Choice of Comparator in Active Control Trials of New Drugs
Abstract
Background: When choosing the active control group in a randomized that, it is important to maintain standard treatment for the therapeutic indication for which a medicine is studied. This choice is relevant not only for demonstrating the efficacy and safety of a new drug, but also for assessing Its place in therapy in comparison with existing medicines. Comparative information is important for decisions on prescribing and reimbursement. However, choosing the most suitable comparator is difficult when recommendations on drugs of first choice vary depending on clinical settings and times. Objective: To evaluate the choice of comparator in premarketing randomized active control trials (RaCTs) in comparison with recommendations lor standard treatment. Methods: We evaluated drugs that were authorized for use in the European Union market between 1999 and 2005. Information on active comparators in RaCTs was extracted from the European Public Assessment Reports and information on recommendations regarding standard treatment was retrieved from the annual editions of the Dutch reference book on pharmacotherapy. Data on prescribing and indications at the time of authorization and 3 years before authorization were included. The comparator was considered to be in line with standard treatment if there was a similarity in both active substance or therapeutic class and the dosage. Results: For 58 new medications identified, treatment in the active control group was in line with the recommended standard treatment in 108 of 153 (71%) RaCTs at the time of the drug's authorization; 47 (81%) of the new drugs had been compared with the recommended standard treatment in at least one trial. When dissimilarities occurred, none of the comparators had been recommended as standard treatment 3 years earlier (the supposed time of defining the trials' protocol). Conclusions: Most comparators in the premarketing RaCTs of new medicines were in line with the recommended standard treatment at the moment of marketing authorization. In view of this similarity, most of these trials are also fit for postmarketing decision-making on prescribing and on inclusion in clinical guidelines and reimbursement systems.
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The choice of comparator has important implications for trial ethics, recruitment, results, and interpretation.
“The choice of comparator has important implications for trial ethics, recruitment, results, and interpretation.”
From SPIRIT 2025 explanation and elaboration: updated guideline for protocols of randomised trials (2025) · cites this paper as [157]
A trial in which the comparator group receives an inappropriately high dose will lead to an underestimate of the relative harms of the study intervention.
“conversely, an inappropriately high dose in the comparator group will lead to an underestimate of the relative harms of the study intervention.157 158”
From SPIRIT 2025 explanation and elaboration: updated guideline for protocols of randomised trials (2025) · cites this paper as [157]
A trial in which the comparator group receives an inappropriately low dose of an active drug will overestimate the relative efficacy of the study intervention in clinical practice.
“For example, a trial in which the comparator group receives an inappropriately low dose of an active drug will overestimate the relative efficacy of the study intervention in clinical practice;”
From SPIRIT 2025 explanation and elaboration: updated guideline for protocols of randomised trials (2025) · cites this paper as [157]
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- Authors
- Luijn, J. C. V., Loenen, A. C. V., Gribnau, F. W., & Leufkens, H. G.
- Affiliations
- Health Care Insurance Board, Diemen, Netherlands; Researcher, Faculty of Science, Division of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands
- Farmacotherapeutisch Kompas, Health Care Insurance Board, Diemen
- Radboud University Nijmegen (NL)
- Utrecht University (NL)
- ORCID
- Leufkens, Hubert GM
- Venue
- Annals of Pharmacotherapy
- Publisher
- SAGE Publications
- Published
- 2008-10-28
- Volume
- 42
- Issue
- 11
- Pages
- 1605-1615
- ISSN
- 0012-6578 (ISSN-L)
- 1060-0280
- 1542-6270
- OpenAlex
- W2113417363
- Cited by
- 21
- References
- 19
- Citations by year
- 2025: 3 · 2019: 1 · 2016: 1 · 2015: 3 · 2014: 1 · 2013: 5 · 2012: 3
- FWCI
- 1.26
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Annals of Pharmacotherapy (publishedVersion)
- PubMed (publishedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Topics
- Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Clinical Trials
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmaceutical industry and healthcare
- Social Sciences › Economics, Econometrics and Finance › Economics and Econometrics › Pharmaceutical Economics and Policy
- Keywords
- comparator selection, new drug approvals, European Public Assessment Reports, drug reimbursement, prescribing decisions, clinical guidelines, drug approval
- MeSH terms
- Pharmaceutical Preparations, European Union, Humans, Randomized Controlled Trials as Topic, Drug Approval, Control Groups
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