Review article: the evolution of endpoint assessments for chemotherapy-induced nausea and vomiting and post-operative nausea and vomiting-a perspective from the US Food and Drug Administration.

BACKGROUND: Nausea and vomiting can result in decreased compliance with oncologic therapies for patients with chemotherapy-induced nausea and vomiting (CINV); and increase complications and recovery time for patients with post-operative nausea and vomiting (PONV). CINV refers to nausea and vomiting after antineoplastic therapy administration and PONV is nausea and/or vomiting that occurs in the post-anaesthesia care unit or during the 24 hours following surgery. AIM: To analyse the evolution of endpoint assessments utilised in clinical trials to support FDA approval of CINV and PONV therapeutics. METHODS: A review supported by the US FDA analysed 31 approved New Drug Applications, respective clinical trial protocols and product labelling for CINV or PONV therapeutics with an emphasis on primary endpoint selection. RESULTS: Analysis revealed primary endpoints have become more refined and now often include the assessment of both vomiting and rescue medication use (ie, Complete Response). Additionally, the visual analogue scale was recognised as the most prevalent instrument to assess nausea as 58% of reviewed applications included this assessment. An imbalance between available therapies for adults and paediatric patients was also identified as only 39% of the reviewed approved products were indicated for paediatric use. CONCLUSION: The goal of this research was to inform and identify future opportunities for enhanced clinical trial design. Nausea assessment was identified as an opportunity for continued research and development due to the large heterogeneity of instruments used. Furthermore, there is a need for the development of safe and efficacious antiemetic treatments for paediatric patients.

Evaluating integration in collaborative cross-disciplinary FDA new drug reviews using an input-process-output model.

BACKGROUND/OBJECTIVES: The US Food and Drug Administration (FDA) is responsible for assessing safety (risks) and effectiveness (benefits) of new drug products using the data provided in a Sponsor's new drug product marketing application before they can be marketed. The FDA forms cross-disciplinary review teams to conduct these assessments. Recently, the FDA began implementing more interdisciplinary approaches to its assessments, reducing redundancy in review processes and documentation by increasing team integration around review issues. METHODS: Through a phenomenological descriptive comparative case study, the impact of FDA's new interdisciplinary approach on review team integration was compared with its traditional multidisciplinary review approach. RESULTS: We identified collaborative integration occurring in one FDA review team using the new interdisciplinary review and another team using the traditional review and then modeled and analyzed the collaborative, cross-disciplinary integration in each case using an input-process-output (IPO) model drawn from the Science-of-Team-Science (SciTS). CONCLUSION: This study provides a systematic method for understanding and visualizing integration in each type of review previously and presently used at FDA and illustrates how the new interdisciplinary approach can ensure more integration than more traditional approaches previously used. In addition, our study suggests that an IPO model of integration can characterize how effectively FDA review teams are integrating around issues and assist in the evaluation of differences in integration between FDA's new interdisciplinary review and the existing multidisciplinary approach. The approach used here is a new application of SciTS scholarship in a unique sector, and it also serves as an example for measuring review team effectiveness.

The Integrated Review: FDA Modernizes the Review of New Drug Marketing Applications.

New Drug Applications and Biologics Licensing Applications submitted to the US Food and Drug Administration (FDA) are reviewed by an interdisciplinary team of regulatory scientists that includes medical officers, clinical pharmacologists, toxicologists, statisticians, and drug labeling experts. Upon review of an applicant's submitted evidence from nonclinical studies, clinical trials, and manufacturing capabilities, the review team evaluates the benefits and risks of the drug and makes a scientifically-informed decision. As part of a multi-year, multi-phase New Drugs Regulatory Program Modernization effort, the FDA has recently redesigned how it reviews and documents its decisions with regard to marketing applications. This article describes the origins and rationale of the new Integrated Assessment process and Integrated Review document, summarizes how these differ from the FDA's traditional review of marketing applications, and discusses what industry can expect from a modernized drug review.

New Drugs Regulatory Program Modernization: Vision, Strategic Objectives, and Impact.

In response to a rapid increase in drug development activity during the past two decades, the Food and Drug Administration's Center for Drug Evaluation and Research launched a multi-year effort in 2017 to modernize the program by which new drug products are regulated, known as the New Drugs Regulatory Program. Following a detailed analysis of FDA activities in new drug development, premarket review, and postmarket monitoring, the Office of New Drugs was restructured to therapeutically align its clinical offices and to add new cross-functional offices for regulatory support. An interdisciplinary review process for new drug and biologics applications was rolled out to reduce redundancy and produce review documents that effectively communicate the scientific basis for the regulatory decision. The investigational new drug (IND) review process was also streamlined. During the next 2 years, the modernization initiative will seek to attract and retain new scientific and regulatory staff, improve postmarket safety monitoring, increase efficiency of drug review via technology-enabled workflows, and standardize the capture and use of scientific data to inform future regulatory decisions. The modernization effort will position the New Drugs Regulatory Program to continually improve and adapt to innovations in science, technology, and drug development.

Ten-Year Experience for the Center for Drug Evaluation and Research, Part 2: FDA's Role in Ensuring Patient Safety.

BACKGROUND: The purpose of this study was to describe the role of the US Food and Drug Administration (FDA) in ensuring the safety of patients receiving investigational drugs under expanded access. METHODS: To better define FDA's role in the review of requests for expanded access, multiple queries of FDA's Center for Drug Evaluation and Research (CDER) document tracking system were performed. The queries identified reasons for, and outcomes of, expanded access requests for investigational drugs that were either not allowed to proceed or denied over a 10-year time period. An in-depth review of a random sample of single-patient, non-emergency investigational new drug (IND) applications that were allowed to proceed was also conducted. RESULTS: Overall, 99.3% of the applications for almost 9000 expanded access of an investigational drug were allowed to proceed. There were 62 requests that were either denied (38 emergency INDs) or not allowed to proceed (24 non-emergency INDs). The most common reasons for denying emergency INDs was that the patient was stable on current therapy and that it was not deemed an emergency. The most common reasons for not allowing non-emergency expanded access INDs to proceed were incomplete application, unsafe dosing, demonstrated lack of efficacy for intended use, availability of adequate alternative therapies, and inadequate information provided in the application on which to base a decision. A review of a random sample of 150 single-patient, non-emergency INDs revealed that FDA recommended changes to dosing, safety monitoring, or informed consent in 11%. CONCLUSIONS: FDA plays a significant role in the protection of patients who receive investigational drugs under expanded access. An extremely small percentage of applications received are not allowed to proceed; however, FDA provides significant input based on information that may not be available to treating physicians in order to ensure patient safety under the applications that do proceed.

Expanded Access of Investigational Drugs: The Experience of the Center of Drug Evaluation and Research Over a 10-Year Period.

BACKGROUND: The purpose of this study was to describe the experience of the Center of Drug Evaluation and Research (CDER) with expanded access of investigational drugs. METHODS: Multiple searches of CDER's document tracking system were performed to identify the number, type, and indication for all expanded access requests over the 10-year time period of January 2005 through December 2014. An additional search was performed to identify all active commercial investigational drug development programs during that time period and whether or not the clinical program was placed on hold. The two searches were then cross-referenced to identify those commercial investigational drug development programs placed on clinical hold due to serious adverse events occurring within expanded access programs. RESULTS: CDER receives over 1000 applications for expanded access each year. The majority are for single patients, roughly evenly split between emergency and nonemergency use. The vast majority, 99.7%, are allowed to proceed. The incidence of clinical holds for all commercial investigational drug development programs is 7.9%, as compared to only 0.2% related to adverse events observed in patients receiving drug treatments under expanded access. CONCLUSIONS: The expanded access program is viewed as a success from FDA's perspective based on the large number of applications processed and allowed to proceed each year. However, the actual number of patients and their health care providers that desire drug treatments available under expanded access is not known. It is exceedingly rare for a serious adverse event under expanded access to affect the development program for that drug.