Publications by authors named "Sandeep Menon"

19 Publications

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Advancing cancer drug development through precision medicine and innovative designs.

J Biopharm Stat 2018 27;28(2):229-244. Epub 2017 Nov 27.

b World Research and Development , Pfizer Inc ., Cambridge , MA , USA.

Precision medicine has been a hot topic in drug development over the last decade. Biomarkers have been proven useful for understanding the disease progression and treatment response in precision medicine development. Advancement of high-throughput omics technologies has enabled fast identification of molecular biomarkers with low cost. Although biomarkers have brought many promises to drug development, steep challenges arise due to a large amount of data, complexity of technology, and lack of full understanding of biology. In this article, we discuss the technologies and statistical issues that are related to omics biomarker discovery. We also provide an overview of the current development of biomarker-enabled cancer clinical trial designs.
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http://dx.doi.org/10.1080/10543406.2017.1402784DOI Listing
July 2019

Ethical Considerations in Adaptive Design Clinical Trials.

Ther Innov Regul Sci 2017 Mar 27;51(2):190-199. Epub 2016 Sep 27.

7 University of Iowa, Iowa City, IA, USA.

Adaptive design clinical trial methodologies offer both opportunities and challenges for observing basic ethical principles in human subject research. Using both published and unpublished adaptive design clinical trials, we have selected and reviewed examples of clinical trials with different design adaptations to discuss the ethical obstacles presented and often successfully resolved by these approaches, including (1) confirmatory trials for treatments widely accepted on the basis of uncontrolled case series or open-label trials (clinical equipoise and "justice" in the sense of which trial groups will "receive the benefits of research and bear its burdens") (infantile hemangioma/propranolol); (2) interim results analysis by unblinded data monitoring committees ("withholding information necessary to make a considered judgment" ["respect for persons"] versus compromising the trial's scientific basis) (BIG 1-98); (3) adaptations involving sample size reassessment or dose adjustment via dropping or adding treatment arms, allowing fewer subjects to produce statistically significant results, fewer subjects treated with ineffective/toxic doses, and more subjects given doses showing tolerance and treatment activity ("beneficence" or "protecting from harm and making efforts to secure wellbeing") (ECMO, Neuromyelitis Optica); (4) adaptive randomization inferential problems balanced against ethical benefits (trastuzumab vs taxane in advanced gastric cancer; ADVENT); (5) more efficient allocation of societal resources for research, in both public and commercial realms, versus uncertain regulatory acceptance (indicaterol; VALOR); and (6) platform, umbrella, and basket trials offering additional efficiencies (I-SPY II, BATTLE, Lung-MAP). The importance of careful design, meticulous planning, and rigorous ethical review of adaptive design trials on a case-by-case basis cannot be overemphasized.
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http://dx.doi.org/10.1177/2168479016667766DOI Listing
March 2017

Clinical dose-response for a broad set of biological products: A model-based meta-analysis.

Stat Methods Med Res 2018 09 8;27(9):2694-2721. Epub 2017 Jan 8.

2 Early Clinical Development, Worldwide Research & Development, Cambridge, MA, USA.

Characterizing clinical dose-response is a critical step in drug development. Uncertainty in the dose-response model when planning a dose-ranging study can often undermine efficiency in both the design and analysis of the trial. Results of a previous meta-analysis on a portfolio of small molecule compounds from a large pharmaceutical company demonstrated a consistent dose-response relationship that was well described by the maximal effect model. Biologics are different from small molecules due to their large molecular sizes and their potential to induce immunogenicity. A model-based meta-analysis was conducted on the clinical efficacy of 71 distinct biologics evaluated in 91 placebo-controlled dose-response studies published between 1995 and 2014. The maximal effect model, arising from receptor occupancy theory, described the clinical dose-response data for the majority of the biologics (81.7%, n = 58). Five biologics (7%) with data showing non-monotonic trend assuming the maximal effect model were identified and discussed. A Bayesian model-based hierarchical approach using different joint specifications of prior densities for the maximal effect model parameters was used to meta-analyze the whole set of biologics excluding these five biologics ( n = 66). Posterior predictive distributions of the maximal effect model parameters were reported and they could be used to aid the design of future dose-ranging studies. Compared to the meta-analysis of small molecules, the combination of fewer doses, narrower dosing ranges, and small sample sizes further limited the information available to estimate clinical dose-response among biologics.
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http://dx.doi.org/10.1177/0962280216684528DOI Listing
September 2018

Safety and Efficacy of SBI-087, a Subcutaneous Agent for B Cell Depletion, in Patients with Active Rheumatoid Arthritis: Results from a Phase II Randomized, Double-blind, Placebo-controlled Study.

J Rheumatol 2016 12 1;43(12):2094-2100. Epub 2016 Oct 1.

From Belgrade University School of Medicine, Belgrade, Serbia; Wojskowy Instytut Medyczny, Warsaw, Poland; Arthritis Clinic and West Tennessee Research Institute, Jackson, Tennessee; Desert Medical Advances, Palm Desert, California; Pfizer, Collegeville, Pennsylvania; Pfizer, Cambridge, Massachusetts; Janssen, Spring House, Pennsylvania, USA.

Objective: To evaluate subcutaneous SBI-087 to treat rheumatoid arthritis (RA).

Methods: A total of 210 adult patients with active RA were randomized to receive either 200 mg SBI-087 or placebo (Pbo), according to one of these patterns: SBI/Pbo/Pbo (SBI on Day 1), SBI/SBI/Pbo (SBI days 1 and 15), SBI/Pbo/SBI (SBI days 1 and 84), SBI/SBI/SBI (SBI days 1, 15, and 84), or Pbo/Pbo/Pbo (Pbo all 3 days). All patients were seropositive and taking background methotrexate. The primary endpoint was proportion of patients achieving 20% improvement from baseline at Week 16 by American College of Rheumatology criteria (ACR20). Other outcomes included 28-joint Disease Activity Score (DAS28)-C-reactive protein (CRP), physician's and patient's global assessments of disease activity (PGA and PtGA, respectively) and Health Assessment Questionnaire-Disability Index (HAQ-DI). Peripheral CD19+ B cells were measured by high-sensitivity flow cytometer. Statistical significance was set at 2-sided α 0.10 level.

Results: The SBI/SBI/SBI group demonstrated significant improvement in ACR20 and DAS28-CRP from Week 8 onward, sustained improvement in CRP levels from Week 12 onward, and significant improvements in PGA and PtGA in weeks 16 through 24, and in HAQ-DI at Week 24. The SBI/Pbo/Pbo and SBI/SBI/Pbo groups did not meet the primary endpoint but demonstrated improvements in several secondary endpoints. All treatment groups exhibited depletion of peripheral CD19+ B cells throughout the study. Overall, 61.5% of patients receiving SBI-087 and 55.0% of patients receiving Pbo reported adverse events.

Conclusion: SBI-087 effectively depleted peripheral CD20 B cells and was well tolerated. Improvements were consistently observed in the SBI/SBI/SBI group for the majority of efficacy and quality-of-life outcomes.
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http://dx.doi.org/10.3899/jrheum.160146DOI Listing
December 2016

Safety, Tolerability, Pharmacokinetic and Pharmacodynamic Properties of SBI-087, a CD20-Directed B-cell Depleting Agent: Phase 1 Dose Escalating Studies in Patients With Either Mild Rheumatoid Arthritis or Systemic Lupus.

Clin Ther 2016 Jun 21;38(6):1417-1434.e2. Epub 2016 Apr 21.

Pfizer Inc, Collegeville, Pennsylvania.

Purpose: SBI-087 is a Small Modular Immunopharmaceutical Protein™(SMIP™) drug that binds to CD20 and has been reported to deplete B cells in murine/primate studies. The safety, tolerability and pharmacokinetic/pharmacodynamic properties of SBI-087 were evaluated in patients with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE).

Methods: Single-dose SBI-087 was evaluated in 2 Phase I, open-label, escalating-dose studies in patients with RA or SLE. The studies included 6 IV/4 SC escalating doses (RA) and 1 IV/4 SC escalating doses (SLE). Escalation was determined by tolerability/rate of B-cell depletion. Serum was collected for analyses of pharmacokinetic and pharmacodynamic (CD19(+) B cells) properties and immunogenicity. Patients were followed until B-cell counts were normalized or stabilized. Safety, tolerability was evaluated from adverse events, physical examinations, vital sign measurements, ECG, and clinical laboratory results.

Findings: Sixty patients with RA (IV, 28; SC, 32) and 30 patients with SLE (6 per cohort) were enrolled. Mild to moderate infusion reactions occurred in several patients at the top doses in the RA study despite a pretreatment regimen of IV doses. Unanticipated reactions after SC administration of SBI-087 included fever, chills, and malaise, seen on the day of dosing in the lowest-dose cohorts in both studies. These events were abrogated in subsequent cohorts by a pre/postdose treatment regimen consisting of oral corticosteroids, acetaminophen, and an antihistamine. SBI-087 clearance (IV) ranged from 22 to 229 mL/h; volume of distribution at steady state ranged from 5 to 12 L. Apparent clearance (SC) ranged from 44.7 to 105 mL/h; volume of distribution ranged from 14.3 to 32.1 L. Overall, PK properties were similar at equivalent doses between IV/SC administrations in patients with RA/SLE. Mean t½ (IV) ranged from 2.1 to 10.7 days (less at lower doses). SBI-087 concentration and B-cell depletion were generally dose proportional across IV and SC cohorts. However, the extent of B-cell depletion was less, and rate of repletion was faster, in patients with SLE versus RA. In both studies, B-cell repletion to baseline did not occur in the majority of patients by the end of the observation period. Overall, the prevalence and type of adverse events were similar to those seen with other anti-CD20-depleting agents.

Implications: In patients with mild RA/SLE, SBI-087 was well tolerated when administered intravenously or subcutaneously with pre- and posttreatment regimens. B-cell depletion is long lasting, and the duration and extent of depletion may be greater in RA compared with SLE. SBI-087 exhibited slow elimination and low distribution in both populations. Clinicaltrials.gov identifiers: NCT00641225 (RA) and NCT00714116 (SLE).
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http://dx.doi.org/10.1016/j.clinthera.2016.03.028DOI Listing
June 2016

Biomarker informed add-arm design for unimodal response.

J Biopharm Stat 2016 26;26(4):694-711. Epub 2015 May 26.

a Department of Biostatistics , Boston University , Boston , Massachusetts , USA.

In this article, we propose a biomarker informed add-arm design for unimodal response. The new design contributes to optimizing the procedure of dose-finding when a biomarker of the study primary endpoint exists and prior evidence indicates a unimodal dose-response relationship. Designs with up to seven active treatment arms were considered. We propose the statistical approach for the Type I error control and carry out extensive simulation studies for the power performance of the design. The proposed design is shown to outperform the corresponding biomarker informed two-stage winner design in power on an average.
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http://dx.doi.org/10.1080/10543406.2015.1052474DOI Listing
November 2017

On model selections for repeated measurement data in clinical studies.

Stat Med 2015 May 23;34(10):1621-33. Epub 2015 Jan 23.

Department of Biostatistics, University of Florida, Gainesville, FL 32611, U.S.A.

Repeated measurement designs have been widely used in various randomized controlled trials for evaluating long-term intervention efficacies. For some clinical trials, the primary research question is how to compare two treatments at a fixed time, using a t-test. Although simple, robust, and convenient, this type of analysis fails to utilize a large amount of collected information. Alternatively, the mixed-effects model is commonly used for repeated measurement data. It models all available data jointly and allows explicit assessment of the overall treatment effects across the entire time spectrum. In this paper, we propose an analytic strategy for longitudinal clinical trial data where the mixed-effects model is coupled with a model selection scheme. The proposed test statistics not only make full use of all available data but also utilize the information from the optimal model deemed for the data. The performance of the proposed method under various setups, including different data missing mechanisms, is evaluated via extensive Monte Carlo simulations. Our numerical results demonstrate that the proposed analytic procedure is more powerful than the t-test when the primary interest is to test for the treatment effect at the last time point. Simulations also reveal that the proposed method outperforms the usual mixed-effects model for testing the overall treatment effects across time. In addition, the proposed framework is more robust and flexible in dealing with missing data compared with several competing methods. The utility of the proposed method is demonstrated by analyzing a clinical trial on the cognitive effect of testosterone in geriatric men with low baseline testosterone levels.
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http://dx.doi.org/10.1002/sim.6414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4390448PMC
May 2015

Protein expression of the chemokine receptor CXCR4 and its ligand CXCL12 in primary cutaneous melanoma--biomarkers of potential utility?

Hum Pathol 2014 Oct 2;45(10):2094-100. Epub 2014 Jul 2.

Dermatopathology section, Department of Dermatology, Boston University School of Medicine, Boston, MA 02118. Electronic address:

Dysregulation of the CXCR4/CXCL12 axis, relevant in melanoma progression, activates cell cycle progression and migration via stimulation of the MAPK pathway. We sought to ascertain the cooperativity of the CXCR4/CXCL12 axis with established prognosticators and BRAF status in melanoma. Samples (n = 107) of primary cutaneous melanoma were assessed for protein expression of CXCR4 and CXCL12, and molecular analyses were performed to ascertain BRAF status. Univariate analyses of CXCR4 protein showed that the proportion of CXCR4 positives was greater in melanomas with absence of mitoses (P < .0001), absence of ulceration (P = .0008), and absence of regression (P = .02). Patients presenting at shallower stages (American Joint Committee on Cancer [AJCC] 1-2) exhibited a larger proportion of CXCR4 positives (76.9%, P < .0001 and 69.0%, P = .008), whereas those at deeper stages (AJCC 3-4) exhibited a larger proportion of negatives (75.0%, P = .004 and 66.7%, P = .22). In a multivariate analysis, lower odds of CXCR4 protein expression were associated with AJCC stage 3 (odds ratio [OR]=0.16, P = .01), AJCC stage 4 (OR=0.17, P = .04), and mitoses (OR=0.21, P = .01). Univariate analyses of CXCL12 protein showed that the proportion of CXCL12 negatives was significantly smaller in melanomas with depth of at least 1 mm, absence of ulceration, and absence of vascular invasion (P < .0001 for all). CXCR4 and CXCL12 appear to be biomarkers associated with established prognosticators of good and poor clinical outcome, respectively, in primary cutaneous melanoma. A BRAF mutation does not appear to be associated with CXCR4/CXCL12 axis upregulation in primary cutaneous melanoma.
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http://dx.doi.org/10.1016/j.humpath.2014.06.018DOI Listing
October 2014

Covariate effect on constancy assumption in noninferiority clinical trials.

J Biopharm Stat 2014 ;24(6):1173-89

a Department of Biostatistics , Boston University , Boston , Massachusetts , USA.

Noninferiority (NI) clinical trials are getting a lot of attention of late due to their direct application in biosimilar studies. Because of the missing placebo arm, NI is an indirect approach to demonstrate efficacy of a test treatment. One of the key assumptions in the NI test is the constancy assumption, that is, that the effect of the reference treatment is the same in current NI trials as in historical superiority trials. However, if a covariate interacts with the treatment arms, then changes in distribution of this covariate will likely result in violation of constancy assumption. In this article, we propose four new NI methods and compare them with two existing methods to evaluate the change of background constancy assumption on the performance of these six methods. To achieve this goal, we study the impact of three elements-(1) strength of covariate, (2) degree of interaction between covariate and treatment, and (3) differences in distribution of the covariate between historical and current trials-on both the type I error rate and power using three different measures of association: difference, log relative risk, and log odds ratio. Based on this research, we recommend using a modified covariate-adjustment fixed margin method.
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http://dx.doi.org/10.1080/10543406.2014.941993DOI Listing
June 2015

Inference of equivalence for the ratio of two normal means with unspecified variances.

J Biopharm Stat 2014 ;24(6):1264-79

a Biostatistics Department , Boston University , Boston , Massachusetts , USA.

Equivalence trials aim to demonstrate that new and standard treatments are equivalent within predefined clinically relevant limits. We focus on when inference of equivalence is made in terms of the ratio of two normal means. In the presence of unspecified variances, methods such as the likelihood-ratio test use sample estimates for those variances; Bayesian models integrate them out in the posterior distribution. These methods limit the knowledge on the extent to which equivalence is affected by variability of the parameter of interest. In this article, we propose a likelihood approach that retains the unspecified variances in the model and partitions the likelihood function into two components: F-statistic function for variances, and t-statistic function for the ratio of two means. By incorporating unspecified variances, the proposed method can help identify a numeric range of variances where equivalence is more likely to be achieved, which cannot be accomplished by current analysis methods. By partitioning the likelihood function into two components, the proposed method provides more inference information than a method that relies solely on one component. Using a published set of real example data, we show that the proposed method produces the same results as the likelihood-ratio test and is comparable to Bayesian analysis in the general case. In a special case where the ratio of two variances is directly proportional to the ratio of two means, the proposed method yields better results in inference about equivalence than either the likelihood-ratio test or the Bayesian method. Using a published set of real example data, the proposed likelihood method is shown to be a better alternative than current analysis methods for equivalence inference.
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http://dx.doi.org/10.1080/10543406.2014.941990DOI Listing
June 2015

An Adaptive Staggered Dose Design for a Normal Endpoint.

J Biopharm Stat 2015 ;25(4):731-56

a Department of Biostatistics , Boston University School of Public Health , Boston , Massachusetts , USA.

In a clinical trial where several doses are compared to a control, a multi-stage design that combines both the selection of the best dose and the confirmation of this selected dose is desirable. An example is the two-stage drop-the-losers or pick-the-winner design, where inferior doses are dropped after interim analysis. Selection of target dose(s) can be based on ranking of observed effects, hypothesis testing with adjustment for multiplicity, or other criteria at interim stages. A number of methods have been proposed and have made significant gains in trial efficiency. However, many of these designs started off with all doses with equal allocation and did not consider prioritizing the doses using existing dose-response information. We propose an adaptive staggered dose procedure that allows explicit prioritization of doses and applies error spending scheme that favors doses with assumed better responses. This design starts off with only a subset of the doses and adaptively adds new doses depending on interim results. Using simulation, we have shown that this design performs better in terms of increased statistical power than the drop-the-losers design given strong prior information of dose response.
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http://dx.doi.org/10.1080/10543406.2014.920862DOI Listing
April 2016

A Practical Guide to Data Monitoring Committees in Adaptive Trials.

Ther Innov Regul Sci 2014 May;48(3):316-326

8 Regulatory Medical Writing and Product Development Consulting, Premier Research Group, Boston, MA, USA.

Adaptive clinical trials require access to interim data to carry out trial modification as allowed by a prespecified adaptation plan. A data monitoring committee (DMC) is a group of experts that is charged with monitoring accruing trial data to ensure the safety of trial participants and that in adaptive trials may also play a role in implementing a preplanned adaptation. In this paper, we summarize current practices and viewpoints and provide guidance on evolving issues related to the use of DMCs in adaptive trials. We describe the common types of adaptive designs and point out some DMC-related issues that are unique to this class of designs. We include 3 examples of DMCs in late-stage adaptive trials that have been implemented in practice. We advocate training opportunities for researchers who may be interested in serving on a DMC for an adaptive trial since qualified DMC members are fundamental to the successful execution of DMC responsibilities.
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http://dx.doi.org/10.1177/2168479013509805DOI Listing
May 2014

Inference of bioequivalence for log-normal distributed data with unspecified variances.

Stat Med 2014 Jul 9;33(17):2924-38. Epub 2014 Jan 9.

Biostatistics, Boston University School of Public Health, 801 Massachusetts Avenue, Boston, MA 02118, U.S.A.

Two drugs are bioequivalent if the ratio of a pharmacokinetic (PK) parameter of two products falls within equivalence margins. The distribution of PK parameters is often assumed to be log-normal, therefore bioequivalence (BE) is usually assessed on the difference of logarithmically transformed PK parameters (δ). In the presence of unspecified variances, test procedures such as two one-sided tests (TOST) use sample estimates for those variances; Bayesian models integrate them out in the posterior distribution. These methods limit our knowledge on the extent that inference about BE is affected by the variability of PK parameters. In this paper, we propose a likelihood approach that retains the unspecified variances in the model and partitions the entire likelihood function into two components: F-statistic function for variances and t-statistic function for δ. Demonstrated with published real-life data, the proposed method not only produces results that are same as TOST and comparable with Bayesian method but also helps identify ranges of variances, which could make the determination of BE more achievable. Our findings manifest the advantages of the proposed method in making inference about the extent that BE is affected by the unspecified variances, which cannot be accomplished either by TOST or Bayesian method.
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http://dx.doi.org/10.1002/sim.6081DOI Listing
July 2014

Views on Emerging Issues Pertaining to Data Monitoring Committees for Adaptive Trials.

Ther Innov Regul Sci 2013 Jul;47(4):495-502

9 Arena Pharmaceuticals Inc, San Diego, CA, USA.

In this paper, the authors express their views on a range of topics related to data monitoring committees (DMCs) for adaptive trials that have emerged recently. The topics pertain to DMC roles and responsibilities, membership, training, and communication. DMCs have been monitoring trials using the group sequential design (GSD) for over 30 years. While decisions may be more complicated with novel adaptive designs, the fundamental roles and responsibilities of a DMC will remain the same, namely, to protect patient safety and ensure the scientific integrity of the trial. It will be the DMC's responsibility to recommend changes to the trial within the scope of a prespecified adaptation plan or decision criteria and not to otherwise recommend changes to the study design except for serious safety-related concerns. Nevertheless, compared with traditional data monitoring, some additional considerations are necessary when convening DMCs for novel adaptive designs. They include the need to identify DMC members who are familiar with adaptive design and to consider possible sponsor involvement in unique situations. The need for additional expertise in DMC members has prompted some researchers to propose alternative DMC models or alternative governance model. These various options and authors' views on them are expressed in this article.
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http://dx.doi.org/10.1177/2168479013486996DOI Listing
July 2013

Design of oncology clinical trials: a review.

Crit Rev Oncol Hematol 2013 Oct 25;88(1):144-53. Epub 2013 Apr 25.

3 Everett Street, #3, Cambridge, MA 02138, USA. Electronic address:

Cancer is a disease that occurs due to the uncontrolled multiplication of cells that invade nearby tissues and can spread to other parts of the body. An increased incidence of cancer in the world has led to an increase in oncology research and in the number of oncology trials. Well designed oncology clinical trials are a key part of developing effective anti-cancer drugs. This review focuses on statistical considerations in the design and analysis of oncology clinical trials.
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http://dx.doi.org/10.1016/j.critrevonc.2013.03.007DOI Listing
October 2013

Corrected profile likelihood confidence interval for binomial paired incomplete data.

Pharm Stat 2013 Jan-Feb;12(1):48-58. Epub 2013 Jan 7.

Boston Scientific, 100 Boston Scientific Way, Marlborough, MA 01752, USA.

Clinical trials often use paired binomial data as their clinical endpoint. The confidence interval is frequently used to estimate the treatment performance. Tang et al. (2009) have proposed exact and approximate unconditional methods for constructing a confidence interval in the presence of incomplete paired binary data. The approach proposed by Tang et al. can be overly conservative with large expected confidence interval width (ECIW) in some situations. We propose a profile likelihood-based method with a Jeffreys' prior correction to construct the confidence interval. This approach generates confidence interval with a much better coverage probability and shorter ECIWs. The performances of the method along with the corrections are demonstrated through extensive simulation. Finally, three real world data sets are analyzed by all the methods. Statistical Analysis System (SAS) codes to execute the profile likelihood-based methods are also presented.
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http://dx.doi.org/10.1002/pst.1551DOI Listing
July 2013

Optimization of adaptive designs: efficiency evaluation.

J Biopharm Stat 2012 ;22(4):641-61

Pfizer, Inc., Cambridge, MA, USA.

The rising cost of clinical trials is impeding the development of new drugs. There is an acute need for critical evaluation and innovate thinking while designing the trial. Adaptive design has been repeatedly called upon in the last decade as one of the prescriptions for this intricate problem. From a pure statistical perspective, the adaptive design framework depends heavily on the appropriate selection of the type of test statistics and stopping boundaries. There are several methods proposed in the literature, based on different test statistics and stopping boundaries. All of these methods are rigorous in controlling type I error. In this paper, we group combination p-value methods into major categories along with their stopping boundaries. We review and compare these methods based on their operating characteristics, including average sample size and maximum sample size under null and alternative hypothesis, power, and early stopping probabilities. The optimal interim analysis timing and alpha spending function were used as the independent factors for this assessment. We propose an evaluation matrix and establish a framework to assess the most efficient design in order to assist in "one stop shopping."
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http://dx.doi.org/10.1080/10543406.2012.676532DOI Listing
October 2012

Integration of cell biology, pharmacological modeling and statistical analysis: part I: cell biology and PK/PD in the Oncology paradigm.

Crit Rev Oncol Hematol 2012 Aug 25;83(2):153-69. Epub 2011 Nov 25.

The motivation of this two-part review article is to provide a comprehensive picture of cancer, cancer drugs and the detection and treatment of cancer. In order to do so, this article integrates the cell biology and biophysics of cancer as well as the modeling of preclinical Oncology drug data and statistical analysis of Oncology clinical trials data. It also discusses novel cancer diagnostic tools and standard and potential treatment options.
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http://dx.doi.org/10.1016/j.critrevonc.2011.10.004DOI Listing
August 2012

Does hormone therapy improve age-related skin changes in postmenopausal women? A randomized, double-blind, double-dummy, placebo-controlled multicenter study assessing the effects of norethindrone acetate and ethinyl estradiol in the improvement of mild to moderate age-related skin changes in postmenopausal women.

J Am Acad Dermatol 2008 Sep 14;59(3):397-404.e3. Epub 2008 Jul 14.

Boston University School of Medicine, Boston, Massachusetts 02118, USA.

Background: In postmenopausal women, declining estrogen levels are associated with a variety of skin changes, many of which are reportedly improved by estrogen supplementation.

Objective: A study was conducted to assess the effects of continuous combined norethindrone acetate (NA) and ethinyl estradiol (EE) in the control of mild to moderate age-related skin changes in postmenopausal women.

Methods: Four hundred eighty-five subjects were enrolled in this 48-week randomized, double-blind study. Subjects were randomized to one of three study arms: placebo group (165 subjects), 1 mg NA/5 microg EE group (162 subjects), or a 1 mg NA/10 microg EE group (158 subjects). The primary efficacy parameters of the study were investigator global assessment of coarse and fine facial wrinkling at week 48 and subjective self-assessment of changes in wrinkling from baseline at week 48. Secondary parameters included investigator global assessment of skin laxity/sagging at week 48, investigator global assessment of skin texture/dryness at week 48, patient self-assessment of laxity/sagging, texture/dryness, and wrinkle depth determined by image analysis of skin replicas of the periorbital (crow's feet) and jowl areas, and skin elasticity determined by timed deformation and recoil.

Results: There were similar scores in investigator global assessment in wrinkling and sagging modules at baseline across all three treatment groups. There were slight decreases in all parameters for all treatment groups for the primary subject end points, but there were no statistically significant differences between the NA/EE groups and placebo. For subject self-assessment of overall severity of skin wrinkling, there were no significant changes at weeks 24 and 48 compared to baseline. These data were unaffected by smoking status or alcohol consumption.

Limitations: This study assessed the effects of 48 weeks of low-dose estrogen upon facial skin in women who were, on average, 5 years postmenopausal. The effects of higher estrogen doses, longer treatment duration, or effects upon perimenopausal women cannot be extrapolated from this study.

Conclusion: Low-dose hormone therapy for 48 weeks in postmenopausal women did not significantly alter mild to moderate age-related facial skin changes.
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http://dx.doi.org/10.1016/j.jaad.2008.05.009DOI Listing
September 2008
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