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1.  Preliminary evaluation of factors associated with premature trial closure and feasibility of accrual benchmarks in phase III oncology trials 
Background
A major challenge for randomized phase III oncology trials is the frequent low rates of patient enrollment, resulting in high rates of premature closure due to insufficient accrual.
Purpose
We conducted a pilot study to determine the extent of trial closure due to poor accrual, feasibility of identifying trial factors associated with sufficient accrual, impact of redesign strategies on trial accrual, and accrual benchmarks designating high failure risk in the clinical trials cooperative group (CTCG) setting.
Methods
A subset of phase III trials opened by five CTCGs between August 1991 and March 2004 was evaluated. Design elements, experimental agents, redesign strategies, and pretrial accrual assessment supporting accrual predictions were abstracted from CTCG documents. Percent actual/predicted accrual rate averaged per month was calculated. Trials were categorized as having sufficient or insufficient accrual based on reason for trial termination. Analyses included univariate and bivariate summaries to identify potential trial factors associated with accrual sufficiency.
Results
Among 40 trials from one CTCG, 21 (52.5%) trials closed due to insufficient accrual. In 82 trials from five CTCGs, therapeutic trials accrued sufficiently more often than nontherapeutic trials (59% vs 27%, p = 0.05). Trials including pretrial accrual assessment more often achieved sufficient accrual than those without (67% vs 47%, p = 0.08). Fewer exclusion criteria, shorter consent forms, other CTCG participation, and trial design simplicity were not associated with achieving sufficient accrual. Trials accruing at a rate much lower than predicted (<35% actual/predicted accrual rate) were consistently closed due to insufficient accrual.
Limitations
This trial subset under-represents certain experimental modalities. Data sources do not allow accounting for all factors potentially related to accrual success.
Conclusion
Trial closure due to insufficient accrual is common. Certain trial design factors appear associated with attaining sufficient accrual. Defining accrual benchmarks for early trial termination or redesign is feasible, but better accrual prediction methods are critically needed. Future studies should focus on identifying trial factors that allow more accurate accrual predictions and strategies that can salvage open trials experiencing slow accrual.
doi:10.1177/1740774510374973
PMCID: PMC3977321  PMID: 20595245
2.  Monitoring futility in a two-by-two factorial design: The SPS3 experience 
Clinical trials (London, England)  2013;10(2):250-256.
Background
For studies with two-by-two factorial designs, the complexity of determining an appropriate futility analysis plan is increased as compared to studies where patients are randomized to one treatment. Issues that must be addressed include the possibility of a significant interaction and the need to determine how to proceed given evidence of futility in one arm. Suggested approaches include a two-stage plan, which first assesses futility of the interaction term and proceeds to examine the main effects, given sufficient evidence that no interaction is present, and variations on one-stage plans, which assume the trial will not be stopped for futility in the interaction.
Purpose
To discuss different approaches to monitoring futility in two-by-two factorial clinical trials and compare their properties.
Methods
We utilized a simulation study, designed to mimic the Secondary Prevention of Small Subcortical Strokes (SPS3) Study, to determine which approach to monitoring futility in two-by-two factorial studies had the most desirable statistical properties.
Results
We found that in most scenarios typical of clinical trials, monitoring futility in each arm simultaneously was superior to or as good as monitoring the interaction and then assessing futility in each arm only when the interaction was deemed futile. Monitoring each arm simultaneously lead to early stopping more often when no treatment effect was present, and lower average sample numbers (ASNs). The exception to this was the unlikely case when a qualitative interaction was present.
Limitations
We assumed that one-sided tests were to be performed, and only assessed some of the possible methods for monitoring futility under the study design.
Conclusions
Futility monitoring in two-by-two factorial studies should proceed by assessing each arm simultaneously, rather than monitoring the interaction first. If sizeable interactions are anticipated, study design, rather than study monitoring, should account for this.
doi:10.1177/1740774512474374
PMCID: PMC3731445  PMID: 23378483
3.  Early phase trial design for assessing several dose levels for toxicity and efficacy for targeted agents 
Clinical trials (London, England)  2013;10(3):422-429.
Background
Traditional phase I trials are designed to be conservative. Many times a traditional phase I trial design stops at a dose level below the maximal tolerated dose (MTD), thus potentially treating patients at a suboptimal level in all subsequent trials. This has been confirmed by our recent simulation studies.
Purpose
We propose a phase I/II trial design to determine the most promising dose level in terms of toxicity and efficacy for cytostatic or targeted agents. This design evaluates three dose levels for efficacy and toxicity using a modified phase II selection design. The dose levels include the phase I recommended dose (RD) in addition to the dose levels immediately below and above that level.
Methods
This phase I/II trial design uses a two-step approach. In the first step, a traditional phase I trial design is used to get close to a good dose level. The second step consists of a modified selection design, randomizing patients to three dose levels: the phase I RD level and the dose levels immediately below and above the phase I RD level. Both efficacy and toxicity are used to determine a good or best dose level. Appropriate toxicity stopping rules in the phase II portion of the trial are implemented as part of such a trial. We perform simulation studies for a variety of toxicity and efficacy scenarios to determine the operating characteristics of this design and compare those to our originally proposed trial where we only explore dose levels at and below the phase I RD in the second phase of the trial, as well as to the traditional setting where a phase I trial is followed by a single-arm phase II trial at the phase I RD.
Results
The 3-arm modified selection design exploring the dose levels immediately above and below as well as the RD performs as well or better than the 2-arm modified selection design or the single-arm design for almost all toxicity and efficacy scenario combinations tested.
Conclusion
We demonstrate that this design has a higher success rate at identifying a good or best dose level when exploring dose levels immediately above and below the RD in the early phase II setting, in most cases without needing larger sample sizes.
doi:10.1177/1740774513480961
PMCID: PMC3744092  PMID: 23529697
4.  Impact of Supplemental Site Grants to Increase African-American Accrual for SELECT 
Background
Low rates of minority recruitment in prevention studies may reduce the generalizability of study results to minority populations, including African Americans. High African American accrual to prevention studies requires additional resources and focused efforts.
Objective
To analyze the impact of Minority Recruitment Enhancement Grants (MREGs) on African American recruitment to the Selenium and Vitamin E Cancer Prevention Trial (SELECT).
Results
Fifteen of 427 SELECT sites received MREGs after they demonstrated early success in minority recruitment. After receiving the grants, the average monthly rate of African American recruitment at these sites increased from 27.2% to 31.5%, and total average monthly recruitment also increased. Sites that did not receive grants, including sites that did not apply, increased average monthly African American recruitment from 11.0% to 14.6% but declined in total average monthly recruitment.
Conclusions and Implications
Sites who received MREGs modestly increased both the proportion of African American recruits and total recruits. These results are tempered by the high cost of the intervention, the relatively low number of SELECT sites that applied for the grants and the administrative delays in implementation. Nevertheless, targeted grants may be a useful multi-site intervention to increase African American accrual for a prevention study where adequate African American recruitment is essential.
doi:10.1177/1740774509357227
PMCID: PMC3956599  PMID: 20156960
5.  How Good Does the Science Have to Be in Proposals Submitted to IRBs?: An Interview Study of IRB personnel 
Clinical trials (London, England)  2013;10(5):761-766.
Background
IRBs have been increasingly criticized for how they review protocols, but how IRBs perceive, and make decisions about, the quality of the science of protocols has not been examined.
Purpose
To explore how and when IRBs view and make decisions about the quality of the science of studies they review.
Methods
I contacted the leadership of 60 IRBs (every fourth one in the list of the top 240 institutions by NIH funding), and interviewed IRB chairs, co-chairs, administrators and a director from 34 (response rate=55%), and an additional 7 members.
Results
Interviewees faced several ambiguities and questions concerning the quality of the science of protocols. IRBs are often not sure how, and to what extent to evaluate the science of protocols; whether the science should be “good enough” (and if so, what that means) vs. as good as possible. Federal regulations state that IRBs should ensure that risks are minimized, and commensurate with benefits. Thus, at times IRBs feel that changing the science is ethically necessary. But IRBs also then struggle with whether to adopt a higher threshold; 1) that social, and thus scientific benefits be maximized; and 2) that scientific efforts and resources should not be wasted. Committees face dilemmas – e.g., if a “perfect” study is not feasible. For protocols already approved elsewhere (e.g., by the National Institutes of Health [NIH]), IRB's vary in how much they feel they can request alterations; and sometimes make changes nonetheless. Larger institutional contexts and biases can shape these issues, and IRBs differ in how much they are “pro-research”, and have sufficient expertise. IRBs at times also approve studies despite reservations about the science.
Limitations
This study includes interviews with IRBs, but not observations of IRB meetings.
Conclusions
IRBs often face ambiguities and conflicting goals in assessing scientific quality. Many IRBs try to improve the science beyond what the regulations mandate. These data have important implications for improving practice, education, research, and policy.
doi:10.1177/1740774513500080
PMCID: PMC3918462  PMID: 24000378
research ethics; research integrity; conflicts of interest; risk/benefit assessment; qualitative research
6.  Predictive biomarker validation in practice: lessons from real trials 
Background
With the advent of targeted therapies, biomarkers provide a promising means of individualizing therapy through an integrated approach to prediction using the genetic makeup of the disease and the genotype of the patient. Biomarker validation has therefore become a central topic of discussion in the field of medicine, primarily due to the changing landscape of therapies for treatment of a disease and these therapies purported mechanism(s) of action.
Purpose
In this report, we discuss the merits and limitations of some of the clinical trial designs for predictive biomarker validation using examples from ongoing or completed clinical trials.
Methods
The designs are broadly classified as retrospective (i.e., using data from previously well-conducted randomized controlled trials (RCT)) versus prospective (enrichment or targeted, unselected or all-comers, hybrid, and adaptive analysis). We discuss some of these designs in the context of real trials.
Results
Well-designed retrospective analysis of prospective RCT can bring forward effective treatments to marker defined subgroup of patients in a timely manner. An example is the KRAS gene status in colorectal cancer – the benefit from cetuximab and panitumumab was demonstrated to be restricted to patients with wild type status based on prospectively specified analyses using data from previously conducted RCTs. Prospective enrichment designs are appropriate when compelling preliminary evidence suggests that not all patients will benefit from the study treatment under consideration; however, this may sometimes leave questions unanswered. An example is the established benefit of trastuzumab as adjuvant therapy for breast cancer; a clear definition of HER2-positivity and the assay reproducibility have, however, remained unanswered. An all-comers design is optimal where preliminary evidence regarding treatment benefit and assay reproducibility is uncertain (e.g., EGFR expression and tyrosine kinase inhibitors in lung cancer), or to identify the most effective therapy from a panel of regimens (e.g., chemotherapy options in breast cancer).
Limitations
The designs discussed here rest on the assumption that the technical feasibility, assay performance metrics, and the logistics of specimen collection are well established and that initial results demonstrate promise with regard to the predictive ability of the marker(s).
Conclusions
The choice of a clinical trial design is driven by a combination of scientific, clinical, statistical, and ethical considerations. There is no one size fits all solution to predictive biomarker validation.
doi:10.1177/1740774510368574
PMCID: PMC3913192  PMID: 20392785
7.  Conducting the ACTIVE Randomized Trial in Hospice Care: Keys to Success 
Clinical trials (London, England)  2012;10(1):10.1177/1740774512461858.
Background
Untreated pain is common for patients at the end of life. Informal caregivers, often family or friends of patients, are responsible for working with hospice staff to provide pain management. Interdisciplinary team meetings conducted in hospices every two weeks provide an opportunity for hospice staff to communicate about pain management with informal caregivers of hospice patients.
Purpose
We present challenges, solutions, and keys strategies for carrying out a randomized trial in the hospice setting.
Methods
We are conducting the ACTIVE study (Assessing Caregivers for Team Intervention through Video Encounters) to determine whether regular videoconferencing between hospice patients' informal caregivers and the hospice care team alters caregivers' perceptions of pain management and patients' pain. Participants must be primary caregivers for a hospice patient, at least 18 years of age, capable of providing informed consent, and have access to a computer with a high-speed Internet connection or a telephone. We randomized caregivers to participate in biweekly team meetings through video or phone conferencing (intervention) or to receive usual care from the hospice. All patients receive standard hospice care regardless of the group assignment of their informal caregiver.
Results
As of July 1, 2012, there has been 1038 new admissions to the participating hospices. Of 391 cases in which no contact was made, 233 patients had died or had life expectancy less than 14 days. Home visits were made to 271 interested and eligible caregivers; 249 caregivers of 233 patients were randomly assigned to the usual care or intervention arm. Enrollment is on pace to meet recruitment goals.
Lessons Learned
Thorough pilot-testing of instruments and procedures helped us overcome barriers to conducting research in this vulnerable population. Keys to success included obtaining support from hospice medical directors, including hospice staff in study preparation, minimizing the burden on hospice staff, housing research staff in each participating hospice, using newsletters to enhance communication, developing and maintaining a detailed procedural manual, producing regular data quality reports, developing a secure site to facilitate coding videos for qualitative studies, and holding regular teleconferences with key staff.
Limitations
Late enrollment of many patients in hospice left little to no time for their caregivers to take part in the intervention. Assisting caregivers of patients with very short life expectancy may require different methods.
Conclusions
The challenges of conducting randomized trials with hospice patients and caregivers can be addressed with appropriate study design, well-tested research methods, and proactive monitoring of any issues or problems.
doi:10.1177/1740774512461858
PMCID: PMC3554844  PMID: 23104974
hospice; randomized trial; pain management; videoconference; caregivers; interdisciplinary teams
8.  Moving a Randomized Clinical Trial into an Observational Cohort 
Clinical trials (London, England)  2012;10(1):131-142.
Background
The Selenium and Vitamin E Cancer Prevention Trial (SELECT) was a randomized, double blind, placebo-controlled prostate cancer prevention study funded by the National Cancer Institute and conducted by SWOG (Southwest Oncology Group). A total of 35,533 men were assigned randomly to one of four treatment groups (vitamin E + placebo, selenium + placebo, vitamin E + selenium, placebo + placebo. The independent Data and Safety Monitoring Committee recommended the discontinuation of study supplements because of the lack of efficacy for risk reduction and because futility analyses demonstrated no possibility of benefit of the supplements to the anticipated degree (25% reduction in prostate cancer incidence) with additional follow-up. Study leadership agreed that the randomized trial should be terminated but believed that the cohort should be maintained and followed as the additional follow-up would contribute important information to the understanding of the biologic consequences of the intervention. Since the participants no longer needed to be seen in person to assess acute toxicities or to be given study supplements, it was determined that the most efficient and cost-effective way to follow them was via a central coordinated effort.
Purpose
A number of changes were necessary at the local Study Sites and SELECT Statistical Center to transition to following participants via a Central Coordinating Center. We describe the transition process from a randomized clinical trial to the observational Centralized Follow-up (CFU) study.
Methods
The process of transitioning SELECT, implemented at more than 400 Study Sites across the United States, Canada and Puerto Rico, entailed many critical decisions and actions including updates to online documents such as the SELECT Workbench and Study Manual, a protocol amendment, reorganization of the Statistical Center, creation of a Transition Committee, development of materials for SELECT Study Sites, development of procedures to close Study Sites, and revision of data collection procedures and the process by which to contact participants.
Results
At the time of the publication of the primary SELECT results in December 2008, there were 32,569 men alive and currently active in the trial. As of December 31, 2011, 17,761 participants had been registered to the CFU study. This number is less than had been anticipated due to unforeseen difficulties with local Study Site IRBs. However, from this cohort we estimate that an additional 580 prostate cancer cases and 215 Gleason 7 or higher cancers will be identified. Over 109,000 individual items have been mailed to participants. Active SELECT ancillary studies have continued. The substantial SELECT biorepository is available to researchers; requests to use the specimens are reviewed for feasibility and scientific merit. As of April 2012, 12 proposals had been approved.
Limitations
The accrual goal of the follow-up study was not met, limiting our power to address the study objectives satisfactorily. The CFU study is also dependent on a number of factors including continued funding, continued interest of investigators in the biorepository and the continued contribution of the participants. Our experience may be less pertinent to investigators who wish to follow participants in a treatment trial or participants in prevention trials in other medical areas.
Conclusions
Extended follow-up of participants in prevention research is important to study the long-term effects of the interventions, such as those used in SELECT. The approach taken by SELECT investigators was to continue to follow participants centrally via an annual questionnaire and with a web-based option. The participants enrolled in the CFU study represent a large, well-characterized, generally healthy cohort. The CFU has enabled us to collect additional prostate and other cancer endpoints and longer follow-up on the almost 18,000 participants enrolled. The utility of the extensive biorepository that was developed during the course of the SELECT is enhanced by longer follow-up.
doi:10.1177/1740774512460345
PMCID: PMC3636982  PMID: 23064404
9.  Bayesian adaptive phase II screening design for combination trials 
Clinical trials (London, England)  2013;10(3):10.1177/1740774512470316.
Background
Trials of combination therapies for the treatment of cancer are playing an increasingly important role in the battle against this disease. To more efficiently handle the large number of combination therapies that must be tested, we propose a novel Bayesian phase II adaptive screening design to simultaneously select among possible treatment combinations involving multiple agents.
Methods
Our design is based on formulating the selection procedure as a Bayesian hypothesis testing problem in which the superiority of each treatment combination is equated to a single hypothesis. During the trial conduct, we use the current values of the posterior probabilities of all hypotheses to adaptively allocate patients to treatment combinations.
Results
Simulation studies show that the proposed design substantially outperforms the conventional multiarm balanced factorial trial design. The proposed design yields a significantly higher probability for selecting the best treatment while allocating substantially more patients to efficacious treatments.
Limitations
The proposed design is most appropriate for the trials combining multiple agents and screening out the efficacious combination to be further investigated.
Conclusions
The proposed Bayesian adaptive phase II screening design substantially outperformed the conventional complete factorial design. Our design allocates more patients to better treatments while providing higher power to identify the best treatment at the end of the trial.
doi:10.1177/1740774512470316
PMCID: PMC3867529  PMID: 23359875
10.  Taking the long view: how to design a series of Phase III trials to maximize cumulative therapeutic benefit 
Background
Traditional clinical trial designs strive to definitively establish the superiority of an experimental treatment, which results in risk-adverse criteria and large sample sizes. Increasingly, common cancers are recognized as consisting of small subsets with specific aberrations for targeted therapy, making large trials infeasible.
Purpose
To compare the performance of different trial design strategies over a long-term research horizon.
Methods
We simulated a series of two-treatment superiority trials over 15 years using different design parameters. Trial parameters examined included the number of positive trials to establish superiority (one-trial vs. two-trial rule), α level (2.5%–50%), and the number of trials in the 15-year period, K (thus, trial sample size). The design parameters were evaluated for different disease scenarios, accrual rates, and distributions of treatment effect. Metrics used included the overall survival gain at a 15-year horizon measured by the hazard ratio (HR), year 15 versus year 0. We also computed the expected total survival benefit and the risk of selecting as new standard of care at year 15 a treatment inferior to the initial control treatment, P(detrimental effect).
Results
Expected survival benefits over the 15-year horizon were maximized when more (smaller) trials were conducted than recommended under traditional criteria, using the criterion of one positive trial (vs. two), and relaxing the α value from 2.5% to 20%. Reducing the sample size and relaxing the α value also increased the likelihood of selecting an inferior treatment at the end. The impact of α and K on the survival benefit depended on the specific disease scenario and accrual rate: greater gains for relaxing α in diseases with good outcome and/or low accrual rates and greater gains for increasing K for diseases with poor outcomes. Trials with smaller sample size did not perform well when using stringent (standard) level of evidence. For each disease scenario and accrual rate studied, the optimal design, defined as the design that the maximized expected total survival benefit while constraining P(detrimental effect) < 2.5%, specified α = 20% or 10%, and a sample size considerably smaller than that recommended by the traditional designs. The results were consistent under different assumed distributions for treatment effect.
Limitations
The simulations assumed no toxicity issues and did not consider interim analyses.
Conclusions
It is worthwhile to consider a design paradigm that seeks to maximize the expected survival benefit across a series of trials, over a longer research horizon. In today’s environment of constrained, biomarker-selected populations, our results indicate that smaller sample sizes and larger α values lead to greater long-term survival gains compared to traditional large trials designed to meet stringent criteria with a low efficacy bar.
doi:10.1177/1740774512443430
PMCID: PMC3904223  PMID: 22569743
11.  Lessons Learned from an Osteoporosis Clinical Trial in Frail Long Term Care Residents 
Background
Although osteoporosis affects women of all ages, the impact is most pronounced in frail residents in long term care. Nevertheless, few interventional trials have been performed in this population and few data on therapeutic alternatives are available in this cohort.
Purpose
We describe the challenges and lessons learned in developing and carrying out a trial in frail long term care residents.
Methods
The ZEST (Zoledronic acid in frail Elders to STrengthen bone) study was designed to examine the safety and efficacy of a single-dose therapy for osteoporosis in frail residents in long term care in the Pittsburgh area. Women with osteoporosis who were 65 years of age and older and currently not on therapy, were randomized in a blinded fashion to intravenous zoledronic acid or placebo. Follow-up of each participant was planned for 2 years. All participants received appropriate calcium and vitamin D supplementation.
Results
Seven hundred and thirty-three contacts were made with long term care residents of 9 participating facilities. Of 252 women screened, 181 women were eligible, enrolled, and were randomized. Multiple barriers to research in long term care facilities were encountered but overcome with direct communication, information sessions, in-service trainings and social events. Lessons learned included designing the study in a manner that avoided placing an additional burden on an already overcommitted facility staff, a two-stage consent process to separate screening from randomization, and a flexible examination schedule to accommodate residents while obtaining the necessary outcome measurements. Furthermore, a mobile unit accessible to participants containing state-of-the-art dual x-ray absorptiometry, assessment for vertebral fractures, and phlebotomy equipment allows all assessments to be performed on-site at each facility. Serious adverse events are collected from affiliated hospitals in real time with a novel electronic surveillance system.
Limitations
The major limitation is selection of outcomes that can be assessed at participating facilities and do not require transport of participants to hospitals or clinics.
Conclusions
Clinical research for osteoporosis can be successfully and safely performed with frail residents in long term care facilities. Lessons learned from this study may inform future investigations among frail elderly residents of these facilities.
doi:10.1177/1740774511430516
PMCID: PMC3889110  PMID: 22157987
osteoporosis; long term care; frail elderly
12.  A multi-center, randomized, double blind placebo-controlled trial of estrogens to prevent Alzheimer’s disease and loss of memory in women: design and baseline characteristics 
Clinical trials (London, England)  2008;5(5):10.1177/1740774508096313.
Background
Observational studies and small clinical trials suggested that hormone replacement therapy (HRT) decreases risk of cognitive loss and Alzheimer’s disease (AD) in postmenopausal women and may have value in primary prevention.
Purpose
A clinical trial was designed to determine if HRT delays AD or memory loss. This report describes the rationale and original design of the trial and details extensive modifications that were required to respond to unanticipated findings that emerged from other studies during the course of the trial.
Methods
The trial was designed as a multi-center, placebo-controlled primary prevention trial for women 65 years of age or older with a family history of dementia. Recruitment from local sites was supplemented by centralized efforts to use names of Medicare beneficiaries. Inclusion criteria included good general health and intact memory functioning. Participants were randomized to HRT or placebo in a 1:1 ratio. Assignment was stratified by hysterectomy status and site. The primary outcomes were incident AD and memory decline on neuropsychological testing.
Results
Enrollment began in March 1998. In response to the Women’s Health Initiative (WHI) May 2002 report of increased incidence of heart disease, stroke, pulmonary embolism, and breast cancer among women randomized to HRT, participants were re-consented with a revised consent form. Procedural modifications, including discontinuation of study medication and a modification of the planned primary outcome based on a final enrollment below the target enrollment (N = 477), were enacted in response to the subsequent WHI Memory Study report of increased risk of dementia and poorer cognitive function with HRT. The mean length of treatment exposure prior to discontinuation was 2.14 years. Participants’ mean age at baseline was 72.8; mean education was 14.2 years. Minority participation was 19% and 34% had a hysterectomy. The study continues to follow these participants for a total of 5 years blind to the original medication assignment.
Limitations
Results reported from the WHI during the course of this study mandated extensive procedural modifications, including discontinuing recruitment before completion and halting study medication. Alternative strategies for study redesign that were considered are discussed.
doi:10.1177/1740774508096313
PMCID: PMC3884686  PMID: 18827045
13.  An analysis of adaptive design variations on the sequential parallel comparison design for clinical trials 
Clinical trials (London, England)  2013;10(2):10.1177/1740774512468806.
Background
Currently, a growing placebo response rate has been observed in clinical trials for antidepressant drugs, a phenomenon that has made it increasingly difficult to demonstrate efficacy. The sequential parallel comparison design (SPCD) is a clinical trial design that was proposed to address this issue. The SPCD theoretically has the potential to reduce the sample size requirement for a clinical trial and to simultaneously enrich the study population to be less responsive to the placebo.
Purpose
Because the basic SPCD design already reduces the placebo response by removing placebo responders between the first and second phases of a trial, the purpose of this study was to examine whether we can further improve the efficiency of the basic SPCD and if we can do so when the projected underlying drug and placebo response rates differ considerably from the actual ones.
Methods
Three adaptive designs that used interim analyses to readjust the length of study duration for individual patients were tested to reduce the sample size requirement or increase the statistical power of the SPCD. Various simulations of clinical trials using the SPCD with interim analyses were conducted to test these designs through calculations of empirical power.
Results
From the simulations, we found that the adaptive designs can recover unnecessary resources spent in the traditional SPCD trial format with overestimated initial sample sizes and provide moderate gains in power. Under the first design, results showed up to a 25% reduction in person-days, with most power losses below 5%. In the second design, results showed up to a 8% reduction in person-days with negligible loss of power. In the third design using sample size re-estimation, up to 25% power was recovered from underestimated sample size scenarios.
Limitations
Given the numerous possible test parameters that could have been chosen for the simulations, the study’s results are limited to situations described by the parameters that were used, and may not generalize to all possible scenarios. Furthermore, drop-out of patients is not considered in this study.
Conclusions
It is possible to make an already complex design such as the SPCD adaptive, and thus more efficient, potentially overcoming the problem of placebo response at lower cost. Ultimately, such a design may expedite the approval of future effective treatments.
doi:10.1177/1740774512468806
PMCID: PMC3612388  PMID: 23283576
clinical trial; adaptive design; sequential parallel comparison design; power; SPCD; placebo response
14.  Discordant MIC Analysis: A New Path to Licensure for Anti-infective Drugs 
Clinical trials (London, England)  2013;10(6):10.1177/1740774513507503.
Summary
Background
Evaluation of anti-infective drugs for licensure often relies on a noninferiority (NI) design where new drug B is noninferior to comparator drug A if the difference in success rates is reliably not worse than some fixed margin. The margin must be based on historical studies that estimate the magnitude of the benefit of drug A over placebo. This approach hampers drug development because the obligatory evidence for margin determination is often nonexistent.
Purpose
To develop a new method for licensure of anti-infective drugs when there is no historical evidence for reliable construction of the NI margin.
Methods
The MIC measures the minimum amount of drug that it takes to inhibit growth of bacteria in vitro. Patients who are infected with bacteria that have a low MIC to a given drug are expected to have good outcome when treated with that drug. Thus a differential effect of drug B versus drug A, if it exists, is likely to occur in patients whose pathogens have discordant MICs (e.g. low MIC for drug B, high MIC for drug A, or vice versa). A new paradigm for licensure of anti-infective drugs is proposed where a clinically acceptable NI margin is selected and licensure supported if the NI margin is met and B is reliably demonstrated superior to A in a subset of patients whose paired MICs favor B. The requirement for some evidence of superiority encourages a study that is carefully designed and executed.
Results
Simulations indicate the approach shows promise in realistic settings provided adequate data are available. A simulated example illustrates use of the methods.
Limitations
If the data have small sample size, weak MIC/success relationship, or high correlation between MIC-A, MIC-B, this procedure will have poor power.
Conclusion
Discordant MIC analysis may offer a novel path to licensure for certain anti-infective drugs.
doi:10.1177/1740774513507503
PMCID: PMC3845416  PMID: 24287133
AUC:MIC ratio; Interaction Test; Logistic Regression; Licensure
15.  Adaptive adjustment of the randomization ratio using historical control data 
Clinical trials (London, England)  2013;10(3):10.1177/1740774513483934.
Background
Prospective trial design often occurs in the presence of “acceptable” [1] historical control data. Typically this data is only utilized for treatment comparison in a posteriori retrospective analysis to estimate population-averaged effects in a random-effects meta-analysis.
Purpose
We propose and investigate an adaptive trial design in the context of an actual randomized controlled colorectal cancer trial. This trial, originally reported by Goldberg et al. [2], succeeded a similar trial reported by Saltz et al. [3], and used a control therapy identical to that tested (and found beneficial) in the Saltz trial.
Methods
The proposed trial implements an adaptive randomization procedure for allocating patients aimed at balancing total information (concurrent and historical) among the study arms. This is accomplished by assigning more patients to receive the novel therapy in the absence of strong evidence for heterogeneity among the concurrent and historical controls. Allocation probabilities adapt as a function of the effective historical sample size (EHSS) characterizing relative informativeness defined in the context of a piecewise exponential model for evaluating time to disease progression. Commensurate priors [4] are utilized to assess historical and concurrent heterogeneity at interim analyses and to borrow strength from the historical data in the final analysis. The adaptive trial’s frequentist properties are simulated using the actual patient-level historical control data from the Saltz trial and the actual enrollment dates for patients enrolled into the Goldberg trial.
Results
Assessing concurrent and historical heterogeneity at interim analyses and balancing total information with the adaptive randomization procedure leads to trials that on average assign more new patients to the novel treatment when the historical controls are unbiased or slightly biased compared to the concurrent controls. Large magnitudes of bias lead to approximately equal allocation of patients among the treatment arms. Using the proposed commensurate prior model to borrow strength from the historical data, after balancing total information with the adaptive randomization procedure, provides admissible estimators of the novel treatment effect with desirable bias-variance trade-offs.
Limitations
Adaptive randomization methods in general are sensitive to population drift and more suitable for trials that initiate with gradual enrollment. Balancing information among study arms in time-to-event analyses is difficult in the presence of informative right-censoring.
Conclusions
The proposed design could prove important in trials that follow recent evaluations of a control therapy. Efficient use of the historical controls is especially important in contexts where reliance on pre-existing information is unavoidable because the control therapy is exceptionally hazardous, expensive, or the disease is rare.
doi:10.1177/1740774513483934
PMCID: PMC3856641  PMID: 23690095
adaptive designs; Bayesian analysis; historical controls
16.  Boosting Enrollment in Clinical Trials: Validation of a Regional Network Model 
Clinical trials (London, England)  2011;8(5):10.1177/1740774511414925.
BACKGROUND
Clinical trials of stroke therapy have been hampered by slow rates of enrollment.
PURPOSE
Our purpose is to validate a previously-developed model for accelerating enrollment in clinical trials by replicating it at new locations. The model employs coordinators who travel from a host institution to enroll participants from a network of participating hospitals. Active surveillance assures identification of all eligible patients.
METHODS
Among 70 US investigators participating in an NIH-funded trial of stroke prevention, five investigators were invited to develop local identification and outreach networks (LIONs). Each LION comprised a LION coordinating center servicing multiple hospitals. Hospitals provided names of patients with stroke or TIA to researchers at the LION coordinating center who initiated contact; patients were offered home visits for consent and randomization. Outcomes were feasibility, enrollment, data quality and cost.
RESULTS
Five LIONs varied in size from 2 to 8 hospitals. All 24 hospitals we approached agreed to participate. The average monthly rate of enrollment at the research sites increased from 1.4 participants to 3.5 after expanding from a single institution model to the LION format (mean change=2.1, range 0.9-3.7). Monthly performance improved over time. Data quality was similar for LIONs and non-LION sites, except for drug adherence which was lower at LIONs. The average cost to randomize and follow one participant during the study interval was 2.4 times the cost under the per-patient, cost-reimbursement strategy at non-LION sites. The cost ratio declined from 3.4 in year one to 1.8 in year two.
LIMITATIONS
The LION strategy requires unprecedented collaboration and trust among institutions. Applicability beyond stroke requires confirmation.
CONCLUSION
LIONs are a practical, reproducible method to increase enrollment in trial research. Twelve months were required for the average site to reach its potential. The per-participant cost at LIONs was higher than conventional sites, but declined over time.
doi:10.1177/1740774511414925
PMCID: PMC3852692  PMID: 21824978
17.  Therapeutic Misconception in Research Subjects: Development and Validation of a Measure 
Background
Therapeutic misconception (TM), which occurs when research subjects fail to appreciate the distinction between the imperatives of clinical research and ordinary treatment, may undercut the process of obtaining meaningful consent to clinical research participation. Previous studies have found TM is widespread, but progress in addressing TM has been stymied by the absence of a validated method for assessing its presence.
Purpose
The goal of this study was to develop and validate a theoretically grounded measure of TM, assess its diagnostic accuracy, and test previous findings regarding its prevalence.
Methods
220 participants were recruited from clinical trials at 4 academic medical centers in the U.S. Participants completed a 28-item Likert-type questionnaire to assess the presence of beliefs associated with TM, and a semi-structured TM interview designed to elicit their perceptions of the nature of the clinical trial in which they were participating. Data from the questionnaires were subjected to factor analysis and items with poor factor loadings were excluded. This resulted in a 10-item scale, with 3 strongly correlated factors and excellent internal consistency; the fit indices of the model across 10 training sets were consistent with the original results, suggesting a stable factor solution.
Results
The scale was validated against the TM interview, with significantly higher scores among subjects coded as displaying evidence of TM. ROC analysis based on a 10-fold internal cross-validation yielded AUC=.682 for any evidence of TM. When sensitivity (0.72) and specificity (0.61) were both optimized, Positive Predictive Value was 0.65 and Negative Predictive Value was 0.68, with a Positive Likelihood Ratio of 1.89, and a Negative Likelihood Ratio of 0.47. 50.5% (n=101) of participants manifested evidence of TM on the TM interview, a somewhat lower rate than in most previous studies.
Limitations
The predictive value of the scale compared with the “gold standard” clinical interview is modest, although similar to other instruments based on self-report assessing states of mind rather than discrete symptoms. Thus, although the scale can offer evidence of which subjects are at risk for distortions in their decisions and to what degree, it will not allow researchers to conclude definitively that TM is present in a given subject.
Conclusions
The development of a reliable and valid TM scale, even with modest predictive power, should permit investigators in clinical trials to identify subjects with tendencies to misinterpret the nature of the situation and to provide additional information to them. It should also stimulate research on how best to decrease TM and facilitate meaningful informed consent to clinical research.
doi:10.1177/1740774512456455
PMCID: PMC3690536  PMID: 22942217
Therapeutic misconception; informed consent; research ethics
18.  Using Audit Information to Adjust Parameter Estimates for Data Errors in Clinical Trials 
Background
Audits are often performed to assess the quality of clinical trial data, but beyond detecting fraud or sloppiness, the audit data is generally ignored. In earlier work using data from a non-randomized study, Shepherd and Yu (2011) developed statistical methods to incorporate audit results into study estimates, and demonstrated that audit data could be used to eliminate bias.
Purpose
In this manuscript we examine the usefulness of audit-based error-correction methods in clinical trial settings where a continuous outcome is of primary interest.
Methods
We demonstrate the bias of multiple linear regression estimates in general settings with an outcome that may have errors and a set of covariates for which some may have errors and others, including treatment assignment, are recorded correctly for all subjects. We study this bias under different assumptions including independence between treatment assignment, covariates, and data errors (conceivable in a double-blinded randomized trial) and independence between treatment assignment and covariates but not data errors (possible in an unblinded randomized trial). We review moment-based estimators to incorporate the audit data and propose new multiple imputation estimators. The performance of estimators is studied in simulations.
Results
When treatment is randomized and unrelated to data errors, estimates of the treatment effect using the original error-prone data (i.e., ignoring the audit results) are unbiased. In this setting, both moment and multiple imputation estimators incorporating audit data are more variable than standard analyses using the original data. In contrast, in settings where treatment is randomized but correlated with data errors and in settings where treatment is not randomized, standard treatment effect estimates will be biased. And in all settings, parameter estimates for the original, error-prone covariates will be biased. Treatment and covariate effect estimates can be corrected by incorporating audit data using either the multiple imputation or moment-based approaches. Bias, precision, and coverage of confidence intervals improve as the audit size increases.
Limitations
The extent of bias and the performance of methods depend on the extent and nature of the error as well as the size of the audit. This work only considers methods for the linear model. Settings much different than those considered here need further study.
Conclusions
In randomized trials with continuous outcomes and treatment assignment independent of data errors, standard analyses of treatment effects will be unbiased and are recommended. However, if treatment assignment is correlated with data errors or other covariates, naive analyses may be biased. In these settings, and when covariate effects are of interest, approaches for incorporating audit results should be considered.
doi:10.1177/1740774512450100
PMCID: PMC3728661  PMID: 22848072
audit; bias; clinical trials; measurement error; multiple imputation
19.  Factors influencing enrollment of African Americans in the Look AHEAD trial 
Clinical trials (London, England)  2011;9(1):10.1177/1740774511427929.
Background
Many factors have been identified that influence the recruitment of African Americans into clinical trials; however, the influence of eligibility criteria may not be widely appreciated. We used the experience from the Look AHEAD (Action for Health in Diabetes) trial screening process to examine the differential impact eligibility criteria had on the enrollment of African Americans compared to other volunteers.
Methods
Look AHEAD is a large randomized clinical trial to examine whether assignment to an intensive lifestyle intervention designed to produce and maintain weight loss reduces the long-term risk of major cardiovascular events in adults with type 2 diabetes. Differences in the screening, eligibility, and enrollment rates between African Americans and members of other racial/ethnic groups were examined to identify possible reasons.
Results
Look AHEAD screened 28,735 individuals for enrollment, including 6226 (21.7%) who were self-identified African Americans. Of these volunteers, 12.9% of the African Americans compared to 19.3% of all other screenees ultimately enrolled (p < 0.001). African Americans no more often than others were lost to follow-up or refused to attend clinic visits to establish eligibility. Furthermore, the enrollment rates of individuals with histories of cardiovascular disease and diabetes therapy did not markedly differ between the ethnic groups. Higher prevalence of adverse levels of blood pressure, heart rate, HbA1c, and serum creatinine among African American screenees accounted for the greater proportions excluded (all p < 0.001).
Conclusions
Compared to non-African Americans, African American were more often ineligible for the Look AHEAD trial due to comorbid conditions. Monitoring trial eligibility criteria for differential impact, and modifying them when appropriate, may ensure greater enrollment yields.
doi:10.1177/1740774511427929
PMCID: PMC3843916  PMID: 22064686
20.  Clinical Trials of Health IT Interventions Intended for Patient Use: Unique Issues and Considerations 
Clinical trials (London, England)  2013;10(6):10.1177/1740774513493149.
Background
Despite the proliferation of health information technology (IT) interventions, descriptions of the unique considerations for conducting randomized trials of health IT interventions intended for patient use are lacking.
Purpose
Our purpose is to evaluate Pocket PATH® (Personal Assistant for Tracking Health), a novel health IT intervention, as an exemplar of how to address issues that may be unique to a randomized controlled trial to evaluate health IT intended for patient use.
Methods
An overview of the study protocol is presented. Unique considerations for health IT intervention trials and strategies to maintain equipoise, monitor data safety and intervention fidelity, and keep pace with changing technology during such trials are described.
Lessons Learned
The sovereignty granted to technology, the rapid pace of changes in technology, ubiquitous use in health care and obligation to maintain the safety of research participants challenge researchers to address these issues in ways that maintain the integrity of intervention trials designed to evaluate the impact of health IT interventions intended for patient use.
Conclusions
Our experience evaluating the efficacy of Pocket PATH may provide practical guidance to investigators about how to comply with established procedures for conducting randomized controlled trials and include strategies to address the unique issues associated with the evaluation of health IT for patient use.
doi:10.1177/1740774513493149
PMCID: PMC3808467  PMID: 23867222
Pocket PATH® (Personal Assistant for Tracking Health); health information technology (health IT); randomized; controlled trials (RCT); consumer health technology; trial of intervention efficacy
21.  Do Bayesian adaptive trials offer advantages for comparative effectiveness research? Protocol for the RE-ADAPT study 
Clinical Trials (London, England)  2013;10(5):807-827.
Background
Randomized clinical trials, particularly for comparative effectiveness research (CER), are frequently criticized for being overly restrictive or untimely for health-care decision making.
Purpose
Our prospectively designed REsearch in ADAptive methods for Pragmatic Trials (RE-ADAPT) study is a ‘proof of concept’ to stimulate investment in Bayesian adaptive designs for future CER trials.
Methods
We will assess whether Bayesian adaptive designs offer potential efficiencies in CER by simulating a re-execution of the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) study using actual data from ALLHAT.
Results
We prospectively define seven alternate designs consisting of various combinations of arm dropping, adaptive randomization, and early stopping and describe how these designs will be compared to the original ALLHAT design. We identify the one particular design that would have been executed, which incorporates early stopping and information-based adaptive randomization.
Limitations
While the simulation realistically emulates patient enrollment, interim analyses, and adaptive changes to design, it cannot incorporate key features like the involvement of data monitoring committee in making decisions about adaptive changes.
Conclusion
This article describes our analytic approach for RE-ADAPT. The next stage of the project is to conduct the re-execution analyses using the seven prespecified designs and the original ALLHAT data.
doi:10.1177/1740774513497293
PMCID: PMC3834735  PMID: 23983160
22.  A Comprehensive Comparison of the Continual Reassessment Method to the Standard 3 + 3 Dose Escalation Scheme in Phase I Dose-Finding Studies 
Background
An extensive literature has covered the statistical properties of the Continual Reassessment Method (CRM) and the modifications of this method. While there are some applications of CRM designs in recent Phase I trials, the standard method (SM) of escalating doses after three patients with an option for an additional three patients SM remains very popular, mainly due to its simplicity. From a practical perspective, clinicians are interested in designs that can estimate the MTD using fewer patients for a fixed number of doses, or can test more dose levels for a given sample size.
Purpose
This article compares CRM-based methods with the SM in terms of the number of patients needed to reach the MTD, total sample size required, and trial duration.
Methods
The comparisons are performed under two alternative schemes: a fixed or a varying sample approach with the implementation of a stopping rule. The stopping rule halts the trial if the confidence interval around the MTD is within a pre-specified bound. Our simulations evaluated several CRM-based methods under different scenarios by varying the number of dose levels from five to eight and the location of the true MTD.
Results
CRM and SM are comparable in terms of how fast they reach the MTD and the total sample size required when testing a limited number of dose levels (≤5), but as the number of dose levels increases, CRM reaches the MTD in fewer patients when used with a fixed sample of 20 patients. However, a sample size of 20–25 patients is not sufficient to achieve a narrow precision around the estimated toxicity rate at the MTD.
Limitations
We focused on methods with practical design features that are of interest to clinicians. However, there are several alternative CRM-based designs that are not investigated in this manuscript, and hence our results are not generalizable to other designs.
Conclusions
We show that CRM-based methods are an improvement over the SM in terms of accuracy and optimal dose allocation in almost all cases, except when the true dose is among the lower levels.
doi:10.1177/1740774508096474
PMCID: PMC2637378  PMID: 18827039
23.  Evolution of the study coordinator role: the 28-year experience in Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and complications (DCCT/EDIC) 
Clinical trials (London, England)  2012;9(4):10.1177/1740774512449532.
Background
The role of the study coordinator (SC) in multi-center studies of long duration has received limited attention.
Purpose
To describe the evolution of the SC's role during the 28-year Diabetes Control and Complications Trial (DCCT) and its follow-up study, the Epidemiology of Diabetes Interventions and Complications (EDIC) study.
Methods
The evolution in the SC position from the traditional role of protocol implementation to that of research collaborator and co-investigator, based on personal experience and observation, is described in detail. Findings from a survey regarding professional demographics and job satisfaction, completed by all 28 SC's in 2010, provided additional information. We used dimensions of the SC role specific to DCCT/EDIC to construct a classification schema of functions and responsibilities that describe the SC role.
Results
Among the 28 SCs, 24 were nurses, 12 held bachelor's degrees, 11 had a master's degree, 19 were Certified Diabetes Educators (CDEs), 12 had worked with DCCT/EDIC for more than 20 years and 5 had been with the study since its inception (> 26 years). Responses confirmed a high degree of functional consistency across sites with data acquisition, performing study procedures, recruitment and consent for additional ancillary studies, regulatory management, scheduling, clinical consultation and ongoing contact with study participants frequently reported. Study-wide leadership activities, a category not generally included in the usual SC role, were reported by approximately 30% of SCs. The level of professional satisfaction was high with two thirds being very satisfied, one third moderately to quite satisfied, and none dissatisfied.
Limitations
The limitations include a relatively small sample size, self-reported data, and a single long-term multicenter trial and observational follow up study on which we based our findings and conclusions.
Conclusions
By optimizing their organizational and scientific contributions to the overall research endeavor, SCs in DCCT/EDIC have made major contributions to the unprecedented success of the study and report high job satisfaction. The efforts of the SCs have been integral to the remarkably high participant retention and data completion rates. The DCCT/EDIC experience may serve as a model for the role of the SC in future diabetes and other multi-center clinical trials.
doi:10.1177/1740774512449532
PMCID: PMC3815574  PMID: 22729476
Clinical Trial; Study Coordinator; Research Nurse; DCCT/EDIC
24.  Testing the Incremental Predictive Accuracy of New Markers 
Clinical trials (London, England)  2013;10(5):690-692.
Background
It has become commonplace to use receiver operating curve (ROC) methodology to evaluate the incremental predictive accuracy of new markers in the presence of existing predictors. However, concerns have been raised about the validity of this practice. We have evaluated this issue in detail.
Results
Simulations have been used that show clearly that use of risk predictors from nested models as data in subsequent tests comparing areas under the ROC curves of the models leads to grossly invalid inferences. Careful examination of the issue reveals two major problems: (1) the data elements are strongly correlated from case to case; and (2) the model that includes the additional marker has a tendency to interpret predictive contributions as positive information regardless of whether observed effect of the marker is negative or positive. Both of these phenomena lead to profound bias in the test.
Conclusions
We recommend strongly against the use of ROC methods derived from risk predictors from nested regression models to test the incremental information of a new marker.
doi:10.1177/1740774513496490
PMCID: PMC3800241  PMID: 23881367
25.  Midcourse correction to a clinical trial when the event rate is underestimated: the Look AHEAD (Action for Health in Diabetes) Study 
The Look AHEAD (Action for Health in Diabetes) Study is a long-term clinical trial that aims to determine the cardiovascular disease (CVD) benefits of an intensive lifestyle intervention (ILI) in obese adults with type 2 diabetes. The study was designed to have 90% statistical power to detect an 18% reduction in the CVD event rate in the ILI Group compared to the Diabetes Support and Education (DSE) Group over 10.5 years of follow-up.
The original power calculations were based on an expected CVD rate of 3.125% per year in the DSE group; however, a much lower-than-expected rate in the first 2 years of follow-up prompted the Data and Safety Monitoring Board (DSMB) to recommend that the Steering Committee undertake a formal blinded evaluation of these design considerations. The Steering Committee created an Endpoint Working Group (EPWG) that consisted of individuals masked to study data to examine relevant issues.
The EPWG considered two primary options: (1) expanding the definition of the primary endpoint and (2) extending follow-up of participants. Ultimately, the EPWG recommended that the Look AHEAD Steering Committee approve both strategies. The DSMB accepted these modifications, rather than recommending that the trial continue with inadequate statistical power.
Trialists sometimes need to modify endpoints after launch. This decision should be well justified and should be made by individuals who are fully masked to interim results that could introduce bias. This article describes this process in the Look AHEAD study and places it in the context of recent articles on endpoint modification and recent trials that reported endpoint modification.
doi:10.1177/1740774511432726
PMCID: PMC3790961  PMID: 22334468

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