Safety and efficacy of active and passive immunotherapy in mild-to-moderate Alzheimer's disease: A systematic review and network meta-analysis.

OBJECTIVE: The objective of this study was to systematically review and conduct a direct and network meta-analysis of randomized controlled trials that have examined the clinical safety and efficacy of using passive and active immunotherapies in Alzheimer's disease (AD). RESEARCH QUESTIONS: (1) Is amyloid-based immunotherapy in patients with mild-to-moderate AD associated with more efficacy benefits compared to placebo? (2) Which immunotherapy agent is associated with more comparative benefit? (3) Is passive or active immunotherapy associated with more benefits? DATA SOURCES: A systematic review of published randomized controlled trials was performed in MEDLINE, EMBASE, PubMed and Cochrane library. Review methods and meta-analysis: Two reviewers independently selected the studies, extracted the data and assessed risk of bias. Important AD cognitive scales as clinical efficacy outcomes were ADAS-cog, CDR and MMSE whereas edema, neoplasms and mortality were included as safety outcomes. A direct comparison meta-analysis using a random effect model and a network (direct and indirect) comparison was conducted to calculate mean differences in treatment effects, SUCRA and ranking probabilities for each medicine per safety and efficacy outcome. Quality of network results were assessed using GRADE methodology. PRINCIPLE FINDINGS: Thirteen RCT-assessed patients with mild-to-moderate AD were included in the final analysis. The results showed that immunotherapies compared with placebo produced a statistically, but not clinically significant, improvement in ADAS-cog (MD=-0.39; 95% CI -0.42, -0.35, P=0.00) and MMSE. In terms of safety, the rate of ARIA-E was significantly higher with monoclonal antibodies. Solanezumab and AN1792 (vaccine) were the drugs of choice both from efficacy and safety perspectives. CONCLUSION: In terms of efficacy, the review showed a statistically, but not clinically significant, improvement in favor of immunotherapy versus placebo. Further clinical trials are required to demonstrate any cognitive benefits of immunotherapies in mild-to-moderate AD.

Safety and efficacy of dipeptidyl peptidase-4 inhibitors vs sulfonylurea in metformin-based combination therapy for type 2 diabetes mellitus: Systematic review and meta-analysis.

PURPOSE: The purpose of this study was to compare the safety and efficacy of DPP-4 inhibitors versus sulfonylurea as adjunctive second-line therapy in patients with type 2 diabetes mellitus, inadequately controlled with metformin mono-therapy. SOURCES: A systematic review of published randomized controlled trials (RCTs) was performed in MEDLINE, EMBASE, PubMed and Cochrane library. Two reviewers independently selected the studies, extracted the data and assessed the risk of bias. Clinical outcomes were cardiovascular events, HbA1c % change from baseline, body weight and hypoglycemic event rate. A direct comparison meta-analysis using a random effect model was conducted to calculate mean differences in treatment effects and risk ratio between DPP-4 inhibitors and sulfonylurea. PRINCIPLE FINDINGS: Ten RCTs on adult patients with type 2 diabetes and inadequate glycemic control were included in the final analysis. DPP-4 inhibitors compared to sulfonylureas produced a non-significant difference in HbA1c% change in 10,139 subjects, whereas a significant decrease in the rate of hypoglycemic events was observed in favor of DPP-4 inhibitors (RR= 0.12; P<0.00001) involving 10,616 patients, with at least one hypoglycemic event during the follow-up period (12-104 weeks). Body weight decreased by 2.2 kg (95% CI 1.7-2.7) with DPP-4 inhibitors, compared with sulfonylureas. There were insufficient data to assess a difference in the risk for cardiovascular events. CONCLUSION: The review shows that, in terms of clinical efficacy, there is no significant difference between DPP4-inhibitors and sulfonylurea when either is added to metformin mono-therapy. In contrast, the safety assessment analysis showed a significant decrease in the risk of hypoglycemic events in patients using DPP4-inhibitors.

Stakeholders' feedback on the proposed recommendations for updating the patented medicine prices review board (pmprb) budget impact analysis guidelines.

INTRODUCTION: The present study aimed to obtain Canadian stakeholders' feedback on a list of proposed recommendations for updating the Patented Medicine Prices Review Board (PMPRB)'s 2007 budget impact analysis (BIA) guidelines. METHODS: A mixed-methods study was designed to obtain feedback from two stakeholder perspectives-(public and private) payers and manufacturers-on the proposed BIA recommendations. We obtained policymakers' opinion through one-on-one interviews and collected feedback from manufacturers and their consultants using a survey. The interview guide and the survey were developed based on the list of recommendations related to BIA key elements, which were either not discussed or addressed differently in the PMPRB 2007 BIA guidelines. The list was derived from 16 Canadian or other national and transnational BIA guidelines. A thematic analysis was applied for analysis of the qualitative (interview) data. RESULTS: Thirty-five policymakers and manufacturers participated in the study. Stakeholders supported the inclusion of 56% of the proposed recommendations into the guidelines pertaining to the use of expert opinions, data extrapolated from the payers' database, scenario analysis, and dynamic population. Inclusion of indirect costs, and cost transfers from other jurisdictions, were not approved. There was no consensus regarding the inclusion of patients' adherence/compliance and cost offsets. CONCLUSIONS: The present study has provided sufficient insights to enable the creation of a penultimate version for updating the PMPRB BIA guidelines. This penultimate version will be subject to a broader consultation among stakeholders prior to a final revision and approval. Further Canadian stakeholder feedback is required for reaching consensus on inconclusive recommendations.

A Comparison of Pharmaceutical Budget Impact Analysis (BIA) Recommendations Amongst the Canadian Patented Medicine Prices Review Board (PMPRB), Public and Private Payers.

The Canadian budget impact analysis (BIA) guidelines were published by the Patented Medicine Prices Review Board (PMPRB) in 2007. Some Canadian federal, provincial and territorial (F/P/T) drug plans have updated their BIA guidelines since then. The aim of the present review was to provide a comprehensive list of the key BIA recommendations from the various Canadian F/P/T drug plans and private payers and to highlight the differences between those guidelines and the recommendations that were in the Canadian PMPRB 2007 BIA guidelines. We searched the websites of fifteen F/P/T public drug benefit programs including the Canadian Agency for Drugs and Technologies in Health (CADTH) and Non-Insured Health Benefits Program (NIHBP) and five private payers' websites. An Excel-based data abstraction form was designed to highlight differences between recommendations relating to the BIA key elements made by different guidelines. Eight BIA guidelines (PMPRB 2007, Alberta, British Columbia, Manitoba, Ontario, Quebec, CADTH, and Medavie Blue Cross) were identified and reviewed, and a comprehensive list of recommendations was abstracted. Recommendations were similar to the 2007 guidelines in terms of time horizon duration, comparators, target population assessment and use of direct drug costs in BIAs. Differences were mostly related to actual acquisition cost, such as whether or not to include markups and dispensing fees, the patients' perspective, cost of supplies, cost of health care utilization, and scenario analysis. The recommendations that were not included in the PMPRB 2007 guidelines but were included in at least one of the Canadian F/P/T or private guidelines were related to the inclusion of the patients' perspective (i.e., co-payment), the costing, the handling of uncertainty and the reporting format. The present study is a comparative review of recommendations between the Canadian PMPRB 2007 guidelines and the F/P/T or private payers' BIA guidelines, and provides a most up-to-date list of recommendations for revising the Canadian BIA guidelines, with applicability for both public and private plan new drug submissions in Canada.

A methodological review of national and transnational pharmaceutical budget impact analysis guidelines for new drug submissions.

INTRODUCTION: Budget impact analysis (BIA) in health care, sometimes referred to as resource impact, is the financial change in the use of health resources associated with adding a new drug to a formulary or the adoption of a new health technology. Several national and transnational organizations worldwide have updated their BIA guidelines in the past 4 years. The aim of the present review was to provide a comprehensive list of the key recommendations of BIA guidelines from different countries that may be of interest for those who wish to build or to update BIA guidelines. METHODS: National and transnational BIA guidelines were searched in databases including MEDLINE, EMBASE, Cochrane, EconLit, CINAHL, Business Source Premier, HealthSTAR, and the gray literature including regulatory agency websites. Data were reviewed and abstracted based on key elements in a standard BIA model (analytical model structure, input and data sources, and reporting format). RESULTS: Eight national (Australia, UK, Belgium, Ireland, France, Poland, Brazil, and Canada) and one transnational (International Society for Pharmacoeconomics and Outcomes Research) BIA guidelines were included in this review, and a comprehensive list of BIA recommendations was identified. The review showed that certain recommendations such as patient population assessment, drug-related direct costs, discounting, and disaggregated results were common across the various jurisdictions. BIA guidelines differed from each other in terms of the number and scope of recommendations, the terminology used (eg, the definition of comparators or cost offsets) and the direction of the recommendations (ie, to include or not to include with respect to such items as off-label indications, indirect costs, clinical outcomes, and resource utilization). CONCLUSION: While there was a common purpose for all of the BIA guidelines that were identified, substantial differences did occur in the specific recommendations. The pharmaceutical financing system structure might explain why guidelines from the UK, Australia, and Canada have more country-specific recommendations. The desire to be consistent with adopted economic evaluation assumptions might be another reason for some observed differences between countries. Further research is required to assess the source of the heterogeneity between BIA recommendations are identified in different guidelines.

Comparative effectiveness and safety of interventions for acute diarrhea and gastroenteritis in children: A systematic review and network meta-analysis.

BACKGROUND: Many interventions have shown effectiveness in reducing the duration of acute diarrhea and gastroenteritis (ADG) in children. Yet, there is lack of comparative efficacy of interventions that seem to be better than placebo among which, the clinicians must choose. Our aim was to determine the comparative effectiveness and safety of the pharmacological and nutritional interventions for reducing the duration of ADG in children. METHODS: Data sources included Medline, Embase, CENTRAL, CINAHL, LILACS, and Global-Health up to May 2017. Eligible trials compared zinc (ZN), vitamin A, micronutrients (MN), probiotics, prebiotics, symbiotics, racecadotril, smectite(SM), loperamide, diluted milk, lactose-free formula(LCF), or their combinations, to placebo or standard treatment (STND), or among them. Two reviewers independently performed screening, review, study selection and extraction. The primary outcome was diarrhea duration. Secondary outcomes were stool frequency at day 2, diarrhea at day 3, vomiting and side effects. We performed a random effects Bayesian network meta-analysis to combine the direct and indirect evidence for each outcome. Mean differences and odds ratio with their credible intervals(CrI) were calculated. Coherence and transitivity assumptions were assessed. Meta-regression, subgroups and sensitivity analyses were conducted to explore the impact of effect modifiers. Summary under the cumulative curve (SUCRA) values with their CrI were calculated. We assessed the evidence quality and classified the best interventions using the Grading of Recommendations, Assessment, Development & Evaluation (GRADE) approach for each paired comparison. RESULTS: A total of 174 studies (32,430 children) proved eligible. Studies were conducted in 42 countries of which most were low-and middle-income countries (LMIC). Interventions were grouped in 27 categories. Most interventions were better than STND. Reduction of diarrhea varied from 12.5 to 51.1 hours. The combinations Saccharomyces boulardii (SB)+ZN, and SM+ZN were considered the best interventions (i.e., GRADE quality of evidence: moderate to high, substantial superiority to STND, reduction in duration of 35 to 40 hours, and large SUCRA values), while symbiotics (combination of probiotics+prebiotics), ZN, loperamide and combinations ZN+MN and ZN+LCF were considered inferior to the best and better than STND [Quality: moderate to high, superior to STND, and reduction of 17 to 25 hours]. In subgroups analyses, effect of ZN was higher in LMIC and was not present in high-income countries (HIC). Vitamin A, MN, prebiotics, kaolin-pectin, and diluted milk were similar to STND [Quality: moderate to high]. The remainder of the interventions had low to very-low evidence quality. Loperamide was the only intervention with more side effects than STND [Quality: moderate]. DISCUSSION/CONCLUSION: Most interventions analyzed (except vitamin A, micronutrients, prebiotics, and kaolin-pectin) showed evidence of superiority to placebo in reducing the diarrhea. With moderate-to high-quality of evidence, SB+ZN and SM+ZN, demonstrated the best combination of evidence quality and magnitude of effect while symbiotics, loperamide and zinc proved being the best single interventions, and loperamide was the most unsafe. Nonetheless, the effect of zinc, SB+ZN and SM+ZN might only be applied to children in LMIC. Results suggest no further role for studies comparing interventions against no treatment or placebo, or studies testing loperamide, MN, kaolin-pectin, vitamin A, prebiotics and diluted milk. PROSPERO REGISTRATION: CRD42015023778.

BUDGET IMPACT ANALYSIS OF USING OMEPRAZOLE IMMEDIATE-RELEASE ORAL SUSPENSION IN REPLACE OF INTRAVENOUS PANTOPRAZOLE IN CRITICALLY ILL PATIENTS.

OBJECTIVES: The aim of the present study was to estimate the financial consequence of using omeprazole immediate-release (IR) oral suspension versus pantoprazole intravenous infusion for preventing stress-related upper gastrointestinal bleeding in critically ill patients from the perspective of the health care system. METHODS: An Excel-based model was developed to compare the cost of prevention of upper gastrointestinal bleeding early after intensive care admission using the current intravenous (IV) pantoprazole formulation versus omeprazole IR oral suspension. Total costs included the cost of acid suppressive drugs and related clinical outcomes. Inputs were obtained from a local clinical trial, the Ministry of Health database, insurance organizations, hospital and pharmacy registries, the relevant literature, and expert opinion. The robustness of the input data was investigated by one-way sensitivity analysis. The model was developed based on the results of a randomized control trial (RCT), in which experimental and control groups received omeprazole and pantoprazole, respectively. RESULTS: According to the proposed model, the cost of gastrointestinal (GI) bleeding prevention using pantoprazole IV was US$ 950,000 while US$ 750,000 was spent on receiving omeprazole oral suspension. These costs led to the annual cost-saving of almost US$ 200,000 (US$4 per member, per month) for the health care system. CONCLUSIONS: In the present study, a budget impact analysis was performed to assess the financial consequences of using omeprazole IR oral suspension in place of pantoprazole IV for prevention of upper gastrointestinal bleeding. The better preventive effect of omeprazole IR oral suspension when compared with conventional therapy using pantoprazole IV was the major reason for the final comparative budgetary savings.

"Budget impact analyses": a practical policy making tool for drug reimbursement decisions.

In the present article, Budget Impact Analysis as an effective, practical financial tool has been introduced to the policy makers for improving drug formulary and reimbursement decision making. In Iran, Ministry of Health (MOH), health insurance organizations, and health care providers such as hospitals could take the most advantage of the BIAs reports.

Costs of Treatment after Renal Transplantation: Is it Worth to Pay More?

The primary aim of the study was to estimate costs of treatment for the first year after renal transplantation from the perspective of health insurance organizations in Iran. An Excel-based and a Monte Carlo model were developed to determine the treatment costs of current clinical practice in renal transplantation therapy (RTT). Inputs were derived from Ministry of Health and insurance organizations database, hospital and pharmacy records, clinical trials and local and international literature. According to the model, there were almost 17,000 patients receiving RTT in Iran, out of which about 2,200 patients underwent the operation within the study year (2011 - 2012; n = 2,200) The estimated first year total treatment cost after renal transplantation was almost $14,000,000. These costs corresponded to annual total cost per patient of almost $6500 for the payers. Renal transplantation therapy is almost fully reimbursed by government in Iran. However, regarding new expensive medicines, cost of medical expenditure is rapidly growing and becoming quite unaffordable for the government; therefore, out-of-pocket (OOP) payments are dramatically increasing over time. In order to improve reimbursement policy making under pressure of current budget constraints, the present study is providing decision makers with practical tools make it possible for them to easily compare budgetary impact of the current therapy strategy with the future financial consequences of purchasing newly proposed medicines. In other words having estimation of the current budget spending on RTT would help policy makers in making efficient resource allocation and decrease quite high OOP expenditures.

Budget impact analysis of conversion from cyclosporine to sirolimus as immunosuppressive medication in renal transplantation therapy.

OBJECTIVES: The aim of this study was to determine budget impact of conversion from cyclosporine (CsA) to sirolimus (SRL) in renal transplant therapy (RTT) from the perspective of insurance organizations in Iran. METHODS: An Excel-based model was developed to determine cost of RTT, comparing current CsA based therapy to an mTOR inhibitor-based therapy regimen. Total cost included both cost of immunosuppressive agents and relative adverse events. The inputs were derived from database of Ministry of Health and insurance organizations, hospital and pharmacy based registries, and available literature that were varied through a one-way sensitivity analysis. According to the model, there were almost 17,000 patients receiving RTT in Iran, out of which about 2,200 patients underwent the operation within the study year. The model was constructed based on the results of a local RCT, in which test and control groups received CsA, SRL, and steroids over the first 3 months posttransplantation and, from the fourth month on, CsA, mycophenolate mofetil (MMF), and steroids were used in the CsA group and SRL, MMF, and steroids were administered in the SRL group, respectively. RESULTS: The estimated cost of RTT with CsA was US$4,850,000 versus US$4,300,000 receiving SRL. These costs corresponded to the cost saving of almost US$550,000 for the payers. CONCLUSION: To evaluate the financial consequence of adding mTOR inhibitors to the insurers' formulary, in the present study, a budget impact analysis was conducted on sirolimus. Fewer cases of costly adverse events along with lower required doses of MMF related to SRL based therapies were major reasons for this saving budgetary impact.