Thomas R. Fleming

University of Washington Seattle, Seattle, Washington, United States

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Publications (208)1686.46 Total impact

  • Article: Response.
    Thomas R Fleming
  • Thomas R Fleming
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    ABSTRACT: There is compelling evidence supporting the importance of maintaining confidentiality of interim data in clinical trials designed to reliably address the benefit-to-risk profile of interventions. While this is widely recognized, creative approaches are needed to achieve this in challenging settings where interim data are released for regulatory review and action, even though the trial would be continued to address its primary hypothesis. An illustration is the recently emerging setting of cardiovascular safety trials in type 2 diabetes mellitus. At the first stage of such trials, if large relative increases in cardiovascular major morbidity/mortality can be ruled out, data can be released solely for the purpose of allowing regulatory decision making about marketing approval. The trial is then continued in the post-marketing setting to address the primary hypothesis regarding whether smaller relative increases can be ruled out. Active rather than passive approaches are needed to protect the integrity of cardiovascular safety trials. Given the importance to trial integrity of maintaining confidentiality of interim data such as the estimated relative effect on cardiovascular risk, a Data Access Plan should be in place in these trials to ensure such data are not revealed to study participants and their caregivers, investigators involved in trial conduct, the sponsor's management team, and the public, until trial completion. A Performance Standards Document also should be developed to pre-specify targeted and minimally acceptable levels for recruitment rate, best real-world achievable adherence, avoidance of cross-ins, and retention rate. This document should specify creative approaches for achieving these targets, oversight procedures during trial conduct to monitor performance levels, and actions to be taken if emerging data indicate minimally acceptable levels are not being reached. In settings where meaningful breaches in confidentiality have occurred, such oversight allows adverse effects on trial integrity to be detected earlier and more effectively addressed. © The Author(s), 2014.
    Clinical Trials 12/2014; 12(1). DOI:10.1177/1740774514561243 · 1.94 Impact Factor
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    ABSTRACT: Background In pulmonary arterial hypertension (PAH), adding oral sildenafil to intravenous (IV) epoprostenol improved 6-minute walk distance (6MWD) and haemodynamics and delayed time to clinical worsening in a 16-week randomised, placebo-controlled trial (PACES-1). Methods Patients completing PACES-1 could receive sildenafil (titrated to 80 mg TID as tolerated) in an open-label extension study (PACES-2) for ≥3 years; additional therapy was added per investigator judgment. Survival and changes from PACES-1 baseline in World Health Organization functional class (FC) and 6MWD were captured. Results In an open-label setting, an effort-dependent outcome measure, 6MWD, was known to have improved or to have been maintained in 59%, 44%, and 33% of patients at 1, 2, and 3 years, respectively; FC was known to have improved or to have been maintained in 73%, 59%, and 46%. At 3 years, 66% of patients were known to be alive, 24% were known to have died, and 10% were lost to follow-up. Patients with PACES-1 baseline 6MWD <325 m without 6MWD improvement during the first 20 weeks of sildenafil treatment subsequently had poorer survival. Conclusion While reliable assessments of safety and efficacy require a long-term randomised trial, addition of sildenafil to background IV epoprostenol therapy appeared generally to be well tolerated in PAH patients.
    The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 07/2014; DOI:10.1016/j.healun.2014.02.019 · 5.61 Impact Factor
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    ABSTRACT: Data monitoring committees (DMCs) have important roles in safeguarding patient interests and enhancing trial integrity and credibility. To effectively fulfill their responsibilities, DMCs should be independent of study sponsors, study investigators, and caregivers managing study participants. Unfortunately, in real-world settings where DMCs are in place, there are some practices that threaten to diminish the level of independence of these committees. To address this, some important approaches should be considered: A DMC charter should outline the roles and responsibilities of the DMC without appearing to be a legal contract; the meetings of the DMC should be led by its chair, ideally with a meeting format that ensures independence from the investigators and sponsor; the DMC and those having leadership roles in the monitoring process should have adequate training and experience; procedures should be in place to enable the DMC to have access to interim safety and efficacy data that are accurate, current, and comprehensive; these data should be presented to the DMC unblinded by treatment group, while being kept confidential from all others; DMC recommendations should be developed through consensus development rather than by casting votes; creative approaches are needed for the engagement of DMC members to increase the transparency such that they are neither employees of nor consultants to the sponsor of the trial; meaningful conflicts of interest should be identified and addressed; and finally, members of DMCs should have adequate indemnification that provides effective protection.
    Journal of Biopharmaceutical Statistics 06/2014; 24(5). DOI:10.1080/10543406.2014.925719 · 0.72 Impact Factor
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    ABSTRACT: To assess the efficacy and safety of enzyme replacement therapy (ERT) with BMN 110 (elosulfase alfa) in patients with Morquio A syndrome (mucopolysaccharidosis IVA). Patients with Morquio A aged ≥5 years (N = 176) were randomised (1:1:1) to receive elosulfase alfa 2.0 mg/kg/every other week (qow), elosulfase alfa 2.0 mg/kg/week (weekly) or placebo for 24 weeks in this phase 3, double-blind, randomised study. The primary efficacy measure was 6-min walk test (6MWT) distance. Secondary efficacy measures were 3-min stair climb test (3MSCT) followed by change in urine keratan sulfate (KS). Various exploratory measures included respiratory function tests. Patient safety was also evaluated. At week 24, the estimated mean effect on the 6MWT versus placebo was 22.5 m (95 % CI 4.0, 40.9; P = 0.017) for weekly and 0.5 m (95 % CI -17.8, 18.9; P = 0.954) for qow. The estimated mean effect on 3MSCT was 1.1 stairs/min (95 % CI -2.1, 4.4; P = 0.494) for weekly and -0.5 stairs/min (95 % CI -3.7, 2.8; P = 0.778) for qow. Normalised urine KS was reduced at 24 weeks in both regimens. In the weekly dose group, 22.4 % of patients had adverse events leading to an infusion interruption/discontinuation requiring medical intervention (only 1.3 % of all infusions in this group) over 6 months. No adverse events led to permanent treatment discontinuation. Elosulfase alfa improved endurance as measured by the 6MWT in the weekly but not qow dose group, did not improve endurance on the 3MSCT, reduced urine KS, and had an acceptable safety profile.
    Journal of Inherited Metabolic Disease 05/2014; 37(6). DOI:10.1007/s10545-014-9715-6 · 4.14 Impact Factor
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    ABSTRACT: OBJECTIVE: To assess the efficacy and safety of enzyme replacement therapy (ERT) with BMN 110 (elosulfase alfa) in patients with Morquio A syndrome (mucopolysaccharidosis IVA). METHODS: Patients with Morquio A aged ≥5 years (N = 176) were randomised (1:1:1) to receive elosulfase alfa 2.0 mg/kg/every other week (qow), elosulfase alfa 2.0 mg/kg/week (weekly) or placebo for 24 weeks in this phase 3, double-blind, randomised study. The primary efficacy measure was 6-min walk test (6MWT) distance. Secondary efficacy measures were 3-min stair climb test (3MSCT) followed by change in urine keratan sulfate (KS). Various exploratory measures included respiratory function tests. Patient safety was also evaluated. RESULTS: At week 24, the estimated mean effect on the 6MWT versus placebo was 22.5 m (95 % CI 4.0, 40.9; P = 0.017) for weekly and 0.5 m (95 % CI -17.8, 18.9; P = 0.954) for qow. The estimated mean effect on 3MSCT was 1.1 stairs/min (95 % CI -2.1, 4.4; P = 0.494) for weekly and -0.5 stairs/min (95 % CI -3.7, 2.8; P = 0.778) for qow. Normalised urine KS was reduced at 24 weeks in both regimens. In the weekly dose group, 22.4 % of patients had adverse events leading to an infusion interruption/discontinuation requiring medical intervention (only 1.3 % of all infusions in this group) over 6 months. No adverse events led to permanent treatment discontinuation. CONCLUSIONS: Elosulfase alfa improved endurance as measured by the 6MWT in the weekly but not qow dose group, did not improve endurance on the 3MSCT, reduced urine KS, and had an acceptable safety profile.
    Journal of Inherited Metabolic Disease 05/2014; Epub online. · 4.14 Impact Factor
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    ABSTRACT: Pulmonary hypertension (PH) is a rare disease in newborns, infants, and children that is associated with significant morbidity and mortality. In the majority of pediatric patients, PH is idiopathic or associated with congenital heart disease and rarely is associated with other conditions such as connective tissue or thromboembolic disease. Incidence data from the Netherlands has revealed an annual incidence and point prevalence of 0.7 and 4.4 for idiopathic pulmonary arterial hypertension and 2.2 and 15.6 for pulmonary arterial hypertension, respectively, associated with congenital heart disease (CHD) cases per million children. The updated Nice classification for PH has been enhanced to include a greater depth of CHD and emphasizes persistent PH of the newborn and developmental lung diseases, such as bronchopulmonary dysplasia and congenital diaphragmatic hernia. The management of pediatric PH remains challenging because treatment decisions continue to depend largely on results from evidence-based adult studies and the clinical experience of pediatric experts.
    Journal of the American College of Cardiology 12/2013; 62(25 Suppl):D117-26. DOI:10.1016/j.jacc.2013.10.028 · 15.34 Impact Factor
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    ABSTRACT: A greater understanding of the epidemiology, pathogenesis, and pathophysiology of pulmonary artery hypertension (PAH) has led to significant advances, but the disease remains fatal. Treatment options are neither universally available nor always effective, underscoring the need for development of novel therapies and therapeutic strategies. Clinical trials to date have provided evidence of efficacy, but were limited in evaluating the scope and duration of treatment effects. Numerous potential targets in varied stages of drug development exist, in addition to novel uses of familiar therapies. The pursuit of gene and cell-based therapy continues, and device use to help acute deterioration and chronic management is emerging. This rapid surge of drug development has led to multicenter pivotal clinical trials and has resulted in novel ethical and global clinical trial concerns. This paper will provide an overview of the opportunities and challenges that await the development of novel treatments for PAH.
    Journal of the American College of Cardiology 12/2013; 62(25 Suppl):D82-91. DOI:10.1016/j.jacc.2013.10.026 · 15.34 Impact Factor
  • Katherine Odem-Davis, Thomas R Fleming
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    ABSTRACT: Evaluation of non-inferiority is based on ruling out a threshold for what would constitute unacceptable loss of efficacy of an experimental treatment relative to an active comparator "Standard". This threshold, the "non-inferiority margin", is often based on preservation of a percentage of Standard's effect. To obtain an estimate of this effect to be used in the development of the "non-inferiority margin", data are needed from earlier trials comparing Standard to placebo if the non-inferiority trial does not have a placebo arm. This approach often provides a biased over-estimate of Standard's true effect in the setting of the current non-inferiority study. We describe two commonly used non-inferiority margin methods that adjust for this bias, the two-confidence interval (95-95) and the Synthesis margins. However, the added 'variance inflation' adjustment made by 95-95 margin diminishes with increasing information from historical trial(s), and the Synthesis margin is based on a strong assumption that the relative bias is known. We introduce an alternative "Bias-adjusted" margin addressing vulnerabilities of each by attenuating the estimate and by accounting for uncertainty in the true level of bias. Examples and asymptotic estimates of non-inferiority hypothesis rejection rates in the proportional hazards setting are used to compare methods.
    Statistics in Biopharmaceutical Research 08/2013; 5(3). DOI:10.1080/19466315.2013.795910 · 0.70 Impact Factor
  • Kevin J. Carroll, Thomas R. Fleming
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    ABSTRACT: Multiregional randomized clinical trials often are conducted to evaluate interventions proposed for treatment or prevention of diseases, especially in clinical settings such as cardiovascular diseases where it is important to enroll a large number of patients in a timely manner. As outlined in the International Conference on harmonization E5 Ethnic Factors in the Acceptability of Foreign Clinical Data, an obvious interest when evaluating the results of such trials is the consistency of effects across regions. The purpose of this article is to review a recent example, a large cardiovascular outcomes trial known as "PLATO," where substantial evidence of regional heterogeneity emerged during the analysis. We present the statistical thinking and methodology that went into the evaluation of the results and the logic that led to the judgment that, while chance cannot be ruled out entirely, the appearance of the regional heterogeneity was likely a manifestation of an underlying interaction with concurrent aspirin dosage. This example may provide a useful reference point for the statistical evaluation of regional effects in future large outcomes trials. Supplementary materials for this article are available online.
    Statistics in Biopharmaceutical Research 04/2013; 5(2):91-101. DOI:10.1080/19466315.2013.783878 · 0.70 Impact Factor
  • John H Powers, Thomas R Fleming
    03/2013; 3(3):215-218. DOI:10.4155/cli.12.157
  • Molecular Genetics and Metabolism 02/2013; 108(2):S48. DOI:10.1016/j.ymgme.2012.11.110 · 2.83 Impact Factor
  • Thomas R Fleming, John H Powers
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    ABSTRACT: One of the most important considerations in designing clinical trials is the choice of outcome measures. These outcome measures could be clinically meaningful endpoints that are direct measures of how patients feel, function, and survive. Alternatively, indirect measures, such as biomarkers that include physical signs of disease, laboratory measures, and radiological tests, often are considered as replacement endpoints or 'surrogates' for clinically meaningful endpoints. We discuss the definitions of clinically meaningful endpoints and surrogate endpoints, and provide examples from recent clinical trials. We provide insight into why indirect measures such as biomarkers may fail to provide reliable evidence about the benefit-to-risk profile of interventions. We also discuss the nature of evidence that is important in assessing whether treatment effects on a biomarker reliably predict effects on a clinically meaningful endpoint, and provide insights into why this reliability is specific to the context of use of the biomarker. Copyright © 2012 John Wiley & Sons, Ltd.
    Statistics in Medicine 11/2012; 31(25):2973-84. DOI:10.1002/sim.5403 · 2.04 Impact Factor
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    ABSTRACT: The HIV Prevention Trial Network (HPTN) 052 Study is a Phase III, two-arm, controlled, open-labeled, randomized clinical trial designed to determine whether early antiretroviral therapy (ART) can prevent the sexual transmission of human immunodeficiency virus type 1 (HIV-1). A total of 1763 couples in which one partner was HIV-1-positive and the other was HIV-1-negative were enrolled in four continents, nine countries and thirteen study sites. The HIV-1-positive partner was randomly assigned to either of the two arms: "immediate" (early) therapy with ART initiated upon enrollment plus HIV primary care, or "delayed" therapy with HIV primary care but ART initiated when the index case would have two consecutive measurements of a CD4+ cell count within or below the range of 200-250cells/mm(3), or develop an AIDS-defining illness. In this paper, we describe several key statistical considerations for the design of this landmark study. Despite that the observed event rates were lower than expected, which might have compromised the study power, an early release of the trial results in May 2011 showed an overwhelming 96% risk reduction for the immediate therapy in the prevention of genetically linked HIV-1 incident transmissions. Nevertheless, the durability of its long-term effectiveness is yet to be assessed. The HPTN 052 Study is still ongoing and will not complete till 2015.
    Contemporary clinical trials 07/2012; 33(6):1280-6. DOI:10.1016/j.cct.2012.07.007 · 1.99 Impact Factor
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    ABSTRACT: Efficacy endpoints for previous registrational trials of antimicrobials for acute bacterial skin and skin structure infections (ABSSSIs) and community-acquired bacterial pneumonia (CABP) were based on nonstandardized, clinician-based observations and decisions, as well as on patient reports. More quantifiable, reproducible, and externally verifiable endpoints could improve the design of future noninferiority trials. At the request of the Food and Drug Administration, the Foundation for the National Institutes of Health convened a broadly representative scientific project team to evaluate potential endpoints for such registrational trials. Review of historical and modern data led to the conclusion that antimicrobial treatment effects are most apparent early in therapy; later outcomes provide important supportive information. Although evidence is incomplete, early response endpoints can anchor noninferiority hypotheses in ABSSSI and CABP registrational trials, thereby allowing evidence-based drug development to continue. Further research is underway to establish which short- and long-term outcomes are well-defined, reliable, and reflective of how patients feel, function, or survive.
    Clinical Infectious Diseases 06/2012; 55(8):1114-1121. DOI:10.1093/cid/cis566 · 9.42 Impact Factor
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    ABSTRACT: Definitive evidence of clinical efficacy in a Phase 3 trial is best shown by a beneficial impact on a clinically meaningful endpoint-that is, an endpoint that directly measures how a patient feels (symptoms), functions (the ability to perform activities in daily life), or survives. In idiopathic pulmonary fibrosis (IPF), we believe the endpoints that best meet these criteria are all-cause mortality and all-cause nonelective hospitalization. There are no validated measures of symptoms or broader constructs such as health status or functional status in IPF. A surrogate endpoint is defined as an indirect measure that is intended to substitute for a clinically meaningful endpoint. Surrogate endpoints can be appropriate outcome measures if validated. However, validation requires substantial evidence that the effect of an intervention on a clinically meaningful endpoint is reliably predicted by the effect of an intervention on the surrogate endpoint. For patients with IPF, there are currently no validated surrogate endpoints.
    American Journal of Respiratory and Critical Care Medicine 04/2012; 185(10):1044-8. DOI:10.1164/rccm.201201-0006PP · 11.99 Impact Factor
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    Mark D Rothmann, Jenny J Zhang, Laura Lu, Thomas R Fleming
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    ABSTRACT: In many settings, testing has been proposed to assess the effect of an experimental regimen within a biomarker-positive subgroup where it is biologically plausible that benefit is stronger in such patients, and in the overall population that also includes biomarker-negative subjects less likely to benefit from that regimen. A statistically favorable result in the biomarker-positive subgroup would lead to a claim for that subgroup, whereas a statistically favorable result for the overall population would lead to a claim that includes both biomarker subgroups. The latter setting is problematic when biomarker-negative patients truly do not benefit from the experimental regimen. When it is prespecified that biomarker-negative patients should not be included in the primary analysis of treatment effect in biomarker-positive patients because of the likelihood that treatment effects would differ between the 2 subgroups, it is logically inconsistent to include biomarker-positive patients in the primary analysis of treatment effect in biomarker-negative patients.
    Drug information journal 03/2012; 46(2):175-179. DOI:10.1177/0092861512436579 · 0.49 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: One of the most important considerations in designing clinical trials is the choice of outcome measures. These outcome measures could be clinically meaningful endpoints that are direct measures of how patients feel, function, and survive. Alternatively, indirect measures, such as biomarkers that include physical signs of disease, laboratory measures, and radiological tests, often are considered as replacement endpoints or ‘surrogates’ for clinically meaningful endpoints. We discuss the definitions of clinically meaningful endpoints and surrogate endpoints, and provide examples from recent clinical trials. We provide insight into why indirect measures such as biomarkers may fail to provide reliable evidence about the benefit‐to‐risk profile of interventions. We also discuss the nature of evidence that is important in assessing whether treatment effects on a biomarker reliably predict effects on a clinically meaningful endpoint, and provide insights into why this reliability is specific to the context of use of the biomarker. Copyright © 2012 John Wiley & Sons, Ltd.
    Statistics in Medicine 01/2012; 31(25). · 2.04 Impact Factor
  • Thomas R Fleming, Scott S Emerson
    New England Journal of Medicine 10/2011; 365(17):1557-9. DOI:10.1056/NEJMp1110639 · 54.42 Impact Factor
  • Source
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    ABSTRACT: Background—Antiretroviral therapy that reduces viral replication could limit the transmission of human immunodeficiency virus type 1 (HIV-1) in serodiscordant couples.
    New England Journal of Medicine 08/2011; 365(6):493-505. · 54.42 Impact Factor

Publication Stats

16k Citations
1,686.46 Total Impact Points

Institutions

  • 1987–2014
    • University of Washington Seattle
      • Department of Biostatistics
      Seattle, Washington, United States
    • Wayne State University
      Detroit, Michigan, United States
  • 1994–2013
    • Fred Hutchinson Cancer Research Center
      • Statistical Center for HIV/AIDS Research and Prevention
      Seattle, Washington, United States
  • 2011
    • University of North Carolina at Chapel Hill
      • Institute for Global Health and Infectious Diseases
      North Carolina, United States
  • 2002
    • Johns Hopkins Medicine
      • Department of Pathology
      Baltimore, MD, United States
  • 1999
    • Boston University
      • Department of Pediatrics
      Boston, Massachusetts, United States
  • 1978–1998
    • Mayo Clinic - Rochester
      • Department of Oncology
      Rochester, Minnesota, United States
    • University of Maryland, College Park
      CGS, Maryland, United States
  • 1987–1994
    • Cleveland Clinic
      Cleveland, Ohio, United States
  • 1993
    • Michiana Hematology Oncology
      Indiana, Pennsylvania, United States
  • 1979–1984
    • University of Virginia
      • Department of Mathematics and Computer Science (Wise)
      Charlottesville, Virginia, United States