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Credibility of subgroup effects used for personalized medicine in oncology: A meta-epidemiological study

Applicant Schandelmaier Stefan
Number 180830
Funding scheme Return CH Postdoc.Mobility
Research institution Institut für klinische Epidemiologie und Biostatistik Universitätsspital Basel
Institution of higher education University of Basel - BS
Main discipline Methods of Epidemiology and Preventive Medicine
Start/End 01.05.2019 - 31.12.2019
Approved amount 76'427.00
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All Disciplines (2)

Discipline
Methods of Epidemiology and Preventive Medicine
Medical Statistics

Keywords (5)

Clinical trials; Effect modification; Oncology; Subgroup analysis; Targeted therapy

Lay Summary (German)

Lead
Target-spezifische Krebstherapie ist ein sehr aktiver Forschungszweig. Studien über Target-spezifische Krebsmedikamente vergleichen häufig Patienten mit unterschiedlichen Tumor-subtypen (Subgruppenanalysen). Es ist bekannt, dass manche Tumor-subtypen besser auf die Target-spezifische Therapie ansprechen. Andere Tumor-subtypen sprechen kaum oder gar nicht an, so dass manche Patienten keinen Nutzen, und möglicherweise sogar einen Schaden davontragen können. Über letzteres ist sehr wenig bekannt.
Lay summary

Ziel dieses Projektes war es, solche Subgruppenanalysen systematisch zu untersuchen in einer großen Anzahl von Studien. Ein Team aus erfahrenen Methodikern hat dafür 292 Krebsstudien untersucht, die in den führenden Zeitschriften publiziert wurden. In den Studien haben wir 67 Behauptungen gefunden, dass ein Target-spezifisches Medikament in unterschiedlichen Subgruppen unterschiedliche Wirkung hat. Die Glaubwürdigkeit dieser Behauptungen war in den allermeisten Fällen sehr gering oder gering, meist wegen unvollständigen Angaben. Nur 13 hatten eine mäßige und nur 1 Behauptung hatte eine hohe Glaubwürdigkeit. In 32 Fällen haben die Forscher auch Tumorarten gefunden, bei denen das ein Target-spezifisches Medikament möglicherweise schädlich für die Patienten ist. Das wurde allerding nur in 8 Studien transparent berichtet. Nur eine Studie hat explizit auf eine mögliche schädliche Wirkung hingewiesen. Zusammenfassen weist die Evidenz zu Subgruppeneffekten bei Target-spezifischen Medikamenten oft erhebliche Qualitätsmängel auf. Einseitige Darstellungen können zu einer Gefährdung von Patienten führen. Die methodische Qualität von Subgruppenanalysen in der Krebsforschung muss dringend verbessert werden.


Direct link to Lay Summary Last update: 18.05.2020

Responsible applicant and co-applicants

Employees

Publications

Publication
Characteristics and interpretation of subgroup analyses based on tumor characteristics in randomized trials testing target-specific anti-cancer drugs: design of a systematic survey
SchandelmaierStefan, SchmittAndreas M, HerbrandAmanda K, GlinzDominik, EwaldHannah, BrielMatthias, HemkensLars G, GuyattGordon H, KasendaBenjamin, Characteristics and interpretation of subgroup analyses based on tumor characteristics in randomized trials testing target-specific anti-cancer drugs: design of a systematic survey, in BMJ open.

Collaboration

Group / person Country
Types of collaboration
University Medical Library, University of Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Department of Health Research Methods, Evidence, and Impact Canada (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Department of Medical Oncology, University Hospital Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Indian Institute of Public Health Delhi India (Asia)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Associated projects

Number Title Start Funding scheme
164750 Development and validation of an instrument to assess the credibility of putative subgroup effects in randomized controlled trials and meta-analyses 01.05.2016 Advanced Postdoc.Mobility

Abstract

BACKGROUND: There is a rapid development of knowledge on molecular alterations within tumors that can be targeted by novel anti-cancer drugs. Randomized clinical trials now increasingly report subgroup analyses based on tumor characteristics including variation of such targets (e.g. cytogenetics, or receptor expression). Compared to traditional subgroup analyses (e.g. based on sex or age groups), that usually have low credibility, target-related subgroup effects have the potential as they might more frequently based on a strong biological rationale. At the same time, one would expect a higher frequency of so-called qualitative subgroup effects, i.e. suggesting benefit in the target-effective subgroup but harm in the target-ineffective subgroup. Motivated by recent examples that showed large qualitative subgroup effects, we performed a systematic survey of randomized controlled trials to systematically assess the characteristics, credibility, and reporting of subgroup analyses based on tumor characteristics. METHODS: We systematically analyzed 292 oncology trials published between 2016 and 2017 in leading journals that investigated target-specific anti-cancer drugs. Teams of methodologically trained investigators characterized, independently and in duplicate, the trials and subgroup analyses. They systematically assessed the strength of subgroup claims using predefined criteria, the credibility of claims using the new Instrument for Assessing the Credibility of Effect Modification ANalyses (ICEMAN), and the reporting of subgroup effects suggesting potential harm.FINDINGS AND INTERPRETATION: Of the 292 included trials, 198 (68%) reported subgroup analyses; 71 (24%) one or more claims of subgroup effects; and 48 (16%) one or more claims of subgroup effects based on a tumor characteristic (67 claims in total). Using ICEMAN, We classified the credibility of the 67 claims as very low (38, 57%), low (15, 22%), moderate (13, 19%), and high (1, 1%).The strength claims as reported were a very a poor indication of their credibility. Of the 67 claims, 32 (48%) were compatible with a qualitative subgroup effect, but only 8 studies acknowledged the possibility of a qualitative subgroup effect, and 1 study explicitly acknowledged the associated risk of harm. INTERPRETATION: The study highlights the urgent need for more appropriate interpretation and more transparent reporting of subgroup analyses in target-specific oncology. The reporting bias towards subgroups suggesting benefit ad the systematic neglect of potentially harmful effects caused by target-specific anti-cancer drugs is concerning.
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