Use of PRO Measures to Inform Tolerability in Oncology Trials: Implications for Clinical Review, IND Safety Reporting, and Clinical Site Inspections.

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 AACRSee related commentary by Nipp and Temel, p. 1777.

Drug development for pediatric neurogenic bladder dysfunction: dosing, endpoints, and study design.

Pediatric drug development is challenging when a product is studied for a pediatric disease that has a different underlying etiology and pathophysiology compared to the adult disease. Neurogenic bladder dysfunction (NBD) is such a therapeutic area with multiple unsuccessful development programs. The objective of this study was to critically evaluate clinical trial design elements that may have contributed to unsuccessful drug development programs for pediatric NBD. Trial design elements of drugs tested for pediatric NBD were identified from trials submitted to the U.S. Food and Drug Administration. Data were extracted from publically available FDA reviews and labeling and included trial design, primary endpoints, enrollment eligibilities, and pharmacokinetic data. A total of four products were identified. Although all four programs potentially provided clinically useful information, only one drug (oxybutynin) demonstrated efficacy in children with NBD. The lack of demonstrable efficacy for the remainder of the products illustrates that future trials should give careful attention to testing a range of doses, using objectively measured, clinically meaningful endpoints, and selecting clinical trial designs that are both interpretable and feasible. Compiling the drug development experience with pediatric NBD will facilitate an improved approach for future drug development for this, and perhaps other, therapeutic areas.

Off-label use of medicine in pediatrics: focus on gastrointestinal diseases.

PURPOSE OF REVIEW: To provide current information on off-label medication use in pediatric gastroenterology, including a discussion on US legislative efforts to address the issue. RECENT FINDINGS: Medications used to treat pediatric gastrointestinal illnesses are frequently prescribed off-label. Acid suppressors, antiemetics, laxatives, and antitumor necrosis factor therapies are types of medications frequently used off-label in the pediatric gastroenterology arena. Pediatric studies conducted under US Federal laws are generating much-needed data on the safety and effectiveness of medications used to treat pediatric patients. Moreover, a new US law, the Food and Drug Administration Safety and Innovation Act, may further the development of pediatric medications in part by requiring pediatric-specific study plans earlier in the overall drug development process. As of today, there still are gaps in our knowledge about these medications, including for the treatment of pediatric gastroenterology diseases. SUMMARY: Medications are widely used off-label in pediatrics, including medications intended to treat gastrointestinal diseases, such as antitumor necrosis factor and laxatives. Although legislation is helping to generate and make available important information about pediatric medications, most still do not contain pediatric data. Therefore, providers need to understand the potential risks and benefits of prescribing off-label products to pediatric patients.

Adolescent dosing and labeling since the Food and Drug Administration Amendments Act of 2007.

IMPORTANCE: During pediatric drug development, dedicated pharmacokinetic studies are generally performed in all relevant age groups to support dose selection for subsequent efficacy trials. To our knowledge, no previous assessments regarding the need for an intensive pharmacokinetic study in adolescents have been performed. OBJECTIVES: To compare U.S. Food and Drug Administration (FDA)-approved adult and adolescent drug dosing and to assess the utility of allometric scaling for the prediction of drug clearance in the adolescent population. DESIGN: Adult and adolescent dosing and drug clearance data were obtained from FDA-approved drug labels and publicly available databases containing reviews of pediatric trials submitted to the FDA. Dosing information was compared for products with concordant indications for adolescent and adult patients. Adolescent drug clearance was predicted from adult pharmacokinetic data by using allometric scaling and compared with observed values. MAIN OUTCOMES AND MEASURES: Adolescent and adult dosing information and drug clearance. RESULTS: There were 126 unique products with pediatric studies submitted to the FDA since the FDA Amendments Act of 2007, of which 92 had at least 1 adolescent indication concordant with an adult indication. Of these 92 products, 87 (94.5%) have equivalent dosing for adults and adolescent patients. For 18 of these 92 products, a minimum weight or body surface area threshold is recommended for adolescents to receive adult dosing. Allometric scaling predicted adolescent drug clearance with an overall mean absolute percentage error of 17.0%. CONCLUSIONS AND RELEVANCE: Approved adult and adolescent drug dosing is equivalent for 94.5% of products with an adolescent indication studied since the FDA Amendments Act of 2007. Allometric scaling may be a useful tool to avoid unnecessary dedicated pharmacokinetic studies in the adolescent population during pediatric drug development, although each development program in adolescents requires a full discussion of drug dosing with the FDA.