Evaluating publication bias for clinical trials supporting new dermatologic drug approvals from 2003 to 2018.

The degree of publication bias and impact of the Food and Drug Administration Amendments Act (FDAAA) of 2007, which aimed to improve clinical trial transparency, has yet to be examined for recent dermatologic drugs. The objective of our study was to estimate the degree of publication bias for clinical trials supporting FDA approval of new dermatologic drugs. This retrospective cohort study examined all phase II and III efficacy trials supporting approval of new dermatologic drugs from 2003 to 2018. FDA drug approval documents were reviewed for supportive clinical trial information, and publications were matched using PubMed and Google Scholar searches. Ratios of relative risks (RRR) comparing positive versus non-positive trials before and after FDAAA enactment served to estimate publication bias. We found that the likelihood of publishing positive versus non-positive drug trials in dermatology was unchanged before and after FDAAA enactment (RRR 0.87, 95% CI 0.37-2.08), as was the likelihood of publishing without misleading interpretation (RRR 1.51, 95% CI 0.22-10.50). There was no measurable publication bias for efficacy trials supporting new drug approvals in dermatology over the past 15 years. Fewer pre-FDAAA trials (n = 21) compared to post-FDAAA trials (n = 106) met inclusion criteria. Though not analyzed in this study, safety and secondary efficacy results are other potential sources for publication bias.

Melanoma cases demonstrate increased carrier frequency of phenylketonuria/hyperphenylalanemia mutations.

Identifying novel melanoma genetic risk factors informs screening and prevention efforts. Mutations in the phenylalanine hydroxylase gene (the causative gene in phenylketonuria) lead to reduced pigmentation in untreated phenylketonuria patients, and reduced pigmentation is associated with greater melanoma risk. Therefore, we sought to characterize the relationship between phenylketonuria carrier status and melanoma risk. Using National Newborn Screening Reports, we determined the United States phenylketonuria/hyperphenylalanemia carrier frequency in Caucasians to be 1.76%. We examined three publically available melanoma datasets for germline mutations in the phenylalanine hydroxylase gene associated with classic phenylketonuria and/or hyperphenylalanemia. Mutations were identified in 29/814 melanoma patients, with a carrier frequency of 3.56%. There was a twofold enrichment (p-value = 3.4 × 10-5 ) compared to the Caucasian frequency of hyperphenylalanemia/phenylketonuria carriers. These data demonstrate a novel association between phenylalanine hydroxylase carrier status and melanoma risk. Further, functional investigation is warranted to determine the link between phenylalanine hydroxylase mutations and melanomagenesis.

Does manual T-wave window adjustment affect microvolt T-wave alternans results in patients with structural heart disease?

INTRODUCTION: Microvolt T-wave alternans (MTWA) analysis can identify patients at low risk of sudden cardiac death who might not benefit from an implantable cardioverter-defibrillator (ICD). Current spectral methodology for performing MTWA analysis may "miss" part of the T-wave in patients with QT prolongation. The value of T-wave window adjustment in patients with structural heart disease has not been studied. METHODS: We assembled MTWA data from 5 prior prospective studies including 170 patients with reduced left ventricular ejection fraction, adjusted the T-wave window to include the entire T-wave, and reanalyzed MTWA. RESULTS: Of 170 patients, 43% required T-wave window adjustment. Only 3 of 170 patients (1.8%) had a clinically significant change in MTWA results. CONCLUSIONS: In 98.2% of patients, T-wave window adjustment did not improve the accuracy of MTWA analysis. Spectral MTWA as currently implemented remains effective for identifying patients with structural heart disease unlikely to benefit from ICD therapy.