Bennett Levitan

Long-acting injectable paliperidone palmitate versus oral paliperidone extended release: a comparative analysis from two placebo-controlled relapse prevention studies

BackgroundIncreasing availability and use of long-acting injectable antipsychotics have generated a need to compare these formulations with their oral equivalents; however, a paucity of relevant data is available.MethodsThis post hoc comparison of the long-term efficacy, safety and tolerability of maintenance treatment with paliperidone palmitate (PP) versus oral paliperidone extended release (ER) used data from two similarly designed, randomised, double-blind (DB), placebo-controlled schizophrenia relapse prevention trials. Assessments included measures of time to relapse, symptom changes/functioning and treatment-emergent adverse events (TEAEs). Time to relapse between treatment groups was evaluated using a Cox proportional hazards model. Between-group differences for continuous variables for change scores during the DB phase were assessed using analysis of co-variance models. Categorical variables were evaluated using Chi-square and Fishers exact tests. No adjustment was made for multiplicity.ResultsApproximately 45% of enrolled subjects in both trials were stabilised and randomised to the DB relapse prevention phase. Risk of relapse was higher in subjects treated with paliperidone ER than in those treated with PP [paliperidone ER/PP hazard ratio (HR), 2.52; 95% confidence interval (CI), 1.46–4.35; p < 0.001]. Similarly, risk of relapse after withdrawal of paliperidone ER treatment (placebo group of the paliperidone ER study) was higher than after withdrawal of PP (paliperidone ER placebo/PP placebo HR, 2.25; 95% CI, 1.59–3.18; p < 0.001). Stabilised schizophrenic subjects treated with PP maintained functioning demonstrated by the same proportions of subjects with mild to no difficulties in functioning at DB baseline and end point [Personal and Social Performance (PSP) scale total score >70, both approximately 58.5%; p = 1.000] compared with a 10.9% decrease for paliperidone ER (58.5% vs 47.6%, respectively; p = 0.048). The least squares mean change for Positive and Negative Syndrome Scale (PANSS) total score at DB end point in these previously stabilised subjects was 3.5 points in favour of PP (6.0 vs 2.5; p = 0.025). The rates of TEAEs and AEs of interest appeared similar.ConclusionsThis analysis supports maintenance of effect with the injectable compared with the oral formulation of paliperidone in patients with schizophrenia. The safety profile of PP was similar to that of paliperidone ER. Future studies are needed to confirm these findings.

Benefit–risk assessment of rivaroxaban versus enoxaparin for the prevention of venous thromboembolism after total hip or knee arthroplasty

Purpose Venous thromboembolism is a common complication after major orthopedic surgery. When prescribing anticoagulant prophylaxis, clinicians weigh the benefits of thromboprophylaxis against bleeding risk and other adverse events. Previous benefit–risk analyses of the REgulation of Coagulation in ORthopaedic surgery to prevent Deep vein thrombosis and pulmonary embolism (RECORD) randomized clinical studies of rivaroxaban versus enoxaparin after total hip (THA) or knee (TKA) arthroplasty generally used pooled THA and TKA results, counted fatal bleeding as both an efficacy and a safety event, and included the active and placebo-controlled portions of RECORD2, which might confound benefit–risk assessments. We conducted a post hoc analysis without these constraints to assess benefit–risk for rivaroxaban versus enoxaparin in the RECORD studies. Patients and methods Data from the safety population of the two THA and two TKA studies were pooled separately. The primary analysis compared the temporal course of event rates and rate differences between rivaroxaban and enoxaparin prophylaxis for symptomatic venous thromboembolism plus all-cause mortality (efficacy events) versus nonfatal major bleeding (safety events). Additionally, these rates were used to derive measures of net clinical benefit, number needed to treat (NNT), and number needed to harm (NNH) for these two end points. Results After THA or TKA, and compared with enoxaparin, rivaroxaban therapy resulted in more efficacy events prevented than safety events caused, with benefits exceeding harms early and throughout treatment and follow-up. Relative to enoxaparin, rivaroxaban treatment prevented six efficacy events per harm event caused for THA, with NNT =262/NNH =1,711. For TKA, rivaroxaban treatment prevented four to five efficacy events per harm event caused, with NNT =102/NNH =442. Sensitivity analysis that included surgical-site bleeding resulted in NNH =345 for THA and NNH =208 for TKA. Conclusion In the RECORD studies, considering death, symptomatic venous thromboembolism, and major bleeding, rivaroxaban resulted in greater benefits than harms compared with enoxaparin. When incorporating surgical-site bleeding, rivaroxaban also results in greater benefit than harm for TKA and is balanced with enoxaparin for THA.

Application of the Benefit-Risk Action Team (BRAT) Framework in Pharmaceutical R&D Results From a Pilot Program

Benefit-risk (B-R) assessments inform decisions regarding drug development and lifecycle management, serve as a basis for regulatory determinations, and help clinicians, patients, and payers make rational, value-based treatment decisions. Nevertheless, no widely accepted, systematic methods exist to guide, justify, and communicate benefit-risk decisions in a transparent and consistent manner. The B-R Action Team (BRAT), formed by the Pharmaceutical Research and Manufacturers of America (PhRMA), has developed a structured approach to B-R assessment—the “BRAT Framework”—that assists decision makers in selecting, organizing, summarizing, and communicating evidence relevant to B-R decisions. The BRAT Framework’s functionality has been demonstrated previously in a series of scenarios with hypothetical drugs as well as in a few real-world applications. Here we report results of a pilot program to assess the value of the Framework in pharmaceutical development and postmarketing settings, for the purpose of informing PhRMA’s regulatory advocacy. A third-party consultant conducted the assessment through a survey of pharmaceutical companies’ experiences using the Framework. We also identify aspects of the Framework that require further development.

A Model for Decision Support in Signal Triage

Spontaneous reporting of suspected adverse drug reactions (ADRs) has long been a cornerstone of pharmacovigilance. With the increasingly large volume of ADRs, regulatory agencies, scientific/academic organizations and marketing authorization holders have applied statistical tools to assist in signal detection by identifying disproportionate reporting relationships in spontaneous reporting databases. These tools have generated large numbers of signals defined as drug-ADR reporting associations that meet specified statistical criteria.The challenge is to identify which signals are most likely to be medically important and therefore warrant priority for further investigation. Decisions related to signal triage are often complex and are based on a combination of clinical, epidemiological, pharmacological and regulatory criteria. There are no specific regulations, guidelines or standards that provide an objective basis for these decisions.This paper describes preliminary work to identify and quantify the specific factors that contribute to a decision to prioritize a specific drug-ADR combination for further in-depth review. We applied a tool from the discipline of decision analysis to systematically assess the important attributes of spontaneously reported ADRs. A model was created that integrates these assessments and produces rankings for the signals generated from quantitative signalling methods. Although more research is necessary to evaluate the performance of this model fully, preliminary results suggest that the use of formal decision analysis approaches to support signal triage can provide potential benefit and will help meet an important need.

A Framework for Incorporating Patient Preferences Regarding Benefits and Risks into Regulatory Assessment of Medical Technologies.

BACKGROUND In response to 2012 guidance in which the US Food and Drug Administrations (FDA) Center for Devices and Radiological Health (CDRH) stated the importance of patient-centric measures in regulatory benefit-risk assessments, the Medical Device Innovation Consortium (MDIC) initiated a project. The project was used to develop a framework to help the Food and Drug Administration (FDA) and industry sponsors understand how patient preferences regarding benefit and risk might be integrated into the review of innovative medical devices. METHODS A public-private partnership of experts from medical device industry, government, academia and non-profits collaborated on development of the MDIC patient centered benefit-risk framework. RESULTS The MDIC Framework examines what patient preference information is and the potential use and value of patient preference information in the regulatory process and across the product development life cycle. The MDIC Framework also includes a catalog of patient preference assessment methods and an agenda for future research to advance the field. CONCLUSIONS This article discusses key concepts in patient preference assessment of particular importance for regulators and researchers that are addressed in the MDIC Framework for patient centered benefit-risk assessment as well as the unique public-private collaboration that led its development.

Giving Patients’ Preferences a Voice in Medical Treatment Life Cycle: The PREFER Public–Private Project

Giving Patients’ Preferences a Voice in Medical Treatment Life Cycle : The PREFER Public–Private Project

Relative importance of benefits and risks associated with antithrombotic therapies for acute coronary syndrome: patient and physician perspectives

Abstract Background: In acute coronary syndrome (ACS), antithrombotic therapies prevent thrombotic events, but also increase bleeding risk. Knowledge is limited about how patients and physicians balance these benefits and risks. Objective: To quantify US patient and physician preferences for outcomes associated with antithrombotic therapies in ACS. Methods: Two independent web-based surveys were conducted using best–worst scaling in board-certified cardiologists and adult patients hospitalized within the last 5 years due to heart attack and who used aspirin or prescription antithrombotic therapies. Participants selected best and worst of three possible outcomes across a series of questions. Outcomes included death, various levels of stroke, myocardial infarction (MI), and bleeding. Data were analyzed using a maximum difference model employing random-parameters logit. Relative importance of each outcome was estimated relative to death. Findings: Patients (n = 206) and physicians (n = 273) who met face validity requirements, viewed death and nonfatal major disabling stroke as nearly equivalent and most important outcomes to avoid. Relative to death and disabling stroke, physicians considered nondisabling stroke, all nonfatal bleeding, and mild MI all as least important to avoid, while patients considered all bleeds, except major bleeding requiring transfusion, as least important to avoid. Physicians considered severe MI equivalent to 0.92 (0.02 SE) deaths. Patients (∼0.35 [0.04] deaths) and physicians (∼0.64 [0.05] deaths) had different views for nonfatal moderate stroke. Patients viewed nonfatal major bleeding requiring transfusion ∼0.13 (0.02) deaths, and nonfatal heart attack ∼0.09 (0.02) deaths. Conclusion: US patients and physicians agree on the relative importance of avoiding death, disabling stroke and bleeding without transfusions. Differing perspectives on bleeding requiring transfusions, MI, and moderately disabling stroke suggest that patients and physicians may have different benefit–risk preferences. Transparent discussion between physicians and patients in ACS treatment shared decision-making seems warranted, although limitations of survey methodology and cultural differences compared with US participants should be considered.

Patient Engagement at a Tipping Point—The Need for Cultural Change Across Patient, Sponsor, and Regulator Stakeholders Insights From the DIA Conference, “Patient Engagement in Benefit Risk Assessment Throughout the Life Cycle of Medical Products”

Benefit-risk assessment is the foundation for decision making throughout the life cycle of medical products. Because patients are the beneficiaries of the efficacy of medical treatments and also bear their possible risks, their perspectives and judgments about value and the relative importance of benefits and risks should be at the heart of the medical decision-making process. Patient engagement is now at a tipping point; there have been a growing number of patient engagement initiatives over the past several years, but there remains the need for a common language, alignment on engagement approaches and best practices, and a shared vision regarding a desired future state. This article discusses insights gleaned from the DIA conference, “Patient Engagement in Benefit-Risk Assessment throughout the Life Cycle of Medical Products” (September 2015). It highlights the changes that will need to occur within the patient, medical-product sponsor, and regulatory cultures in order for patient engagement to become integrated into the medical-product development process and life cycle maintenance. Furthermore, it emphasizes that reaching the desired future state will require a conscious commitment from all stakeholders to work collaboratively to develop shared solutions and to map a common path forward.

Physician and patient benefit-risk preferences from two randomized long-acting injectable antipsychotic trials:

Purpose To quantify clinical trial participants’ and investigators’ judgments with respect to the relative importance of efficacy and safety attributes of antipsychotic treatments for schizophrenia, and to assess the impact of formulation and adherence. Methods Discrete-choice experiment surveys were completed by patients with schizophrenia and physician investigators participating in two phase-3 clinical trials of paliperidone palmitate 3-month long-acting injectable (LAI) antipsychotic. Respondents were asked to choose between hypothetical antipsychotic profiles defined by efficacy, safety, and mode of administration. Data were analyzed using random-parameters logit and probit models. Results Patients (N=214) and physicians (N=438) preferred complete improvement in positive symptoms (severe to none) as the most important attribute, compared with improvement in any other attribute studied. Both respondents preferred 3-month and 1-month injectables to oral formulation (P<0.05), irrespective of prior adherence to oral antipsychotic treatment, with physicians showing greater preference for a 3-month over a 1-month LAI for nonadherent patients. Physicians were willing to accept treatments with reduced efficacy for patients with prior poor adherence. The maximum decrease in efficacy (95% confidence interval [CI]) that physicians would accept for switching a patient from daily oral to 3-month injectable was as follows: adherent: 9.8% (95% CI: 7.2–12.4), 20% nonadherent: 25.4% (95% CI: 21.0–29.9), and 50% nonadherent: >30%. For patients, adherent: 10.1% (95% CI: 6.1–14.1), nonadherent: the change in efficacy studied was regarded as unimportant. Conclusion Improvement in positive symptoms was the most important attribute. Patients and physicians preferred LAIs over oral antipsychotics, with physicians showing a greater preference for 3-month over 1-month LAI. Physicians and patients were willing to accept reduced efficacy in exchange for switching a patient from an oral formulation to a LAI.

Benefit-Risk Assessment, Communication, and Evaluation (BRACE) throughout the life cycle of therapeutic products

Optimizing a therapeutic products benefit–risk profile is an on‐going process throughout the products life cycle. Different, yet related, benefit–risk assessment strategies and frameworks are being developed by various regulatory agencies, industry groups, and stakeholders. This paper summarizes current best practices and discusses the role of the pharmacoepidemiologist in these activities, taking a life‐cycle approach to integrated Benefit–Risk Assessment, Communication, and Evaluation (BRACE).