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Products liability lawyers often believe that if they can prove a product was defectively manufactured, they can easily convince a jury to find the manufacturer liable for injuries. But without [...]

A substantial number of studies have reported the development of gene expression--based prognostic signatures for lung cancer. The ultimate aim of such studies should be the development of well-validated clinically useful prognostic signatures that improve therapeutic decision making beyond current practice standards. We critically reviewed published studies reporting the development of gene expression--based prognostic signatures for non-small cell lung cancer to assess the progress made toward this objective. Studies published between January 1, 2002, and February 28, 2009, were identified through a PubMed search. Following hand-screening of abstracts of the identified articles, 16 were selected as relevant. Those publications were evaluated in detail for appropriateness of the study design, statistical validation of the prognostic signature on independent datasets, presentation of results in an unbiased manner, and demonstration of medical utility for the new signature beyond that obtained using existing treatment guidelines. Based on this review, we found little evidence that any of the reported gene expression signatures are ready for clinical application. We also found serious problems in the design and analysis of many of the studies. We suggest a set of guidelines to aid the design, analysis, and evaluation of prognostic signature studies. These guidelines emphasize the importance of focused study planning to address specific medically important questions and the use of unbiased analysis methods to evaluate whether the resulting signatures provide evidence of medical utility beyond standard of care-based prognostic factors. DOI: 10.1093/jnci/djq025

The development of tumor biomarkers ready for clinical use is complex. We propose a refined system for biomarker study design, conduct, analysis, and evaluation that incorporates a hierarchal level of evidence scale for tumor marker studies, including those using archived specimens. Although fully prospective randomized clinical trials to evaluate the medical utility of a prognostic or predictive biomarker are the gold standard, such trials are costly, so we discuss more efficient indirect 'prospective-retrospective' designs using archived specimens. In particular, we propose new guidelines that stipulate that 1) adequate amounts of archived tissue must be available from enough patients from a prospective trial (which for predictive factors should generally be a randomized design) for analyses to have adequate statistical power and for the patients included in the evaluation to be clearly representative of the patients in the trial; 2) the test should be analytically and preanalytically validated for use with archived tissue; 3) the plan for biomarker evaluation should be completely specified in writing before the performance of biomarker assays on archived tissue and should be focused on evaluation of a single completely defined classifier; and 4) the results from archived specimens should be validated using specimens from one or more similar, but separate, studies. J Natl Cancer Inst 2009;101:1446-1452 DOI: 10.1093/jnci/djp335 Published by Oxford University Press 2009. Advance Access publication on October 8, 2009.

Background Many molecularly targeted anticancer agents entering the definitive stage of clinical development benefit only a subset of treated patients. This may lead to missing effective agents by the traditional broad-eligibility randomized trials due to the dilution of the overall treatment effect. We propose a statistically rigorous biomarker-adaptive threshold phase III design for settings in which a putative biomarker to identify patients who are sensitive to the new agent is measured on a continuous or graded scale. Methods The design combines a test for overall treatment effect in all randomly assigned patients with the establishment and validation of a cut point for a prespecified biomarker of the sensitive subpopulation. The performance of the biomarker-adaptive design, relative to a traditional design that ignores the biomarker, was evaluated in a simulation study. The biomarker-adaptive design was also used to analyze data from a prostate cancer trial. Results In the simulation study, the biomarker-adaptive design preserved the power to detect the overall effect when the new treatment is broadly effective. When the proportion of sensitive patients as identified by the biomarker is low, the proposed design provided a substantial improvement in efficiency compared with the traditional trial design. Recommendations for sample size planning and implementation of the biomarker-adaptive design are provided. Conclusions A statistically valid test for a biomarker-defined subset effect can be prospectively incorporated into a randomized phase III design without compromising the ability to detect an overall effect if the intervention is beneficial in a broad population.

Background Both the validity and the reproducibility of microarray-based clinical research have been challenged. There is a need for critical review of the statistical analysis and reporting in published microarray studies that focus on cancer-related clinical outcomes. Methods Studies published through 2004 in which microarray-based gene expression profiles were analyzed for their relation to a clinical cancer outcome were identified through a Medline search followed by hand screening of abstracts and full text articles. Studies that were eligible for our analysis addressed one or more outcomes that were either an event occurring during follow-up, such as death or relapse, or a therapeutic response. We recorded descriptive characteristics for all the selected studies. A critical review of outcome-related statistical analyses was undertaken for the articles published in 2004. Results Ninety studies were identified, and their descriptive characteristics are presented. Sixty-eight (76%) were published in journals of impact factor greater than 6. A detailed account of the 42 studies (47%) published in 2004 is reported. Twenty-one (50%) of them contained at least one of the following three basic flaws: 1) in outcome-related gone finding, an unstated, unclear, or inadequate control for multiple testing; 2) in class discovery, a spurious claim of correlation between clusters and clinical outcome, made after clustering samples using a selection of outcome-related differentially expressed genes; or 3) in supervised prediction, a biased estimation of the prediction accuracy through an incorrect cross-validation procedure. Conclusions The most common and serious mistakes and misunderstandings recorded in published studies are described and illustrated. Based on this analysis, a proposal of guidelines for statistical analysis and reporting for clinical microarray studies, presented as a checklist of 'Do's and Don'ts,' is provided.

Key words: bronchiectasis; comprehensive health care; cystic fibrosis; nutrition; pancreatic insufficiency Abbreviations: ADA = Americans with Disabilities Act: BMD = bone mineral density; BMI = body mass index; CBAVD = [...]

Background: The reported incidence of primary malignant brain tumors among children in the United States increased by 35% during the period from 1973 through 1994. The purpose of our study was twofold: 1) to determine whether the reported incidence rates for this period are better represented by a linear increase over the entire period ('linear model') or, alternatively, by a step function, with a lower rate in the years preceding 1984-1985 and a constant higher rate afterward ('jump model'); and 2) to identify the specific brain regions and histologic subtypes that have increased in incidence. Methods: Incidence data from the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute for the period from 1973 through 1994 for primary malignant brain tumors in children were used to model the number of cases in a year as a random variable from a Poisson distribution by use of either a linear model or a jump model. Results/Conclusions: The increase in reported incidence of childhood primary malignant brain tumors is best explained by the jump model, with a step increase in incidence occurring in the mid-1980s. The brain stem and the cerebrum are the primary sites for which an increase in tumor incidence has been reported. The increase in reported incidence of low-grade gliomas in the cerebrum and the brain stem (unaccompanied by an increase in mortality for these sites) supports the substantial contribution of low-grade gliomas to the overall increase in reported incidence for childhood brain tumors. Implications: The significantly better fit of the data to a jump model supports the hypothesis that the observed increase in incidence somehow resulted from changes in detection and/or reporting of childhood primary malignant brain tumors during the mid-1980s. [J Natl Cancer Inst 1998;90:1269-77]

Background: Many cancer patients in phase I clinical trials are treated at doses of chemotherapeutic agents that are below the biologically active level, thus reducing their chances for therapeutic benefit. Current phase I trials often take a long time to complete and provide little information about interpatient variability or cumulative toxicity. Purpose: Our objective was to develop alternative designs for phase I trials so that fewer patients are treated at subtherapeutic dose levels, trials are of reduced duration, and important information (i.e., cumulative toxicity and maximum tolerated dose) needed to plan phase II trials is obtained. Methods: We fit a stochastic model to data from 20 phase I trials involving the study of nine different drugs. We then simulated new data from the model with the parameters estimated from the actual trials and evaluated the performance of alternative phase I designs on this simulated data. Four designs were evaluated. Design 1 was a conventional design (similar to the commonly used modified Fibonacci method) using cohorts of three to six patients, with 40% dose-step increments and no intrapatient dose escalation. Designs 2 through 4 included only one patient per cohort until one patient experienced dose-limiting toxic effects or two patients experienced grade 2 toxic effects (during their first course of treatment for designs 2 and 3 or during any course of treatment for design 4). Designs 3 and 4 used 100% dose steps during this initial accelerated phase. After the initial accelerated phase, designs 2 through 4 resorted to standard cohorts of three to six patients, with 40% dose-step increments. Designs 2 through 4 used intrapatient dose escalation if the worst toxicity is grade 0-1 in the previous course for that patient. Results: Only three of the actual trials demonstrated cumulative toxic effects of the chemotherapeutic agents in patients. The average number of patients required for a phase I trial was reduced from 39.9 for design 1 to 24.4, 20.7, and 21.2 for designs 2, 3, and 4, respectively. The average number of patients who would be expected to have grade 0-1 toxicity as their worst toxicity over three cycles of treatment is 23.3 for design 1, but only 7.9, 3.9, and 4.8 for designs 2, 3, and 4, respectively. The average number of patients with grade 3 toxicity as their worst toxicity increases from 5.5 for design 1 to 6.2, 6.8, and 6.2 for designs 2, 3, and 4, respectively. The average number of patients with grade 4 toxicity as their worst toxicity increases from 1.9 for design 1 to 3.0, 4.3, and 3.2 for designs 2, 3, and 4, respectively. Conclusion: Accelerated titration (i.e., rapid intrapatient drug dose escalation) designs appear to effectively reduce the number of patients who are undertreated, speed the completion of phase I trials, and provide a substantial increase in the information obtained. [J Natl Cancer Inst 1997;89:1138-47]

Background: Patients with sleep disorders are common in primary care, yet most physicians lack training in the diagnosis and treatment of such patients. Objectives: To enhance recognition of sleep disorders by community physicians and transfer the diagnostic testing and care of such patients from tertiary care centers to the local community. To present our polysomnogram experience relevant to sleep apnea. Methods: Sleep disorders specialists provided a community with education, diagnostic equipment, and ongoing support as sleep disorders expertise was established locally. Outcomes for a 2-year period were assessed by chart review, patient questionnaire, tabulation of polysomnographic data, and comparison with published reports from specialized centers. Results: Referral for sleep testing increased by almost 8-fold in patients at the Walla Walla Clinic in Walla Walla, Wash, from 0.27% (2 of 752 cases reviewed) to 2.1% (294 of 14 330 internal medicine patients). Data were collected from all community physicians for a 2-year period on 360 new patients who underwent polysomnogram testing. This resulted in the diagnosis of sleep-related breathing disorders in 81% and periodic leg movements of sleep in 18%. Nasal continuous positive airway pressure treatment was given to 228 patients (average baseline apnea index of 19.1), representing a higher volume of patients than at many traditional sleep centers, yet compliance with continuous positive airway pressure was comparable. Conclusions: Sleep apnea is significantly underrecognized by primary care physicians. As a result of the intervention, local sleep expertise was established and large numbers of patients were discovered and treated in the community. Thus, a significant public health problem is identified and a solution established.

Background: A confirmatory randomized clinical trial is a trial that is aimed at assessing whether a treatment effect observed in a previous randomized trial (or trials) is real and important. There is often considerable disagreement about the need for such confirmatory trials. Purpose: Our aim is to provide a general statistical framework for evaluating whether a confirmatory trial is warranted in a particular situation. Methods and Results: The results of two clinical trials are considered: 1) a Cancer and Leukemia Group B trial comparing induction chemotherapy plus radiotherapy with radiotherapy alone in the treatment of patients with locally advanced non-small-cell lung cancer and 2) a North Central Cancer Treatment Group trial comparing surgery plus adjuvant chemotherapy with surgery alone in the :treatment of patients with advanced colon cancer. In our analysis, we argue that differences in the interpretation of results from a randomized trial are based on differences in prior beliefs about the efficacy of the treatment(s) under study. We believe that a major factor in the decision to perform a confirmatory trial is prior skepticism about the clinical worth of the treatment in question. Both the level of prior skepticism and the minimum treatment effect deemed clinically worthwhile require subjective judgment. We develop a Bayesian framework to allow differences in interpretation to be examined systematically and the need for a confirmatory trial to be assessed. Our model allows the addition of prior belief (specified in the form of a prior distribution of treatment effect) to the results of a trial to yield a posterior distribution. The interpretation of trial results is based on the posterior distribution and will vary as the prior distribution (i.e., the prior belief) varies. To aid in the interpretation of trial results, we also advocate the specification of a minimum clinically worthwhile treatment effect at the start of a trial. Conclusions and Implications: Our approach acknowledges that a number of different prior beliefs are possible, giving rise to a range of interpretations of results from a clinical trial. This approach provides a formal and systematic basis for considering both the range of likely opinions and the subsequent decision to be made with regard to the need for a confirmatory trial. We recommend that this approach be considered in the discussion of future confirmatory randomized clinical trials.

Cancer clinical trials have two broad objectives: To identify promising treatments and to determine whether such treatments really do reduce morbidity and mortality. These two objectives generally require different types of clinical trials. The guiding principle of clinical trials is to ask an important question and get a reliable answer. Asking an important question generally means asking a question that has the potential for influencing medical practice, using a control treatment that is widely accepted, using an experimental treatment that is widely applicable, using an endpoint that is a direct measure of patient benefit, and studying a group of patients who are broadly representative. Getting a reliable answer also has many components, including randomized treatment assignment, adequate sample size, intent-to-treat analysis, and testing of prestated hypotheses on mature data. These components are discussed. Several recent developments in clinical trials methodology: interim monitoring boundaries, large simple trials, and metaanalysis, are highlighted here. Major obstacles to conducting randomized clinical trials are also described. Cancer 1994;74:2614-9.

Background: In the previous meta-analysis of dose intensity (dosage) of chemotherapy in advanced ovarian cancer, we analyzed data on cyclophosphamide, altretamine (hexamethylmelamine), doxorubicin, and cisplatin. Only cisplatin showed statistically significant association of complete and partial clinical response with dose intensity. Purpose: This analysis updates the previous results and further characterizes response to cisplatin alone or in multiagent regimens. Methods: We analyzed data from 18 regimens containing platinum (cisplatin or carboplatin) that were used in nine new randomized trials, in addition to data from the 60 groups of patients in our previous study in which responses were reported. Relative dose intensity was calculated as a fraction of the dosage of a drug in the standard regimen of cyclophosphamide, altretamine, doxorubicin, and platinum (CHAP). We performed single and multiple regression analyses to determine the relationship between disease outcome and relative dose intensity for cyclophosphamide, platinum, and doxorubicin alone or in combination. Results: The association between outcome and dose intensity for platinum alone or in multiagent regimens was statistically significant. This association was of borderline significance for cyclophosphamide alone but was not significant for this drug in multiagent regimens. There were insufficient data to test the relationship for doxorubicin as a single agent, but in multiagent regimens, the relationship was borderline (P = .05). Multiagent regimens containing platinum produced greater response rates than platinum alone for any fixed, planned relative dose intensity for platinum. Conclusions: Our results support other published findings that use of cyclophosphamide and doxorubicin increases the efficacy of single-agent platinum. Relative dose intensity values for cyclophosphamide used alone were larger than those used in multiagent regimens, which might explain why the relationship between relative dose intensity and outcome for cyclophosphamide was not significant for use in multiagent regimens. Similarly, none of the multiagent regimens incorporated doxorubicin at a relative dose intensity for which the drug is found to be effective as a single agent. Implications: Prospective clinical trials are required to test the effect of higher relative dose intensity for doxorubicin and cyclophosphamide added to platinum in advanced ovarian cancer. An important element in the design of prospective trials will be to test for the relative importance of dose intensity versus total dose. This testing is best achieved in a three-arm study design such as that reported in adjuvant treatment of stage II breast cancer conducted by the Cancer and Leukemia Group B.

The Cancer Therapy Evaluation Program, National Cancer Institute (CTEP, NCI) strongly supports the role of controlled clinical trials in improving the care of children with cancer, and particularly the central role that the pediatric Cooperative Groups play in this process. Trends that threaten the ability to perform these trials include the increasingly limited financial resources available for clinical investigations and the sentiment within some circles that controlled clinical trials may be inappropriate for ethical reasons. The inherent risks of accepting a new therapy without rigorous comparison to existing therapy strongly support the need for randomized trials with adequate accrual to answer important therapeutic questions in a timely and reliable fashion. Retrospective analysis of multiple clinical trials is one method for identifying compelling hypotheses to be tested prospectively. Using this method, we have demonstrated the association between doxorubicin dose intensity and positive response and outcome for patients with Ewing sarcoma and osteosarcoma, thereby providing direction for the selection of important therapeutic questions to be addressed in future clinical trials for these malignancies. Cancer 1993; 71:3422-8.

Background: Many more phase II studies have favorable outcomes than the subsequent phase III trials. We used historical data from phase II and phase III studies for patients with extensive-stage small-cell lung cancer (SCLC) to generate a statistical model to provide assistance in selecting chemotherapy regimens from phase II studies for subsequent use in phase III randomized studies. Methods: Information from 21 phase III trials for patients with extensive-stage SCLC initiated during the period from 1972 through 1990 was reviewed to identify those that were preceded by phase II studies of the same regimen. We used data from all the trial pairs to develop a statistical model in which the number of patients, the median survival of patients, and the number of deaths observed in the phase II trial are used to estimate the statistical power of the subsequent phase III trial. All statistical tests were two-sided. Results: Nine phase II studies were identified that preceded phase III trials of the same regimen. The regimens from two phase II studies with the greatest expected power in the phase III trial (0.62 and 0.58) both demonstrated significantly prolonged survival when compared with standard treatment in subsequent phase III trials (P [is less than] .001 and P = .002, respectively). The regimens from six of the other phase II studies, for which the median power expected in the phase III trial was 0.28 (range, 0.19-0.52), showed no difference when compared with standard treatment in a phase III trial. Conclusions: Phase II studies for particular regimens that have an expected power of greater than 0.55 provide a reasonable basis for proceeding with a phase III trial. [J Natl Cancer Inst 2000;92: 1061-7]

Background: Several randomized clinical trials have tested the hypothesis that tamoxifen is effective in preventing breast cancer. The largest such trial, the National Surgical Adjuvant Breast and Bowel Project's Breast Cancer Prevention Trial (BCPT), reported a 49% reduction in risk of invasive breast cancer for the tamoxifen group. However, it is unclear whether the effect of tamoxifen in this trial was mainly due to prevention of newly forming tumors or to treatment of occult disease. Methods: We used various tumor growth models (i.e., exponential and Gompertzian [growth limited by tumor size]) and a computer simulation to approximate the percentage of detected tumors that were initiated after study entry. Maximum likelihood techniques were then used to estimate separately the efficacy of tamoxifen in treating occult disease and in preventing the formation and growth of new tumors. Results: Under the assumptions of most of the growth models, the trial was sufficiently long for substantial numbers of new tumors to form, grow, and be detected during the trial. With the Gompertzian model and all available incidence data from the BCPT, it was estimated that 60% (95% confidence interval [CI]= 40%-80%) fewer new tumors were detected in the tamoxifen group than in the placebo group. Likewise, 35% (95% CI = 6%-63%) fewer occult tumors were detected in the tamoxifen group. With this model, the estimated incidence rate of invasive breast cancer among women in the placebo group of the BCPT was 7.7 (95% CI = 6.6-8.9) per 1000 women per year. Similar results were obtained with three exponential tumor growth models. Conclusions: These results support the concept that tamoxifen reduced cancer incidence in the BCPT through both treatment of occult disease and prevention of new tumor formation and growth. However, data from prevention trials may never be sufficient to completely distinguish prevention of new tumor formation from treatment of occult disease. [J Natl Cancer lnst 2000;92:48-53]