Nathan Taback

Poor reporting of scientific leadership information in clinical trial registers.

Background In September 2004, the International Committee of Medical Journal Editors (ICMJE) issued a Statement requiring that all clinical trials be registered at inception in a public register in order to be considered for publication. The World Health Organization (WHO) and ICMJE have identified 20 items that should be provided before a trial is considered registered, including contact information. Identifying those scientifically responsible for trial conduct increases accountability. The objective is to examine the proportion of registered clinical trials providing valid scientific leadership information. Methodology/Principal Findings We reviewed clinical trial entries listing Canadian investigators in the two largest international and public trial registers, the International Standard Randomized Controlled Trial Number (ISRCTN) register, and ClinicalTrials.gov. The main outcome measures were the proportion of clinical trials reporting valid contact information for the trials Principal Investigator (PI)/Co-ordinating Investigator/Study Chair/Site PI, and trial e-mail contact address, stratified by funding source, recruiting status, and register. A total of 1388 entries (142 from ISRCTN and 1246 from ClinicalTrials.gov) comprised our sample. We found non-compliance with mandatory registration requirements regarding scientific leadership and trial contact information. Non-industry and partial industry funded trials were significantly more likely to identify the individual responsible for scientific leadership (ORu200a=u200a259, 95% CI: 95–701) and to provide a contact e-mail address (ORu200a=u200a9.6, 95% CI: 6.6–14) than were solely industry funded trials. Conclusions/Significance Despite the requirements set by WHO and ICMJE, data on scientific leadership and contact e-mail addresses are frequently omitted from clinical trials registered in the two leading public clinical trial registers. To promote accountability and transparency in clinical trials research, public clinical trials registers should ensure adequate monitoring of trial registration to ensure completion of mandatory contact information fields identifying scientific leadership

Bereavement Practices of Physicians in Oncology and Palliative Care

BACKGROUNDnCancer physicians frequently interact with dying patients, but little is known about these physicians practices. The purpose of this study was to evaluate the frequency and nature of bereavement practices among medical oncologists (MOs), radiation oncologists (ROs), and palliative care specialists (PCs); and to identify factors associated with bereavement follow-up.nnnMETHODSnSurvey of all Canadian MOs, ROs, and PCs via their respective national organizations using an anonymous electronic and postal mail survey.nnnRESULTSnA total of 535 of 756 eligible physicians completed the survey (71%). Overall, 33.3% (95% confidence interval [CI], 29.3%-37.4%) of respondents indicated that they usually or always make a telephone call, send a condolence card, or attend a funeral following a patients death; 30.5% (95% CI, 26.5%-34.4%) reported performing at least 1 of these practices sometimes; and 36.2% (95% CI, 32.1%-40.3%) reported performing at least 1 of these practices rarely or never. Among the specific practices, respondents were more likely to call a family at least sometimes than to send a condolence card or attend funeral services. Palliative care specialists reported the highest rates of bereavement follow-up. In multivariate regression analysis, female sex, working in an academic setting, palliative care specialty, lack of formal palliative care program, endorsement of the statement that physicians had a responsibility to send a condolence card, and high number of patient deaths were associated with more frequent bereavement follow-up.nnnCONCLUSIONSnFew cancer physicians provide bereavement follow-up routinely. This suggests that consensus is lacking among cancer physicians regarding their role in bereavement care.

Pathological Predictors for Site of Local Recurrence After Radiotherapy for Prostate Cancer

PURPOSEnRational design of targeted radiotherapy (RT) in prostate cancer (Pca) hinges on a better understanding of spatial patterns of recurrence. We sought to identify pathological factors predictive for site of local recurrence (LR) after external beam RT.nnnMETHODS AND MATERIALSnProspective databases were reviewed to identify men with LR after RT from 1997 through 2009. Patients with biochemical failure and biopsy-confirmed Pca more than 2 years after RT were evaluated. Prediction for site of recurrence based on the following pretreatment factors was determined on independent and cluster-sextant basis: presence of malignancy, dominant vs. nondominant percentage core length (PCL) involvement, PCL ≥ or <40%, and Gleason score. Sites of dominant PCL were defined as sextants with peak PCL involvement minus 10%, and >5% for each patient.nnnRESULTSnForty-one patients with low-intermediate risk Pca constituted the study cohort. Median time to biopsy after RT was 51 months (range, 24-145). Of 246 sextants, 74 were involved with tumor at baseline. When sextants are treated as independent observations the presence of malignancy (77% vs. 22%, p = 0.0001), dominant PCL (90% vs. 46%, p = 0.0001), and PCL ≥40% (89% vs. 68 %, p = 0.04) were found to be significant predictors for LR, although PCL ≥40% did not retain statistical significance if sextants were considered correlated. The vast majority of patients (95%) recurred at the original site of dominant PCL or PCL ≥40%, and 44% also recurred in regions of nondominant PCL <40% (n = 8) and/or benign sampling (n = 14) at baseline.nnnCONCLUSIONSnLR after RT predominantly occurs in regions bearing higher histological tumor burden but are not isolated to these sites. Our data highlights the value of spatially resolved baseline pathological sampling and may assist in the design of clinical trials tailoring RT dose prescriptions to subregions of the prostate gland.

Properties of the estimated variance component for subject-by-formulation interaction in studies of individual bioequivalence

Characteristics of the variance component for the subject-by-formulation interaction (sigma(2)(D)), estimated in simulated studies of individual bioequivalence and in three- and four-period cross-over trials reported by the FDA, were compared. sigma(2)(D) was estimated by (i) restricted maximum likelihood (REML) and (ii) the method of moments (MM). Variation of the variance component, estimated by both procedures (s(2)(D)) and for both the simulated and FDA data, increased with rising intra-individual variation. Consequently, a constant level of s(2)(D) (such as 0.0225 suggested by the FDA) may not be regarded as a basis for demonstrating substantial interactions. Features of the FDA and simulated parameters were similar. The results suggested that the FDA data were compatible with assuming sigma(D)=0.05 or perhaps 0.00. Therefore, there is no foundation for concerns about public health. Both simulations and calculations demonstrated that s(2)(D) estimated by MM was unbiased and its variance was proportional to sigma(4)(WF) when sigma(2)(D)=0.

Investigator experiences with financial conflicts of interest in clinical trials

BackgroundFinancial conflicts of interest (fCOI) can introduce actions that bias clinical trial results and reduce their objectivity. We obtained information from investigators about adherence to practices that minimize the introduction of such bias in their clinical trials experience.MethodsEmail survey of clinical trial investigators from Canadian sites to learn about adherence to practices that help maintain research independence across all stages of trial preparation, conduct, and dissemination. The main outcome was the proportion of investigators that reported full adherence to preferred trial practices for all of their trials conducted from 2001-2006, stratified by funding source.Results844 investigators responded (76%) and 732 (66%) provided useful information. Full adherence to preferred clinical trial practices was highest for institutional review of signed contracts and budgets (82% and 75% of investigators respectively). Lower rates of full adherence were reported for the other two practices in the trial preparation stage (avoidance of confidentiality clauses, 12%; trial registration after 2005, 39%). Lower rates of full adherence were reported for 7 practices in the trial conduct (35% to 43%) and dissemination (53% to 64%) stages, particularly in industry funded trials. 269 investigators personally experienced (n = 85) or witnessed (n = 236) a fCOI; over 70% of these situations related to industry trials.ConclusionFull adherence to practices designed to promote the objectivity of research varied across trial stages and was low overall, particularly for industry funded trials.

Adverse Pregnancy Outcomes Among Foreign-Born Canadians

OBJECTIVEnNumerous non-Canadian studies have shown that immigrant women experience higher rates of adverse maternal and perinatal events than the general non-immigrant population. Limited information about the pregnancy outcomes of immigrant Canadian women is available.nnnMETHODSnWe conducted a retrospective cohort study at St. Michaels Hospital between October 2002 and June 2006 to estimate the risk of adverse obstetrical and perinatal outcomes among foreign-born women residing in Toronto. The main study outcomes were the incidences of preterm delivery between 32 and 36 completed weeks gestation, low infant birth weight, and delivery by Caesarean section.nnnRESULTSnCompared with Canadian-born women, those who were foreign-born had an associated adjusted odds ratio of 0.85 (95% CI 0.64 to 1.14) for preterm delivery, 1.92 (95% CI 1.29 to 2.85) for low infant birth weight, and 1.16 (95% CI 1.01 to 1.34) for delivery by Caesarean section.nnnCONCLUSIONnIn this study, foreign-born women had a non-significantly lower risk of preterm birth, but a significantly higher risk of low birth weight infants and Caesarean section than Canadian-born women. In this urban setting, recent immigrant women have worse pregnancy outcomes, warranting increased attention to this group during antenatal and intrapartum care.

Towards Collation and Modelling of the Global Cost of Armed Violence on Civilians

A method is described which translates qualitative reports about armed violence into meaningful quantitative data allowing an evidence-based approach to the causes and effects of the global health impact of armed violence on unarmed people. Analysis of 100 randomly selected news reports shows that the type of weapon used, the psychological aspect of the violence, the number of weapons in use and the victims vulnerability independently influence the mortality of victims. Data collated by the same method could be analysed together with indicators of poverty, development and health so illuminating the relationship between such indicators and degradation of peoples physical security through acts of armed violence. The method could also help uphold the laws of war and human rights.

National Evaluation of Policies on Individual Financial Conflicts of Interest in Canadian Academic Health Science Centers

BackgroundConflicts of interest (COI) in research are an important emerging topic of investigation and are frequently cited as a serious threat to the integrity of human participant research.ObjectiveTo study financial conflicts of interest (FCOI) policies for individual investigators working in Canadian academic health centers.DesignSurvey instrument containing 61 items related to FCOI.SettingAll Canadian academic health science centers (universities with faculties of medicine, faculties of medicine and teaching hospitals) were requested to provide their three primary FCOI policies.MeasurementsNumber of all centers and teaching hospitals with policies addressing each of the 61 items related to FCOI.Main ResultsOnly one item was addressed by all 74 centers. Thirteen items were present in fewer than 25% of centers. Fewer than one-quarter of hospitals required researchers to disclose FCOI to research participants. The role of research ethics boards (REBs) in hospitals was marginal.LimitationsAsking centers to identify only three policies may not have inclusively identified all FCOI policies in use. Additionally, policies at other levels might apply. For instance, all institutions receiving federal grant money must comply with the Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans.ConclusionsCanadian centers within the same level (for instance, teaching hospitals) differ significantly in the areas that their policies address and these policies differ widely in their coverage. Presently, no single policy in any Canadian center informs researchers about the broad range of individual FCOI issues. Canadian investigators need to understand the environment surrounding FCOI, be able to access and follow the relevant policies and be confident that they can avoid entering into a FCOI.

Validation of the genital herpes treatment satisfaction questionnaire (GHerpTSQ) in status and change versions

A new measure of treatment satisfaction (GHerpTSQ) for recurrent genital herpes simplex virus (HSV) was validated and used to evaluate two therapeutic strategies widely used for the management of HSV: episodic treatment, where individual herpes outbreaks are treated as they arise; suppressive therapy, where treatment is taken daily to prevent HSV outbreaks. Satisfaction with treatment is important since daily dosing with suppressive therapy is necessary in the absence of symptoms. A 12-item questionnaire was designed using a modified form of the Diabetes treatment satisfaction questionnaire (DTSQ). The psychometric properties of the GHerpTSQ were evaluated within a sample of 125 Canadians with a history of HSV (type 1, 2) infection participating in a 48xa0week randomised cross-over trial. Factor analysis suggested that the items can be analysed as two separate subscales corresponding to Control/effectiveness, and Convenience/lifestyle; the single item concerning side effects was retained for separate analysis. Forced one-factor analysis showed that the two subscales can be combined to obtain a total score relating to overall treatment satisfaction. The GHerpTSQ has good internal reliability, clear structure with little overlap of subscales and evidence of good sensitivity to changes in treatment.

A survey of abstracts of high-impact clinical journals indicated most statistical methods presented are summary statistics

OBJECTIVESnTo assess what statistical methods are commonly used in high-impact clinical research and how they are presented in abstracts of articles published in high-impact medical journals.nnnSTUDY DESIGN AND SETTINGnA cross-sectional survey of abstracts of original articles published in July 2003 in four high-impact medical journals was conducted. The primary outcome was the distribution of statistical methods used in study results presented in the abstract of articles.nnnRESULTSnSeventy articles met inclusion criteria. One hundred twenty-five unique statistical method presentations were analyzed. Sixty-eight percent of statistical methods used summary statistics, and 27.2% used regression analysis. When summary statistics were used, clinical evidence was presented with a P-value or confidence interval (CI) in 51.8% of statistical methods compared to 72.5% when summary statistics were not used (P=0.0282). Clinical evidence was presented verbally in 7.1% of statistical methods when summary statistics were used and in 20.0% when summary statistics were not used (P=0.0323).nnnCONCLUSIONSnSummary statistics are the most frequently used statistical method to generate high-impact clinical evidence presented in the abstract of a medical article. Evidence described by summary statistics is significantly associated with less frequent reporting of a P-value or CI, and less frequent verbal presentations.