APF530 (granisetron injection extended-release) in a three-drug regimen for delayed CINV in highly emetogenic chemotherapy.

AIM: APF530, extended-release granisetron, provides sustained release for ≥5 days for acute- and delayed-phase chemotherapy-induced nausea and vomiting (CINV). We compared efficacy and safety of APF530 versus ondansetron for delayed CINV after highly emetogenic chemotherapy (HEC), following a guideline-recommended three-drug regimen. METHODS: HEC patients received APF530 500 mg subcutaneously or ondansetron 0.15 mg/kg intravenously, with dexamethasone and fosaprepitant. Primary end point was delayed-phase complete response (no emesis or rescue medication). RESULTS: A higher percentage of APF530 versus ondansetron patients had delayed-phase complete response (p = 0.014). APF530 was generally well tolerated; treatment-emergent adverse event incidence was similar across arms, mostly mild-to-moderate injection-site reactions. CONCLUSION: APF530 versus the standard three-drug regimen provided superior control of delayed-phase CINV following HEC. ClinicalTrials.gov : NCT02106494.

Individual case safety reports--how to determine the onset date of an adverse reaction: a survey.

BACKGROUND: The building blocks of a pharmacovigilance system depend primarily on good quality individual case safety reports (ICSRs), which are stand-alone summaries describing one or more suspected adverse reactions that occur while a subject is taking either an investigational or marketed medicinal product and may require expedited reporting to regulatory authorities. For regulatory reporting purposes, the information of an ICSR is usually captured on forms such as MedWatch 3500/3500A, CIOMS I, Vaccine Adverse Event Report System (VAERS) or Adverse Events Following Immunization (AEFI). ICSRs that are sent electronically must meet the standards for electronic transmission specified in the International Conference on Harmonisation (ICH) E2B (R2) guideline. In filling out these regulatory forms, there are some areas of ambiguity. One of these is what the 'date of event' (MedWatch) or 'reaction onset date' (CIOMS) is interpreted to be. OBJECTIVE: The aim of the survey was to determine the uniformity of responses for the onset date of an adverse reaction. METHODS: A pilot and three surveys of pharmacovigilance professionals were undertaken between February and July 2009 to determine the range of responses for the onset of an adverse reaction. A narrative of a subject admitted to hospital with a diagnosis of pneumonia was presented and the respondent was asked to pick the date of onset of the adverse reaction. RESULTS: The total number of respondents was 129. The results of the surveys indicated there was considerable variation in responses. These differences were based on different perspectives regarding the suspected adverse reaction. Some viewed the 'reaction' to be the first onset of signs and symptoms (even if non-specific), others considered the onset of the reaction to be the date of the diagnosis, while others considered the date to be when the reaction became serious. CONCLUSION: By means of a survey, we have illustrated an example of the variability of determining the onset date of a suspected adverse reaction, and recommend that a criterion for onset time, i.e. beginning of signs or symptoms of the event, or date of diagnosis, be chosen as the standard. Once decided, this information should be incorporated into the company's case assessment documentation and staff appropriately trained, thus ensuring consistency across cases and minimizing the time spent in determining what date to use.

The periodic safety update report as a pharmacovigilance tool.

The periodic safety update report for marketed drugs (PSUR) was designed to be a stand-alone document that allows a periodic but comprehensive assessment of the worldwide safety data of a marketed drug or biological product. The PSUR can be an important source for the identification of new safety signals, a means of determining changes in the benefit-risk profile, an effective means of risk communication to regulatory authorities and an indicator for the need for risk management initiatives, as well as a tracking mechanism monitoring the effectiveness of such initiatives. For these reasons, the PSUR can be an important pharmacovigilance tool. Numerous steps are involved in the PSUR process including: intake of adverse drug reaction information, case processing, data retrieval, data analysis, and medical review and risk assessment. These processes are heavily reliant on the availability of adequate resources. An overarching principle throughout the PSUR process is the need for a proactive approach in order to identify the critical steps in the process and to have a clear understanding of the consequences of any critical 'mis-step'. With this information comes appropriate planning, building quality into each step of the PSUR process and monitoring performance will maximise the likelihood of generating a quality report. Any failure of a key PSUR process will have the opposite effect - a poor quality report that will give little insight into emerging safety signals or provide misleading information that can adversely affect public health. A pragmatic approach that will avoid or minimise these pitfalls includes the following: adequate resource planning, training, development of 'scripts' designed to maximise the capture of key information for medically important reactions, standardised and harmonised Medical Dictionary for Regulatory Activities (MedDRA) coding procedures, pre-specified search criteria for data retrieval, ongoing medical review, and metrics to evaluate the effectiveness and efficiencies of these processes. With these quality measures in place, the utility of the PSUR as an effective pharmacovigilance tool is enhanced.

Subclinical Hypothyroidism and Euthyroid Sick Syndrome in Patients with Moderate-to-Severe Congestive Heart Failure.

Thyroid function tests were performed on baseline plasma that had been taken from 34 patients with NYHA Class II or Class III congestive heart failure (CHF). All patients were negative for thyroid disease on history and physical examination and none was taking medication known to alter thyroid metabolism. Analysis of thyroid function revealed abnormalities in 16 of 31 patients. These abnormalities fell into two categories: nine patients had elevated baseline thryroid stimulating hormone (TSH) above the normal limit while only one of these nine had subnormal thyroxine (T(4)) concentrations, suggesting the possibility of subclinical hypothyroidism. Seven patients demonstrated changes consistent with euthyroid sick syndrome (ESS). Weak correlations were observed between age and concentrations of T(4) and tri-iodothyronine (T(3)) and this suggests that changes in thyroid function cannot be explained solely on the basis of age. Although previous studies have demonstrated the presence of ESS in CHF, the present study suggests the possibility of a significant prevalence of subclinical hypothyroidism.