The run-in period in clinical trials. The effect of misclassification on efficiency

This article considers the effect of misclassification of potential participants during the run-in period preceding randomization in a clinical trial. We present a simple mathematical model of adherence that allows for misclassification. Simulations based on this model assess the impact of a run-in period on statistical power. The run-in period is most effective when there is a high proportion of poor adherers and a low rate of misclassification. In situations with either a high degree of adherence or substantial misclassification, the run-in period may reduce the efficiency of the trial, particularly when the cost of recruitment is high. We also discuss the early adherence in two recently conducted trials that had no run-in periods in order to estimate the extent of misclassification and consequent effect on power that would have been observed had a run-in occurred.     

Estimating effect sizes in clinical trials

Even though reporting of effect sizes is recommended in methodological guidelines such as the CONSORT Statement (Consolidated Standard of Reporting Trials), these quantities are still rarely included in reports on studies in rehabilitation medicine. The aim of this paper is to emphasize the relevance of reporting effect sizes and to illustrate different methods for their calculation. The implications of using different methods for calculating effect sizes are also discussed.     

The DICOM standard

The DICOM Standard for network communication has been approved by ACR and NEMA in October 1993. The ACC has joined the effort in 1992 and drives the extension of DICOM for Media Interchange with a focus on defining a digital recording standard for communication between catheterisation laboratories. This is a necessary foundation towards cinefilm replacement. DICOM networking is being adopted as a European Standard called MEDICOM and the increasing interest of the ESC is likely to result in the adoption of DICOM Media Storage and interchange as an extension of MEDICOM in 1995. This represents a major breakthrough in the communication of medical images in electronic form. DICOM has been designed to offer an integrated approach to the increasing use of high speed computer networks in health care as well as larger and higher throughput storage media. This article focuses on the network communication as well as introduces the extension of DICOM for Media interchange which has been approved early 1995.     

The Lugano statements on controlled clinical trials

During a consensus conference in Lugano, Switzerland, 175 statements on controlled clinical trials were drafted by 47 representatives from academia, governmental registration agencies and industry in nine countries. Their opinion on these statements was similar to that of 47 'matched pairs' who did not attend the conference. Thus, the opinion of participants and non-participants appears to reflect the general opinion of those currently involved in designing, conducting and analysing controlled clinical trials. The Lugano statements give answers to the following questions: Is the controlled clinical trial in a crisis? What is the motivation to perform controlled clinical trials? Is it possible for a physician participating in a controlled clinical trial to act in the patient's best interest? Is it possible to obtain truly informed consent in a controlled clinical trial? When is it ethical to withhold active treatment in a controlled clinical trial? What are the controversial issues in the design of a good controlled clinical trial? Is there a double standard with respect to efficacy and adverse drug reactions in controlled clinical trials? What are the alternatives to controlled clinical trials and when should they be performed? How can sponsor bias be minimized? How should an ethics committee decide whether a controlled clinical trial is ethical? Should registration agencies become directly involved in the planning and conduct of controlled clinical trials? Do the declarations of Tokyo and Helsinki facilitate the conduct of ethically valid controlled clinical trials? Is it possible to create an international standard for the conduct and regulation of controlled clinical trials? Why do messages from controlled clinical trials filter into medicine so slowly? Is it possible to bridge the gap between controlled clinical trials and clinical reality? What are the costs of doing and not doing controlled clinical trials? When should drug companies decide to start a trial programme with a specific compound? Is there public hostility against controlled clinical trials? If so, how can it be reduced? The respondents almost unanimously felt that controlled clinical trials are a must: the public must be told that progress in medicine depends on controlled clinical trials, that patients often benefit from participating in them and that the alternative, practising in the face of constant uncertainty, is worse than the possible disadvantages related to the conduct of the trial.     

Direct effect on validity of response run-in selection in clinical trials

A run-in is a period prior to randomization during which potential participants who have met all entry criteria for a randomized clinical trial are assigned the same regimen, either the control (possibly placebo) or the experimental treatment. Typically, the intention is to exclude from the subsequent study (i.e., randomization) some segment of this cohort, based on their experiences during the run-in period. Selecting patients based on the run-in thereby forces differential representation of certain subpopulations relative to others. Previous studies have addressed the potential for a run-in to jeopardize validity through unintended mechanisms. While these concerns are valid, they leave open the possibility that modifications to the design of the run-in might be able to preserve validity, even if patient selection is based on the results of the run-in. As such, we address the potential for selecting patients based on response during a run-in period to jeopardize validity directly, through its intended effect of overrepresenting (relative to the screened population) some segments in the randomized portion of the trial and underrepresenting others.     

The effect of scientific misconduct on the results of clinical trials: a Delphi survey

OBJECTIVES: To discover what types of scientific misconduct are most likely to influence the results of a clinical trial. DESIGN: Delphi survey of expert opinion with three rounds of consultation. SETTING: Non-industry clinical trial "community". PARTICIPANTS: Experts identified from invitees to a previous MRC consultation on clinical trials. 32 out of the 40 experts approached agreed to participate. RESULTS: We identified thirteen forms of scientific misconduct for which there was majority agreement (>50%) that they would be likely or very likely to distort the results and majority agreement (>50%) that they would be likely or very likely to occur. Of these, the over-interpretation of 'significant' findings in small trials, selective reporting and inappropriate subgroup analyses were the main themes. CONCLUSIONS: According to this expert group, the most important forms of scientific misconduct in clinical trials are selective reporting and the opportunistic use of the play of chance. Data fabrication and falsification were not rated highly because it was considered that these were unlikely to occur. Registration and publication of detailed clinical trial protocols could make an important contribution to preventing scientific misconduct.     

The effect of therapeutic treatment crossovers on the power of clinical trials. The Silicone Study Group

The Silicone Study is a randomized clinical trial comparing two surgical methods for reattaching the retina when detachment is associated with proliferative vitreoretinopathy. If the retina redetaches subsequently, the patient will usually undergo additional surgery using the assigned treatment. In a limited number of cases the patient may be switched to the alternative treatment, if a "therapeutic crossover" is endorsed by an independent committee of ophthalmologists. A successful outcome is continued anatomic attachment of the retina and an adequate visual result 6 months after the final surgery. The therapeutic treatment crossovers affect the power of the trial to detect a difference between the two treatments. A simulation study shows that the loss in power depends on the magnitude and degree of bias in the probability of being switched from one treatment to the other. Unlike the usual case of lack of compliance, complete information about treatment history may allow statistical adjustment for the crossover. The outcome may be modeled using a multinomial distribution. Much of the power lost due to switching may be recouped under some strong assumptions.     

The investigator-sponsored IND in clinical trials

The Food, Drug, and Cosmetic Act requires that clinical investigations conducted in the United States involving unapproved drugs be done under an Investigational New Drug Application (IND). INDs are often sponsored by pharmaceutical firms or noncommercial research institutions. Most INDs, however, are sponsored by individual researchers. Since the procedures for filing an IND may not be well understood, this article seeks to clarify these procedures. Specifically, this article describes a "Sponsor-Investigator IND," the conditions under which one is required, and the possible advantages of filing one. The information presented aids the investigator in determining whether an IND need be submitted. The authors have developed an IND workbook that can be used to organize and present the IND application in a form likely to facilitate expeditious review and approval by the FDA. The authors have also developed IND guidelines to assist investigators in preparing, submitting, and maintaining an IND. Obligations and responsibilities of both sponsors and investigators are discussed.     

Inept media trials of clinical trials

The Indian media in general, with the exception of a few domain expert journalists, have failed to comprehend the complexities involved in the clinical trial process. In the run up to the deadline-based coverage of a story, a majority of them fall short in conveying the right perspective to readers, but nevertheless they have been successful in sensationalizing an event in this arena. Possibly by unintended misrepresentation, or mostly out of ignorance of the nuances involved in the clinical trials process, the media has done more harm than good, and got away with it. On the other side, the industry has been reluctant to engage with the media in a meaningful dialog for too long now. It bears not only the consequences of damage to its professional reputation following such reportage, but also the repercussions of unnecessary clampdowns by the regulators. Science journalism in India has yet to rise as a profession.     

The use of minimization in clinical trials

Since its introduction in 1974 the use of the term Minimization has been broadened to include other algorithms. All algorithms use patient characteristics to determine the assignment that produces the best overall balance between treatment groups. They differ in whether or not they use all of the data from each previously assigned subject to assign subsequent subjects so the methods are classified as complete or partial minimization. PubMed, Citation Index and Cochrane searches determined the frequency of articles using these types of minimization and a subset was selected for detailed review regarding the adequacy of the usage and reporting of minimization. In the past 10 years usage has increased three fold over the previous decade but is still less than 2% of clinical trials. None of the studies makes maximum use of minimization and they are not following good reporting practices. Concerns about the use of minimization have involved selection bias and statistical analysis. Several modifications to minimization are suggested to reduce the possibility of selection bias so that adding randomization will rarely be required. Separating primary and secondary analyses can avoid the statistical problems that minimization poses. The two types of analyses are distinguished by opposite limiting signs, providing reliable, simplified statistical results. This will improve data utilization and make clinical trials more reproducible. Minimization should be the method of choice in assigning subjects in all clinical trials.     

The role and potential contribution of clinical research nurses to clinical trials

Aims and objectives. This study explores the scope and potential contribution of the Clinical Research Nurse (CRN) role to clinical trials of a nursing‐specific topic. Background. Over the past two decades, there have been increases in the numbers of nurses working as CRNs because of the increasing global demand for clinical trials. CRNs can influence the quality of clinical trials but the scope and contribution of the role to clinical trials is not known. Design. Qualitative focus group study. Methods. A focus group interview was carried out with CRNs (n = 9) employed on a large, multi‐centre (six NHS Trusts) randomized controlled trial of pressure area care. The focus group interview was recorded, alongside field notes of participant interactions and behaviours, and transcribed verbatim. Data were analysed for thematic content and process. Findings. CRNs described their transition to a clinical research role. They reported a lack of confidence, role conflict as researcher and nurse, the challenges of gaining cooperation of clinical nursing staff to comply with trial protocols and difficulties maintaining their own motivation. CRNs provided their perceptions and observations of pressure area care and prevention. They identified areas of inadequate treatment, management and care, influenced by organizational and clinical aspects of care delivery. Conclusions. The study reveals challenges associated with training and management of CRNs. CRNs are usually associated with trial recruitment and data collection. This study highlights the additional contributions of CRNs for the study of topics specific to nursing as the result of their unique placement in the research centres as informal ‘participant observers.’ Such observations enhance understanding of the contexts being studied. Relevance to clinical practice. These findings are relevant to the design and conduct of research studies of nursing care and practice and present ways for investigators to optimize the skills and knowledge of nurses working as CRNs.