Elektra J. Papadopoulos
Food and Drug Administration
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Featured researches published by Elektra J. Papadopoulos.
Clinical Cancer Research | 2016
Paul G. Kluetz; Ashley Slagle; Elektra J. Papadopoulos; Laura Lee Johnson; Martha Donoghue; Virginia E. Kwitkowski; Wen-Hung Chen; Rajeshwari Sridhara; Ann T. Farrell; Patricia Keegan; Geoffrey Kim; Richard Pazdur
Cancer clinical trials have relied on overall survival and measures of tumor growth or reduction to assess the efficacy of a drug. However, benefits are often accompanied by significant symptomatic toxicities. The degree to which a therapy improves disease symptoms and introduces symptomatic toxicity affects how patients function in their daily lives. These concepts are important contributors to health-related quality of life (HRQOL). In this article, we discuss patient-reported outcome (PRO) assessment in cancer trials and challenges relying solely on static multi-item HRQOL instruments. We propose focusing on three separate measures of well-defined concepts: symptomatic adverse events, physical function, and disease-related symptoms, which are key contributors to the effect of a therapy on HRQOL. Separate measures of these three concepts may facilitate the incorporation of emerging contemporary instruments that can tailor the PRO assessment strategy to different trial contexts. Irrespective of the PRO measures used, continued improvement in trial design and conduct is crucial to decrease missing data and optimize the quality of PRO information. International stakeholder collaboration and continued research into optimal practices for PRO and other clinical outcome assessments are necessary to advance a common framework for generating and reporting rigorous patient-centered data from cancer clinical trials. Clin Cancer Res; 22(7); 1553–8. ©2016 AACR.
Pain | 2013
Shannon M. Smith; Anthony Wang; Anthony Pereira; R. Daniel Chang; Andrew McKeown; Kaitlin Greene; Michael C. Rowbotham; Laurie B. Burke; Paul Coplan; Ian Gilron; Sharon Hertz; Nathaniel P. Katz; Allison H. Lin; Michael P. McDermott; Elektra J. Papadopoulos; Bob A. Rappaport; Michael O. Sweeney; Dennis C. Turk; Robert H. Dworkin
Summary Widespread discrepancies between registered vs published primary outcomes raise questions about whether published primary outcomes are prespecified. Recommendations are proposed to ensure the veracity of published primary outcome specifications. Abstract The National Institutes of Health released the trial registry ClinicalTrials.gov in 2000 to increase public reporting and clinical trial transparency. This systematic review examined whether registered primary outcome specifications (POS; ie, definitions, timing, and analytic plans) in analgesic treatment trials correspond with published POS. Trials with accompanying publications (n = 87) were selected from the Repository of Registered Analgesic Clinical Trials (RReACT) database of all postherpetic neuralgia, diabetic peripheral neuropathy, and fibromyalgia clinical trials registered at ClinicalTrials.gov as of December 1, 2011. POS never matched precisely; discrepancies occurred in 79% of the registry–publication pairs (21% failed to register or publish primary outcomes [PO]). These percentages did not differ significantly between industry and non‐industry‐sponsored trials. Thirty percent of the trials contained unambiguous POS discrepancies (eg, omitting a registered PO from the publication, “demoting” a registered PO to a published secondary outcome), with a statistically significantly higher percentage of non‐industry‐sponsored than industry‐sponsored trials containing unambiguous POS discrepancies. POS discrepancies due to ambiguous reporting included vaguely worded PO registration; or failing to report the timing of PO assessment, statistical analysis used for the PO, or method to address missing PO data. At best, POS discrepancies may be attributable to insufficient registry requirements, carelessness (eg, failing to report PO assessment timing), or difficulty uploading registry information. At worst, discrepancies could indicate investigator impropriety (eg, registering imprecise PO [“pain”], then publishing whichever pain assessment produced statistically significant results). Improvements in PO registration, as well as journal policies requiring consistency between registered and published PO descriptions, are needed.
Journal of Pediatric Gastroenterology and Nutrition | 2014
Haihao Sun; Jessica J. Lee; Elektra J. Papadopoulos; Catherine S. Lee; Robert M. Nelson; Hari C. Sachs; William J. Rodriguez; Andrew E. Mulberg
Objectives: Presently, there is no consensus on endpoint measures to assess clinical outcomes for pediatric ulcerative colitis (UC). This study reviewed the endpoints used in the registration trials of approved drugs for pediatric UC. Methods: The primary efficacy endpoints of all registration trials completed from 1950 to 2008 that led to Food and Drug Administration approval for indications in pediatric and adult UC were reviewed. Results: Colazal and Remicade have been approved for pediatric UC indication, and clinical response was used as a primary endpoint in these registration trials. The clinical response in the adult Colazal trials was defined as a reduction of rectal bleeding and improvement in at least one of the other assessed symptoms (stool frequency, patient functional assessment, abdominal pain, sigmoidoscopic grade, and physicians global assessment) assessed by the Sutherland UC Activity Index. The pediatric Colazal trial defined clinical response using the Modified Sutherland UC Activity Index, which excluded abdominal pain and functional assessment. Both adult and pediatric Remicade trials used clinical response defined by the Mayo score as the primary endpoint. The Pediatric Ulcerative Colitis Activity Index was used to measure various secondary endpoints in the pediatric Remicade trial. Conclusions: Pediatric-specific endpoints were used, but outcome measures and definition of clinical response were not consistent in pediatric UC trials. Consensus on the definition of successful treatment outcome (clinical response and/or remission) and collaboration in the development of well-defined and reliable measures of signs and symptoms for use in conjunction with endoscopic parameters of mucosal healing will facilitate pediatric drug development.
Gastroenterology | 2016
Daniel A. Leffler; Sonia S. Kupfer; Benjamin Lebwohl; Kevin Bugin; Donna Griebel; Julia Lathrop; Jessica J. Lee; Andrew E. Mulberg; Elektra J. Papadopoulos; Juli Tomaino; Sheila E. Crowe
80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 CL IN IC AL PR AC TI CE UP DA TE Ceases. Although not as prevalent as irritable bowel syndrome, it is significantly more common than inflammatory bowel disease. Although patients are rarely hospitalized or undergo surgery due to celiac disease, attributable mortality is increased and burden of treatment, defined as the degree of difficulty in following treatment, is higher than other common luminal diseases. Despite the prevalence, morbidity, and treatment burden, there is significant unmet medical need for pharmacologic interventions beyond a gluten-free diet (GFD). At the time of the workshop, fewer than a dozen randomized controlled therapeutic trials had been published. Major historical obstacles to drug development include misperceptions that celiac disease is rare and mild, and that the GFD is a near-optimal therapy. In addition, there has been no precedent product approval for celiac disease that defines a guiding regulatory pathway for product developers. On March 31, 2015, the third Gastroenterology Regulatory Endpoints and Advancement of Therapeutics (GREAT 3) workshop was held, which was sponsored by the Food and Drug Administration (FDA) Center for Drug Evaluation and Research, with co-sponsorship by the American Gastroenterological Association; the American College of Gastroenterology; the American Society for Pediatric Gastroenterology, Hepatology, and Nutrition; and the North American Society for the Study of Celiac Disease. The meeting covered defining target populations for pharmacologic therapies, and defining and measuring clinical benefit in celiac disease trials to support marketing approval.
Clinical Cancer Research | 2017
Harpreet Singh; Michael Brave; Julia A. Beaver; Joyce Cheng; Shenghui Tang; Eias Zahalka; Todd R. Palmby; Rajesh Venugopal; Pengfei Song; Qi Liu; Chao Liu; Jingyu Yu; Xiao Hong Chen; Xing Wang; Yaning Wang; Paul G. Kluetz; Selena R. Daniels; Elektra J. Papadopoulos; Rajeshwari Sridhara; Amy E. McKee; Amna Ibrahim; Geoffrey Kim; Richard Pazdur
On April 25, 2016, the FDA approved cabozantinib (Cabometyx; Exelixis, Inc.) for the treatment of advanced renal cell carcinoma (RCC) in patients who have received prior antiangiogenic therapy. The approval was based on data from one randomized, open-label, multicenter study in which patients with RCC who had received prior antiangiogenic therapy were treated with either cabozantinib 60 mg orally once daily (n = 330) or everolimus 10 mg orally once daily (n = 328). The major efficacy outcome measure was progression-free survival (PFS) as assessed by a blinded independent radiology review committee in the first 375 randomized patients. A statistically significant improvement in PFS was seen, with a median PFS of 7.4 and 3.8 months in the cabozantinib and everolimus arms, respectively [hazard ratio (HR), 0.58; 95% confidence interval (CI), 0.45–0.74; P < 0.0001]. At a second interim analysis, a statistically significant improvement in overall survival (OS) in the intent-to-treat population was also demonstrated, with a median OS of 21.4 and 16.5 months in the cabozantinib and everolimus arms, respectively (HR, 0.66; 95% CI, 0.53–0.83; P = 0.0003). The most common (greater than or equal to 25%) adverse reactions included diarrhea, fatigue, nausea, decreased appetite, palmar–plantar erythrodysesthesia syndrome, hypertension, vomiting, weight loss, and constipation. Clin Cancer Res; 23(2); 330–5. ©2016 AACR.
Journal of Pediatric Gastroenterology and Nutrition | 2015
Haihao Sun; Elektra J. Papadopoulos; Jeffrey S. Hyams; Donna Griebel; Jessica J. Lee; Juli Tomaino; Andrew E. Mulberg
Objectives: The aim of the present study was to identify areas for further development of clinical outcome assessment (COA) in pediatric Crohn disease (CD). Methods: The study analyzed the measurement properties of all existing COA tools for pediatric CD in literature and published registration trials of approved drugs for pediatric CD based on criteria described in Food and Drug Administration guidance for patient-reported outcome (PRO) development. Results: The Pediatric Crohns Disease Activity Index (PCDAI) and its derivatives (abbreviated, short, modified, and weighted PCDAIs) were reviewed. The Crohns Disease Activity Index (CDAI) and Harvey-Bradshaw index (HBI), designed for adult patients, have been adapted for use in a few pediatric CD studies. The use of PCDAI as an endpoint in Remicade and Humira trials led to the Food and Drug Administration–approved indication in pediatric CD. Common issues in measurement properties of COA tools included the absence of direct patient or caregivers’ input to generate the items measuring signs and symptoms; absence of evidence demonstrating correlation with clinically relevant inflammation observed with endoscopic measures; lack of standardization in measurement, age-appropriate interviewer script, and response rating criteria for the physician interviewer. Conclusions: Available evidence indicates that CDAI, HBI, and 5 versions of the PCDAI lack adequate measurement properties for use as a primary endpoint for phase 3 trials intended to support approval of products intended to treat pediatric CD. In order to facilitate pediatric drug development, a well-defined, reliable, sensitive, and globally recognized PRO that measures signs and symptoms in children with CD and that can be used in conjunction with endoscopy-based endpoints and/or biomarkers is sorely needed.
Clinical Cancer Research | 2017
Janice Kim; Harpreet Singh; Kassa Ayalew; Kristina Borror; Michelle Campbell; Laura Lee Johnson; Alyson Karesh; Ni A. Khin; Joanne R. Less; Jerry Menikoff; Lori Minasian; Sandra A. Mitchell; Elektra J. Papadopoulos; Richard L. Piekarz; Kevin Prohaska; Susan Thompson; Rajeshwari Sridhara; Richard Pazdur; Paul G. Kluetz
Cancer therapeutics frequently lead to symptomatic adverse events (AE) that can affect treatment tolerability. The NCI has developed the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) to assess symptomatic AEs by direct patient self-report. Although longitudinal assessment of patient-reported symptomatic AEs holds promise to better inform treatment tolerability, using patient-reported outcome (PRO) measures to assess symptomatic AEs has raised several regulatory and good clinical practice issues among those who conduct cancer clinical trials. These include concerns regarding trial monitoring, clinical review of PRO results by investigators and delegated clinical staff, whether PRO data on symptomatic AEs require investigational new drug (IND) safety reporting, and how the trial conduct and resultant PRO data will be assessed during clinical investigator site inspections. This article addresses current thinking regarding these issues in cancer clinical trials from the FDA, the NCI, and the Office for Human Research Protections. PRO measures, such as PRO-CTCAE, that assess symptomatic AEs in cancer trials are considered similar to other PRO assessments of symptoms, function, and health-related quality of life and can generate complementary data that may inform tolerability. Clarity on operational concerns related to incorporating PRO measures to inform tolerability is critical to continue the advancement of rigorous PRO assessment in cancer clinical trials. Clin Cancer Res; 24(8); 1780–4. ©2017 AACR. See related commentary by Nipp and Temel, p. 1777
Therapeutic Innovation & Regulatory Science | 2018
Elizabeth Richardson; Jessica Burnell; Heather R. Adams; Richard W. Bohannon; Elizabeth Nicole Bush; Michelle Campbell; Wen Hung Chen; Stephen Joel Coons; Elektra J. Papadopoulos; Bryce R. Reeve; Daniel Rooks; Gregory Daniel
The use of performance outcome (PerfO) assessments to measure cognitive or physical function in drug trials presents several challenges for both sponsors and regulators, owing in part to a relative lack of scientific guidance on their development, implementation, and interpretation. In December 2016, the Duke-Margolis Center for Health Policy convened a 2-day workshop to explore the evidentiary, methodologic, and operational challenges associated with PerfO measures, and to identify potential paths to addressing these challenges. This paper presents both a summary of the discussion as well as additional input from a working group of experts from FDA, industry, academia, and public-private consortia. It is intended to advance the discussion around the development and use of PerfO measures to assess patient functioning in clinical trials intended to support registration of new treatments, and to highlight the key gaps in knowledge where additional research, collaboration, and discussion are needed.
Clinical Infectious Diseases | 2012
Joseph G. Toerner; Laurie B. Burke; Scott Komo; Elektra J. Papadopoulos
The Journal of Pain | 2015
Shannon M. Smith; Florence Paillard; Andrew McKeown; Laurie B. Burke; Robert R. Edwards; Nathaniel P. Katz; Elektra J. Papadopoulos; Bob A. Rappaport; Ashley Slagle; Eric C. Strain; Ajay D. Wasan; Dennis C. Turk; Robert H. Dworkin