Limitations of Randomized Clinical Trials. Proposed Alternative Designs
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Ton J. Cleophas
Abstract
Background: The classical two-period crossover and two-parallel-groups designs for clinical drug trials are unable to answer many current scientific questions, and are sometimes ethically or financially difficult. For example, the classical designs do not allow the study of the effects of combined treatments and their interactions. Also, the generation of parallel data that are no more than a repetition of previous research is ethically debatable and in a sense a waste of money.
Objectives are to identify what a classical clinical trial cannot manage, to summarize and discuss alternative trial designs that are helpful for such purposes.
Results: A classical clinical trial cannot: (i) assess combined therapies, (ii) take historical data into account, (iii) safeguard ethics and efficacy during the course of long-term trials, (iv) study drugs, before well-established toxicity information is available, (v) account for the possibility of therapeutic equivalence between test and reference treatment, (vi) study multiple treatments in one trial, and (vii) adjust change scores for baseline levels.
Alternative designs helpful for such purposes are respectively: (i) factorial designs, (ii) historical controls designs, (iii) group-sequential interim analysis designs, (iv) sequential designs for continuous monitoring, (v) therapeutic equivalence designs, (vi) multiple crossover-periods/multiple parallel-groups design, and (vii) increased precision designs through multivariate adjustment.
Main problems include the increased risks of type I and type II errors and the loss of validity criteria.
Conclusions: Non-classical trial designs are reviewed. They offer relevant scientific, ethical, and financial advantages. The increased risks of type I and type II errors should be accounted for in the design stage of the trial.
Copyright © 2000 by Walter de Gruyter GmbH & Co. KG
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- Subject Index
- Author Index
- Contents
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Articles in the same Issue
- Subject Index
- Author Index
- Contents
- Limitations of Randomized Clinical Trials. Proposed Alternative Designs
- Haemochromatosis: Automated Detection of the Two Point Mutations in the HFE Gene: Cys282Tyr and His63Asp
- Presence of Group IIa Secretory Phospholipase A2 in Mast Cells and Macrophages in Normal Human Ileal Submucosa and in Crohn's Disease
- Relationship between Plasma Ammonia Concentration and β-N-Acetylhexosaminidase Isoenzyme Activities in Liver Cirrhosis
- Thiol Redox Status Influences Extracellular Concentration of Homocysteine in HeLa Cell Cultures
- Serum Total and Lipid-Bound Sialic Acid Levels Following Acute Myocardial Infarction
- Concentration of Leukocyte Elastase in Plasma and Polymorphonuclear Neutrophil Extracts in Type 2 Diabetes
- Hypertriglyceridemia Characterized by Low-Density Lipoprotein Phenotype and Lipoprotein Lipase Gene Mutation
- Different Stability of Free and Complexed Prostate-Specific Antigen in Serum in Relation to Specimen Handling and Storage Conditions
- Erythrocyte Superoxide Dismutase and Glutathione Peroxidase Activities, and Malondialdehyde and Reduced Glutathione Levels in Schizophrenic Patients
- Reference Change Value for HbA1c in Patients with Type 2 Diabetes Mellitus
- Specific Oxidase Activity of Cord Serum Ceruloplasmin in the Newborn
- Sequential Evaluation of Serum Urate Concentrations in AIDS Patients with Infections of the Central Nervous System
- Evaluation of Iron Status in Anemic Patients with Rheumatoid Arthritis Using an Automated Immunoturbidimetric Assay for Transferrin Receptor
- IFCC Recommended Reference Method for the Determination of the Substance Concentration of Ionized Calcium in Undiluted Serum, Plasma or Whole Blood
- Current Situation of Clinical Chemistry in Mainland China
- Point of Care Testing. Editors: Christopher P. Price / Jocelyn M. Hicks
- Erratum: Familial Studies on the Genetics of Cardiovascular Diseases: the Stanislas Cohort
- Acknowledgement
