Do You Want to Stay Single? Considerations on Single-Arm Trials in Drug Development and the Postregulatory Space.

Single-arm trials (SATs), while not preferred, remain in use throughout the drug development cycle. They may be accepted by regulators in particular contexts (e.g., in oncology or rare diseases) when the potential effects of new treatments are very large and placebo treatment is unethical. However, in the postregulatory space, SATs are common, and perhaps even more poorly suited to address the questions of interest. In this manuscript, we review regulatory and HTA positions on SATs; challenges posed by SATs to address research questions beyond regulators, evolving statistical methods to provide context for SATs, case studies where SATs could and could not address questions of interest, and communication strategies to influence decision making and optimize study design to address evidence needs.

Generating the Right Evidence at the Right Time: Principles of a New Class of Flexible Augmented Clinical Trial Designs.

To support informed decision making, clear descriptions of the beneficial and harmful effects of a treatment are needed by various stakeholders. The current paradigm is to generate evidence sequentially through different experiments. However, data generated later, perhaps through observational studies, can be difficult to compare with earlier randomized trial data, resulting in confusion in understanding and interpretation of treatment effects. Moreover, the scientific questions these later experiments can serve to answer often remain vague. We propose Flexible Augmented Clinical Trial for Improved eVidence gEneration (FACTIVE), a new class of study designs enabling flexible augmentation of confirmatory randomized controlled trials with concurrent and close-to-real-world elements. Our starting point is to use clearly defined objectives for evidence generation, which are formulated through early discussion with health technology assessment (HTA) bodies and are additional to regulatory requirements for authorization of a new treatment. These enabling designs facilitate estimation of certain well-defined treatment effects in the confirmatory part and other complementary treatment effects in a concurrent real-world part. Each stakeholder should use the evidence that is relevant within their own decision-making framework. High quality data are generated under one single protocol and the use of randomization ensures rigorous statistical inference and interpretation within and between the different parts of the experiment. Evidence for the decision making of HTA bodies could be available earlier than is currently the case.

Decision rules for identifying combination therapies in open-entry, randomized controlled platform trials.

Platform trials have become increasingly popular for drug development programs, attracting interest from statisticians, clinicians and regulatory agencies. Many statistical questions related to designing platform trials-such as the impact of decision rules, sharing of information across cohorts, and allocation ratios on operating characteristics and error rates-remain unanswered. In many platform trials, the definition of error rates is not straightforward as classical error rate concepts are not applicable. For an open-entry, exploratory platform trial design comparing combination therapies to the respective monotherapies and standard-of-care, we define a set of error rates and operating characteristics and then use these to compare a set of design parameters under a range of simulation assumptions. When setting up the simulations, we aimed for realistic trial trajectories, such that for example, a priori we do not know the exact number of treatments that will be included over time in a specific simulation run as this follows a stochastic mechanism. Our results indicate that the method of data sharing, exact specification of decision rules and a priori assumptions regarding the treatment efficacy all strongly contribute to the operating characteristics of the platform trial. Furthermore, different operating characteristics might be of importance to different stakeholders. Together with the potential flexibility and complexity of a platform trial, which also impact the achieved operating characteristics via, for example, the degree of efficiency of data sharing this implies that utmost care needs to be given to evaluation of different assumptions and design parameters at the design stage.

Similar Clinical Outcomes in Patients with Systemic Juvenile Idiopathic Arthritis and Adult-Onset Still's Disease Treated with Canakinumab: Bayesian and Population Model-Based Analyses.

INTRODUCTION: Systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still's disease (AOSD) represent pediatric and adult variants of the Still's disease continuum. To determine whether clinical outcomes between patients with sJIA and AOSD were similar, Bayesian and population model-based analyses were conducted on endpoints from studies of canakinumab in both patient populations. The objective was to further support the efficacy of canakinumab in patients with AOSD. METHODS: A Bayesian analysis of endpoints from a study of canakinumab in AOSD was conducted borrowing information from five pooled sJIA studies using a robust meta-analytic predictive (MAP) approach. Similarity of clinical outcomes across populations was fulfilled if the AOSD study posterior median fell within the 95% predicted credible interval for the outcome of interest, based on the pooled sJIA data. Population model-based analyses (pharmacokinetic [PK] and PK/pharmacodynamic [PKPD]) were conducted to compare the pharmacokinetics and exposure-response relationships between populations. RESULTS: The AOSD study posterior medians for adapted American College of Rheumatology (ACR)30 response, continuous adapted ACR response, number of active joints, C-reactive protein, and absence of fever were within the 95% credible interval for the prediction of the MAP analysis from the pooled sJIA data, supporting the similarity in outcomes between patient populations. PK analysis demonstrated comparable exposure across sJIA age groups and patients with AOSD. PKPD relationships were consistent across patient populations. Analyses indicated that no therapeutic benefit can be expected from a dose increase in patients with AOSD. CONCLUSION: The analyses presented support the similarity of clinical outcomes following treatment with canakinumab in patients with sJIA and AOSD.

Effectiveness and safety of ranibizumab in patients with central retinal vein occlusion: results from the real-world, global, LUMINOUS study.

OBJECTIVE: To evaluate the effectiveness, treatment patterns and long-term safety of ranibizumab 0.5 mg in treatment-naïve patients with central retinal vein occlusion (CRVO) in a real-world setting. METHODS: LUMINOUS, a 5-year, global, prospective, multicentre, multi-indication, observational, open-label study, recruited treatment naïve or prior treated patients who were treated as per the local ranibizumab label. Here, we report the mean change in visual acuity (VA; Early Treatment Diabetic Retinopathy Study [ETDRS] letters), treatment exposure over year (Y) 1 and 5-year safety in treatment-naïve CRVO patients. RESULTS: At baseline, the mean age of treatment-naïve CRVO patients (n = 327) was 68.9 years, with a mean (Standard deviation [SD]) VA of 40.6 (23.9) letters. At Y1, patients (n = 144) had a mean (SD) VA gain from baseline of 10.8 (19.66) letters, with a mean (SD) of 5.4 (2.65) ranibizumab injections. Patients demonstrated mean (SD) VA gains of 2.7 (19.35), 11.6 (20.56), 13.9 (18.08), 11.1 (18.46) and 8.2 (24.86) letters with 1, 2-3, 4-5, 6-8 and >8 ranibizumab injections, respectively. Mean (SD) VA gains at Y1 in patients receiving loading (67.4%) and no loading dose (32.6%) was 11.9 (20.42) and 8.4 (17.99) letters, respectively. Over five years, the incidence of ocular/non-ocular adverse events (AEs) and serious AEs was 11.3%/8.6% and 1.2%/6.7%, respectively. CONCLUSIONS: These results demonstrate the effectiveness of ranibizumab in treatment-naïve CRVO patients at Y1 with clinically meaningful VA gains and no new safety findings over five years. These findings may help inform routine practice and enable better clinical management to achieve optimal visual outcomes.

The Evolution of Master Protocol Clinical Trial Designs: A Systematic Literature Review.

PURPOSE: Recent years have seen a change in the way that clinical trials are being conducted. There has been a rise of designs more flexible than traditional adaptive and group sequential trials which allow the investigation of multiple substudies with possibly different objectives, interventions, and subgroups conducted within an overall trial structure, summarized by the term master protocol. This review aims to identify existing master protocol studies and summarize their characteristics. The review also identifies articles relevant to the design of master protocol trials, such as proposed trial designs and related methods. METHODS: We conducted a comprehensive systematic search to review current literature on master protocol trials from a design and analysis perspective, focusing on platform trials and considering basket and umbrella trials. Articles were included regardless of statistical complexity and classified as reviews related to planned or conducted trials, trial designs, or statistical methods. The results of the literature search are reported, and some features of the identified articles are summarized. FINDINGS: Most of the trials using master protocols were designed as single-arm (n = 29/50), Phase II trials (n = 32/50) in oncology (n = 42/50) using a binary endpoint (n = 26/50) and frequentist decision rules (n = 37/50). We observed an exponential increase in publications in this domain during the last few years in both planned and conducted trials, as well as relevant methods, which we assume has not yet reached its peak. Although many operational and statistical challenges associated with such trials remain, the general consensus seems to be that master protocols provide potentially enormous advantages in efficiency and flexibility of clinical drug development. IMPLICATIONS: Master protocol trials and especially platform trials have the potential to revolutionize clinical drug development if the methodologic and operational challenges can be overcome.

Effectiveness and safety of ranibizumab 0.5 mg in treatment-naïve patients with diabetic macular edema: Results from the real-world global LUMINOUS study.

PURPOSE: To assess the one-year effectiveness and safety of ranibizumab 0.5 mg in treatment- naïve patients with diabetic macular edema (DME) enrolled in the real-world LUMINOUS study. PATIENTS AND METHODS: A 5-year, prospective, observational, open-label, global study which recruited 30,138 patients across all approved indications. Consenting patients (≥18 years) who were treatment-naïve or previously treated with ranibizumab or other ocular treatments were treated as per the local ranibizumab label. Here, we present the change in visual acuity (VA) (Early Treatment Diabetic Retinopathy Study letter score; primary treated eye) at Year 1, as well as the change in VA based on injection frequencies (≤4 and ≥5), treatment exposure, and the overall adverse events (AEs) and serious AEs (SAEs) in treatment-naïve DME patients. RESULTS: Of the 4,710 DME patients enrolled in the study, 1,063 were treatment-naïve. At baseline, mean age was 64.5 years, 54.7% were male, and 69.2% were white. At 1 year, mean VA letter score improved by +3.5 (n = 502) from a baseline of 57.7 with a mean of 4.5 injections. Presented by injection frequencies ≤4 and ≥5, VA letter score gains were 0.5 (n = 264) and 6.9 (n = 238) from baseline letter scores of 56.6 and 59.0, respectively. Over 5 years, the incidence of ocular/non-ocular AEs and SAEs was 7.2%/10.1% and 0.3%/5.8%, respectively. No endophthalmitis cases were reported. CONCLUSIONS: The LUMINOUS study included patients with DME with more diverse baseline characteristics than those in randomized clinical trials. The 1-year data showed improvement in VA with low number of injections in treatment- naïve patients with DME. Greater VA gains were observed in patients who received ≥5 injections. No new safety findings were identified. LUMINOUS confirms the effectiveness and safety of ranibizumab for the treatment of patients with DME in a real-world clinical practice.

Real-world outcomes with ranibizumab in branch retinal vein occlusion: The prospective, global, LUMINOUS study.

OBJECTIVE: To evaluate the effectiveness, safety, and treatment patterns of ranibizumab 0.5 mg in treatment-naïve patients with branch retinal vein occlusion (BRVO) enrolled in the LUMINOUS™ study. STUDY DESIGN: A 5-year, global, prospective, multicenter, observational, open-label study conducted in a clinical practice (real-world) setting at outpatient ophthalmology clinics that recruited 30,138 consenting adult patients from all approved indications for ranibizumab across 42 countries. Patients with BRVO were treated according to the local ranibizumab label of the participating countries. Mean change in visual acuity (VA) in Early Treatment Diabetic Retinopathy Study letters from baseline to Year 1, treatment exposure during Year 1, and adverse events (AEs) over 5 years were assessed. RESULTS: Of the 1366 recruited BRVO patients, 405 were treatment-naïve at baseline with a mean (standard deviation [SD]) age of 67.9 (12.5) years, 57.5% were female, and 71.8% were White. At Year 1 (n = 189), the mean (SD) VA gain was 11.9 (17.66) letters from a baseline of 49.2 (±20.32) letters with a mean (SD) of 5.0 (2.34) injections. VA gains were higher in patients (n = 83) who received 6-9 injections (13.6 [20.16] letters) than in those who received 2-5 injections (n = 92, 11.7 [15.43] letters), or 1 injection (n = 14, 3.6 [13.72] letters). Patients with baseline VA <23 letters had numerically highest VA gains (n = 20, 31.1 [24.48] letters). Over 5 years, the rate of ocular/non-ocular AEs was 7.4%/9.1% and serious AEs was 0.3%/4.4% in treatment-naïve BRVO patients (n = 405). CONCLUSIONS: One year results from the LUMINOUS real-world study showed a clinically meaningful VA improvement with ranibizumab in treatment-naïve patients with BRVO; numerically higher VA gains were achieved in patients who received more injections and those with poor baseline VA. No new safety signals were observed.

Real-world effectiveness and safety of ranibizumab for the treatment of myopic choroidal neovascularization: Results from the LUMINOUS study.

PURPOSE: To assess the 1-year effectiveness, safety, and treatment patterns of ranibizumab in patients with myopic choroidal neovascularization (mCNV) enrolled in the LUMINOUS study. METHODS: This 5-year, prospective, multicenter, observational, study enrolled 30,138 patients across all approved ranibizumab indications from outpatient ophthalmology clinics. 297 consenting patients (≥18 years) with mCNV who were treatment-naïve or prior-treated with ranibizumab or other ocular treatments were enrolled, and treated with ranibizumab according to the local product label. The main outcomes are visual acuity (VA; Early Treatment Diabetic Retinopathy Study letters or equivalent), adverse events during the study, and treatment exposure over 1 year. Results are presented by prior treatment status of the study eye and injection frequency. RESULTS: Of the 297 mCNV patients recruited in the study, 108 were treatment-naïve and 175 were prior ranibizumab-treated. At baseline, the mean age of patients was 57.6 years, and 59.0 years and 80.6% and 65.7% were female in the treatment-naïve and prior ranibizumab-treated groups, respectively. Most were Caucasian (treatment-naïve, 88.9%; prior ranibizumab-treated, 86.9%). The mean (±standard deviation [SD]) VA letter changes to 1 year were +9.7 (±17.99) from 49.5 (±20.51) and +1.5 (±13.15) from 58.5 (±19.79) and these were achieved with a mean (SD) of 3.0 (±1.58) and 2.6 (±2.33) injections in the treatment-naïve and prior ranibizumab-treated groups, respectively. Presented by injection frequencies 1-2, 3-4 and ≥5 injections in Year 1, the mean (SD) VA changes were +15.0 (±14.70), +7.7 (±19.91) and -0.7 (±16.05) in treatment-naïve patients and +1.5 (±14.57), +3.1 (±11.53) and -3.6 (±11.97) in prior ranibizumab-treated patients, respectively. The safety profile was comparable with previous ranibizumab studies. CONCLUSIONS: Ranibizumab treatment for mCNV showed robust VA gains in treatment-naïve patients and VA maintenance in prior ranibizumab-treated patients in a clinical practice setting, consisting mainly of Caucasians. No new safety signals were observed during the study.

Functional versus functional and anatomical criteria-guided ranibizumab treatment in patients with neovascular age-related macular degeneration - results from the randomized, phase IIIb OCTAVE study.

BACKGROUND: To evaluate the efficacy and safety of two individualized ranibizumab retreatment schemes in neovascular age-related macular degeneration. METHODS: Patients (N = 671) were randomized (1:1) to receive three initial monthly ranibizumab 0.5 mg injections, then retreatment guided by either best-corrected visual acuity (BCVA) loss (Group I) or BCVA loss and/or signs of disease activity on optical coherence tomography (OCT; Group II). The study was terminated prematurely and the decision to discontinue the study was made by the sponsor. Efficacy analyses were performed on patients who completed 12 months of the originally planned 24-month study. Safety analyses are presented for all safety analyzable patients. RESULTS: Of 671 randomized patients, 305 completed 12 months of the study. For the 12-month completers, baseline mean (standard deviation) BCVA and reading-center evaluated central subfield thickness (CSFT) were comparable [Group I: 60.9 (13.10) letters and 517.7(201.79) µm; Group II: 60.2 (12.21) letters and 515.3 (198.37) µm]. The change from baseline at Month 12 in BCVA was 6.7 (13.48) letters in Group I and 8.3 (13.53) letters in Group II and the change in CSFT was - 161.3 (163.48) µm and - 175.3 (170.45) µm, respectively. The mean number of ranibizumab injections was 8.2 in Group I and 8.4 in Group II. CONCLUSION: Ranibizumab treatment resulted in visual and anatomic gains at 12 months for both retreatment strategies, with a trend in favor of OCT-guided vs BCVA loss guided retreatment. No new safety signals were seen. TRIAL REGISTRATION: www.ClinicalTrials.gov (NCT01780935). Registered 31 January 2013.

REAL-WORLD EFFECTIVENESS AND SAFETY OF RANIBIZUMAB TREATMENT IN PATIENTS WITH AND WITHOUT POLYPOIDAL CHOROIDAL VASCULOPATHY: Twelve-Month Results From the LUMINOUS Study.

PURPOSE: To evaluate the real-world effectiveness and safety of intravitreal ranibizumab 0.5 mg in treatment-naive patients with and without polypoidal choroidal vasculopathy (PCV). METHODS: Assessment of neovascular age-related macular degeneration patients with or without PCV after 12 months of ranibizumab treatment during the LUMINOUS study. Outcome measures were visual acuity and central retinal thickness changes from baseline and the rate of ocular adverse events. RESULTS: At baseline, 572 and 5,644 patients were diagnosed with and without PCV, respectively. The mean visual acuity gain from baseline at Month 12 in the PCV and non-PCV groups was +5.0 and +3.0 letters, respectively; these gains were achieved with a mean of 4.4 and 5.1 ranibizumab injections. Eighty percent of PCV patients and 72.2% of non-PCV patients who had baseline visual acuity ≥73 letters maintained this level of vision at Month 12; 20.6% and 17.9% of patients with baseline visual acuity <73 letters achieved visual acuity ≥73 letters in these groups. Greater reductions in central retinal thickness from baseline were also observed for the PCV group versus the non-PCV group. The rate of serious ocular adverse events was 0.7% (PCV group) and 0.9% (non-PCV group). CONCLUSION: LUMINOUS confirms the effectiveness and safety of ranibizumab in treatment-naive patients with PCV.

RANIBIZUMAB TREATMENT IN TREATMENT-NAIVE NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: Results From LUMINOUS, a Global Real-World Study.

PURPOSE: To evaluate the effectiveness, safety, and treatment patterns of ranibizumab 0.5 mg in treatment-naive patients with neovascular age-related macular degeneration enrolled in LUMINOUS study. METHODS: This 5-year, prospective, multicenter, observational study recruited 30,138 adult patients (treatment-naive or previously treated with ranibizumab or other ocular treatments) who were treated according to the local ranibizumab label. RESULTS: Six thousand two hundred and forty-one treatment-naive neovascular age-related macular degeneration patients were recruited. Baseline (BL) demographics were, mean (SD) age 75.0 (10.2) years, 54.9% females, and 66.5% Caucasian. The mean (SD) visual acuity (VA; letters) gain at 1 year was 3.1 (16.51) (n = 3,379; BLVA, 51.9 letters [Snellen: 20/92]) with a mean (SD) of 5.0 (2.7) injections and 8.8 (3.3) monitoring visits. Presented by injection frequencies <3 (n = 537), 3 to 6 (n = 1,924), and >6 (n = 918), visual acuity gains were 1.6 (14.93), 3.3 (16.57), and 3.7 (17.21) letters, respectively. Stratified by BLVA <23 (n = 382), 23 to <39 (n = 559), 39 to <60 (n = 929), 60 to <74 (n = 994), and ≥74 (n = 515), visual acuity change was 12.6 (20.63), 6.7 (17.88), 3.6 (16.41), 0.3 (13.83), and -3.0 (11.82) letters, respectively. The incidence of ocular/nonocular adverse events was 8.2%/12.8% and serious adverse events were 0.9%/7.4%, respectively. CONCLUSION: These results demonstrate the effectiveness and safety of ranibizumab in treatment-naive neovascular age-related macular degeneration patients.

Systemic Safety in Ranibizumab-Treated Patients with Neovascular Age-Related Macular Degeneration: A Patient-Level Pooled Analysis.

TOPIC: This study evaluated the cardiovascular/cerebrovascular safety profile of ranibizumab 0.5 mg versus sham ± verteporfin in patients with neovascular age-related macular degeneration (nAMD). In addition, comparisons of ranibizumab 0.3 mg with sham and ranibizumab 0.5 mg to 0.3 mg were performed. CLINICAL RELEVANCE: Intravitreal anti-vascular endothelial growth factor (VEGF) agents carry potential increased systemic risks, including cardiovascular or cerebrovascular events. Pooled safety analyses allow better interpretation of safety outcomes seen in individual clinical trials, especially for less common events. To our knowledge, this is the largest patient-level pooled analysis of patients with nAMD treated with ranibizumab. METHODS: Patient-level pooled analysis of data from 7 Genentech- and Novartis-sponsored phase II, III, and IV studies in nAMD that were completed by December 31, 2013. Pairwise comparisons (primary comparison: ranibizumab 0.5 mg [globally approved dose for nAMD] vs. sham or verteporfin) were performed using Cox proportional hazard regression (hazard ratios [HRs], 95% confidence intervals [CIs]) and rates per 100 patient-years. Standardized Medical Dictionary for Regulatory Activities queries (SMQs) and extended searches were used to identify relevant safety endpoints, including arterial thromboembolic events (ATEs), myocardial infarction (MI), stroke or transient ischemic attack (TIA), stroke (excluding TIA), vascular deaths, and major vascular events as defined by the Antiplatelet Trialists' Collaboration (APTC). RESULTS: The HRs (95% CIs) for the primary comparison of ranibizumab 0.5 mg (n=480) versus sham or verteporfin (n=462) were 1.16 (0.72-1.88) for ATE, 1.33 (0.59-2.97) for MI, 1.43 (0.54-3.77) for stroke excluding TIA, 1.25 (0.61-2.55) for stroke or TIA, 0.57 (0.18-1.78) for vascular death, and 1.12 (0.64-1.98) for APTC events. Hazard ratio 95% CIs included 1, indicating no significant treatment differences, for all endpoints for comparison of ranibizumab 0.5 mg versus sham or verteporfin. CONCLUSIONS: The rates of cardiovascular and cerebrovascular events were low in these patients with nAMD and not clinically meaningfully different for patients treated with ranibizumab 0.5 mg versus sham or verteporfin, which supports the favorable benefit-risk profile of ranibizumab in the patient population with nAMD. Pooling these studies allows an analysis with higher power and precision compared with individual study analyses.

Vascular Safety of Ranibizumab in Patients With Diabetic Macular Edema: A Pooled Analysis of Patient-Level Data From Randomized Clinical Trials.

Importance: Patients with diabetic macular edema (DME) are at high risk of vascular complications, including stroke and myocardial infarction (MI). Concerns have been raised that intravitreal dosing of vascular endothelial growth factor inhibitors in DME could be associated with an increase in cardiovascular and cerebrovascular adverse events. Objective: To evaluate the cardiovascular and cerebrovascular safety of ranibizumab, 0.5 mg and 0.3 mg, compared with sham with and without laser in DME. Data Sources: Patient-level data from 6 randomized, double-masked, sham- and laser-controlled clinical trials. Study Selection: Company-sponsored (Genentech or Novartis) studies in DME completed as of December 31, 2013. Data Extraction and Synthesis: Pairwise comparisons (ranibizumab, 0.5 mg, vs sham and laser; ranibizumab, 0.3 mg, vs sham) were performed using Cox proportional hazard regression (hazard ratios, 95% CIs) and rates per 100 person-years. Data analysis was conducted from June 1 to July 15, 2015. Main Outcomes and Measures: Standardized Medical Dictionary for Regulatory Activities queries and extended searches were prospectively defined to identify relevant safety end points, including arterial thromboembolic events, MI, stroke or transient ischemic attack, vascular deaths, and major vascular events as defined by the Antiplatelet Trialists' Collaboration (APTC). Results: Overall, 936 patients were treated with ranibizumab, 0.5 mg; 250 patients with ranibizumab, 0.3 mg; and 581 patients with sham/laser. The hazard ratios associated with all pairwise comparisons included 1 for all key cardiovascular and cerebrovascular safety end points. For ranibizumab, 0.5 mg, vs sham/laser and ranibizumab, 0.3 mg, vs sham, the hazard ratios were, respectively, arterial thromboembolic events, 1.05 (95% CI, 0.66-1.68) and 0.78 (95% CI, 0.43-1.40); MI, 0.84 (95% CI, 0.41-1.72) and 0.94 (95% CI, 0.43-2.06); stroke or transient ischemic attack, 0.94 (95% CI, 0.44-1.99) and 0.53 (95% CI, 0.19-1.42); stroke (excluding transient ischemic attack), 1.63 (95% CI, 0.65-4.07) and 0.59 (95% CI, 0.14-2.46); vascular death, 2.17 (95% CI, 0.57-8.29) and 2.51 (95% CI, 0.49-12.94); and APTC-defined events, 1.09 (95% CI, 0.63-1.88) and 1.00 (95% CI, 0.51-1.96). Conclusions and Relevance: This pooled analysis includes 1 of the largest patient-level data sets on treatment of DME with ranibizumab. Although still underpowered to detect small differences for infrequent events, such as stroke, the findings suggest that intravitreous ranibizumab does not increase the risk of systemic vascular events. However, uncertainty remains for patients with DME who are at high risk for vascular disease and were not included in these trials.

Ranibizumab in Diabetic Macular Oedema - A Benefit-risk Analysis of Ranibizumab 0.5 mg PRN Versus Laser Treatment.

INTRODUCTION: The structured Benefit-risk Action Team (BRAT) approach aims to assist healthcare decision makers in treatment assessments. We applied BRAT to compare the benefit-risk profile of ranibizumab 0.5 mg versus laser photocoagulation for the treatment of diabetic macular oedema (DMO). METHODS: One-year data for the ranibizumab 0.5 mg pro re nata (PRN) and laser arms of the phase III trials RESPOND (NCT01135914; n=220), RESTORE (NCT00687804; n=345), and REVEAL (NCT00989989; n=396) were included in the analysis. The benefit measures included ≥10 letters gain/avoidance of loss in best-corrected visual acuity (BCVA), achieving central retinal thickness (CRT) <275 µm, and 25-item Visual Function Questionnaire (VFQ-25) outcomes. The risks measures included endophthalmitis, intraocular pressure increase, hypertension, proteinuria, arterial/venous thromboembolic events and deaths. RESULTS: Ranibizumab treatment provided significant benefits compared with laser for ≥10 letter BCVA gain at month 12 (387/1,000 versus 152/1,000 patients), CRT <275 µm at 12 months (474/1,000 versus 348/1,000 patients), and improvement of ≥6.06 on the VFQ-25 near activities subscale (325/1,000 versus 245/1,000 patients). Results for the risk measures were similar for both treatments. CONCLUSIONS: Superior clinically relevant outcomes were observed with ranibizumab 0.5 mg PRN compared with laser without compromising on safety. This analysis further supports the positive benefit-risk profile of ranibizumab 0.5 mg PRN.

Experimental designs for small randomised clinical trials: an algorithm for choice.

BACKGROUND: Small clinical trials are necessary when there are difficulties in recruiting enough patients for conventional frequentist statistical analyses to provide an appropriate answer. These trials are often necessary for the study of rare diseases as well as specific study populations e.g. children. It has been estimated that there are between 6,000 and 8,000 rare diseases that cover a broad range of diseases and patients. In the European Union these diseases affect up to 30 million people, with about 50% of those affected being children. Therapies for treating these rare diseases need their efficacy and safety evaluated but due to the small number of potential trial participants, a standard randomised controlled trial is often not feasible. There are a number of alternative trial designs to the usual parallel group design, each of which offers specific advantages, but they also have specific limitations. Thus the choice of the most appropriate design is not simple. METHODS: PubMed was searched to identify publications about the characteristics of different trial designs that can be used in randomised, comparative small clinical trials. In addition, the contents tables from 11 journals were hand-searched. An algorithm was developed using decision nodes based on the characteristics of the identified trial designs. RESULTS: We identified 75 publications that reported the characteristics of 12 randomised, comparative trial designs that can be used in for the evaluation of therapies in orphan diseases. The main characteristics and the advantages and limitations of these designs were summarised and used to develop an algorithm that may be used to help select an appropriate design for a given clinical situation. We used examples from publications of given disease-treatment-outcome situations, in which the investigators had used a particular trial design, to illustrate the use of the algorithm for the identification of possible alternative designs. CONCLUSIONS: The algorithm that we propose could be a useful tool for the choice of an appropriate trial design in the development of orphan drugs for a given disease-treatment-outcome situation.

Safety, tolerability, and efficacy of tegaserod over 13 months in patients with chronic constipation.

OBJECTIVE: To assess the long-term safety and tolerability of tegaserod in patients with chronic constipation (CC). METHODS: This 13-month, uncontrolled extension study enrolled CC patients who completed a 12-wk randomized, double-blind, placebo-controlled core study. Patients receiving tegaserod 6 or 2 mg b.i.d. during the core study continued on the same dose; those receiving placebo were switched to tegaserod 6 mg b.i.d (placebo-to-tegaserod). Safety and tolerability were assessed by monitoring adverse events (AEs), laboratory parameters, vital signs, and electrocardiograms. Symptom evaluations included patient satisfaction with bowel habit and bothersomeness of constipation, abdominal distension/bloating, and abdominal discomfort/pain. RESULTS: A total of 842 patients entered the extension study; 451 (54%) completed. AEs typically occurred within the first month of tegaserod treatment. Long-term treatment neither increased AE incidence nor revealed new safety risks. Headache (11.3%, 14.5%, and 16.1% in the tegaserod 6 mg b.i.d., 2 mg b.i.d., and placebo-to-tegaserod groups, respectively) and abdominal pain (8.8%, 8.8%, 10.9%) were the most common AEs. Diarrhea, the most common drug-related AE (4.9%, 2.5%, 8.0%), rarely led to discontinuation (0.7%, 0.0%, 2.2%). Diarrhea was transient, resolved without treatment interruption or rescue medication, and had no clinically significant consequences. Of 27 serious AEs, none were considered treatment related. No deaths or reports of ischemic colitis occurred in tegaserod-treated patients. No clinically relevant changes occurred in other safety parameters. Safety findings were similar in patients switched from placebo to tegaserod and those maintained on tegaserod. CONCLUSIONS: Tegaserod has a favorable safety profile and is well tolerated during continuous long-term treatment in patients with CC.

Testing and estimation in flexible group sequential designs with adaptive treatment selection.

Integrating selection and confirmation phases into a single trial can expedite the development of new treatments and allows to use all accumulated data in the decision process. In this paper we review adaptive treatment selection based on combination tests and propose overall adjusted p-values and simultaneous confidence intervals. Also point estimation in adaptive trials is considered. The methodology is illustrated in a detailed example based on an actual planned study.

Subject's Global Assessment of Relief: an appropriate method to assess the impact of treatment on irritable bowel syndrome-related symptoms in clinical trials.

The lack of validated outcome measures is a key limitation for the evaluation of drug efficacy in the treatment of irritable bowel syndrome (IBS). In clinical trials with tegaserod, the Subject's Global Assessment (SGA) of Relief (a global measure that includes overall wellbeing, abdominal pain/discomfort, and bowel function) was used to identify responders. A total of 1680 patients with IBS with constipation were included in two clinical studies comparing tegaserod with placebo. The SGA of Relief was obtained weekly by a single, self-administered question with five possible answers. Responders for the SGA of Relief reported statistically significant (P<.001) and clinically relevant improvements in multiple IBS-related symptoms compared with nonresponders. Response was also associated with a significant improvement in quality of life. The SGA of Relief is reliable as a new outcome measure for assessing response to therapy in IBS patients and has demonstrated responsiveness and reproducibility.