Early Use of Erenumab vs Nonspecific Oral Migraine Preventives: The APPRAISE Randomized Clinical Trial.

Importance: Patients with migraine often cycle through multiple nonspecific preventive medications due to poor tolerability and/or inadequate efficacy leading to low adherence and increased disease burden. Objective: To compare the efficacy, tolerability, patient adherence, and patient satisfaction between erenumab and nonspecific oral migraine preventive medications (OMPMs) in patients with episodic migraine (EM) who had previously failed 1 or 2 preventive treatments. Design, Setting, and Participants: The 12-month prospective, interventional, global, multicenter, active-controlled, randomized clinical trial comparing sustained benefit of 2 treatment paradigms (erenumab qm vs oral prophylactics) in adult episodic migraine patients (APPRAISE) trial was a 12-month open-label, multicenter, active-controlled, phase 4 randomized clinical trial conducted from May 15, 2019, to October 1, 2021. This pragmatic trial was conducted at 84 centers across 17 countries. Overall, participants 18 years or older with a 12-month or longer history of migraine, and 4 or more but fewer than 15 monthly migraine days (MMDs) were included. Interventions: Patients were randomized (2:1) to receive erenumab or OMPMs. Dose adjustment was permitted (label dependent). Main Outcomes and Measures: The primary end point was the proportion of patients completing 1 year of the initially assigned treatment and achieving a reduction of 50% or greater from baseline in MMDs at month 12. Secondary end points included the cumulative mean change from baseline in MMDs during the treatment period and the proportion of responders according to the Patients' Global Impression of Change (PGIC) scale at month 12 for patients taking the initially assigned treatment. Results: A total of 866 patients were screened, of whom 245 failed the screening and 621 completed the screening and baseline period. Of the 621 randomized patients (mean [SD] age, 41.3 [11.2] years; 545 female [87.8%]; 413 [66.5%] in the erenumab group; 208 [33.5%] in the OMPM group), 523 (84.2%) completed the treatment phase, and 98 (15.8%) discontinued the study. At month 12, significantly more patients assigned to erenumab vs OMPM achieved the primary end point (232 of 413 [56.2%] vs 35 of 208 [16.8%]; odds ratio [OR], 6.48; 95% CI, 4.28-9.82; P <.001). Compared with OMPMs, treatment with erenumab showed higher responder rate (314 of 413 [76.0%] vs 39 of 208 [18.8%]; OR, 13.75; 95% CI, 9.08-20.83; P <.001) on the PGIC scale (≥5 at month 12). Significant reduction in cumulative average MMDs was reported with erenumab treatment vs OMPM treatment (-4.32 vs -2.65; treatment difference [SE]: -1.67 [0.35] days; P < .001). Substantially fewer patients in the erenumab arm compared with the OMPM arm switched medication (9 of 413 [2.2%] vs 72 of 208 [34.6%]) and discontinued treatment due to adverse events (12 of 408 [2.9%] vs 48 of 206 [23.3%]). No new safety signals were identified. Conclusions and Relevance: Results of this randomized clinical trial demonstrated that earlier use of erenumab in patients with EM who failed 1 or 2 previous preventive treatments provided greater and sustained efficacy, safety, and adherence than continuous OMPM. Trial Registration: ClinicalTrials.gov Identifier: NCT03927144.

Enhancing pediatric clinical trial feasibility through the use of Bayesian statistics.

BackgroundPediatric clinical trials commonly experience recruitment challenges including limited number of patients and investigators, inclusion/exclusion criteria that further reduce the patient pool, and a competitive research landscape created by pediatric regulatory commitments. To overcome these challenges, innovative approaches are needed.MethodsThis article explores the use of Bayesian statistics to improve pediatric trial feasibility, using pediatric Type-2 diabetes as an example. Data for six therapies approved for adults were used to perform simulations to determine the impact on pediatric trial size.ResultsWhen the number of adult patients contributing to the simulation was assumed to be the same as the number of patients to be enrolled in the pediatric trial, the pediatric trial size was reduced by 75-78% when compared with a frequentist statistical approach, but was associated with a 34-45% false-positive rate. In subsequent simulations, greater control was exerted over the false-positive rate by decreasing the contribution of the adult data. A 30-33% reduction in trial size was achieved when false-positives were held to less than 10%.ConclusionReducing the trial size through the use of Bayesian statistics would facilitate completion of pediatric trials, enabling drugs to be labeled appropriately for children.

Addressing Challenges and Opportunities of "Less Well-Understood" Adaptive Designs.

The draft adaptive design guidance released by FDA in 2010 included references to adaptive study designs that were described as "less well-understood." At that time, there was relatively little regulatory experience with such designs, and their properties were felt to be insufficiently understood. In order to promote greater use of adaptive designs, especially those categorized as less well-understood, the Best Practice Subteam of the DIA Adaptive Designs Scientific Working Group (ADSWG) has worked on describing and characterizing these designs, identifying challenges associated with them and suggesting improvements to design or study conduct aspects that might make them more acceptable. This paper summarizes the work from the subteam.

DIA's Adaptive Design Scientific Working Group (ADSWG): Best Practices Case Studies for "Less Well-understood" Adaptive Designs.

Adaptive design (AD) clinical trials use accumulating subject data to modify the parameters of the design of an ongoing study, without compromising the validity and integrity of the study. The 2010 US Food and Drug Administration (FDA) Draft Guidance on Adaptive Design Clinical Trials described a subset of 7 primary design types as "less well-understood." FDA defined these designs as those with limited regulatory experience. To better understand the properties of these less well-understood ADs and to promote their use when applicable, the Best Practices Subteam for DIA's Adaptive Design Scientific Working Group conducted an extensive nonsystematic search and reviewed trials from multiple sponsors who had employed these designs. Here, we review 10 specific case studies for which less well-understood ADs were employed and share feedback about their challenges and successes, as well as details about the regulatory interactions from these trials. We learned that these designs and associated statistical methodologies can make difficult research situations more amenable for study and, therefore, are needed in our toolbox. While they can be used to study many diseases, they are particularly valuable for rare diseases, small populations, studies involving terminal illnesses, and vaccine trials, in which it is important to find efficient ways to bring effective treatments to market more rapidly. It is imperative, however, that these methodologies be utilized appropriately, which requires careful planning and precise operational execution.

Adaptive Clinical Trials: Overview of Phase III Designs and Challenges.

Adaptive designs use accruing data to make changes in an ongoing trial according to a prespecified plan and potentially offer great efficiencies for clinical development. There are many types of adaptive designs and many trial aspects that could in theory be adapted. However, the scope of adaptive designs with relevance in confirmatory trials is narrower, and in addition, extensive pre-planning is needed and various types of challenges need to be addressed in order to use these designs in this stage of development. Nevertheless, with careful planning, there are opportunities for these designs to offer important benefits even in the confirmatory stage of development. We provide an overview of adaptive designs that have relevance for confirmatory trials and discuss considerations that may affect whether they should or should not be used in particular trials or programs as well as the challenges that need to be addressed.

Multiplicity: discussion points from the Statisticians in the Pharmaceutical Industry multiplicity expert group.

In May 2012, the Committee of Health and Medicinal Products issued a concept paper on the need to review the points to consider document on multiplicity issues in clinical trials. In preparation for the release of the updated guidance document, Statisticians in the Pharmaceutical Industry held a one-day expert group meeting in January 2013. Topics debated included multiplicity and the drug development process, the usefulness and limitations of newly developed strategies to deal with multiplicity, multiplicity issues arising from interim decisions and multiregional development, and the need for simultaneous confidence intervals (CIs) corresponding to multiple test procedures. A clear message from the meeting was that multiplicity adjustments need to be considered when the intention is to make a formal statement about efficacy or safety based on hypothesis tests. Statisticians have a key role when designing studies to assess what adjustment really means in the context of the research being conducted. More thought during the planning phase needs to be given to multiplicity adjustments for secondary endpoints given these are increasing in importance in differentiating products in the market place. No consensus was reached on the role of simultaneous CIs in the context of superiority trials. It was argued that unadjusted intervals should be employed as the primary purpose of the intervals is estimation, while the purpose of hypothesis testing is to formally establish an effect. The opposing view was that CIs should correspond to the test decision whenever possible.

Barriers and opportunities for implementation of adaptive designs in pharmaceutical product development.

BACKGROUND: This review discusses barriers to implementing adaptive designs in a pharmaceutical R&D environment and provides recommendations on how to overcome challenges. A summary of findings from a survey conducted through PhRMA's working group on adaptive designs is followed by a report based on our experience as statistical and clinical consultants to project teams charged with establishing the clinical development strategy for investigational compounds and interested in applying innovative approaches. FINDINGS AND RECOMMENDATIONS: Adaptive designs require additional work in that clinical trial simulations are needed to develop the design. Some project teams, due to time and resource constraints, are unable to invest the additional effort required to conduct necessary scenario analyses of options through simulation. We recommend formally integrating the planning time for scenario analyses and to incentivize optimal designs (e.g., designs offering the highest information value per resource unit invested). Regardless of the trial design ultimately chosen, quantitatively comparing alternative trial design options through simulation will enable earlier and better decision making in the context of the overall clinical development plan. Adhering to 'Good Adaptive Practices' will be key to achieving this goal. OUTLOOK: Implementing adaptive designs efficiently requires top-down and bottom- up support and the willingness to invest into integrated process and information technology infrastructures. Success is conditional on the willingness of the R&D environment to embrace the implementation of adaptive designs as a Change Management Initiative in the spirit of the Critical Path of the Food and Drug Administration.

Enteric-coated mycophenolate sodium is therapeutically equivalent to mycophenolate mofetil in de novo renal transplant patients.

The introduction of mycophenolate mofetil (MMF) represented a major advance in transplant medicine, although optimal use may be limited by gastrointestinal (GI) side-effects. An enteric-coated formulation of mycophenolate sodium (EC-MPS; myfortic) has been developed with the aim of improving the upper GI tolerability of mycophenolic acid. Therapeutic equivalence of EC-MPS (720 mg b.i.d.) and MMF (1000 mg MMF b.i.d.), with concomitant cyclosporine microemulsion (Neoral) and corticosteroids, was assessed in 423 de novo kidney transplant patients recruited to a 12-month, double-blind study. Efficacy failure (biopsy-proven acute rejection [BPAR], graft loss, death or loss to follow up) at 6 months (EC-MPS 25.8% vs. MMF 26.2%; 95% CI: [-8.7, +8.0]) demonstrated therapeutic equivalence. At 12 months, the incidence of BPAR, graft loss or death was 26.3% and 28.1%, and of BPAR alone was 22.5% and 24.3% for EC-MPS and MMF, respectively. Among those with BPAR, the incidence of severe acute rejection was 2.1% with EC-MPS and 9.8% with MMF (p=ns). The safety profile and incidence of GI adverse events were similar for both groups. Within 12 months, 15.0% of EC-MPS patients and 19.5% of MMF patients required dose changes for GI adverse events (p=ns). Enteric-coated-MPS 720 mg b.i.d. is therapeutically equivalent to MMF 1000 mg b.i.d. with a comparable safety profile.