Platform trial design for neurofibromatosis type 1, NF2-related schwannomatosis and non-NF2-related schwannomatosis: A potential model for rare diseases.

Background: Neurofibromatosis type 1, NF2-related schwannomatosis and non-NF2-related schwannomatosis (grouped under the abbreviation "NF") are rare hereditary tumor predisposition syndromes. Due to the low prevalence, variability in the range, and severity of manifestations, as well as limited treatment options, these conditions require innovative trial designs to accelerate the development of new treatments. Methods: Within European Patient-Centric Clinical Trial Platforms (EU-PEARL), we designed 2 platform-basket trials in NF. The trials were designed by a team of multidisciplinary NF experts and trial methodology experts. Results: The trial will consist of an observational and a treatment period. The observational period will serve as a longitudinal natural history study. The platform trial design and randomization to a sequence of available interventions allow for the addition of interventions during the trial. If a drug does not meet the predetermined efficacy endpoint or reveals unacceptable toxicities, participants may stop treatment on that arm and re-enter the observational period, where they can be re-randomized to a different treatment arm if eligible. Intervention-specific eligibility criteria and endpoints are listed in intervention-specific-appendices, allowing the flexibility and adaptability needed for highly variable and rare conditions like NF. Conclusions: These innovative platform-basket trials for NF may serve as a model for other rare diseases, as they will enhance the chance of identifying beneficial treatments through optimal learning from a small number of patients. The goal of these trials is to identify beneficial treatments for NF more rapidly and at a lower cost than traditional, single-agent clinical trials.

Regulatory Issues of Platform Trials: Learnings from EU-PEARL.

Although platform trials have many benefits, the complexity of these designs may result not only in increased methodological but also regulatory and ethical challenges. These aspects were addressed as part of the IMI project EU Patient-Centric Clinical Trial Platforms (EU-PEARL). We reviewed the available guidelines on platform trials in the European Union and the United States. This is supported and complemented by feedback received from regulatory interactions with the European Medicines Agency and the US Food and Drug Administration. Throughout the project we collected the needs of all relevant stakeholders including ethics committees, regulators, and health technology assessment bodies through active dialog and dedicated stakeholder workshops. Furthermore, we focused on methodological aspects and where applicable identified the corresponding guidance. Learnings from the guideline review, regulatory interactions, and workshops are provided. Based on these, a master protocol template was developed. Issues that still need harmonization or clarification in guidelines or where further methodological research is needed are also presented. These include questions around clinical trial submissions in Europe, the need for multiplicity control across the whole master protocol, the use of non-concurrent controls, and the impact of different randomization schemes. Master protocols are an efficient and patient-centered clinical trial design that can expedite drug development. However, they can also introduce additional operational and regulatory complexities. It is important to understand the different requirements of stakeholders upfront and address them in the trial. While relevant guidance is increasing, early dialog with relevant stakeholders can help to further support such designs.

Developing generic templates to shape the future for conducting integrated research platform trials.

BACKGROUND: Interventional clinical studies conducted in the regulated drug research environment are designed using International Council for Harmonisation (ICH) regulatory guidance documents: ICH E6 (R2) Good Clinical Practice-scientific guideline, first published in 2002 and last updated in 2016. This document provides an international ethical and scientific quality standard for designing and conducting trials that involve the participation of human subjects. Recently, there has been heightened awareness of the importance of integrated research platform trials (IRPs) designed to evaluate multiple therapies simultaneously. The use of a single master protocol as a key source document to fulfill trial conduct obligations has resulted in a re-examination of the templates used to fulfill the dynamic regulatory and modern drug development environment challenges. METHODS: Regulatory medical writing, biostatistical, and other members of EU Patient-cEntric clinicAl tRial pLatforms (EU-PEARL) developed the suite of templates for IRPs over a 3.5-year period. Stakeholders contributing expertise included academic hospitals, pharmaceutical companies, non-governmental organizations, patient representative groups, and small and medium-sized enterprises (SMEs). RESULTS: The suite of templates for IRPs based on TransCelerate's Common Protocol Template (CPT) and statistical analysis plan (SAP) should help authors navigate relevant guidelines as they create study design content relevant for today's IRP studies. It offers practical suggestions for adaptive platform designs which offer flexible features such as dropping treatments for futility or adding new treatments to be tested during a trial. The EU-PEARL suite of templates for IRPs comprises a preface, followed by the actual resource. The preface clarifies the intended use and underlying principles that inform resource utility. The preface lists references contributing to the development of the resource. The resource includes TransCelerate CPT guidance text, and EU-PEARL-derived guidance text, distinguished from one another using shading. Rationale comments are used throughout for clarification purposes. In addition, a user-friendly, functional, and informative Platform Trials Best Practices tool to support the setup, design, planning, implementation, and conduct of complex and innovative trials to support multi-sourced/multi-company platform trials is also provided. Together, the EU-PEARL suite of templates and the Platform Trials Best Practices tool constitute the reference user manual. CONCLUSIONS: This publication is intended to enhance the use, understanding, and dissemination of the EU-PEARL suite of templates for designing IRPs. The reference user manual and the associated website ( http://www.eu-pearl ) should facilitate the designing of IRP trials.

Systematic review of available software for multi-arm multi-stage and platform clinical trial design.

BACKGROUND: In recent years, the popularity of multi-arm multi-stage, seamless adaptive, and platform trials has increased. However, many design-related questions and questions regarding which operating characteristics should be evaluated to determine the potential performance of a specific trial design remain and are often further complicated by the complexity of such trial designs. METHODS: A systematic search was conducted to review existing software for the design of platform trials, whereby multi-arm multi-stage trials were also included. The results of this search are reported both on the literature level and the software level, highlighting the software judged to be particularly useful. RESULTS: In recent years, many highly specialized software packages targeting single design elements on platform studies have been released. Only a few of the developed software packages provide extensive design flexibility, at the cost of limited access due to being commercial or not being usable as out-of-the-box solutions. CONCLUSIONS: We believe that both an open-source modular software similar to OCTOPUS and a collaborative effort will be necessary to create software that takes advantage of and investigates the impact of all the flexibility that platform trials potentially provide.

Subgroup analysis and interpretation for phase 3 confirmatory trials: White paper of the EFSPI/PSI working group on subgroup analysis.

Subgroup by treatment interaction assessments are routinely performed when analysing clinical trials and are particularly important for phase 3 trials where the results may affect regulatory labelling. Interpretation of such interactions is particularly difficult, as on one hand the subgroup finding can be due to chance, but equally such analyses are known to have a low chance of detecting differential treatment effects across subgroup levels, so may overlook important differences in therapeutic efficacy. EMA have therefore issued draft guidance on the use of subgroup analyses in this setting. Although this guidance provided clear proposals on the importance of pre-specification of likely subgroup effects and how to use this when interpreting trial results, it is less clear which analysis methods would be reasonable, and how to interpret apparent subgroup effects in terms of whether further evaluation or action is necessary. A PSI/EFSPI Working Group has therefore been investigating a focused set of analysis approaches to assess treatment effect heterogeneity across subgroups in confirmatory clinical trials that take account of the number of subgroups explored and also investigating the ability of each method to detect such subgroup heterogeneity. This evaluation has shown that the plotting of standardised effects, bias-adjusted bootstrapping method and SIDES method all perform more favourably than traditional approaches such as investigating all subgroup-by-treatment interactions individually or applying a global test of interaction. Therefore, these approaches should be considered to aid interpretation and provide context for observed results from subgroup analyses conducted for phase 3 clinical trials.

Comparing oncology clinical programs by use of innovative designs and expected net present value optimization: Which adaptive approach leads to the best result?

Designing an oncology clinical program is more challenging than designing a single study. The standard approaches have been proven to be not very successful during the last decade; the failure rate of Phase 2 and Phase 3 trials in oncology remains high. Improving a development strategy by applying innovative statistical methods is one of the major objectives of a drug development process. The oncology sub-team on Adaptive Program under the Drug Information Association Adaptive Design Scientific Working Group (DIA ADSWG) evaluated hypothetical oncology programs with two competing treatments and published the work in the Therapeutic Innovation and Regulatory Science journal in January 2014. Five oncology development programs based on different Phase 2 designs, including adaptive designs and a standard two parallel arm Phase 3 design were simulated and compared in terms of the probability of clinical program success and expected net present value (eNPV). In this article, we consider eight Phase2/Phase3 development programs based on selected combinations of five Phase 2 study designs and three Phase 3 study designs. We again used the probability of program success and eNPV to compare simulated programs. For the development strategies, we considered that the eNPV showed robust improvement for each successive strategy, with the highest being for a three-arm response adaptive randomization design in Phase 2 and a group sequential design with 5 analyses in Phase 3.

Effective Drug Supply for Adaptive Clinical Trials: Recommendations by the DIA Adaptive Design Scientific Working Group Drug Supply Subteam.

During the past decade, there has been increasing interest in adaptive clinical trials in pharmaceutical drug development as a means to improved decision making, better dose selection, and reduction in cost and time to market. Nevertheless, the operational challenge of drug supply continues to be a barrier preventing greater uptake of adaptive designs. Such studies require the ability to quickly accommodate changes in treatment allocation while maintaining the integrity of the blind. The DIA Adaptive Design Scientific Working Group formed a subteam to discuss solutions to the drug supply dilemma. In this paper, the subteam discusses effective strategies for drug manufacturing, labeling, packaging, and randomization and addresses financial concerns.

Advances in Statistical Approaches Oncology Drug Development.

We describe some recent developments in statistical methodology and practice in oncology drug development from an academic and an industry perspective. Many adaptive designs were pioneered in oncology, and oncology is still at the forefront of novel methods to enable better and faster Go/No-Go decision making while controlling the cost.

Adaptive Design Applied to Identification of the Minimum Effective Dose in Schizophrenia: Simulations of Scientific and Commercial Value.

The International Society for CNS Clinical Trials and Methodology (ISCTM) Adaptive Design Working Group (IADWG) designed a case study simulation exercise to compare the value of traditional versus adaptive design approaches to phase II clinical trial design in schizophrenia in statistical and economic terms. Operational characteristics of both designs were compared across 7 likely dose-response curves. Based on IADWG members' recent research experience in schizophrenia, estimates of expected net present value (eNPV) for the molecule were compared for the traditional and adaptive designs. Across dose-response curve scenarios with a minimum effective dose (MED), the adaptive design was more likely to show proof of concept and correctly identify the MED than was the traditional design. Even with a conservative weighting of possible dose-response curves, using an adaptive design in phase II resulted in higher eNPV. This simulation supports the statistical and economic value for decision makers exploring the use of adaptive approaches to phase II research in schizophrenia.

Improving Oncology Clinical Programs by Use of Innovative Designs and Comparing Them via Simulations.

The design of an oncology clinical program is much more challenging than the design of a single study. The standard approach has been proven to be not very successful during the past decade; the failure rate of phase 3 studies in oncology is about 66%. Improving the development strategy by applying innovative statistical methods is one of the major objectives for study teams designing and supporting oncology clinical programs. However, evaluating trial design alternatives is difficult; the designs may have different advantages-better power, better type I error control, shorter duration, or more accuracy-and their relative performance may depend on assumptions about the drugs' performance. Evaluating different early phase designs in particular suffers from both these problems. This paper is built on the work of the DIA's Adaptive Design Scientific Working Group oncology subteam on an Adaptive Program. With representatives from a number of institutions, this group compared 4 hypothetical oncology development programs that each was to select between 2 treatments and decide whether to proceed to phase 3, using probability of the clinical program's success and expected net present value (eNPV). Simulated scenarios were used to motivate and illustrate the key ideas. For the development strategies, we believed that the eNPV showed a distinct and robust improvement for each successive strategy.

ISCTM: Implementing phase 2 dose finding adaptive clinical trials.

Adaptive clinical trial designs offer significant opportunities to optimize the conduct of clinical trials for the benefit of the subjects in the trial, the subjects that may be treated after the trial and the trial sponsor. However currently, the use of adaptive designs is limited, due to statistical, regulatory and logistical concerns. In this article we share our experience of overcoming the last of these over a range of phase 2, response adaptive, dose finding studies. Based on our experience we feel quite strongly that the logistics of executing adaptive trials should not be a barrier to their use.

Innovative approaches for designing and analyzing adaptive dose-ranging trials.

Inadequate selection of the dose to bring forward in confirmatory trials has been identified as one of the key drivers of the decreasing success rates observed in drug development programs across the pharmaceutical industry. In recognition of this problem, the Pharmaceutical Research and Manufacturers of America (PhRMA), formed a working group to evaluate and develop alternative approaches to dose finding, including adaptive dose-ranging designs. This paper summarizes the work of the group, including the results and conclusions of a comprehensive simulation study, and puts forward recommendations on how to improve dose ranging in clinical development, including, but not limited to, the use of adaptive dose-ranging methods.