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Biomedical subjects

Boris Freidlin

Publications and source records attributed to Boris Freidlin.

At least 19 recordsLinked to original sources
PubMed2007

Phase II clinical trial of chemotherapy-naive patients > or = 70 years of age treated with erlotinib for advanced non-small-cell lung cancer.

PURPOSE: This is a phase II, multicenter, open-label study of chemotherapy-naïve patients with non-small-cell lung cancer (NSCLC) and age > or = 70 years who were treated with erlotinib and evaluated to determine the median, 1-year, and 2-year survival. The secondary end points include radiographic response rate, time to progression (TTP), toxicity, and symptom improvement. PATIENTS AND METHODS: Eligible patients with NSCLC were treated with erlotinib 150 mg/d until disease progression or significant toxicity. Tumor response was assessed every 8 weeks by computed tomography scan using Response Evaluation Criteria in Solid Tumors. Tumor samples were analyzed for the presence of somatic mutations in EGFR and KRAS. RESULTS: Eighty eligible patients initiated erlotinib therapy between March 2003 and May 2005. There were eight partial responses (10%), and an additional 33 patients (41%) had stable disease for 2 months or longer. The median TTP was 3.5 months (95% CI, 2.0 to 5.5 months). The median survival time was 10.9 months (95% CI, 7.8 to 14.6 months). The 1- and 2- year survival rates were 46% and 19%, respectively. The most common toxicities were acneiform rash (79%) and diarrhea (69%). Four patients developed interstitial lung disease of grade 3 or higher, with one treatment-related death. EGFR mutations were detected in nine of 43 patients studied. The presence of an EGFR mutation was strongly correlated with disease control, prolonged TTP, and survival. CONCLUSION: Erlotinib monotherapy is active and relatively well tolerated in chemotherapy-naïve elderly patients with advanced NSCLC. Erlotinib merits consideration for further investigation as a first-line therapeutic option in elderly patients.

Age Factors↗
PubMed2006

Conditional power calculations for clinical trials with historical controls.

A trial of a new therapy is to be compared to results from a previous trial of patients treated with a standard therapy. For a given sample size for the trial of the new therapy, we desire the power, against a specific alternative hypothesis, for the hypothesis test of the null hypothesis that the therapies are equivalent. Alternatively, the sample size required for the trial of the new therapy is needed for a target power. We explain why a popular method for doing these calculations is wrong, and discuss alternative methods in the context of normal outcomes, binary outcomes, and time-to-event outcomes.

Clinical Trials as Topic↗
PubMed2006

The likelihood as statistical evidence in multiple comparisons in clinical trials: no free lunch.

The likelihood ratio summarizes the strength of statistical evidence for one simple pre-determined hypothesis versus another. However, it does not directly address the multiple comparisons problem. In this paper we discuss some concerns related to the application of likelihood ratio methods to several multiple comparisons issues in clinical trials, in particular, subgroup analysis, multiple variables, interim monitoring, and data driven choice of hypotheses.

Artificial Intelligence↗
PubMed2005

Robust genomic control for association studies.

Population-based case-control studies are a useful method to test for a genetic association between a trait and a marker. However, the analysis of the resulting data can be affected by population stratification or cryptic relatedness, which may inflate the variance of the usual statistics, resulting in a higher-than-nominal rate of false-positive results. One approach to preserving the nominal type I error is to apply genomic control, which adjusts the variance of the Cochran-Armitage trend test by calculating the statistic on data from null loci. This enables one to estimate any additional variance in the null distribution of statistics. When the underlying genetic model (e.g., recessive, additive, or dominant) is known, genomic control can be applied to the corresponding optimal trend tests. In practice, however, the mode of inheritance is unknown. The genotype-based chi (2) test for a general association between the trait and the marker does not depend on the underlying genetic model. Since this general association test has 2 degrees of freedom (df), the existing formulas for estimating the variance factor by use of genomic control are not directly applicable. By expressing the general association test in terms of two Cochran-Armitage trend tests, one can apply genomic control to each of the two trend tests separately, thereby adjusting the chi (2) statistic. The properties of this robust genomic control test with 2 df are examined by simulation. This genomic control-adjusted 2-df test has control of type I error and achieves reasonable power, relative to the optimal tests for each model.

Case-Control Studies↗
PubMed2005

Adaptive signature design: an adaptive clinical trial design for generating and prospectively testing a gene expression signature for sensitive patients.

PURPOSE: A new generation of molecularly targeted agents is entering the definitive stage of clinical evaluation. Many of these drugs benefit only a subset of treated patients and may be overlooked by the traditional, broad-eligibility approach to randomized clinical trials. Thus, there is a need for development of novel statistical methodology for rapid evaluation of these agents. EXPERIMENTAL DESIGN: We propose a new adaptive design for randomized clinical trials of targeted agents in settings where an assay or signature that identifies sensitive patients is not available at the outset of the study. The design combines prospective development of a gene expression-based classifier to select sensitive patients with a properly powered test for overall effect. RESULTS: Performance of the adaptive design, relative to the more traditional design, is evaluated in a simulation study. It is shown that when the proportion of patients sensitive to the new drug is low, the adaptive design substantially reduces the chance of false rejection of effective new treatments. When the new treatment is broadly effective, the adaptive design has power to detect the overall effect similar to the traditional design. Formulas are provided to determine the situations in which the new design is advantageous. CONCLUSION: Development of a gene expression-based classifier to identify the subset of sensitive patients can be prospectively incorporated into a randomized phase III design without compromising the ability to detect an overall effect.

Antineoplastic Agents↗
PubMed2005

Design issues of randomized phase II trials and a proposal for phase II screening trials.

Future progress in improving cancer therapy can be expedited by better prioritization of new treatments for phase III evaluation. Historically, phase II trials have been key components in the prioritization process. There has been a long-standing interest in using phase II trials with randomization against a standard-treatment control arm or an additional experimental arm to provide greater assurance than afforded by comparison to historic controls that the new agent or regimen is promising and warrants further evaluation. Relevant trial designs that have been developed and utilized include phase II selection designs, randomized phase II designs that include a reference standard-treatment control arm, and phase II/III designs. We present our own explorations into the possibilities of developing "phase II screening trials," in which preliminary and nondefinitive randomized comparisons of experimental regimens to standard treatments are made (preferably using an intermediate end point) by carefully adjusting the false-positive error rates (alpha or type I error) and false-negative error rates (beta or type II error), so that the targeted treatment benefit may be appropriate while the sample size remains restricted. If the ability to conduct a definitive phase III trial can be protected, and if investigators feel that by judicious choice of false-positive probability and false-negative probability and magnitude of targeted treatment effect they can appropriately balance the conflicting demands of screening out useless regimens versus reliably detecting useful ones, the phase II screening trial design may be appropriate to apply.

Clinical Trials, Phase II as Topic↗
PubMed2005

Preliminary data release for randomized clinical trials of noninferiority: a new proposal.

Noninferiority trials often require a long follow-up period for the data to reach the maturity needed for definitive analysis. A proposal is presented that allows for early release of outcome data from a carefully specified subset of noninferiority trials. This subset is defined so that the early release of the data will be potentially useful to patients who face a treatment decision but will not compromise the integrity of the trial or interfere with the completion of the trial to its definitive analysis. In particular, the release of the data will only occur after the last participant has been randomly assigned and is off treatment-arm-specific therapy and only if it is unlikely that subsequent treatment and/or follow-up practices will change based on the knowledge of released data. In contrast to standard interim monitoring, (1) the release of the data would be automatic and independent of the observed data, and (2) the trial would continue on to its planned final analysis and not be stopped. Examples are given demonstrating how the proposal would work, along with a discussion of possible objections to the proposal.

Clinical Trials Data Monitoring Committees↗
PubMed2005

Evaluation of randomized discontinuation design.

PURPOSE: Single-arm phase II trials may not be appropriate for testing cytostatic agents. We evaluate two kinds of randomized designs for the early development of target-based cytostatic agents. METHODS: We compared power of the randomized discontinuation and upfront randomization designs under two models for the treatment effect of targeted cytostatic agents. RESULTS: The randomized discontinuation design is not as efficient as upfront randomization if treatment has a fixed effect on tumor growth rate or if treatment benefit is restricted to slower-growing tumors. On the other hand, the randomized discontinuation design can be advantageous under a model where only a subset of patients, those expressing the molecular target, is sensitive to the agent. To achieve efficiency, the design parameters must be carefully structured to provide adequate enrichment of the randomly assigned patients. CONCLUSION: With careful planning, the randomized discontinuation designs can be useful in some settings in the early development of targeted agents where a reliable assay to select patients expressing the target is not available.

Antineoplastic Agents↗
PubMed2005

Testing treatment effects in the presence of competing risks.

Competing risks are often encountered in clinical research. In the presence of multiple failure types, the time to the first failure of any type is typically used as an overall measure of the clinical impact for the patients. On the other hand, use of endpoints based on the type of failure directly related to the treatment mechanism of action allows one to focus on the aspect of the disease targeted by treatment. We review the methodology commonly used for testing failure specific treatment effects. Simulation results demonstrate that the cause-specific log-rank test is robust (in the sense of preserving the nominal level of the test) and has good power properties for testing for differences in the marginal latent failure-time distributions, whereas the use of a popular cumulative incidence based approach may be problematic for this aim.

Computer Simulation↗
PubMed2005

Genomic control for association studies under various genetic models.

Case-control studies are commonly used to study whether a candidate allele and a disease are associated. However, spurious association can arise due to population substructure or cryptic relatedness, which cause the variance of the trend test to increase. Devlin and Roeder derived the appropriate variance inflation factor (VIF) for the trend test and proposed a novel genomic control (GC) approach to estimate VIF and adjust the test statistic. Their results were derived assuming an additive genetic model and the corresponding VIF is independent of the candidate allele frequency. We determine the appropriate VIFs for recessive and dominant models. Unlike the additive test, the VIFs for the optimal tests for these two models depend on the candidate allele frequency. Simulation results show that, when the null loci used to estimate the VIF have allele frequencies similar to that of the candidate gene, the GC tests derived for recessive and dominant models remain optimal. When the underlying genetic model is unknown or the null loci and candidate gene have quite different allele frequencies, the GC tests derived for the recessive or dominant models cannot be used while the GC test derived for the additive model can be.

Biometry↗
PubMed2004

Strength of accumulating evidence and data monitoring committee decision making.

The data monitoring committee (DMC) is a vital component of a randomized clinical trial. Its responsibilities include stopping the trial early for extreme results. The decision to stop the trial must be based on a careful synthesis of statistical methodology and clinical judgment. It is critical to ensure the validity of this complex process. In this paper we present results of a survey of 21 DMC members conducted to investigate how they evaluate accumulating evidence. The results indicate that some DMC members may be over-interpreting developing trends in the data.

Antineoplastic Agents↗
PubMed2004

A note on appropriate use of statistical tests of mutation rates from ordered groups.

Recently it was found that the frequency of familial dysautonomia (FD) carriers in Ashkenazi Jews (AJ) was higher in AJ of Polish descent compared to AJ of non-Polish descent. The study population was classified into groups ranging from no to full Polish origin. The statistical procedure used to compare the frequencies of FD carriers did not incorporate this intrinsic ordering of individuals by degree of Polish ancestry. In this paper we describe a test designed to utilize this information and show that it is more powerful than the standard test of equality of proportions. In particular, the p value of the trend test on their data is noticeably lower (0.003) than 0.012 found by the standard test, providing stronger evidence for a relationship between allele frequency and Polish descent.

Data Interpretation, Statistical↗
PubMed2003

Targeting epidermal growth factor receptor--are we missing the mark?

CONTEXT: Aberrant signalling through the epidermal growth factor receptor (EGFR) is associated with neoplastic cell proliferation, migration, stromal invasion, resistance to apoptosis, and angiogenesis. The high frequency of abnormalities in EGFR signalling in human carcinomas and gliomas and laboratory studies showing that inhibition of EGFRcan impair tumour growth means that EGFR is an attractive target for the development of cancer therapeutics. Among the classes of agents targeting EGFR in clinical development are monoclonal antibodies against the extracellular ligand-binding domain of the receptor, and small molecules that inhibit activation of the receptor tyrosine kinase. Although there are pharmacological and mechanistic differences between the two classes of inhibitor, preclinical studies suggest they both inhibit cell proliferation and have additive or synergistic cytotoxicity with standard therapies. Results from early clinical trials indicate that these agents are well tolerated and have anti-tumour activity. STARTING POINT: In May, 2003, the Australian Therapeutic Goods Administration and the US Food and Drug Administration approved the EGFR inhibitor gefitinib (ZD1839, Iressa) for the treatment of patients with advanced non-small-cell lung cancer (NSCLC) previously treated with chemotherapy. The US approval was based on results of a phase 2 study of 216 patients with NSCLC, including 142 patients with refractory disease. In this subgroup, the response rate was about 10%. The approval of the drug was granted despite negative results from two randomised controlled trials in over 2000 previously untreated patients with NSCLC, which showed no benefit in survival, objective tumour response, or time to progression when gefitinib was added to chemotherapy. WHERE NEXT? Research is needed to identify and validate predictive factors that can be used to select patients with disease likely to respond to EGFR inhibitors, and to elucidate the mechanism of interaction of these agents with standard therapies and other molecularly targeted agents. Appropriately designed clinical trials are required to define the optimum dose, schedule, and sequence for these agents in combination with conventional therapies and other targeted agents.

Antineoplastic Agents↗
PubMed2003

Efficiency robust tests for mapping quantitative trait loci using extremely discordant sib pairs.

In 1972, Haseman and Elston proposed a pioneering regression method for mapping quantitative trait loci using randomly selected sib pairs. Recently, the statistical power of their method was shown to be increased when extremely discordant sib pairs are ascertained. While the precise genetic model may not be known, prior information that constrains IBD probabilities is often available. We investigate properties of tests that are robust against model uncertainty and show that the power gain from further constraining IBD probabilities is marginal. The additional linkage information contained in the trait values can be incorporated by combining the Haseman-Elston regression method and a robust allele sharing test.

Chromosome Mapping↗
PubMed2003

A model to select regimens for phase III trials for patients with advanced-stage non-small cell lung cancer.

PURPOSE: Historical data from pilot, Phase II, and Phase III studies for patients with advanced-stage non-small cell lung cancer (NSCLC) were used to evaluate a statistical model developed to provide assistance in selecting regimens from pilot studies for subsequent use in larger Phase III randomized studies. EXPERIMENTAL DESIGN: Information from 33 Phase III trials for patients with advanced-stage NSCLC performed from 1973 and 1994 in the United States and Canada was collected. The data from antecedent pilot or Phase II and subsequent Phase III trials were analyzed using a predictive statistical model. This model uses the number of patients in the pilot/Phase II study, the median survival of patients in the pilot, and the number of deaths observed, to estimate the statistical likelihood that the pilot regimen will be shown superior to standard therapy in a subsequent Phase III trial. RESULTS: Ten pilot/Phase II studies were identified that preceded eleven subsequent Phase III studies. The three pilot regimens associated with Phase III trials, revealing statistically significant longer survival, had an expected power of 0.69, 0.85, and 0.94 respectively. The regimens from the seven other pilot studies for which the median power expected was 0.38 (range, 0.07-0.80) showed no difference when compared with standard treatment in a Phase III trial. CONCLUSION: The use of the expected power model provides an important enhancement to the screening of new therapies. Regimens with an expected power of >0.55 may be good candidates for testing in Phase III trials.

Carcinoma, Non-Small-Cell Lung↗