BackgroundSensitivity analyses play a crucial role in assessing the robustness of the findings or conclusions based on primary analyses of data in clinical trials. They are a critical way to assess the impact, effect or influence of key assumptions or variations—such as different methods of analysis, definitions of outcomes, protocol deviations, missing data, and outliers—on the overall conclusions of a study.The current paper is the second in a series of tutorial-type manuscripts intended to discuss and clarify aspects related to key methodological issues in the design and analysis of clinical trials.DiscussionIn this paper we will provide a detailed exploration of the key aspects of sensitivity analyses including: 1) what sensitivity analyses are, why they are needed, and how often they are used in practice; 2) the different types of sensitivity analyses that one can do, with examples from the literature; 3) some frequently asked questions about sensitivity analyses; and 4) some suggestions on how to report the results of sensitivity analyses in clinical trials.SummaryWhen reporting on a clinical trial, we recommend including planned or posthoc sensitivity analyses, the corresponding rationale and results along with the discussion of the consequences of these analyses on the overall findings of the study.

PURPOSE We report the final, protocol-specified analysis of overall survival (OS) in GOG-0218, a phase III, randomized trial of bevacizumab in women with newly diagnosed ovarian, fallopian tube, or primary peritoneal carcinoma. METHODS A total of 1,873 women with incompletely resected stage III to IV disease were randomly assigned 1:1:1 to six 21-day cycles of intravenous carboplatin (area under the concentration v time curve 6) and paclitaxel (175 mg/m2) versus chemotherapy plus concurrent bevacizumab (15 mg/kg, cycles 2 to 6) versus chemotherapy plus concurrent and maintenance bevacizumab (cycles 2 to 22). Inclusion criteria included a Gynecologic Oncology Group performance status of 0 to 2 and no history of clinically significant vascular events or evidence of intestinal obstruction. OS was analyzed in the intention-to-treat population. A total of 1,195 serum and/or tumor specimens were sequenced for BRCA1/2 and damaging mutations in homologous recombination repair (HRR) genes. Intratumoral microvessel density was studied using CD31 immunohistochemistry. RESULTS Median follow-up was 102.9 months. Relative to control (n = 625), for patients receiving bevacizumab-concurrent (n = 625), the hazard ratio (HR) of death was 1.06 (95% CI, 0.94 to 1.20); for bevacizumab-concurrent plus maintenance (n = 623), the HR was 0.96 (95% CI, 0.85 to 1.09). Disease-specific survival was not improved in any arm. No survival advantage was observed after censoring patients who received bevacizumab at crossover or as second line. Median OS for stage IV bevacizumab-concurrent plus maintenance was 42.8 v 32.6 months for stage IV control (HR, 0.75; 95% CI, 0.59 to 0.95). Relative to wild type, the HR for death for BRCA1/2 mutated carcinomas was 0.62 (95% CI, 0.52 to 0.73), and for non- BRCA1/2 HRR, the HR was 0.65 (95% CI, 0.51 to 0.85). BRCA1/2, HRR, and CD31 were not predictive of bevacizumab activity. CONCLUSION No survival differences were observed for patients who received bevacizumab compared with chemotherapy alone. Testing for BRCA1/2 mutations and homologous recombination deficiency is essential.

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Purpose The success of any research process relies, in part, on how well investigators are able to translate a clinical problem into a research question-a task that is not so simple for novice investigators. The PICOT approach requires that the framing of the research question specify the target Population, the Intervention of interest, the Comparator intervention, key Outcomes, and the Time frame over which the outcomes are assessed. This paper describes the use of the PICOT structure in framing research questions and examines PICOT criteria as applied to the anesthesia literature. We also provide a roadmap for applying the PICOT format in identifying and framing clear research questions. Methods In addition to searching MEDLINE for the literature on framing research questions, we performed a systematic review of articles published in four key anesthesia journals in 2006, including Anesthesiology, Anesthesia & Analgesia, the British Journal of Anaesthesia, and the Canadian Journal of Anesthesia. Results Three hundred thirteen articles (n = 313) were included in this review, with the following distribution by study design: 139 (44%) randomized controlled trials, 129 (41%) cohort studies, and 45 (15%) case-controlled, crosssectional studies or systematic reviews. Overall, 96% (95% confidence interval: 91,100) of articles did not apply the PICOT approach in reporting the research question. Conclusions The PICOT approach may be helpful in defining and clearly stating the research question. It remains to be determined whether or not compliance with the PICOT style, or any other format for framing research questions, is associated with a higher quality of research reporting. RésuméObjectif La re´ussite de tout processus de recherche s'appuie en partie sur la capacite´des chercheurs a`traduire un proble`me clinique en question de recherche, une taˆche ardue pour les chercheurs de´butants. L'approche PICOT exige que la formulation de la question de recherche spe´cifie la Population cible, l'Intervention al 'e´tude, l'intervention de Comparaison, les devenirs cle´s (Outcomes) et un cadre Temporel au cours duquel les devenirs sont e´value´s. Cet article de´crit l'utilisation de la structure PICOT dans la formulation des questions de recherche et examine les crite`res PICOT lorsqu'ils sont applique´s à la litte´rature en anesthe´sie. Nous fournissons e´galement une feuille de route visant a`l'application du format PICOT pour identifier et formuler des questions de recherche claires. Méthode En plus de recherches sur MEDLINE pour trouver la litte´rature touchant a`la formulation de questions de recherche, nous avons effectue´une re´vision