Generalizability of clinical trial efficacy results to a real-world population: An example in migraine prevention.

BACKGROUND: Health care decision makers are often concerned about the external validity of randomized controlled trials (RCTs), as their results may not apply to certain patients in the real world who intend to receive treatment. OBJECTIVE: To demonstrate a methodology for assessing the generalizability of clinical trial results to a real-world population, before sufficient and appropriate real-world effectiveness data are available, using individual patient-level data from an RCT and aggregated baseline data from a real-world French registry in migraine. METHODS: The analyses were conducted in 2 steps. First, individual patient-level baseline data from the multinational CONQUER RCT were weighted to match aggregated real-world InovPain registry patient characteristic data. Matched patient characteristics were sex, age, migraine type and duration, number of monthly migraine headache days, and number of monthly headache days at baseline. Second, the weighted CONQUER patient data were used to reanalyze the primary endpoint of CONQUER (least squares mean change from baseline in the number of monthly migraine headache days during the 3-month double-blind treatment phase) using predefined methodology. Sensitivity analyses were conducted to assess the robustness of findings. RESULTS: A total of 462 patients with migraine were randomized and treated with galcanezumab or placebo in CONQUER; aggregated InovPain data were available from 130 patients with migraine. We identified no important differences in baseline patient characteristics between the 2 prespecified populations, suggesting good external validity for CONQUER. Although this limited the extent of observed differences between the original and matched CONQUER populations, weighting of CONQUER data did help harmonize the 2 datasets and allow the results obtained in CONQUER to be generalized to patients more representative of the real-world French population with migraine. Results of weighted analyses suggested that galcanezumab would be superior to placebo for reducing monthly migraine headache days in a clinical trial in patients with episodic or chronic migraine who reflected the characteristics of patients eligible to receive the drug in France. CONCLUSIONS: Findings suggest that our methods may be helpful for assessing the generalizability of clinical trial results to a real-world population before the availability of substantial real-world clinical data.

Efficacy of galcanezumab in patients with migraine and history of failure to 3-4 preventive medication categories: subgroup analysis from CONQUER study.

BACKGROUND: Chronic migraine (CM) and episodic migraine (EM) are associated with substantial headache-related disability, poor quality of life and global societal burden. In this subgroup analysis from the CONQUER study, we report efficacy outcomes from a pre-specified analysis of galcanezumab versus placebo in patients with CM or EM and 3-4 prior preventive medication category failures due to inadequate efficacy (after at least 2 months at maximum tolerated dose), or safety or tolerability reasons. The patient population is of particular interest due to evidence of decreased quality of life and increased economic burden among patients with migraine that is inadequately managed and is of interest to decision-makers globally. METHODS: Key outcomes included overall mean change from baseline in monthly migraine headache days and proportions of patients achieving ≥30% (CM), ≥50%, and ≥ 75% reduction (response rates) in monthly migraine headache days across Months 1-3. Patient functioning and disability were evaluated at Month 3. RESULTS: Of the 462 randomized patients, 186 (40.3%) had a history of 3-4 preventive category failures. Galcanezumab versus placebo resulted in significantly (P ≤ .001) larger overall mean reduction in monthly migraine headache days (total: - 5.49 versus - 1.03; CM: - 6.70 versus - 1.56; EM: - 3.64 versus - 0.65). Similarly, the ≥50% response rate was significantly (P ≤ .001) higher with galcanezumab versus placebo (total: 41.0 versus 12.7; CM: 41.5 versus 8.4; EM: 41.1 versus 16.5). In the CM group, the ≥30% response rate was significantly higher in the galcanezumab group than the placebo group (CM, 57.5 versus 19.8, P ≤ .0001) as was the ≥75% response rate (13.3 versus 2.6, P ≤ .05). Galcanezumab also resulted in significant (P < .0001) improvements in patient functioning and reductions in disability. CONCLUSIONS: Galcanezumab was effective in a difficult-to-treat population of patients with CM or EM who had failed 3-4 prior preventive medication categories. TRIAL REGISTRATION: CONQUER. Clinicaltrials.gov identifier: NCT03559257 .

Subgroup analyses in cost-effectiveness analyses to support health technology assessments.

'Success' in drug development is bringing to patients a new medicine that has an acceptable benefit-risk profile and that is also cost-effective. Cost-effectiveness means that the incremental clinical benefit is deemed worth paying for by a healthcare system, and it has an important role in enabling manufacturers to obtain new medicines to patients as soon as possible following regulatory approval. Subgroup analyses are increasingly being utilised by decision-makers in the determination of the cost-effectiveness of new medicines when making recommendations. This paper highlights the statistical considerations when using subgroup analyses to support cost-effectiveness for a health technology assessment. The key principles recommended for subgroup analyses supporting clinical effectiveness published by Paget et al. are evaluated with respect to subgroup analyses supporting cost-effectiveness. A health technology assessment case study is included to highlight the importance of subgroup analyses when incorporated into cost-effectiveness analyses. In summary, we recommend planning subgroup analyses for cost-effectiveness analyses early in the drug development process and adhering to good statistical principles when using subgroup analyses in this context. In particular, we consider it important to provide transparency in how subgroups are defined, be able to demonstrate the robustness of the subgroup results and be able to quantify the uncertainty in the subgroup analyses of cost-effectiveness.

The efficacy of duloxetine, non-steroidal anti-inflammatory drugs, and opioids in osteoarthritis: a systematic literature review and meta-analysis.

BACKGROUND: This meta-analysis assessed the efficacy of duloxetine versus other oral treatments used after failure of acetaminophen for management of patients with osteoarthritis. METHODS: A systematic literature review of English language articles was performed in PUBMED, EMBASE, MedLine In-Process, Cochrane Library, and ClinicalTrials.gov between January 1985 and March 2013. Randomized controlled trials of duloxetine and all oral non-steroidal anti-inflammatory drugs and opioids were included if treatment was ≥12 weeks and the Western Ontario and McMaster Universities Index (WOMAC) total score was available. Studies were assessed for quality using the assessment tool from the National Institute for Health and Clinical Excellence guidelines for single technology appraisal submissions.WOMAC baseline and change from baseline total scores were extracted and standardized. A frequentist meta-analysis, meta-regression, and indirect comparison were performed using the DerSimonian-Laird and Bucher methods. Bayesian analyses with and without adjustment for study-level covariates were performed using noninformative priors. RESULTS: Thirty-two publications reported 34 trials (2 publications each reported 2 trials) that met inclusion criteria. The analyses found all treatments except oxycodone (frequentist) and hydromorphone (frequentist and Bayesian) to be more effective than placebo. Indirect comparisons to duloxetine found no significant differences for most of the compounds. Some analyses showed evidence of a difference with duloxetine for etoricoxib (better), tramadol and oxycodone (worse), but without consistent results between analyses. Forest plots revealed positive trends in overall efficacy improvement with baseline scores. Adjusting for baseline, the probability duloxetine is superior to other treatments ranges between 15% to 100%.Limitations of this study include the low number of studies included in the analyses, the inclusion of only English language publications, and possible ecological fallacy associated with patient level characteristics. CONCLUSIONS: This analysis suggests no difference between duloxetine and other post-first line oral treatments for osteoarthritis (OA) in total WOMAC score after approximately 12 weeks of treatment. Significant results for 3 compounds (1 better and 2 worse) were not consistent across performed analyses.

Efficacy of duloxetine versus alternative oral therapies: an indirect comparison of randomised clinical trials in chronic low back pain.

INTRODUCTION: The objective of this study was to obtain parameter estimates for the efficacy of duloxetine versus alternative oral therapies for the treatment of chronic low back pain. MATERIALS AND METHODS: Electronic databases were searched to identify randomised, double-blind placebo-controlled trials. Studies reporting pain intensity, with parallel-group design of oral treatments with length of treatment of more than 8 weeks were included. A Bayesian approach to indirect comparisons was applied, using standardised mean difference as a measure of relative treatment effect. RESULTS: Fifteen studies were identified comparing duloxetine with the following oral drug classes: non-scheduled opioids, cyclooxygenase-2 inhibitors, scheduled opioids, selective serotonin reuptake inhibitors, and 'other' (i.e. glucosamine). The primary analysis found scheduled opioids to be more effective than duloxetine for the fixed effects model. However, the estimate of the treatment difference reflected a less than small magnitude of effect (|standardised mean difference| <0.2), and there was no difference for the random effects model. No differences were found in sensitivity analyses involving the subset of patients not receiving concomitant non-steroidal anti-inflammatory medication. CONCLUSION: The available evidence shows that there does not seem to be any difference in efficacy between duloxetine and other oral pharmacological therapies, providing a valuable alternative for this disabling condition.

Differences in the use of guideline-recommended therapies among 14 European countries in patients with acute coronary syndromes undergoing PCI.

AIMS: Despite common European Society of Cardiology recommendations, adherence to guideline therapy varies, both temporally and geographically. We sought to examine current differences in the use of guideline-recommended therapies among 14 European countries in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). METHODS AND RESULTS: Data were obtained from the Antiplatelet Therapy Observational Registry (APTOR), a non-interventional, prospective observational cohort study enrolling patients with ACS undergoing PCI. Medication data were captured through 1 year. The large majority of patients in the APTOR registry received statins at hospital discharge (89%) and remained on statins at 1 year (87%), a finding that was consistent across countries. Likewise, beta-blocker use was similar at discharge and 1 year (83 and 81%, respectively). There was large disparity in aspirin loading dose between countries, but the discharge maintenance dose was more consistent, with most receiving ≤ 100 mg (87%). While 95% of patients were discharged on dual antiplatelet therapy, 71% remained on both treatments by 1 year, with wide variation by country in 1-year use. CONCLUSIONS: These data from the APTOR study provide key information on current European ACS patient care management from hospitalization through 1 year. Even with European Society of Cardiology (ESC) guidelines, variations in practice patterns exist among ACS patients treated with PCI between the 14 European countries studied, including the use of proven therapies, as well as appropriate duration and dosing of antiplatelet regimens. Efforts are needed to further explain why such variation exists and to continue to improve adherence to ESC guidelines to improve patient care.

Subgroup analyses of clinical effectiveness to support health technology assessments.

Subgroup analysis is an integral part of access and reimbursement dossiers, in particular health technology assessment (HTA), and their HTA recommendations are often limited to subpopulations. HTA recommendations for subpopulations are not always clear and without controversies. In this paper, we review several HTA guidelines regarding subgroup analyses. We describe good statistical principles for subgroup analyses of clinical effectiveness to support HTAs and include case examples where HTA recommendations were given to subpopulations only. Unlike regulatory submissions, pharmaceutical statisticians in most companies have had limited involvement in the planning, design and preparation of HTA/payers submissions. We hope to change this by highlighting how pharmaceutical statisticians should contribute to payers' submissions. This includes early engagement in reimbursement strategy discussions to influence the design, analysis and interpretation of phase III randomized clinical trials as well as meta-analyses/network meta-analyses. The focus on this paper is on subgroup analyses relating to clinical effectiveness as we believe this is the first key step of statistical involvement and influence in the preparation of HTA and reimbursement submissions.

Aspects of sexual satisfaction in men with erectile dysfunction: a factor analytic and logistic regression approach.

INTRODUCTION: The International Index of Erectile Function (IIEF), Sexual Encounter Profile (SEP), and Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) assess efficacy of phosphodiesterase type 5 (PDE5) inhibitor treatment of erectile dysfunction (ED). AIMS: To determine the degree that multiplicity of satisfaction questions in ED treatment evaluation instruments are congruent, to better understand the concept of sexual "satisfaction," and to identify factors that correlate with improvement. METHODS: Questionnaire data from 4,174 placebo- or tadalafil-treated patients with ED were analyzed. Principal component analysis (PCA) was performed on IIEF and SEP satisfaction questions. Spearman correlation coefficients were determined. Data from 431 of the 4,174 patients who completed EDITS questionnaires were analyzed. Logistic regression was used to investigate improvement of each IIEF satisfaction question. RESULTS: PCA rotated on three factors explained 91% of total variance and separated IIEF Q6 (intercourse frequency) from a SEP and a remaining IIEF factor. All correlations between and among questions were close (rho = 0.62-0.98; P < 0.0001), except for those with IIEF Q6 (rho = 0.28-0.34; P < 0.0001). In a sub-sample, PCA of five IIEF, two SEP, and three EDITS questions identified four factors that explained 90% of all variance: EDITS questions, IIEF questions except Q6, SEP questions, and IIEF Q6. Greater improvement in IIEF-EF domain score was consistently and positively associated with satisfaction measures (P < 0.0001). CONCLUSIONS: Factor analysis detected close relationships among satisfaction questions in IIEF, SEP, and EDITS instruments, each of which, apart from IIEF Q6 (intercourse frequency), appeared to be an independent measure of satisfaction. Cultural differences may explain different satisfaction correlations with baseline ED severity in different regions. Clinicians may make use of the correlation between intercourse frequency (Q6) and satisfaction when prescribing a PDE5 inhibitor for ED, by explaining that the inhibitor should enable more frequent intercourse.