Long-term Clinical Trial Data Research Articles

Health Technology Reassessment: Addressing Uncertainty in Economic Evaluations of Oncology Drugs at Time of Reimbursement Using Long-Term Clinical Trial Data.

The evidence base to support reimbursement decision making for oncology drugs is often based on short-term follow-up trial data, and attempts to address this uncertainty are not typically undertaken once a reimbursement decision is made. To address this gap, we sought to conduct a reassessment of an oncology drug (pembrolizumab) for patients with advanced melanoma which was approved based on interim data with a median 7.9 months of follow-up and for which long-term data have since been published. We developed a three-health-state partitioned survival model based on the phase 3 KEYNOTE-006 clinical trial data using patient-level data reconstruction techniques based on an interim analysis. We used a standard survival analysis and parametric curve fitting techniques to extrapolate beyond the trial follow-up time, and the model structure and inputs were derived from the literature. Five-year long-term follow-up data from the trial were then used to re-evaluate the cost-effectiveness of pembrolizumab versus ipilimumab for treatment of advanced melanoma. The best fitting parametric curves and corresponding survival extrapolations for reconstructed interim data and long-term data reconstructed from KEYNOTE-006 were different. An analysis of the 5 year long-term follow-up data generated a base case incremental cost-effectiveness ratio (ICER) that was 28% higher than the ICER based on interim trial data. Our findings suggest that there may be a trade-off between certainty and the ICER. Conducting health technology re-assessments of certain oncology products on the basis of longer-term data availability, especially for those health technology adoption decisions made based on immature clinical data, may be of value to decision makers.

Safety and effectiveness of tofacitinib in Korean adult patients with rheumatoid arthritis: A post-marketing surveillance study.

The aim of this article is to assess the safety and effectiveness of tofacitinib in patients with rheumatoid arthritis in routine clinical settings in Korea. This is a prospective, multi-centre post-marketing surveillance study. Data were prospectively collected within 6 months after the start of tofacitinib therapy. Safety was evaluated based on the presence of adverse events (AEs) observed in patients who received at least one dose of tofacitinib. Effectiveness was assessed according to the proportion of patients who achieved low disease activity and remission, American College of Rheumatology 20 criteria (ACR20), European League Against Rheumatism (EULAR) response, and change of Disease Activity Score in 28 Joints (DAS28). The incidence rates [patients with events per 100 patient-years (PY)] of AEs and serious AEs were 56.92 and 10.69, respectively. Regarding AEs of special interest, the incidence rates were 4.33 per 100 PY for serious infections and infestations, 5.78 per 100 PY for herpes zoster, no event of tuberculosis, 0.29 per 100 PY for malignancy, 0.29 per 100 PY for venous thromboembolism (one event of deep vein thrombosis and no event of pulmonary embolism), 0.87 per 100 PY for major adverse cardiovascular event, and 0.58 per 100 PY for mortality. Moreover, ∼40.48% and 21.60% of patients achieved low disease activity and remission of DAS28-erythrocyte sedimentation rate. The EULAR response was classified as good responders with 39.12% in the DAS28-erythrocyte sedimentation rate. The benefit/risk profile of tofacitinib in adult patients with rheumatoid arthritis in routine clinical settings in Korea was similar to long-term clinical trial data.

JAK Inhibitor Safety Compared to Traditional Systemic Immunosuppressive Therapies.

Dermatologists treating atopic dermatitis are interested in the safety profile of the recently available JAK inhibitors, upadacitinib and abrocitinib, especially after they received boxed safety warnings. Long-term clinical trial data using these JAK inhibitors for the treatment of atopic dermatitis suggest that they are associated with very low incidence rates of malignancy, major adverse cardiac events, and thromboembolic events. However, a knowledge gap exists regarding the incidence of adverse events for JAK inhibitors compared to traditional systemic therapies used to treat poorly controlled atopic dermatitis as well as baseline rates in both atopic dermatitis and reference control populations. To address this gap, we analyzed data regarding adverse events of special interest for methotrexate, cyclosporine, and systemic corticosteroids and calculated the incidence of adverse events per 100 patient-years for these drugs. We also examined data regarding baseline incidence of adverse events in atopic dermatitis and control patients. We found that compared to upadacitinib and abrocitinib, traditional systemic therapies for atopic dermatitis demonstrated equal or higher incidence rates for malignancy (excluding non-melanoma skin cancer), non-melanoma skin cancer, major adverse cardiac events, and venous thromboembolism. Moreover, the use of upadacitinib and abrocitinib also exhibited either comparable or lower incidence of malignancy (excluding non-melanoma skin cancer), major adverse cardiac events, and venous thromboembolism, but higher rates of non-melanoma skin cancer, in comparison to baseline rates in atopic dermatitis or control patients. These findings indicate that JAK inhibitors should be positioned, at least based on safety, ahead of traditional systemic therapies for atopic dermatitis treatment.J Drugs Dermatol. 2022;21(12):1298-1303. doi:10.36849/JDD.7187.

Comparison of performance of varicella vaccines via infectious disease modeling

BackgroundPopulation-level infectious disease models for varicella require vaccine parameters, namely 'take' and 'duration of protection' (defined here as vaccine performance), to quantify the impact of vaccination. Current published models for varicella use vaccine parameters derived from various methodologies which does not allow for the direct comparison of different vaccines. MethodsWe estimated take and duration of protection using deterministic compartmental models to simulate clinical trials of one- or two-dose varicella vaccination using Varivax® (V-MSD) and Varilrix® (V-GSK). We fit different models to clinical trial data on breakthrough infections and evaluated their respective goodness-of-fit using the Akaike Information Criterion (AIC). ResultsBased upon the clinical trial data, we estimated that 90.3% (95% CI: 87.8–92.9%) of the cohort gained permanent protection from breakthrough varicella after the first dose of V-MSD compared to 61.7% (95% CI: 58.2–65.3%) with the first dose of V-GSK. We further estimated that a total of 97.0% (95% CI: 95.2–98.8%) and 93.8% (95% CI: 92.2–95.4%) of the cohort were permanently protected after two-doses of V-MSD and V-GSK, respectively. According to the AIC, our new model (V-MSD AIC = 92.7; V-GSK AIC = 170.3) provided a better fit than an existing model (V-MSD AIC = 108.9; V-GSK AIC = 216.1). ConclusionsThe model developed fits the long-term clinical trial data on breakthrough infections for both V-MSD and V-GSK, thus, allowing for the direct comparison of vaccine performance. We estimated that a single dose of V-MSD was more likely to provide permanent protection than a single dose of V-GSK, while the protection offered by two doses was similar for both vaccines.

Evaluating upadacitinib for the treatment of psoriatic arthritis

ABSTRACT Introduction Psoriatic arthritis is an extra-cutaneous manifestation affecting up to 40% of psoriasis patients with multiple therapies recommended by international guidelines including conventional and targeted synthetic disease-modifying anti-rheumatic drugs (DMARDs) as well as biologics. Janus kinase inhibitors (JAKis) have emerged as a unique therapeutic target with tofacitinib the first to gain FDA approval in 2017. The non-selectivity of older JAKis increases the risk of off-target effects such as suppression of hemopoiesis hence the rationale for more selective alternatives. Areas covered This paper explores the use of upadacitinib (a selective JAK1 inhibitor) for the treatment of psoriatic arthritis. It covers its chemical properties, pharmacokinetics, pharmacodynamics, efficacy, safety and regulation. Expert opinion In our opinion, upadacitinib is set to play an important role in the treatment of psoriatic arthritis as demonstrated by the SELECT-PsA trials especially in patients with poor or non-response to current first-line therapies. It's JAK1 receptor selectivity promises a lower side effect profile compared to the older nonselective JAKis but this will require confirmation with long-term clinical trial data.

Risk of Malignancies in Patients with Rheumatoid Arthritis Treated with Rituximab: Analyses of Global Postmarketing Safety Data and Long-Term Clinical Trial Data.

IntroductionPatients with rheumatoid arthritis (RA) are at an increased risk of developing malignancies, but it is unclear whether this increased risk is the result of disease pathobiology or immunosuppressant treatments for RA. This analysis evaluated the potential risk of malignancy in patients with RA treated with rituximab (MabThera®/Rituxan®) a CD20+ B-cell depleting agent manufactured by F. Hoffmann-La Roche Ltd.MethodsMalignancy rates were obtained from the rituximab global company safety database for adverse event reporting and from the rituximab global clinical trial program for RA consisting of eight randomized clinical trials, two long-term open-label extensions, and one open-label prospective study. Global company safety database searches were performed using the standard Medical Dictionary for Regulatory Activities (MedDRA) queries “Malignant tumors wide” and “Skin malignant tumors wide” up to April 30, 2017. Age- and sex-specific comparator values from the general population were obtained from the US National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) database.ResultsFor the 409,706 patients with RA in the rituximab global company safety database since first market approval in 2006, 1739 cumulative malignant events were reported, with an overall malignancy reporting rate of approximately 4.2 events per 1000 patients. No evidence of increased risk of malignancy, of any organ-specific type, was found following rituximab treatment. The rate of malignancies from rituximab-treated patients in RA clinical trials was 7.4 per 1000 patient-years. This is within the expected range, with no evidence for increased risk over time or with additional rituximab courses.ConclusionsAnalyses of the global postmarketing safety database and long-term clinical trial data showed no evidence of an increased risk of malignancy of any type following rituximab treatment in patients with RA.FundingF. Hoffmann-La Roche Ltd.

Integrating expert opinion with clinical trial data to extrapolate long-term survival: a case study of CAR-T therapy for children and young adults with relapsed or refractory acute lymphoblastic leukemia

BackgroundLong-term clinical outcomes are necessary to assess the cost-effectiveness of new treatments over a lifetime horizon. Without long-term clinical trial data, current practice to extrapolate survival beyond the trial period involves fitting alternative parametric models to the observed survival. Choosing the most appropriate model is based on how well each model fits to the observed data. Supplementing trial data with feedback from experts may improve the plausibility of survival extrapolations. We demonstrate the feasibility of formally integrating long-term survival estimates from experts with empirical clinical trial data to provide more credible extrapolated survival curves.MethodsThe case study involved relapsed or refractory B-cell pediatric and young adult acute lymphoblastic leukemia (r/r pALL) regarding long-term survival for tisagenlecleucel (chimeric antigen receptor T-cell [CAR-T]) with evidence from the phase II ELIANA trial. Seven pediatric oncologists and hematologists experienced with CAR-T therapies were recruited. Relevant evidence regarding r/r pALL and tisagenlecleucel provided a common basis for expert judgments. Survival rates and related uncertainty at 2, 3, 4, and 5 years were elicited from experts using a web-based application adapted from Sheffield Elicitation Framework. Estimates from each expert were combined with observed data using time-to-event parametric models that accounted for experts’ uncertainty, producing an overall distribution of survival over time. These results were validated based on longer term follow-up (median duration 24.2 months) from ELIANA following the elicitation.ResultsExtrapolated survival curves based on ELIANA trial without expert information were highly uncertain, differing substantially depending on the model choice. Survival estimates between 2 to 5 years from individual experts varied with a fair amount of uncertainty. However, incorporating expert estimates improved the precision in the extrapolated survival curves. Predictions from a Gompertz model, which experts believed was most appropriate, suggested that more than half of the ELIANA patients treated with tisagenlecleucel will survive up to 5 years. Expert estimates at 24 months were validated by longer follow-up.ConclusionsThis study provides an example of how expert opinion can be elicited and synthesized with observed survival data using a transparent and formal procedure, capturing expert uncertainty, and ensuring projected long-term survival is clinically plausible.

Abstract CT160: Modeling long-term survival outcomes in glioblastoma patients treated with TTFields plus temozolomide and temolozomide monotherapy

Abstract Background: Glioblastoma is the most common and aggressive primary brain tumor. Survival times for GBM have improved significantly since 2005. Researchers in 2005 demonstrated that adding TMZ, an oral alkylating agent, to surgery and radiation extended median overall survival from 12 to 15 months, and 2-year survival rates from 11% to 27%. More recently the addition of Tumor Treating Fields (TTFields), a loco-regionally delivered anti-mitotic treatment, to TMZ demonstrated an increase in median overall survival of 5 months, and survival rates of 43% and 17% at 2-years and 4-years respectively. Trial data for TMZ and TTFields both demonstrated increasing conditional probabilities of survival as patients survived longer from diagnosis. Increasing conditional probability of surviving GBM has also been reported in epidemiological literature. Accordingly, standard parametric survival models based on regression analysis will not provide reliable estimates of lifetime survival benefits and an alternative modelling method is provided here. Clinicians and policy makers need to understand the lifetime survival estimates for GBM patients, as the rate of GBM patients surviving to 4-years and 5-years is now significant. Methods: Lifetime patient survival was simulated using a synthesis of parametric survival curves fit to the recently completed EF-14 Trial’s 4-year follow-up data and conditional survival probabilities from a SEER state cancer registries database analysis. The 4-year parametric curves were extrapolated to estimate 5-year survival. We then used GBM-specific conditional survival estimates to model patient survival at 10 and 15 years given survival to year 5, and assumed patients surviving beyond 15 years had survival equivalent to population averages. We performed one-way and probabilistic sensitivity analyses to assess result uncertainty due to parameter variability. Results: Our modeled analysis showed that TTFields plus TMZ resulted in 3.63 (95% credible range [CR], 3.32 to 3.93) life-years versus 2.53 (95% CR, 2.36 to 2.69) life-years for TMZ monotherapy, a difference of 1.10 years (95% CR, 0.96 to 1.23) discounted; the difference was 1.56 years (95% CR, 1.33 to 1.80) undiscounted. The results were most sensitive to uncertainty in the 10- and 15- year survival estimates conditional on survival to years 5 and 10, respectively. Conclusions. This analysis presents a new approach to model lifetime survival benefits of adding TTFields to TMZ for GBM by combining long-term clinical trial data and epidemiological data. The model demonstrates that adding TTFields to TMZ for GBM increases lifetime survival substantially. Citation Format: Greg Guzauskas, Bruce Wang, Marc Salzberg. Modeling long-term survival outcomes in glioblastoma patients treated with TTFields plus temozolomide and temolozomide monotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT160. doi:10.1158/1538-7445.AM2017-CT160

Indirect treatment comparison of belatacept versus tacrolimus from a systematic review of immunosuppressive therapies for kidney transplant patients

Objective: End-stage renal disease is the final and irreversible stage in chronic kidney disease, leading to patient mortality, unless managed by dialysis or transplantation (the treatment of choice). This study aimed to compare a currently recommended immunosuppressive treatment, tacrolimus, against a newer treatment, belatacept, using indirect treatment comparison (ITC) techniques since no head-to-head randomized controlled trials (RCTs) comparing tacrolimus against belatacept currently exist. Methods: ITC was employed to calculate estimates for the relative risks and mean difference of tacrolimus against belatacept. The choice of the Bucher ITC model was driven by the available data and the simple indirect treatment comparison involving three treatments was considered appropriate. Results: The results of the indirect analysis showed no significant differences between belatacept and tacrolimus treatments for mortality and graft loss. The acute rejection rate was significantly lower with tacrolimus (Prograf* and Advagraf) compared with belatacept (0.22 [0.13, 0.39] to 0.44 [0.20, 0.99]). Conclusions: The results of this systematic review and meta-analysis suggests that tacrolimus is significantly superior to belatacept in terms of acute rejection outcomes but comparable for graft and patient survival. Further research should include a properly designed clinical trial comparing tacrolimus against belatacept directly. Limitations: These include variations in terms of clinical and design differences among the trials, weaknesses in the Bucher method and the lack of long-term clinical trial data with tacrolimus to compare with the recent long-term (7 years) belatacept trial data.

Asian Age-Related Macular Degeneration: Current Concepts and Gaps in Knowledge.

Data on the epidemiology and treatment of age-related macular degeneration (AMD) in Asian populations have been scarce. Recently, significant advances in the current knowledge of AMD in Asia have been made, but deficiencies in important areas remain. Epidemiological data on AMD in those 80 years or older are lacking.There are also few incidence data on AMD or polypoidal choroidal vasculopathy (PCV), an important variant of AMD that seems to be more common in Asia. The risk factors for PCV have not been clearly defined to the extent that those for AMD have. No trials of nutritional supplementation for AMD prevention in Asia exist, and there is also a lack of long-term clinical trial data on combination therapy for PCV and indeed very few trial data on PCV. These represent opportunities for future research. With aging populations in Asia, increased data on the prevalence, risk factors, prevention, and treatment of AMD and PCV in Asian populations will be needed to formulate evidence-based public health and clinical guidelines.

Controversies in ablation of atrial fibrillation

Catheter ablation is increasingly widely used to treat atrial fibrillation (AF) and constantly evolving techniques and protocols have led to improved success rates and lower risks of complications in a broad range of patients. However, long-term clinical trial data are still limited and as a result many questions remain unanswered. Particularly in patients with symptomatic paroxysmal AF, high success rates in restoring sinus rhythm (SR) with a low risk of complications are reported by experienced centres. Nevertheless, the continued suppression of AF over time, particularly with regard to the recurrence of asymptomatic episodes of AF which could influence stroke risk, is not yet adequately documented and therefore the safety of discontinuing oral anticoagulation remains unclear. The risk of silent or subclinical complications associated with ablation procedures, the likelihood of autonomic modulation and the long-term impact of ablation on left atrial mechanical function have not yet been fully determined. Limited clinical trial data suggest that catheter ablation may be particularly beneficial for patients suffering from heart failure (HF) secondary to AF, indicating improved left ventricular function and quality of life with the restoration of SR. However, the processes underlying HF and the co-existing morbidities vary from one patient to another and the factors predicting a successful outcome of ablation have not yet been fully defined. Similarly, the consistently higher rates of AF suppression achieved with catheter ablation vs. antiarrhythmic drug therapy shown in comparative clinical trials encourage consideration of this treatment as a potential first-line treatment in certain patients, but whether this is currently justifiable and if so, in which patient subsets, are open questions. This article reviews current approaches to catheter ablation and attempts to address some of the controversies regarding its use.

Use of Nonsteroidal Antiinflammatory Drugs

Clinical trial data have prompted questions about the degree to which patients and their physicians should consider an increased risk of cardiovascular or cerebrovascular events when selecting medications for pain relief. Since the 2005 publication of a Science Advisory on the use of nonsteroidal antiinflammatory drugs (NSAIDs) by the American Heart Association,1 several important events have occurred that have served as the catalyst for this update for clinicians. (1) Additional data from randomized controlled trials of cyclooxygenase (COX)-2–selective agents have been reported and summarized in meta-analyses, which has reinforced the concern about cardiovascular events with COX-2 inhibitors (coxibs; Figure 1). (2) Several reports have appeared that have identified an increased risk of cardiovascular events even with the nonselective NSAIDs, which has raised concern about the use of those agents as well (Table). (3) Regulatory authorities in several regions of the world have introduced warning statements and advisories to both healthcare professionals and the lay public about the use of various NSAIDs (Figures 2 and 3⇓). Figure 1. Comparison of effects of different selective COX-2 inhibitors vs placebo on myocardial infarction. Event numbers and person-years of exposure, with corresponding mean annual event rates in parentheses, are presented for patients allocated to selective COX-2 inhibitor or placebo. Event rate ratios for pooled data with 95% CIs are indicated by a diamond; rate ratios for individual selective COX-2 inhibitors, with 99% CIs, are indicated by a square and horizontal line. Diamonds to the right of the solid line indicate hazard with a selective COX-2 inhibitor compared with placebo. As noted, there was a significant increase in the rate ratio for myocardial infarction with COX-2 inhibitors compared with placebo. Similar analyses (data not shown) include rate ratios of 1.42 (1.13 to 1.78; P =0.003) for vascular events, 1.02 (0.71 to 1.47; P …

Long-term experience with alendronate in the treatment of osteoporosis

Osteoporosis is characterised by increased bone turnover, low bone mass and impaired bone microarchitecture, leading to increased fracture risk. Effective anticatabolic therapies decrease fracture risk by reducing the rate of bone turnover, thereby maintaining bone microarchitecture and increasing bone mineral density. At present, potent oral bisphosphonates, such as alendronate (FOSAMAX®; Merck & Co.), are preferred for the treatment of osteoporosis. Long-term clinical trial data demonstrate that alendronate is effective and generally well tolerated. Results from head-to-head studies and meta-analyses suggest that alendronate is more effective than certain other anticatabolic agents in the treatment of patients with osteoporosis.

Prediction of acute and chronic complications by a new computer simulation model for type 1 and type 2 diabetes: the Diabetes Mel l it us Model (DMM)

SummaryAn epidemiological simulation model for patients with type 1 and type 2 diabetes (the Diabetes Mellitus Model (DMM)) was developed based on published clinical and observational data and expert estimations, for prediction of short- and long-term outcomes in defined patient cohorts. A computer program was developed with an interface for definition of patient cohorts and for results display. Patient cohorts can be user-defined by gender, age, duration and type of diabetes, glycosylated haemoglobin, blood pressure, albumin excretion and therapy. Based on riskequations and current risk variable levels, the DMM simulates complications over 10 years (hypoglycaemia; retinopathy; blindness; microalbuminuria and macroalbuminuria; end-stage renal disease; neuropathy; amputation; diabetic foot syndrome; myocardial infarction; stroke; angina pectoris; heart failure; and death). The DMM is suitable for simulation of complications and for estimation of clinical implications of various diabetes care strategies, and may be particularly valuable in lieu of long-term clinical trial data.

Current status of tamoxifen use: An update for the surgical oncologist.

The surgical oncologist is frequently responsible for the screening and diagnosis of women with breast cancer. In this pivotal role, they are often the first to discuss treatment options, including nonsurgical interventions, with breast cancer patients. Recent long-term clinical trial data provide support for the use of tamoxifen to prevent breast cancer in women at high risk of the disease. A breast cancer risk assessment can help identify women at higher than average risk for the disease, who may be appropriate candidates for chemoprevention. It is important for the surgical oncologist to understand the current indications and evidence regarding the use of tamoxifen for breast cancer prevention and treatment as they counsel their patients on available options.

Safety evaluation of nabumetone in United States clinical trials

A total of 1,924 persons (rheumatoid arthritis, 835; osteoarthritis, 1,073; volunteers, 16) received nabumetone in United States clinical trials. Nine hundred eighty-eight patients have received nabumetone treatment for periods of more than one year, and 375 patients have received treatment for longer than two years. Four hundred eighty patients over 65 years of age have received treatment with nabumetone, and 224 of these elderly patients have received treatment for periods of more than one year. The nabumetone dose most commonly used in all double-blind trials was 1,000 mg at night. In long-term, open-label studies, which were usually extensions of the double-blind trials, patients could increase the dose to 2,000 mg per day. Nine hundred nineteen patients received doses of more than 1,000 mg per day. Adverse experience information was collected at each visit, including information for some patients receiving treatment for more than three years. Laboratory data were collected periodically throughout the trials, and the data were assessed for trends over time. The adverse experience pattern observed for nabumetone is similar to that described for clinical trial data for other nonsteroidal anti-inflammatory drugs. However, it is noteworthy that the pattern observed for nabumetone is from clinical trials with approximately 1,000 patients receiving treatment for periods of one year or more. This long-term patient exposure in clinical trials far exceeds long-term clinical trial data for other agents. The types and frequencies of adverse experiences reported by persons treated with nabumetone are relatively constant over the long time period covered by these trials. Also, the adverse experience patterns remained generally constant over time for various populations: all patients, patients 65 or older, female patients, male patients, and patients who received an increased dose of nabumetone. Although some statistically significant trends were detected for some laboratory parameters, there was little indication of significant clinical patterns. Although there were patients with individually important laboratory values, nabumetone was not associated with clinically important adverse laboratory patterns. Overall, the adverse experience data and laboratory data indicate that nabumetone is safe for the treatment of adult patients with rheumatoid arthritis or osteoarthritis.