The statistical analysis of a clinical trial when a protocol amendment changed the inclusion criteria
Open accessAbstract
BACKGROUND: Sometimes, protocol amendments that change the inclusion and exclusion criteria are required in clinical trials. Then, the patient populations before and after the amendment may differ. METHODS: We propose to perform separate statistical tests for the different phases, i.e. for the patients recruited before and after the amendment, and to combine the tests using Fisher's combination test. After a significant combination test a multiple testing procedure can be applied to identify the phase(s) to which a proof of efficacy refers. We assume that the amendment(s) are not based on any type of unblinded data. The proposed method is investigated within a simulation study. RESULTS: The proposed combination approach is superior to the 'naïve' strategy to ignore the differences between the phases and pooling the data to perform just one statistical test. This superiority disappears when there are hardly any differences between the two phases. CONCLUSION: When one or more protocol amendments change the inclusion and exclusion criteria, one should realize that the populations may differ. In this case, separate tests for the different phases together with a combination test are a powerful method that can be applied in a variety of settings. The (first) amendment should specify the combination test to be applied in order to combine the different phases.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Substantive amendments can create challenges to data analysis and interpretation if they occur part way through the trial.
“Substantive amendments can create challenges to data analysis and interpretation if they occur part way through the trial (eg, changes in eligibility criteria),481”
From SPIRIT 2025 explanation and elaboration: updated guideline for protocols of randomised trials (2025) · cites this paper as [481]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Wasserman, S. S., Hedges, L. V., & Olkin, I. (1988) · Journal of Educational Statistics · doi:10.2307/1164953 · Cited by 10,347 · see citing works
Statistical Methods for Meta-Analysis
(1985) · Elsevier eBooks · doi:10.1016/c2009-0-03396-0 · Cited by 2,549 · see citing works
Evaluation of Experiments with Adaptive Interim Analyses
Bauer, P., & Kohne, K. (1994) · Biometrics · doi:10.2307/2533441 · Cited by 869 · see citing works
Section XXIV. Partition Chromatographs
Haider, S. I., & Ashtok, A. (2009) · Biotechnology · doi:10.1201/9781420084498-31 · Cited by 590 · see citing works
Statistical Principles for Clinical Trials
Kay, R. (1998) · Journal of International Medical Research · doi:10.1177/030006059802600201 · Cited by 573 · see citing works
Combining different phases in the development of medical treatments within a single trial
Bauer, P., & Kieser, M. (1999) · Statistics in Medicine · doi:10.1002/(sici)1097-0258(19990730)18:14 · Cited by 289 · see citing works
A systematic comparison of methods for combining p-values from independent tests
Loughin, T. M. (2004) · Computational Statistics & Data Analysis · doi:10.1016/j.csda.2003.11.020 · Cited by 220 · see citing works
A general statistical principle for changing a design any time during the course of a trial
Müller, H., & Schäfer, H. (2004) · Statistics in Medicine · doi:10.1002/sim.1852 · Cited by 152 · see citing works
Dubertret, L., Sterry, W., Bos, J. D., Chimenti, S., Shumack, S. P., Larsen, C. G., Shear, N. H., Papp, K. A., & CLEAR Multinational Study Group (2006) · British Journal of Dermatology · doi:10.1111/j.1365-2133.2006.07344.x · Cited by 143 · see citing works
Estimation in flexible two stage designs
Brannath, W., König, F., & Bauer, P. (2005) · Statistics in Medicine · doi:10.1002/sim.2258 · Cited by 83 · see citing works
Statistics Applied to Clinical Trials
Cleophas, T. J., Zwinderman, A. H., & Cleophas, T. F. (2006) · Springer eBooks · doi:10.1007/978-1-4020-4650-6 · Cited by 73 · see citing works
Banik, N., Kohne, K., & Bauer, P. (1996) · Biometrical Journal · doi:10.1002/bimj.4710380103 · Cited by 48 · see citing works
Inference for Clinical Trials with Some Protocol Amendments
Chow, S., & Shao, J. (2005) · Journal of Biopharmaceutical Statistics · doi:10.1081/bip-200062286 · Cited by 48 · see citing works
Confirmatory Clinical Trials with an Adaptive Design
Koch, A. (2006) · Biometrical Journal · doi:10.1002/bimj.200510239 · Cited by 40 · see citing works
Tan, M. T., Qu, Y., Mascha, E. J., & Schubert, A. (1999) · Statistics in Medicine · doi:10.1002/(sici)1097-0258(19990815)18:15 · Cited by 26 · see citing works
Statistical Quality Control in Clinical Trials
Svolba, G., & Bauer, P. (1999) · Controlled Clinical Trials · doi:10.1016/s0197-2456(99)00029-x · Cited by 23 · see citing works
The Effect of Screening on Some Pretest-Posttest Test Variances
Follmann, D. A. (1991) · Biometrics · doi:10.2307/2532164 · Cited by 15 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials
Chan, A.-W., Tetzlaff, J. M., Gotzsche, P. C., Altman, D. G., Mann, H., Berlin, J. A., Dickersin, K., Hrobjartsson, A., Schulz, K. F., Parulekar, W. R., et al. (2013) · BMJ · doi:10.1136/bmj.e7586 · Cited by 6,251 · see citing works
Fogel, D. B. (2018) · Contemporary Clinical Trials Communications · doi:10.1016/j.conctc.2018.08.001 · Cited by 1,035 · see citing works
SPIRIT 2025 explanation and elaboration: updated guideline for protocols of randomised trials
Hróbjartsson, A., Boutron, I., Hopewell, S., Moher, D., Schulz, K. F., Collins, G. S., Tunn, R., Aggarwal, R., Berkwits, M., Berlin, J. A., et al. (2025) · BMJ · doi:10.1136/bmj-2024-081660 · Cited by 171 · see citing works
Measuring the Incidence, Causes, and Repercussions of Protocol Amendments
Getz, K. A., Zuckerman, R., Cropp, A. B., Hindle, A. L., Krauss, R., & Kaitin, K. I. (2011) · Drug Information Journal · doi:10.1177/009286151104500307 · Cited by 76 · see citing works
Onakpoya, I., Lee, J. J., Mahtani, K. R., Aronson, J. K., & Heneghan, C. J. (2020) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.14210 · Cited by 76 · see citing works
Analysis of eligibility criteria in Alzheimer’s and related dementias clinical trials
Mitchell, A. K., Ehrenkranz, R. C., Franzen, S., Han, S. H., Shakur, M., McGowan, M., & Massett, H. A. (2024) · Scientific Reports · doi:10.1038/s41598-024-65767-x · Cited by 17 · see citing works
Leuchs, A., & Neuhäuser, M. (2011) · Journal of Statistical Computation and Simulation · doi:10.1080/00949655.2011.638635 · Cited by 15 · see citing works
Self-citationThe Statistical Analysis of Small Data Sets
Neuhäuser, M., & Ruxton, G. D. (2024) · doi:10.1093/oso/9780198872979.001.0001 · Cited by 12 · see citing works
Self-citationCragg, W. J., McMahon, K., Oughton, J. B., Sigsworth, R., Taylor, C., & Napp, V. (2021) · Trials · doi:10.1186/s13063-021-05723-6 · Cited by 12 · see citing works
Artificial Intelligence in Clinical Trials
Saeed, H., & Naqa, I. E. (2022) · Springer eBooks · doi:10.1007/978-3-030-83047-2_19 · Cited by 12 · see citing works
Politics and trust in Ebola vaccine trials
Aggrey, J. K., & Shrum, W. (2020) · Politics and the Life Sciences · doi:10.1017/pls.2020.1 · Cited by 8 · see citing works
Tang, P., van den Broek, D. H. N., Jepson, R. E., Geddes, R. F., Chang, Y., Lötter, N., Moniot, D., Biourge, V. C., & Elliott, J. (2024) · Journal of Veterinary Internal Medicine · doi:10.1111/jvim.17134 · Cited by 6 · see citing works
Visual Text Mining: Ensuring the Presence of Relevant Studies in Systematic Literature Reviews
Felizardo, K. R., Barbosa, E. F., Martins, R. M., Valle, P. H. D., & Maldonado, J. C. (2015) · International Journal of Software Engineering and Knowledge Engineering · doi:10.1142/s0218194015500114 · Cited by 5 · see citing works
Yang, L., Chi, Y., & Chow, S. (2011) · Journal of Biopharmaceutical Statistics · doi:10.1080/10543406.2010.481803 · Cited by 3 · see citing works
Costs of Quality in Clinical Development
Eriksson, B. (2018) · Therapeutic Innovation & Regulatory Science · doi:10.1177/2168479018809693 · Cited by 3 · see citing works
Neuhäuser, M., & Ruxton, G. D. (2024) · Oxford University Press eBooks · doi:10.1093/oso/9780198872979.003.0005 · Cited by 2 · see citing works
Self-citationNote on permutation and bootstrap tests
Neuhäuser, M., & Ruxton, G. D. (2024) · Oxford University Press eBooks · doi:10.1093/oso/9780198872979.003.0002 · Cited by 2 · see citing works
Self-citationA Statistical Method for Protocol Modifications With Heterogeneous Population Variances
Chiang, C., Wu, Y., Cheng, L.-H., Liu, C., & Hsiao, C. (2024) · Statistics in Biopharmaceutical Research · doi:10.1080/19466315.2024.2369267 · Cited by 1 · see citing works
Magwenzi, M. M. (2020) · MedEdPublish · doi:10.15694/mep.2020.000223.1 · Cited by 1 · see citing works
Type I error for a chi-square test when the response probability changes during a trial
Hu, F., Lu, J., & Tai, F. (2012) · Statistics and Its Interface · doi:10.4310/sii.2012.v5.n4.a10
Giesbrecht, E. (2016) · cIRcle (University of British Columbia) · doi:10.14288/1.0302682
Bayesian Approach for Analysis of Binary Responses in Clinical Trials with Protocol Amendments
Yang, L. ‐., Chow, S., & Chi, Y. (2010)
How to Document a Clinical Study and Avoid Common Mistakes in Study Conduct?
Mouton, C., de Girolamo, L., Theisen, D., & Seil, R. (2019) · Springer eBooks · doi:10.1007/978-3-662-58254-1_14
Comparing continuous data across levels of one or more factors
Neuhäuser, M., & Ruxton, G. D. (2024) · Oxford University Press eBooks · doi:10.1093/oso/9780198872979.003.0004
Self-citationNeuhäuser, M., & Ruxton, G. D. (2024) · Oxford University Press eBooks · doi:10.1093/oso/9780198872979.002.0004
Self-citationNeuhäuser, M., & Ruxton, G. D. (2024) · Oxford University Press eBooks · doi:10.1093/oso/9780198872979.003.0007
Self-citationNeuhäuser, M., & Ruxton, G. D. (2024) · Oxford University Press eBooks · doi:10.1093/oso/9780198872979.003.0011
Self-citationNeuhäuser, M., & Ruxton, G. D. (2024) · Oxford University Press eBooks · doi:10.1093/oso/9780198872979.002.0003
Self-citationNeuhäuser, M., & Ruxton, G. D. (2024) · Oxford University Press eBooks · doi:10.1093/oso/9780198872979.002.0006
Self-citationNeuhäuser, M., & Ruxton, G. D. (2024) · Oxford University Press eBooks · doi:10.1093/oso/9780198872979.003.0009 · Cited by 1 · see citing works
Self-citationNeuhäuser, M., & Ruxton, G. D. (2024) · Oxford University Press eBooks · doi:10.1093/oso/9780198872979.003.0001
Self-citationSequential analysis and adaptive designs
Neuhäuser, M., & Ruxton, G. D. (2024) · Oxford University Press eBooks · doi:10.1093/oso/9780198872979.003.0008
Self-citationNeuhäuser, M., & Ruxton, G. D. (2024) · Oxford University Press eBooks · doi:10.1093/oso/9780198872979.003.0006
Self-citationNeuhäuser, M., & Ruxton, G. D. (2024) · Oxford University Press eBooks · doi:10.1093/oso/9780198872979.003.0010
Self-citationA single sample of continuous data
Neuhäuser, M., & Ruxton, G. D. (2024) · Oxford University Press eBooks · doi:10.1093/oso/9780198872979.003.0003
Self-citation
- Authors
- Lösch, C., & Neuhäuser, M.
- Affiliations
- Institut für Medizinische Informatik, Biometrie und Epidemiologie (DE)
- Koblenz University of Applied Sciences (DE)
- Corresponding author
- Lösch, Christian
- ORCID
- Neuhäuser, Markus
- Venue
- BMC Medical Research Methodology
- Published
- 2008-04-08
- Volume
- 8
- Issue
- 1
- Pages
- 16-16
- ISSN
- 1471-2288 (ISSN-L)
- PMC
- PMC2359757
- OpenAlex
- W2114874476
- Cited by
- 35
- References
- 18
- Citations by year
- 2025: 1 · 2024: 18 · 2022: 1 · 2021: 1 · 2020: 3 · 2019: 1 · 2018: 2 · 2016: 1 · 2015: 1 · 2013: 1 · 2012: 1
- FWCI
- 1.26
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- BMC Medical Research Methodology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Topics
- Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Clinical Trials
- Social Sciences › Decision Sciences › Statistics, Probability and Uncertainty › Meta-analysis and systematic reviews
- Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods and Bayesian Inference
- Keywords
- protocol modification, inclusion criteria, exclusion criteria, clinical trials, multiple comparisons, heterogeneous patient populations
- MeSH terms
- Clinical Protocols, Clinical Trials as Topic, Data Interpretation, Statistical, Humans, Research Design, Patient Selection
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
