Extrapolation of Efficacy in Pediatric Drug Development and Evidence-based Medicine: Progress and Lessons Learned.

BACKGROUND: "Complete Extrapolation" of efficacy from adult or other pediatric data, to the pediatric population, is an important scientific tool that reduces the need for pediatric efficacy trials. Dose finding and safety studies in pediatrics are still needed. "No Extrapolation" requires 2 pediatric efficacy trials. "Partial Extrapolation" eliminates the need to conduct 2 pediatric efficacy trials; 1 efficacy or exposure/response study may be sufficient. We examined pediatric extrapolation from 2009 to 2014 evaluating any changes in extrapolation assumptions and the causes for these changes since a prior analysis published in 2011. METHODS: We reviewed all 157 products with 388 pediatric studies submitted to the FDA from 2009 through 2014. We assessed whether efficacy was extrapolated from adult or other pediatric data and categorized extrapolation as Complete, Partial, or No, and identified the reasons for the changes. RESULTS: Partial extrapolation decreased, whereas use of No and Complete extrapolation noticeably increased. Complete, Partial, or No extrapolations changed from 14%, 68%, and 18% in the 2011 study to 34%, 29%, and 37% respectively in the current study. The changes were mostly due to a better understanding of pediatric pathophysiology, why trials have failed, and improved endpoints. CONCLUSIONS: Evolving science and data obtained from clinical trials increases the certainty of extrapolation assumptions and drives decisions to utilize extrapolation. Lessons learned from the conduct of these trials are critical to improving evidence-based medicine. Extrapolation of Efficacy is a powerful scientific tool that streamlines pediatric product development. Increased knowledge and evolving science inform utilization of this tool.

Pediatric post-marketing safety systems in North America: assessment of the current status.

PURPOSE: It is critical to have pediatric post-marketing safety systems that contain enough clinical and epidemiological detail to draw regulatory, public health, and clinical conclusions. The pediatric safety surveillance workshop (PSSW), coordinated by the Food and Drug Administration (FDA), identified these pediatric systems as of 2010. This manuscript aims to update the information from the PSSW and look critically at the systems currently in use. METHODS: We reviewed North American pediatric post-marketing safety systems such as databases, networks, and research consortiums found in peer-reviewed journals and other online sources. We detail clinical examples from three systems that FDA used to assess pediatric medical product safety. RESULTS: Of the 59 systems reviewed for pediatric content, only nine were pediatric-focused and met the inclusion criteria. Brief descriptions are provided for these nine. The strengths and weaknesses of three systems (two of the nine pediatric-focused and one including both children and adults) are illustrated with clinical examples. CONCLUSIONS: Systems reviewed in this manuscript have strengths such as clinical detail, a large enough sample size to capture rare adverse events, and/or a patient denominator internal to the database. Few systems include all of these attributes. Pediatric drug safety would be better informed by utilizing multiple systems to take advantage of their individual characteristics.

What the Orphan Drug Act has done lately for children with rare diseases: a 10-year analysis.

OBJECTIVES: The 1983 US Orphan Drug Act (ODA) provided incentives to stimulate treatment product development for patients with rare disease. This article highlights a decade of ODA contributions to this goal for children with RDs. METHODS: An internal US Food and Drug Administration database was the information source for orphan designations, marketing approvals, and prevalence numbers for 2000 to 2009. Product categorization was based on the disease age of onset for which they received designation. Category 1 products were for diseases with onset exclusively in Childhood; Category 2 products were for diseases with onset at any age; and Category 3 products were for diseases with adult onset only. Disease prevalence distributions were analyzed by using population intervals of 20 000. RESULTS: From 2000 to 2009, 1138 orphan drugs were designated and 148 received marketing approval, of which 38 (26%) were for pediatric diseases. The proportion of approvals for pediatric products increased from 17.5% (10 of 57) in the first half of the decade, to 30.8% (28 of 91) in the second. More products received designation and marketing approval for pediatric diseases with prevalence numbers fewer than 20 000 than for any other prevalence subgroup. The median disease prevalence for all pediatric orphan designations that received marketing approval was 8972. Among the pediatric orphan drug approvals categorized by therapeutic class, the endocrine/metabolic drugs had the largest representation (39%). CONCLUSIONS: The ODA incentives have led to increased product availability for RDs overall, with an increasing number of marketing approvals for children this past decade.

Comparison of reporting of Stevens-Johnson syndrome and toxic epidermal necrolysis in association with selective COX-2 inhibitors.

BACKGROUND: Stevens-Johnson syndrome and toxic epidermal necrolysis are closely related severe acute life-threatening, drug-induced skin disorders. The US FDA Adverse Events Reporting System (AERS) has received reports of Stevens-Johnson syndrome and toxic epidermal necrolysis associated with the use of the recently introduced selective cyclo-oxygenase (COX)-2 inhibitor NSAIDs, two of which are also sulfonamides. OBJECTIVE: The objective of this study is to review cases of Stevens-Johnson syndrome and toxic epidermal necrolysis reported to the FDA associated with the use of the selective COX-2 inhibitor NSAIDs celecoxib, rofecoxib and valdecoxib, and to compare reporting rates of the two conditions associated with these drugs to each other, meloxicam (an oxicam NSAID that came on the US market at a similar time) and the background incidence rate. METHODS: We reviewed all US cases of Stevens-Johnson syndrome and toxic epidermal necrolysis reported to the FDA AERS database associated with the use of celecoxib, rofecoxib, valdecoxib and meloxicam since these agents were first marketed. We utilised AERS and drug use data to calculate reporting rates for each drug after the first 2 years of marketing. We obtained the background rate from the medical literature. RESULTS: Up to the end of March 2004, there were 63 cases of Stevens-Johnson syndrome/toxic epidermal necrolysis reported with valdecoxib use, 43 with celecoxib, 17 with rofecoxib (the non-sulfonamide coxib) and none for meloxicam. In the first 2 years of marketing the reporting rate for Stevens-Johnson syndrome/toxic epidermal necrolysis with valdecoxib was 49 cases per million person-years of use, 6 cases per million person-years for celecoxib and 3 cases per million person-years for rofecoxib. The reporting rates for the sulfonamide coxibs were substantially higher than the background rate of 1.9 cases per million population per year, with the valdecoxib rate being 8-9 times that of celecoxib and approximately 25 times that of the background rate. CONCLUSION: There is a strong association between Stevens-Johnson syndrome/toxic epidermal necrolysis and the use of the sulfonamide COX-2 inhibitors, particularly valdecoxib. Physicians should be aware of the possibility of this serious life-threatening event when prescribing these drugs and advise patients to discontinue use at the earliest possible sign or symptom.

Peripheral neuropathy in patients treated with leflunomide.

OBJECTIVE: Our objective was to describe the clinical features, time course, and outcome of new-onset peripheral neuropathy occurring in patients treated with leflunomide. METHODS: Case reports of peripheral neuropathy submitted to the US Food and Drug Administration in association with leflunomide use were reviewed. Data on patient demographics, underlying medical conditions and medications, details of leflunomide therapy, and treatment and outcome of the neuropathy event were abstracted. Time to neuropathy onset and time to improvement or recovery were analyzed by survival analysis. RESULTS: Of 80 reported patients, 61% were women. The patients' mean age was 62 years. Symptoms of peripheral neuropathy began after a mean of 6 months of leflunomide use (range, 3 days to 3 years). Electrodiagnostic testing in 37 patients was consistent with a distal axonal, sensory, or sensorimotor polyneuropathy in most patients. Patients who stopped leflunomide use within 30 days of neuropathy symptom onset were more likely to have improvement or recovery than those who continued taking leflunomide for a longer period (P <.001). CONCLUSION: Leflunomide use is associated with peripheral neuropathy in some patients. This neuropathy is usually axonal in nature, affecting multiple sensory or motor nerves of distal extremities. Patients who stopped leflunomide use within 30 days of symptom onset were more likely to have improvement of symptoms or complete recovery than were patients who continued to use the drug for longer periods of time.

Spontaneous reports of hypertension leading to hospitalisation in association with rofecoxib, celecoxib, nabumetone and oxaprozin.

BACKGROUND AND OBJECTIVE: Data on file with the US FDA, and other published studies, suggest that the selective cyclo-oxygenase (COX)-2 inhibitor NSAID rofecoxib has a greater hypertensive adverse effect than other NSAIDs, including celecoxib. In this study we describe a pharmacoepidemiologic analysis of spontaneous adverse event reports of acute, clinically serious hypertension (as defined by hospitalisation) reported in association with rofecoxib, celecoxib, nabumetone and oxaprozin. The objective of this analysis is to assess whether postmarketing data are consistent with results of clinical trials. We also collapse cases into series for the identification of possible risk factors for clinically severe, NSAID-associated hypertension. METHODS: Domestic (US) cases of apparently unconfounded, acute hypertension leading to hospitalisation were collected and reviewed from the spontaneous adverse events database of the FDA for rofecoxib, celecoxib, nabumetone and oxaprozin for the initial 3 years of marketing. Drug use data for the same intervals enabled calculation of reporting rates. RESULTS: In an analysis of reporting rates, hospitalisation for acute blood pressure (BP) elevation was reported more frequently (3.8-fold) for rofecoxib compared with celecoxib. A total of 34 cases are collapsed into case series. No cases were identified for either nabumetone or oxaprozin. Inspection of reviewed cases for celecoxib and rofecoxib suggest that these patients (average age 72 years) were potentially high-risk candidates for NSAID therapy. DISCUSSION AND CONCLUSION: During early marketing, hospitalisation for acute BP elevation appears to have been reported more frequently for rofecoxib compared with celecoxib. This is consistent with clinical trial data on file with the FDA, and other published studies that found rofecoxib to have a greater effect on BP than other NSAIDs, including celecoxib. This finding may be particularly relevant in older patients given the prevalence of hypertension and cardiovascular disease in this age group.

Allergic contact dermatitis from topical doxepin: Food and Drug Administration's postmarketing surveillance experience.

A total of 26 postmarketing cases of allergic contact dermatitis to doxepin 5% cream were reported to the Food and Drug Administration. Our findings suggest that allergic contact dermatitis was more common when treatment duration exceeded the recommended 8 days. Allergic contact dermatitis to doxepin cream should be considered in patients whose condition fails to improve or worsens with doxepin use.

Deaths associated with inappropriate intravenous colchicine administration.

Intravenous (IV) colchicine is occasionally prescribed for the treatment of acute gouty arthritis. The Food and Drug Administration (FDA) recently received a report of death in a patient that was associated with inappropriate IV dosing of colchicine. This report prompted further investigation of other deaths associated with IV colchicine use in the FDA Adverse Event Reporting System (AERS) and the medical literature. A total of 20 deaths were identified. Eight patients were females, 11 were males, and the gender was unknown in 1. In all cases, the recommended maximum cumulative dose of 2 to 4 mg during a course of therapy was exceeded. Dose reductions are recommended in patients with renal or hepatic disease and in the elderly. All reported adverse events were associated with colchicine toxicity, including thrombocytopenia, leukopenia, pancytopenia, agranulocytosis, aplastic anemia, acute renal failure, and disseminated intravascular coagulopathy. Death occurred within 1 to 40 days after drug administration. Therapeutic guidelines exist for use of IV colchicine and these guidelines should be followed to prevent serious toxicities and death.

Aseptic meningitis associated with rofecoxib.

Rofecoxib is a nonsteroidal anti-inflammatory drug that is reported to act by selectively inhibiting cyclooxygenase-2. A review and analysis of reports sent to the Spontaneous Reporting System of the Food and Drug Administration, Rockville, Md, suggest that aseptic meningitis is associated with rofecoxib use. To our knowledge, there have been no published reports of aseptic meningitis occurring in association with rofecoxib use to date. We report 5 serious cases of aseptic meningitis associated with rofecoxib use.