part of an EU risk management plan to monitor the use and short-term safety of asenapine, licensed for the treatment of moderate to severe manic episodes associated with bipolar I disorder in adults. Targeted safety outcomes were oral hypoaesthesia, oropharyngeal swelling, somnolence and sedation, acute allergic reactions and weight gain (defined as weight (kg) and/or BMI (kg/m2) increase of ≥7% at end of study vs. index).

Objectives

To describe the utilisation and safety of asenapine prescribed in secondary care in the UK.

Methods

An observational cohort study identified patients (pts) via a network of psychiatrists in collaboration with the Mental Health Research Network from Nov 2012-Sept 2016. Pt characteristics, drug utilisation and outcome data were collected via questionnaires completed by specialists sent at baseline and after 12 weeks of observation. Summary descriptive statistics were calculated.

Results

The final cohort consisted of 125 pts; the median age was 44 years [IQR 35-52]; 63 (50.4%) were male. Asenapine was most frequently prescribed for bipolar disorder (n=81, 64.8%); 15 of these patients (18.5%) had bipolar I disorder reported. There were also a number of off-label indications e.g., schizophrenia (n=18, 14.4%). Asenapine was largely prescribed in accordance with the product label; 56 pts (44.8%) were started on 5mg bd and at 12 weeks 34 pts (27.2%) were taking 10mg bd.

The incidence of targeted events was as follows; oral hypoaesthesia n=9 (7.2%), oropharyngeal swelling n=0 (0.0%), sedation n=13 (10.4%), somnolence n=11 (8.8%), acute allergic reactions n=0 (0.0%), weight gain n=1 (0.8%).

No deaths or pregnancies were reported in the OBSERVA study.

Conclusion

Asenapine was largely prescribed in accordance with prescribing recommendations; the majority of pts were taking asenapine for bipolar disorder at the recommended dose. Event counts were small and no new safety signals were identified. This study provides valuable real-word data to support the post marketing risk-benefit profile of asenapine, however as a result of the small cohort size, any conclusions from this study should be put into context with results from other research evidence.

Title

Abstract 2082: Distribution of CHA2DS2-VASc scores in patients with atrial fibrillation treated with Rivaroxaban in primary vs. secondary care settings.

Davies M, Wise L and Shakir S.

Background

Since its incorporation in the European Society of Cardiology guidelines in 2010, the CHA2DS2-VASc score is widely used to characterise the risk of stroke in patients (pts) with atrial fibrillation (AF). It is frequently calculated in pharmacoepidemiological studies through retrospective application of the component criteria included in the risk score. CHA2DS2-VASc Scores of 0, 1, or ≥2 indicate low, moderate, or high stroke risk, respectively.

Objectives

To describe the distribution of CHA2DS2-VASc scores and individual stroke risk components in two cohorts of pts prescribed rivaroxaban for AF in primary (1 o) vs. secondary (2 o) care.

Methods

Two PASS were conducted to investigate the safety of rivaroxaban in pts with AF in 1o care (Modified-Prescription Event Monitoring) and 2 o care (Specialist Cohort Event Monitoring) (2012-2016). Baseline characteristics were provided by general practitioners (1o care) and specialist prescribers (2 o care) using customised questionnaires. An algorithm was used to compute a CHA2DS2-VASc score (0 – 9) for each pt from fixed response options or open questions, according to published guidelines.

Results

The response rate for baseline questionnaires was lower in 1o care vs. 2 o care (22.3% vs. 99.7%). The 1o care cohort consisted of 10225 pts with a primary indication of AF (median age 78 yrs [IQR 70-84]; 5253 [51.4%] male). The median CHA2DS2-VASc score was 4 (IQR 3-5) reflecting a high risk of stroke. The 2 o care cohort consisted of 965 pts with a primary indication of AF (median age 76 yrs [IQR 69-83]; 517 [53.6%] male), with a median CHA2DS2-VASc score of 4 (IQR 3-6). There were a higher proportion of pts with a score of 6 – 9 in 2 o care vs. 1 o care. The proportions of pts in 1o care vs. 2 o care with each criterion were:

• Age 65-74 yrs (25.7% vs. 25.8%)
• ≥75 yrs (61.8% vs. 58.0%)
• Female (48.6% vs. 46.5%)
• Congestive Heart Failure/Left ventricular Dysfunction (14.3% vs. 14.6%)
• History Hypertension (82.6% vs. 73.2%)
• History Stroke, Transient Ischaemic Attack (TIA) or Thromboembolism (TE) (19.8% vs. 46.9%)
• Vascular disease (11.3% vs. 26.9%)
• Diabetes Mellitus (17.2% vs. 18.8%)

Conclusion

These results suggest that pts initiated rivaroxaban for AF in 2 o care are more likely to have a history of stroke, TIA, TE or vascular disease than pts treated in 1o care. This may mean that pts considered to be at ‘higher risk’ with greater co-morbidities are more likely to be managed in 2 o care, or that co-morbidities may be less well recorded in 1o care.

Ref: Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation. Chest. 2010;137(2):263-72.

Title

Abstract 2516: Characteristics of patients initiated on a reduced dose of rivaroxaban for atrial fibrillation (AF) – results from the ROSE (Rivaroxaban Observational Safety Evaluation) study.

Davies M, Evans A, Coukan F, Wise L and Shakir S.

Background

Rivaroxaban is used to treat a range of conditions, including prevention of stroke and systemic embolism in patients with AF. This indication requires a fixed once-daily (od) dose (20mg) with dosage reduction to 15 mg once daily only recommended in patients (pts) with renal impairment (creatinine clearance 15-49 ml/min). However other clinical factors might be considered by the prescriber when choosing an initial dose.

Objectives

To describe the clinical characteristics of pts prescribed an initial dose of (≥ 20mg and <20 mg daily) for treatment of AF in secondary care.

Methods

The ROSE study was a specialist cohort event monitoring study of pts prescribed rivaroxaban. Specialists provided information from medical records via questionnaires at baseline and ≥ 12 weeks. Information on the prescribed initial dose and baseline characteristics including risk factors for bleeding (HAS-BLED criteria) was collected. For pts prescribed a reduced initial dose (<20 mg daily), we assessed clinical characteristics vs. pts prescribed ≥ 20mg daily.

Results

The cohort consisted of 965 pts with AF; of whom (18.3%, n=177), were prescribed an initial dose of <20 mg daily (15mg od [n=173]; 10mg od [n=3]; 4mg od [n=1]). The majority were female (57.6%, median age 84 yrs) vs. pts prescribed ≥ 20mg daily (20mg od [n=750]; 30mg od [n=16]), where the majority were male (56.4%, median age 75 yrs). 36/177 (20.3%) pts had a history of CKD 3-4 or 5. For 22 patients the start dose was unknown. Frequency of HAS-BLED criteria in pts prescribed <20 mg daily vs. ≥ 20mg daily was: Hypertension (37.3% vs. 38.5%), Abnormal renal function (Chronic dialysis, renal transplant, serum creatinine ≥ 2.3 mg/dL or 200 µmol/L) (3.4% vs. 1.2%), Abnormal liver function (0.6% vs. 1.0%), History of Stroke (31.1% vs. 30.4%), History of Bleeding/predisposition (18.6% vs. 16.3%), Labile INR (N/A), Age ≥65 yrs (96.1% vs. 81.2%), Drug therapy (52.0% vs. 51.4%), Alcohol (0% vs. 4.8%).

Conclusion

In pts prescribed a reduced total daily dose of rivaroxaban <20 mg od, there were a higher proportion of females and those aged ≥65 yrs. Patients prescribed this lower dose were also more likely to have abnormal renal function, defined as per HAS-BLED, than those patients prescribed ≥ 20mg daily. Although the label recommends dose reduction in AF pts with renal impairment, other factors seem to impact the choice of the initial dose in the clinical setting.

Title

Abstract 2521: Assessment of initiation dose in patients prescribed rivaroxaban for stroke prevention in non-valvular AF (SPAF) and chronic kidney disease – results from the ROSE (Rivaroxaban Observational Safety Evaluation) study.

Davies M, Evans A, Coukan F, Wise L and Shakir S.

Background

Rivaroxaban is used to treat patients with non-valvular AF for the prevention of stroke and systemic embolism. This requires a fixed daily dose (20mg) with dosage reduction only recommended in patients with a reduced creatinine clearance (15-49 ml/min), a range encompassed within chronic kidney disease (CKD) stage 3-4 (eGFR 15-59) although CKD 3a (eGFR 45-59) is largely outside this range. Rivaroxaban is not recommended in patients with severe renal impairment (creatinine clearance < 15 ml/min).

Objectives

To assess starting dose amongst patients with chronic kidney disease stage 3-4 or 5.

Methods

The ROSE study was a specialist cohort event monitoring study of patients prescribed rivaroxaban. Specialists provided information via detailed questionnaires at baseline (and ≥ 12weeks). Baseline characteristics included starting dose and presence of either CKD stage 3-4 (eGFR 15-59) or CKD stage 5 (eGFR < 15). Starting dose was examined amongst patients with CKD stage 3-4 and 5 to assess how many patients had a reduced starting dose of less than 20mg od.

Results

The cohort consisted of 965 patients with AF: 75 patients with history of either stage 3-4 CKD (n=73, 7.6%) or stage 5 CKD (n=2, 0.2%). Of the patients with CKD stage 3-4, 36 (49.3 %) were started on <20 mg daily (15mg od [n=35]; 10mg od [n=1]). 35 patients (48.0 %) were started on ≥ 20mg (20mg od [n=34]; 30mg od [n=1]). Starting dose was missing for two patients (2.7%). Neither patient with CKD stage 5 had a dose reduction.

Conclusion

Our results suggest that amongst patients with CKD stage 3-4, approximately half were started on the recommended reduced dose of < 20mg od. Not all patients with CKD stage 3-4 would be recommended a dose reduction as per the product label. A UK audit suggests that approximately 20% of patients in the UK with CKD 3 are 3b rather than 3a although the frequency may be higher in a hospital cohort.

Title

Abstract 2051: Incidence of Major and Clinically Relevant Non-Major (CRNM) Bleeding in Patients Prescribed Rivaroxaban in Secondary Care: Results from the Rivaroxaban Observational Safety Evaluation (ROSE) Study

Evans A, Davies M, Wise L and Shakir S.

Background

The ROSE Specialist Cohort Event Monitoring (SCEM) study was conducted to monitor the safety and use of rivaroxaban for Stroke Prevention in patients (pts) with non-valvular AF (SPAF) and the prevention and/or treatment of Deep Vein Thrombosis and/or Pulmonary Embolism (DVT/PE). Bleeding risk has been previously estimated in various settings; this study aimed to estimate risk in secondary (2°) care real-world pts ≤ 12 weeks (wks

Objectives

To estimate the incidence of major and CRNM bleeding in pts prescribed rivaroxaban for SPAF and DVT/PE indications in 2° care in England and Wales.

Methods

Pts identified through speciality groups (2013-2016), supported by UK Clinical Research Networks. Risk factors for bleeding (HAS-BLED) and bleeding outcomes were collected via detailed questionnaires completed by hospital specialists at baseline and ≥ 12 wks. Summary descriptive statistics and 12 wk incidence estimates were calculated.

Results

Cohort consisted of 2542 pts: 965 pts with AF (38.0% of cohort; median age 76 years (yrs) [IQR 69, 83], 517 [53.6%] male), median HAS-BLED score 2 (IQR 1-3) (moderate risk of major bleeding); 1532 pts with DVT/PE (60.3% of cohort; median age 63 yrs [IQR 48, 73], 836 [54.6%] male), median HAS-BLED score 1 (IQR 0-2) (low risk of major bleeding). AF group: Rate Major + CRNM bleeding 28.2 per 100 pt yrs (95% CI 21.0, 37.1; n=51). Rate Major Bleed (MB) 5.5 (95% CI 2.6-10.1; n=10), CRNM bleeding 22.7 (95% CI 16.3-30.8; n=41). MB risk in pre-specified sites: gastrointestinal (GI) (0.2%; n=2), urogenital (UG) (0.2%; n=2), intracranial (IC) (0.2%; n=2) and all other critical organ (excluding IC) (0.1%; n=1). DVT/PE group: Rate Major + CRNM bleeding 36.2 (95% CI 29.4, 44.1; n=98). Rate MB 8.3 (95% CI 5.3, 12.5; n=23), CRNM bleeding 27.6 (95% CI 21.7, 34.6; n=75). MB risk in pre-specified sites: GI (0.7%; n=11), UG (0.3%; n=5), IC (0.1%; n=1) and all other critical organ (excluding IC) (0.0%; n=0).

Conclusion

The incidence of major bleeding was low and no new safety concerns were raised. Unique aspects of this study design enabled collection of highly detailed information from cardiologists, facilitating accurate calculation of risk scores and the application of clinical trial outcome definitions, in a real-word setting. Differences in methodology between this and other study designs prevents meaningful comparison.

Title

Abstract 2085: Passive enhanced safety surveillance in children receiving Fluenz ® Tetra vaccination in England during the early 2017 influenza season.

Hazell L, Shakir S, Denith J, Hammond, E and Brooks D.

Background

Fluenz® Tetra is a quadrivalent, live attenuated, intranasal, influenza vaccine recommended for use in children aged 2 to 17 years vaccination as part of the seasonal influenza immunisation campaign in the UK. This is the third post-approval season of passive enhanced safety surveillance (ESS) for the vaccine in 2017/18

Objectives

To measure and assess the frequencies of suspected adverse drug reactions (sADRs) in children receiving Fluenz® Tetra during the early 2017/18 influenza season in England.

Methods

Vaccinees or parents/guardians received a Safety Report Card (SRC) to return if children experienced sADRs after vaccination with Fluenz® Tetra. At participating sites, 38 general practices and 36 primary schools in England, immunisation teams recorded numbers of SRCs distributed. The project was approved by an NHS Research Ethics Committee (Hampshire B South Central NRES Committee).

Results

Between 29th September and 2nd December 2017, 12,193 children were vaccinated at participating sites, with 16 different vaccine lots used. In total, 10,793 SRCs were issued for children aged 2 to 17 years including 5,189 children (48.1%) aged 2 to 4 years, 5,036 (46.7%) aged 5 to 10 years and 568 aged 11 to 17 years. Of 114 SRCs returned (by 9th January 2018 datalock), 101 SRCs reported at least one sADR (0.9% of all SRCs issued). The most frequently reported sADRs were rhinorrhoea (n=36), pyrexia (31) and cough (14). Three reported sADRs were classified as serious due to hospitalisation (0.03% of SRCs issued) including nasal symptoms, general cold/flu symptoms and croup, from which all three children recovered. The frequency of sADRs reported in the current ESS season was consistent with that reported in previous seasons.

Conclusion

Overall, the number of sADRs reported for Fluenz® Tetra in the 2017/18 ESS remains low. Reported sADRs were typically minor expected events with serious sADRs rarely reported. The pattern and frequency of reported sADRs in the current season were consistent with previous seasons with no safety signals detected. Despite the limited number of reports received, the ESS method continues to be a useful extension to routine pharmacovigilance activities in the monitoring of possible sADRs. Project co-sponsored by DSRU and AstraZeneca.

Title

Abstract 1823: Sources of evidence supporting post-marketing pharmacovigilance regulatory actions since 2012.

Lane S, Lynn E and Shakir S.

Background

Major updates to the European Union (EU) pharmacovigilance (PV) legislation were implemented in July 2012. One objective of the update was “rapid and robust assessment of issues related to the safety of medicines.”(1) Since PV legislation updates were applied there have been no studies investigating sources of evidence and time to reach regulatory decision for products withdrawn, revoked, or suspended from EU market (“regulatory actions”). This study builds on previous DSRU research for 1999-2001 and 2002-2011.(2, 3)

Objectives

To assess sources of publicly available evidence supporting regulatory actions due to safety reasons in the EU since 2012. To investigate time taken from authorisation to reach each regulatory decision.

Methods

Types of publicly available evidence, time to decision and duration of marketing for each identified product were examined. We considered prescription products subject to regulatory action in the EU market (plus Norway, Iceland and Liechtenstein) for safety reasons between 1 July 2012 and 31 December 2016 for inclusion. Evidence supporting each regulatory action was identified and categorised; frequencies and proportions were calculated. Median time to regulatory decision and duration of marketing prior to regulatory action were calculated. ANOVA was performed for time to regulatory decision.

Results

18 medicinal products withdrawn, revoked or suspended in the EU for safety reasons between 2012 and 2016 met our inclusion criteria. Case reports most frequently supported regulatory actions (n=17, 94.4%). Epidemiological study designs were least commonly cited (n=8, 44.4%). Multiple sources of evidence contributed to 94.4% of regulatory decisions (n=17). Death most commonly led to regulatory action (n=5; 27.8%), with four of these related to medication error or overdose. Median (IQR) time taken to reach a decision from the start of regulatory review was 204.5 days (143, 535 days) and fell across the study period (p=0.87). Duration of marketing prior to regulatory action from each authorisation date increased between 2012 and 2016.

Conclusion

Sources of evidence supporting PV regulatory activities appear to have changed since implementation of updated EU PV legislation, particularly in favour of multiple supporting study designs. Case reports remain a common evidence source in regulatory decision-making, while epidemiological designs were least frequently cited. A small drop in time to reach regulatory decisions suggests better regulatory efficiency.

References

1. European Medicines Agency. Legal Framework London: European Medicines Agency; 2017 [Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/special_topics/general/general_content_000491.jsp&mid=WC0b01ac058058f32d.]
2. Clarke A, Deeks JJ, Shakir SA. An assessment of the publicly disseminated evidence of safety used in decisions to withdraw medicinal products from the UK and US markets. Drug Saf. 2006;29(2):175-81.
3. McNaughton R, Huet G, Shakir S. An investigation into drug products withdrawn from the EU market between 2002 and 2011 for safety reasons and the evidence used to support the decision-making. BMJ Open. 2014;4(1):e004221.