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.

FDA's Generic Drug Program: Decreasing Time to Approval and Number of Review Cycles.

Implementation of the Generic Drug User Fee Amendments (GDUFA I) as part of the Food and Drug Administration Safety and Innovation Act of 2012 (Generic Drug User Fee Amendments. https://www.fda.gov/industry/fda-user-fee-programs/generic-drug-user-fee-amendments) successfully allowed the U.S. Food and Drug Administration (FDA) to modernize review of Abbreviated New Drug Applications (ANDAs) with goal dates. The goal of this study was to assess the success of GDUFA I in decreasing ANDA time to approval and the number of review cycles across the five fiscal years of GDUFA I. Results of this study underscore FDA's continuous progress within its generic drug program and highlight the ongoing collaborative communication process between FDA and ANDA applicants that must continue for the timely approval of high-quality, safe, and effective generic drugs for the American public.

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.

A culturally targeted intervention to promote breast cancer screening among low-income women in East Baltimore, Maryland.

In Maryland, outreach initiatives have been unsuccessful in engaging low-income African American women in mammography screening. This study aimed to identify factors influencing screening rates for low-income African American women. Based on the Health Belief Model, a modified time series design was used to implement a culturally targeted intervention to promote a no-cost mammography-screening program. Data were collected from women 40 years of age and older on their history of mammography use and their knowledge and beliefs about breast cancer. A 50% screening rate was achieved among 119 eligible participants. Significant predictors of screening behaviors were perceived barriers, lack of insurance, and limited knowledge. This culturally targeted intervention resulted in an unprecedented screening rate among low-income African American women in Baltimore, Maryland.

Structured weight-loss programs: meta-analysis of weight loss at 24 weeks and assessment of effects of intervention intensity.

Obesity is increasing in epidemic proportions globally while current therapies continue to be suboptimal. In this investigation, weight loss in obese individuals after 24 weeks with different nutrition interventions was compared. The impact of intervention intensity was assessed. Inclusion criteria were established and a comprehensive literature review was performed. These nutrition interventions were identified and analyzable: meal replacements (MRs); energy-restricted (>1500 kcal/d) diets (ERDs); low-energy (800-1500 kcal/d) diets (LEDs); soy very low energy (<800 kcal/d) diets (VLEDs) referred to as SOYs; and VLEDs. Intensity was assessed using the following parameters: physician visits, clinic visits, and hours of class over 24 weeks; an intensity score represents an adjusted sum of the values. Weight losses at 24 weeks as percentage of baseline weights (95%, confidence intervals) were as follows: MRs, 9.1% (5.7-12.5); ERDs, 8.5% (4.9-12.1); LEDs, 11.4% (8.9-13.1); SOYs, 16.5% (13.9-19.1); and VLEDs, 21.3% (20.1-22.5). Weight loss with SOYs was significantly greater than with MRs and ERDs; weight loss with VLEDs was significantly greater than with any other diet. Energy intake was the most significant (P<.0001) regression variable related to weight loss; however, the intensity of intervention (P=.0003) was significantly stronger than initial body weight or duration of treatment. Medically supervised VLEDs are the most effective intervention for facilitating substantial weight loss over 24 weeks. SOY may promote more rapid weight loss over the first 8 weeks than other interventions. MRs appear to be equally effective with ERDs and LEDs with lower levels of intervention intensity.

Factors associated with higher levels of injury severity in occupants of motor vehicles that were severely damaged in traffic crashes in Kentucky, 2000-2001.

OBJECTIVES: The majority of motor vehicle occupants who were killed or hospitalized in crashes in Kentucky in 2000-2001 occupied vehicles that were severely damaged in the crash. Even so, overall only a small percentage of all severely damaged vehicle occupants were killed or hospitalized. The purpose was to identify occupant, vehicle, crash, and roadway/environmental factors that were associated with increased risk of severe injury in crashes where the occupant's vehicle was severely damaged. METHODS: This study probabilistically linked Kentucky's statewide motor vehicle crash and inpatient hospital discharge data files for 2000 and 2001, and selected cases representing occupants of vehicles that were reported by police as having either "severe" or "very severe" damage. For occupants who were identified through data linkage as having been hospitalized, the Injury Severity Score (ISS) was calculated using ICDMAP-90 software, and the scores were stratified into the following categories: critical (>24), severe (15-24), moderate (9-14), and mild (<9). We then created an outcome variable, injury severity level, with five levels: killed; hospitalized with at least moderate injuries (ISS = critical, severe, or moderate); hospitalized with mild injuries (ISS = mild); injured according to the police report but not hospitalized; and no apparent injury according to the police report. We performed a stepwise, ordinal logistic regression of injury severity, using independent variables identified from the existing crash literature. RESULTS: Occupant risk factors for higher levels of injury severity selected by the regression were age (risk increased with age, other factors being equal), female gender, restraint non-use, ejection from the vehicle, and driver impairment (by alcohol and/or drugs). Crash risk factors included head-on collision, collision with a fixed object, vehicle rollover, and vehicle fire. Roadway/environmental factors were federal- or state-maintained roadway and posted speed limit 89 kph (55 mph) or greater. CONCLUSIONS: Many of the identified risk factors are explicitly or implicitly mentioned in the strategic plans of key organizations involved in highway safety and injury prevention in Kentucky. Our analysis provides additional evidence of their importance, and confirms that their mitigation will reduce injury severity in crashes involving severe vehicle damage. Additionally, older occupants and female occupants showed increased risks of serious injury, but to our knowledge these factors are not currently addressed in any state plans. An opportunity exists to clarify the nature of these risks through further studies, which might lead to the identification of countermeasures specific to these populations.