Randomized database studies: a new method to assess drugs' effectiveness?

The need to evaluate drugs' effects in real clinical practice is increasingly important. Randomized clinical trials (RCTs) and database analyses (DBA) are the two main methods to assess treatments effectiveness. RCTs remain the "gold standard" for comparing alternative treatments. However, they are conducted under strict, protocol-driven conditions that may limit their generalizability. Advantages of new high quality clinical databases, on the other hand, include the simple and economic access to large number and range of cases, and the ability to capture all aspects of actual medical practice. The main potential limitation of DBA is the potential for comparison bias due to the lack of randomization. Despite the efforts to design naturalistic trials and to use sophisticated statistical techniques to minimize selection bias, the inherent limitations of both methods (problems of external and internal validity, respectively) have not been completely solved. Thus, the actual challenge is the development of some new strategy capable of generating results with an acceptable balance between internal and external validity. As randomization is essential to minimize comparison bias, we point out the possibility to include randomization modules in computer-based patient records. The theoretical foundation of these "randomized database studies" is the simultaneous use of both experimental and observational methods in the assessment of drugs' effectiveness. The progressive standardization of clinical practice and the development and adoption of improved computer-based patient records could facilitate the use of this new research strategy.

A review of methodologies for assessing drug effectiveness and a new proposal: randomized database studies.

The need to evaluate the effects of health technologies in clinical practice is increasingly important. In this article, we review the advantages and limitations of naturalistic randomized clinical trials (RCTs) and database analyses, the two primary methods for evaluating treatment effectiveness. Also, we comment on a newer research strategy, cross-design synthesis, which proposes the complementary use of both experimental RCTs and observational database methodologies to avoid the main weaknesses of each: respectively, the lack of external and internal validity. Finally, we propose a new strategy--randomized database studies--capable of generating results with an acceptable balance between internal and external validity. This strategy consists of the simultaneous use of both experimental and observational tools in the assessment of drugs' effectiveness. Randomization is essential to minimize comparison bias, and one possibility for such studies is that randomization modules could be included in computer-based patient records. Although we identify some of the difficulties in implementing the process, the progressive standardization of clinical practice and the development and widespread adoption of improved computer-based patient records could facilitate the use of randomized database studies as a new method of research.

[Clinical trials with drugs: the influence of the authorization process]. / Ensayos clínicos con medicamentos: influencia del proceso de autorización.

BACKGROUND: The prevailing regulations require previous review and approval by the administrative authority for clinical trials with drugs in Spain. These regulations have led to the development of a data base of clinical trials submitted for authorization by the Ministry of Health and Welfare. The influence of the evaluation process of authorized clinical trials and the final quality of these trials were studied through this data base. METHODS: The following data corresponding to 1989 and 1990 and grouped in 9 aspects were collected: clarifications applied to protocols of clinical trials, modifications carried out and the causes motivating refusal. Likewise were analyzed the evaluation of quality of each of the aspects considered and the methodological characteristics of the authorized trials. RESULTS: In 1989 and 1990, 298 and 349 protocols of clinical trials were presented; clarifications were requested to 72% in 1989 and to 55% in 1990 (p = 0.0001). Sixty-eight percent and 83% of the trials, respectively were authorized and 19% and 4% were refused and 20% and 13% were annulled, respectively (p = 0.0001). Out of the authorized protocols, 139 (69%) and 144 (50%) received approval following the introduction of modifications (p = 0.0001); of the authorized clinical trials which received clarifications, 94% and 95%, respectively were modified. Among the causes for refusal of the trial 54% and 29% were refused for considering that the trial would not provide relevant information, 58% and 71% for design aspects and 37% and 14% for inadequate patient selection. Of the authorized clinical trials 83% were controlled and randomized in both years with 76% and 73% being blind. CONCLUSIONS: Administrative intervention positively influences in the methodologic and ethical aspects of a relevant part of the authorized clinical trials. The final quality of the clinical trial protocols appears to be comparable to the quality observed by other authors in the clinical trials published in the international literature.

[The quality of clinical trials published in Spain: an evaluation by an analysis of 3 journals during the 1985-1991 period]. / Calidad de los ensayos clínicos publicados en España: valoración a través del análisis de 3 revistas durante el período 1985-1991.

BACKGROUND: The evaluation by readers of a published clinical trial requires that the methodology used in its design and realization be specified in detail. In the present study the quality of clinical trials published in Spain during 1985-1991 has been appraised. METHODS: This is a revision of all clinical studies published from 1985 to 1991 in the following Spanish medical journals: Medicina Clínica, Revista Clínica Española and Revista Española de Enfermedades Digestivas; the studies were assessed by three persons through the use of a questionnaire (checklist) which contained 15 evaluation sections relative to the methodology used in carrying out a study. RESULTS: Only an average of 5.5 (+/- 2.8) aspects of the 15 evaluated aspects were considered adequate in the total of clinical trials. Three of the aspects evaluated: "objective of the study", "end point" and "criteria for assessment of outcome" were considered adequate in more than 75% of the cases. Aspects relative to "loss to follow-up", "statistical methods", "analysis of the results", "collection of adverse events", and "approval by an ethical committee" accounted for most methodological defects, being the percentage of studies with correct information below 20%. As to the remaining sections considered, they were found adequate in an intermediate to low percentage (near 30%). There were no differences in quality among the three journals. A slight increase in quality was observed during the last years. CONCLUSIONS: Major methodological deficiencies appear in the clinical studies published in Spain during the last seven years. The recently approved regulations on clinical trials plus the use of checklists by investigators and journal editors, where detailed ethic and methodological aspects are appraised, can contribute to an increase in quality.

Evaluation of pharmacoeconomic studies: utilization of a checklist.

OBJECTIVE: To review the fundamental concepts used in clinical economic analysis and establish a simple model to systematically evaluate the quality of pharmacoeconomic studies. DATA SOURCES: A MEDLINE search was used to identify pertinent pharmacoeconomic literature, including reviews. STUDY SELECTION: Selected literature evaluating the methodology of health economics studies was used. CONCLUSIONS: The number of studies presenting a pharmacoeconomic evaluation has increased progressively; however, the quality of the studies has not improved in parallel. The existence of different types of pharmacoeconomic studies does not justify their arbitrary use and the achievement of valid conclusions must be based on sound knowledge of the concepts employed, as well as on use of the most adequate tool in each instance. By evaluating pharmacoeconomic studies systematically, the more common errors (i.e., in planning the study or interpreting the results) can be detected and thus prevented. The checklist we present has 12 sections, each of which includes several subsections. After evaluating the corresponding subsections, each section is labeled as "correct," "acceptable," "doubtful," "incorrect," or "not applicable." From this qualitative evaluation, aspects that have been dealt with correctly and those needing improvement will become apparent. Also, the checklist permits the user to verify whether the results have been correctly obtained and, therefore, whether the conclusions are valid. The use of a checklist for evaluating pharmacoeconomic studies may be useful for researchers, journal editors, and the audience when performing, receiving, reading, or accepting a clinical economic study.

Autoradiographic mapping of 5-HT1 receptors in the guinea-pig brain with particular reference to the 5-HT1D receptor sites.

The anatomical distribution of 5-HT1 receptors in the guinea-pig brain was studied by means of in vitro quantitative autoradiography using [3H]-5-HT as ligand. The relative presence of the subtypes of the 5-HT1 binding site was investigated by adding selective concentrations of 8-OH-DPAT, (-)21,009, mesulergine and 5-CT. In addition, differentiation of 5-HT1D receptors was achieved by incubation of the tissues with [3H]-5-HT in the presence of 100 nmol/l 8-OH-DPAT together with 100 nmol/l mesulergine. Areas presenting high densities of 5-HT1A receptors included the neocortex (internal layers), hippocampal formation (dentate gyrus, CA1 field), septum and raphe nuclei, while 5-HT1C sites accounted for most of the [3H]-5-HT binding to the choroid plexus. Non 5-HT1A-non 5-HT1C sites (mainly 5-HT1D and, also probably, 5-HT1E receptors) were clearly predominant in the guinea-pig brain. These sites were mainly present in the neocortex (external layers), basal ganglia, hypothalamus and midbrain (substantia nigra, superior colliculus). As previously described, sites with the properties of 5-HT1B receptors could not be clearly identified in the guinea-pig brain. The present results, in addition to providing a detailed map of the 5-HT1 receptors in the guinea-pig brain, indicate that the guinea-pig is a useful laboratory animal for the study of 5-HT1D receptors.