Glycerol phenylbutyrate efficacy and safety from an open label study in pediatric patients under 2 months of age with urea cycle disorders.

BACKGROUND/AIMS: Neonatal onset Urea cycle disorders (UCDs) can be life threatening with severe hyperammonemia and poor neurological outcomes. Glycerol phenylbutyrate (GPB) is safe and effective in reducing ammonia levels in patients with UCD above 2 months of age. This study assesses safety, ammonia control and pharmacokinetics (PK) of GPB in UCD patients below 2 months of age. METHODS: This was an open-label study in UCD patients aged 0 - 2 months, consisting of an initiation/transition period (1 - 4 days) to GPB, followed by a safety extension period (6 months to 2 years). Patients presenting with a hyperammonemic crisis (HAC) did not initiate GPB until blood ammonia levels decreased to below 100 µmol/L while receiving sodium phenylacetate/sodium benzoate and/or hemodialysis. Ammonia levels, PK analytes and safety were evaluated during transition and monthly during the safety extension for 6 months and every 3 months thereafter. RESULTS: All 16 patients with UCD (median age 0.48 months, range 0.1 to 2.0 months) successfully transitioned to GPB within 3 days. Average plasma ammonia level excluding HAC was 94.3 µmol/L at baseline and 50.4 µmol/L at the end of the transition period (p = 0.21). No patient had a HAC during the transition period. During the safety extension, the majority of patients had controlled ammonia levels, with mean plasma ammonia levels lower during GPB treatment than baseline. Mean glutamine levels remained within normal limits throughout the study. PK analyses indicate that UCD patients <2 months are able to hydrolyze GPB with subsequent absorption of phenylbutyric acid (PBA), metabolism to phenylacetic acid (PAA) and conjugation with glutamine. Plasma concentrations of PBA, PAA, and phenylacetylglutamine (PAGN) were stable during the safety extension phase and mean plasma phenylacetic acid: phenylacetylglutamine ratio remained below 2.5 suggesting no accumulation of GPB. All patients reported at least 1 treatment emergent adverse event with gastroesophageal reflux disease, vomiting, hyperammonemia, diaper dermatitis (37.5% each), diarrhea, upper respiratory tract infection and rash (31.3% each) being the most frequently reported. CONCLUSIONS: This study supports safety and efficacy of GPB in UCD patients aged 0 -2 months who cannot be managed by dietary protein restriction and/or amino acid supplementation alone. GPB undergoes intestinal hydrolysis with no accumulation in this population.

Long-term safety and efficacy of glycerol phenylbutyrate for the management of urea cycle disorder patients.

INTRODUCTION: Glycerol phenylbutyrate (GPB) is currently approved for use in the US and Europe for patients of all ages with urea cycle disorders (UCD) who cannot be managed with protein restriction and/or amino acid supplementation alone. Currently available data on GPB is limited to 12 months exposure. Here, we present long-term experience with GPB. METHODS: This was an open-label, long-term safety study of GPB conducted in the US (17 sites) and Canada (1 site) monitoring the use of GPB in UCD patients who had previously completed 12 months of treatment in the previous safety extension studies. Ninety patients completed the previous studies with 88 of these continuing into the long-term evaluation. The duration of therapy was open ended until GPB was commercially available. The primary endpoint was the rate of adverse events (AEs). Secondary endpoints were venous ammonia levels, number and causes of hyperammonemic crises (HACs) and neuropsychological testing. RESULTS: A total of 45 pediatric patients between the ages of 1 to 17 years (median 7 years) and 43 adult patients between the ages of 19 and 61 years (median 30 years) were enrolled. The treatment emergent adverse events (TEAE) reported in ≥10% of adult or pediatric patients were consistent with the TEAEs reported in the previous safety extension studies with no increase in the overall incidence of TEAEs and no new TEAEs that indicated a new safety signal. Mean ammonia levels remained stable and below the adult upper limit of normal (<35 µmol/L) through 24 months of treatment in both the pediatric and adult population. Over time, glutamine levels decreased in the overall population. The mean annualized rate of HACs (0.29) established in the previously reported 12-month follow-up study was maintained with continued GPB exposure. CONCLUSION: Following the completion of 12-month follow-up studies with GPB treatment, UCD patients were followed for an additional median of 1.85 (range 0 to 5.86) years in the present study with continued maintenance of ammonia control, similar rates of adverse events, and no new adverse events identified.

Variability in Institutional Board Review for a Multisite Assessment of Resident Professionalism.

Residents serve as both trainees and employees and can be considered potentially vulnerable research participants. This can lead to variation in the institutional review board (IRB) review. We studied sites participating in the Assessment of Professional Behaviors Study sponsored by the National Board of Medical Examiners (2009-2011). Of the 19 sites, all but one were university affiliated. IRB review varied; 2/19 did not submit to a local IRB, 4/17 (23%) were exempt, 11/17 (65%) were expedited, and 2/17 (12%) required full Board review; 12/17 (71%) required written informed consent. The interval from submission to approval was 1 to 2 months (8/17); the range was 1 to 7 months. Although most stated there were no major barriers to approval, the most common concern was resident coercion and loss of confidentiality. Local IRB review of this educational research study varied.

Feasibility of implementing a standardized multisource feedback program in the graduate medical education environment.

BACKGROUND: Multisource feedback (MSF) is emerging as a central assessment method for several medical education competencies. Planning and resource requirements for a successful implementation can be significant. Our goal is to examine barriers and challenges to a successful multisite MSF implementation, and identify the benefits of MSF as perceived by participants. METHODS: We analyzed the 2007-2008 field trial implementation of the Assessment of Professional Behaviors, an MSF program of the National Board of Medical Examiners, conducted with 8 residency and fellowship programs at 4 institutions. We use a multimethod analysis that draws on quantitative process indicators and qualitative participant experience data. Process indicators include program attrition, completion of implementation milestones, number of participants at each site, number of MSF surveys assigned and completed, and adherence to an experimental rater training protocol. Qualitative data include communications with each program and semistructured interviews conducted with key field trial staff to elicit their experiences with implementation. RESULTS: Several implementation challenges are identified, including communication gaps and difficulty scheduling implementation and training workshops. Participant interviews indicate several program changes that should enhance feasibility, including increasing communication and streamlining the training process. CONCLUSIONS: Multisource feedback is a complex educational intervention that has the potential to provide users with a better understanding of performance expectations in the graduate medical education environment. Standardization of the implementation processes and tools should reduce the burden on program administrators and participants. Further study is warranted to broaden our understanding of the resource requirements for a successful MSF implementation and to show how outcomes change as MSF gains broader acceptance.

The quality of written comments on professional behaviors in a developmental multisource feedback program.

BACKGROUND: Written feedback on professional behaviors is an important part of medical training, but little attention has been paid to the quality of written feedback and its expected impact on learning. A large body of research on feedback suggests that feedback is most beneficial when it is specific, clear, and behavioral. Analysis of feedback comments may reveal opportunities to improve the value of feedback. METHOD: Using a directed content analysis, the authors coded and analyzed feedback phrases collected as part of a pilot of a developmental multisource feedback program. The authors coded feedback on various dimensions, including valence (positive or negative) and whether feedback was directed at the level of the self or behavioral performance. RESULTS: Most feedback comments were positive, self-oriented, and lacked actionable information that would make them useful to learners. CONCLUSIONS: Comments often lack effective feedback characteristics. Opportunities exist to improve the quality of comments provided in multisource feedback.

Collecting validity evidence for an assessment of professionalism: findings from think-aloud interviews.

BACKGROUND: This study investigated whether participants' subjective reports of how they assigned ratings on a multisource feedback instrument provide evidence to support interpreting the resulting scores as objective, accurate measures of professional behavior. METHOD: Twenty-six participants completed think-aloud interviews while rating students, residents, or faculty members they had worked with previously. The items rated included 15 behavioral items and one global item. RESULTS: Participants referred to generalized behaviors and global impressions six times as often as specific behaviors, rated observees in the absence of information necessary to do so, relied on indirect evidence about performance, and varied in how they interpreted items. CONCLUSIONS: Behavioral change becomes difficult to address if it is unclear what behaviors raters considered when providing feedback. These findings highlight the importance of explicitly stating and empirically investigating the assumptions that underlie the use of an observational assessment tool.