Real-World Data as External Controls: Practical Experience from Notable Marketing Applications of New Therapies.

INTRODUCTION: Real-world data (RWD) can contextualize findings from single-arm trials when randomized comparative trials are unethical or unfeasible. Findings from single-arm trials alone are difficult to interpret and a comparison, when feasible and meaningful, to patient-level information from RWD facilitates the evaluation. As such, there have been several recent regulatory applications including RWD or other external data to support the product's efficacy and safety. This paper summarizes some lessons learned from such contextualization from 20 notable new drug or biologic licensing applications in oncology and rare diseases. METHODS: This review focuses on 20 notable new drug or biologic licensing applications that included patient-level RWD or other external data for contextualization of trial results. Publicly available regulatory documents including clinical and statistical reviews, advisory committee briefing materials and minutes, and approved product labeling were retrieved for each application. The authors conducted independent assessments of these documents focusing on the regulatory evaluation, in each case. Three examples are presented in detail to illustrate the salient issues and themes identified across applications. RESULTS: Regulatory decisions were strongly influenced by the quality and usability of the RWD. Comparability of cohort attributes such as endpoints, populations, follow-up, index and censoring criteria, as well as data completeness and accuracy of key variables appeared to be essential to ensure the quality and relevance of the RWD. Given adequate sample size of the clinical trials or external control, the use of appropriate analytic methods to properly account for confounding, such as regression or matching, and pre-specification of these methods while blinded to patient outcomes seemed good strategies to address baseline differences. DISCUSSION: Contextualizing single-arm trials with patient-level RWD appears to be an advance in regulatory science; however, challenges remain. Statisticians and epidemiologists have long focused on analytical methods for comparative effectiveness but hurdles in use of RWD have often occurred upstream of the analyses. More specifically, we noted hurdles in evaluating data quality, justifying cohort selection or initiation of follow-up, and demonstrating comparability of cohorts and endpoints.

Abbreviated New Drug Applications: Generic Drug User Fee Amendments Act Analysis of Application Quality Metrics.

Implementation of the first Generic Drug User Fee Amendments of 2012 (GDUFA I) provided funding to the US Food and Drug Administration (FDA) for modernizing review of the FDA/CDER Generic Drug Program. Under GDUFA I, FDA agreed to reduce the backlog of pending generic Abbreviated New Drug Applications (ANDAs), improve the efficiency of generic drug review, and reduce the number of review cycles with the goal of reducing overall time to approval. This study presents a preliminary analysis of initial filing and regulatory first actions on ANDAs during GDUFA I cohort year 3 (CY3) and cohort year 4 (CY4). It highlights initial successes and areas of improvement in the ANDA review process for both FDA and ANDA applicants to improve the efficiency of providing the public with high-quality, affordable generic drugs.

Comparison of Treatment Effects Between US and Non-US Study Sites in Multiregional Alzheimer Disease Clinical Trials.

BACKGROUND: Conducting clinical trials across multiple regions of the world has become common practice. A multiregional clinical trial (MRCT) presents opportunities as well as challenges. However, regional differences of treatment effects appear in many MRCTs, which make the interpretation of clinical trial results difficult and presents challenges for clinical trial design. Alzheimer disease (AD) is a progressive neurodegenerative disorder that affects approximately 5 million people in the United States and is the sixth leading cause of death in the country. In 2014, AD cost the United States $214 billion, and the cost is expected to rise to $1.2 trillion by 2050. METHODS: In this article, we utilize data from New Drug Applications (NDAs) that have been approved for the treatment of AD to study whether there are differences in treatment effect between US and non-US study sites. Using an analysis of covariance (ANCOVA) model and forest plot, we analyze the treatment difference by region (US and non-US) from 3 separate perspectives: by region for each trial, by region for each endpoint, and by region and trial for each endpoint. RESULTS: Overall, the analyses indicate that treatment effects in clinical trials for AD are generally in the expected direction in both US and non-US sites. There was no clear evidence of heterogeneity in treatment effects between US and non-US sites. CONCLUSIONS: It appears that there is no clear evidence to suggest that MRCTs should not be used to study AD.

Communication about complementary and alternative medicine: perspectives of primary care clinicians.

BACKGROUND: People in the United States are using complementary and alternative medicine (CAM) increasingly while they are also receiving conventional care. National population-based surveys and studies in primary care settings have documented inadequate communication about CAM between patients and their conventional healthcare providers. Most studies about CAM communication have surveyed urban practices and focused on physicians. Information about how physicians and non-physician in rural areas clinicians communicate with their patients about CAM is needed to develop strategies for improving the quality of care for patients in rural areas. OBJECTIVE: To investigate how primary care clinicians in the Kentucky Ambulatory Network (KAN) communicate with patients about CAM and to determine interest in additional education about CAM. METHODS: A self-administered survey was mailed to 112 community clinicians in a research network of largely rural practices. KAN members include primary care physicians, nurse practitioners, certified nurse midwives, and physician assistants practicing in 32 counties in central and eastern Kentucky. RESULTS: Of 102 deliverable surveys, 65 (64%) were returned. Sixty-one (94%) clinicians reported patient CAM use. Few clinicians consistently asked patients about CAM. A positive attitude toward patient CAM use was associated with clinician comfort in advising patients. Most clinicians recommended CAM to patients. Seventy percent of KAN clinicians expressed interest in continuing education about CAM. CONCLUSIONS: Kentucky primary care clinicians are aware of their patients' CAM use and are motivated to learn more about CAM so that they can appropriately advise their patients. They need evidence-based, clinically relevant education about CAM to provide better patient care.