Clinical Trials

Background The Women's Health Initiative (WHI) randomized trial of estrogen plus progestin (E + P) was terminated early based on an assessment of harms exceeding benefits for disease prevention. The results contravened prevailing wisdom and a large body of literature regarding benefits of menopausal hormone therapy. The results and their interpretation have been the subject of considerable debate.

Purpose/methods To describe the process of developing a trial monitoring plan, the key interim and final data, and to explain the choice of statistical methods used in trial monitoring and reporting.

Results A formalized monitoring plan was developed using statistical methods that acknowledged protocol-defined design and analysis plans, input of monitoring board members especially regarding the role of various study outcomes, and multiple comparisons. Major early departures from design assumptions concerning treatment effects indicated a need for additional flexibility in safety monitoring. When the trials were stopped early, questions arose as to how closely the statistical methods in published reports should correspond to those defined by protocol or used in monitoring. Methods were selected to provide a simple and transparent summary of the primary results, with a cautious interpretation promoted by acknowledgement of multiple testing.

Conclusions Developing a formal trial monitoring plan with a view towards influencing clinical practice is useful for creating consensus among DSMB members regarding the evidence that would justify stopping a trial and the framework to be used to address statistical complexities. Departures from design assumptions typically occur. These reinforce the role of the DSMB in exercising their judgment, and the judicious adaptation of these statistical guidelines in monitoring and reporting trials. In communicating the results in such circumstances, priority should be given to presenting as fair, accurate and transparent a view of the data and findings as current methods and technology allow.

Data Safety Monitoring Committees (DSMB) for large, long-term randomized trials of agents in common use face challenging problems especially when the emerging data indicate unanticipated effects. The DSMB for the Women's Health Initiative Clinical Trials, on observing early indication of a surprising adverse cardiovascular effect of post-menopausal hormones, spent several years deliberating what recommendations it should make. This paper describes the dilemmas faced by the DSMB and the considerations it made over the course of its existence. The paper concludes with some recommendations for other DSMBs.

Background Most phase I clinical trials conducted at the M. D. Anderson Cancer Center use the algorithmic 3 + 3 design, despite the availability of more advanced model-based designs such as the continual reassessment method.

Purpose Through simple statistical modeling and computing, we develop a dose-finding design that can be easily understood and implemented by non-statisticians.

Methods We propose a beta/binomial Bayesian model and a probabilistic up-and-down rule that allow all possible dose-assignment actions to be tabulated in a spreadsheet. We have developed an Excel macro (available at http://odin.mdacc. tmc.edu/~yuanj) that generates trial monitoring tables, which contain the dose-assignment actions corresponding to various toxicity outcomes.

Results The new design outperforms the 3 + 3 design and performs comparably to other model-based methods in the literature.

Limitations The proposed method assumes that the observed toxicity is a binary variable and that toxicity increases with dose level.

Conclusion The new dose-finding design enables physicians to readily determine dose assignments for new patients by referencing a trial monitoring table. Clinical Trials 2007; 4: 235—244; http://ctj.sagepub.com

Background The published clinical research literature may be distorted by the pursuit of statistically significant results.

Purpose We aimed to develop a test to explore biases stemming from the pursuit of nominal statistical significance.

Methods The exploratory test evaluates whether there is a relative excess of formally significant findings in the published literature due to any reason (e.g., publication bias, selective analyses and outcome reporting, or fabricated data). The number of expected studies with statistically significant results is estimated and compared against the number of observed significant studies. The main application uses α = 0.05, but a range of α thresholds is also examined. Different values or prior distributions of the effect size are assumed. Given the typically low power (few studies per research question), the test may be best applied across domains of many meta-analyses that share common characteristics (interventions, outcomes, study populations, research environment).

Results We evaluated illustratively eight meta-analyses of clinical trials with >50 studies each and 10 meta-analyses of clinical efficacy for neuroleptic agents in schizophrenia; the 10 meta-analyses were also examined as a composite domain. Different results were obtained against commonly used tests of publication bias. We demonstrated a clear or possible excess of significant studies in 6 of 8 large meta-analyses and in the wide domain of neuroleptic treatments.

Limitations The proposed test is exploratory, may depend on prior assumptions, and should be applied cautiously.

Conclusions An excess of significant findings may be documented in some clinical research fields. Clinical Trials 2007; 4: 245—253; http://ctj.sagepub.com

Objective To evaluate the factors associated with refusal to participate in acute cardiac clinical trials.

Background Cardiac clinical trials in the acute setting pose a set of unique challenges to enrollment, such as the ability to obtain meaningful informed consent. In addition, it is unclear whether enrollment is associated with the sociodemographic characteristics (such as age, race and gender) of those being recruited. While policies have been instituted to enhance the representation of women and minorities in research, limited data exist on current enrollment patterns and reasons for refusal to participate in cardiac clinical trials.

Methods 184 patients approached to participate in one of 25 cardiac clinical trials at Duke University Medical Center from 11/01 to 05/04 were surveyed regarding reasons for or against participation in clinical trials to identify predictors of non-enrollment.

Results The mean age of the respondents was 61.6 years (SD 12.2), with 36% female and 32% non-white patients. There were no differences in refusal rates by age, gender or ethnicity. Higher acuity trials had higher refusal rates OR 3.6 (1.68—7.75) as well as not reading the informed consent form OR 2.99 (1.37—6.54). The main reasons people refused enrollment were due to inconvenience and not wanting to be experimented upon.

Limitations This study was cross-sectional and conducted at a single institution that conducts a high-volume of clinical research. In addition, a majority of the patients in the procedure/device studies were enrolled in one relatively low-risk cardiac catheterization laboratory trial with a low refusal rate. These attributes may limit the generalizability of the findings reported here.

Conclusion Older persons, women and minorities are equally likely to agree to enroll in cardiac clinical trials as younger persons, men and non-minorities. Future efforts to increase the efficiency of recruitment should focus on improving convenience for participants in this acute setting and improving basic understanding of clinical trials. Clinical Trials 2007; 4: 258—263; http://ctj.sagepub.com

References

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Background Considerable attention has focused on increasing clinical trial participation for members of “underrepresented groups”. However, doing so involves clarifying how to meet the demands of justice, or fairness, which provides the ethical mandate to enhance broad trial representation.

Purpose To examine the ethical principle of justice as it applies to recruiting diverse populations to clinical trials representation.

Methods In this paper, we analyse the conceptual and practical challenges in applying the principle of justice to clinical trials representation.

Results Different facets of justice include demands for both fair outcomes and fair processes. Including both of these facets in clinical trials policy should not only promote access to trials, but also help to provide a framework to improve fairness in representation in clinical trials. Efforts to evaluate recruitment of representation should include outcome and process measures.

Limitations The suggestions offered based on this conceptual analysis need to be tested empirically.

Conclusions Those involved in the design, conduct and oversight of clinical trials should consider all of the facets of justice when assessing representation in clinical trials and attempt to balance fair access to trials with a fair process that may require protection from being unduly pressured to participate. Clinical Trials 2007; 4: 264—269; http://ctj.sagepub.com

Background Disclosing financial interests to potential research participants during the informed consent process is one strategy for managing conflicts of interest. Given that clinical research coordinators are typically charged with administering the informed consent process, it is critical to understand their experiences, attitudes and beliefs regarding the disclosure of financial interests in research.

Purpose To understand the role of clinical research coordinators in disclosing financial interests in research, and potential barriers to such disclosures.

Methods We developed a survey designed to measure clinical research coordinators' awareness of financial interests in clinical research, previous experience with disclosing financial interests, comfort with answering questions about financial interests and barriers to disclosing financial interests to potential research participants. Next we conducted cognitive interviews with 10 clinical research coordinators to assess understandability and content validity and to further refine the survey. We then administered the survey to clinical research coordinators attending the 2006 Global Conference of the Association of Clinical Research Professionals.

Results Among 300 clinical research coordinators who completed the survey, there was a general awareness of financial interests in research. Forty-one percent reported disclosing such financial interests to potential research participants, and 28% reported being asked about them. Greater comfort in responding to questions about financial interests was associated with previous experience with disclosure, previous experience answering questions about financial interests, and greater length of time obtaining informed consent. Respondents indicated that there were barriers to disclosure, including lack of information (76%) and that participants would not understand disclosures (26%).

Limitations Possible sample bias due to using a convenience sample.

Conclusions Making information about financial interests in research readily available to clinical research coordinators, as well as providing education and training, should facilitate the disclosure of financial interests in research to potential research participants during the informed consent process. Clinical Trials 2007; 4: 272—278. http://ctj.sagepub.com

Background The results of the HOPE study, a randomized clinical trial, provide strong evidence that 1) ramipril prevents the composite outcome of cardiovascular death, myocardial infarction or stroke in patients who are at high risk of a cardiovascular event and 2) ramipril is cost-effective at a threshold willingness-to-pay of $10 000 to prevent an event of the composite outcome. In this report the concept of the expected value of information is used to determine if the information provided by the HOPE study is sufficient for decision making in the US and Canada.

Methods and results Using the cost-effectiveness data from a clinical trial, or from a meta-analysis of several trials, one can determine, based on the number of future patients that would benefit from the health technology under investigation, the expected value of sample information (EVSI) of a future trial as a function of proposed sample size. If the EVSI exceeds the cost for any particular sample size then the current information is insufficient for decision making and a future trial is indicated. If, on the other hand, there is no sample size for which the EVSI exceeds the cost, then there is sufficient information for decision making and no future trial is required. Using the data from the HOPE study these concepts are applied for various assumptions regarding the fixed and variable cost of a future trial and the number of patients who would benefit from ramipril.

Conclusions Expected value of information methods provide a decision-analytic alternative to the standard likelihood methods for assessing the evidence provided by cost-effectiveness data from randomized clinical trials. Clinical Trials 2007; 4: 279—285. http://ctj.sagepub.com

In analysing clinical trials designed to show superiority of one treatment compared to another, it is standard to use an intention to treat analytic approach. In active-controlled noninferiority studies, this is not standard, due to concerns that such an analysis will inflate the chance of falsely rejecting the null hypothesis, accepting therapeutic noninferiority when it is not justified. The reasons for using intention to treat (ITT) approaches in superiority studies include a desire to capture all information on study subjects, a need to prevent bias, and assurance that comparative groups are, on average, equivalent in prognostic factors. In this commentary, we argue that these same justifications carry over to noninferiority studies, and that for those and other reasons it should be the preferred analytic approach. We review regulatory guidelines, and propose a number of approaches to minimizing the potential disadvantages of the ITT approach in the noninferiority setting. Clinical Trials 2007; 4: 286—291; http://ctj.sagepub.com