New Benchmarks on Protocol Amendment Practices, Trends and their Impact on Clinical Trial Performance
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Abstract
The Tufts Center for the Study of Drug Development (Tufts CSDD) conducted a follow-up study in 2022 to assess trends in protocol amendment experiences and the impact amendments have had on clinical trial performance, particularly during the COVID-19 pandemic. Sixteen pharmaceutical companies and contract research organizations provided data on 950 protocols and 2188 amendments. The results show that, since 2015, the prevalence of protocols with at least one amendment in phases I-IV has increased substantially (from 57 to 76%) and the mean number of amendments per protocol has increased 60% to 3.3, up from 2.1. Phase I and III protocols saw the highest increases in the mean number of amendments implemented per protocol. A much higher percentage of amendments-77%-were deemed unavoidable with regulatory agency requests and changes to the study strategy as the top reasons cited for amending a protocol. The total average duration to implement an amendment has nearly tripled during the past decade. The time from identifying the need-to-amend to last oversight approval now takes an average of 260 days and the mean duration during which investigative sites operate with different versions of the clinical trial protocol spans 215 days. Protocols that implemented at least one amendment were more effective at increasing patient screening volume and reducing the actual number of patients enrolled relative to plan. Lastly, the prevalence of protocols with at least one amendment and mean number of amendments was significantly higher for protocols conducted during the pandemic.
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Gaps in protocol content can lead to avoidable protocol amendments, inconsistent or poor trial conduct, and lack of transparency in terms of what was planned and implemented.
“Gaps in protocol content can lead to avoidable protocol amendments,13 inconsistent or poor trial conduct, and lack of transparency in terms of what was planned and implemented.”
From SPIRIT 2025 statement: updated guideline for protocols of randomised trials (2025) · cites this paper as [13]
Amendments to the trial protocol are common.
“Amendments to the trial protocol are common.35 36”
From SPIRIT 2025 explanation and elaboration: updated guideline for protocols of randomised trials (2025) · cites this paper as [36]
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Measuring the Incidence, Causes, and Repercussions of Protocol Amendments
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“This study found that one-third of all protocol amendments could have been avoided[4].”
Self-citationThe Impact of Protocol Amendments on Clinical Trial Performance and Cost
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“Pro-tocols Pro-tocols with amendments, however, resulted in fewer actual screened and enrolled patients relative to original plan than protocols without amendments [1].”
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“…having at least one amendment and the mean number of amendments implemented per protocol are explained, in part, by the corresponding increase observed in protocol complexity (e.g., higher relative number of endpoints, eligibility criteria, procedures, countries, and investigative sites) [5].”
Self-citationProtocol Design Variables Highly Correlated with, and Predictive of, Clinical Trial Performance
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- Kaitin K, editor. Rising protocol complexity is hindering study performance, cost, and efficiency. Tufts CSDD Impact Report. 2018;20(4):1–4.
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Chan, A.-W., 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-2024-081477 · Cited by 460 · 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
SPIRIT 2025 statement: updated guideline for protocols of randomized trials
Chan, A., Boutron, I., Hopewell, S., Moher, D., Schulz, K. F., Collins, P. G. S., Tunn, R., Aggarwal, R., Berkwits, M., Berlin, J. A., et al. (2025) · Nature Medicine · doi:10.1038/s41591-025-03668-w · Cited by 143 · see citing works
“Gaps in protocol content can lead to avoidable protocol amendments 13 , inconsistent or poor trial conduct, and lack of transparency in terms of what was planned and implemented.”
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Chan, A., Boutron, I., Hopewell, S., Moher, D., Schulz, K. F., Collins, P. G. S., Tunn, R., Aggarwal, R., Berkwits, M., Berlin, J. A., et al. (2025) · PLoS Medicine · doi:10.1371/journal.pmed.1004589 · Cited by 77 · see citing works
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New Benchmarks on Protocol Amendment Experience in Oncology Clinical Trials
Botto, E., Smith, Z., & Getz, K. A. (2024) · Therapeutic Innovation & Regulatory Science · doi:10.1007/s43441-024-00629-2 · Cited by 1 · see citing works
“Please see Getz [6] for additional information on data collected and amendment classification[6].”
InfluentialSelf-citationExamining the Association Between DCT Solutions Use and Participant Diversity in Clinical Trials
Smith, Z., & Getz, K. A. (2024) · Therapeutic Innovation & Regulatory Science · doi:10.1007/s43441-024-00659-w · Cited by 1 · see citing works
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Self-citationImplementation of a clinical research “One Signature Initiative” at a large academic medical center
Robison, E. E., Moy, T. L., & Trigg, K. L. (2024) · Journal of Clinical and Translational Science · doi:10.1017/cts.2024.667
“The One Signature Initiative has also addressed the concerns and inefficiencies surrounding retraining and capturing additional signatures when there are protocol amendments [4,5].”
СТАТИСТИКА СУТТЄВИХ ЗМІН ЯК ІНСТРУМЕНТ ВИЯВЛЕННЯ РИЗИКІВ У ПРОЕКТАХ КЛІНІЧНИХ ДОСЛІДЖЕНЬ
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- Authors
- Getz, K., Smith, Z., Botto, E., Murphy, E., & Dauchy, A.
- Affiliations
- Tufts University (US)
- Johnson & Johnson (United States) (US)
- Sanofi (France) (FR)
- Corresponding author
- Getz, Kenneth
- Venue
- Therapeutic Innovation & Regulatory Science
- Published
- 2024-03-04
- Volume
- 58
- Issue
- 3
- Pages
- 539-548
- ISSN
- 2168-4790 (ISSN-L)
- 2168-4804
- OpenAlex
- W4392367320
- Semantic Scholar
- 5b5b97a7807e69be6c402a6e0bba9bf1ef129b6e
- Cited by
- 21
- References
- 5
- Citations by year
- 2026: 8 · 2025: 9 · 2024: 4
- FWCI
- 7.26
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Therapeutic Innovation & Regulatory Science (publishedVersion)
- Research Square (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Amgen
- Bristol-Myers Squibb
- Eli Lilly and Company
- AstraZeneca
- Gilead Sciences
- Biogen
- Regeneron Pharmaceuticals
- Jazz Pharmaceuticals
- Seagen
- Genentech
- EMD Serono
- Topics
- Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Clinical Trials
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Ethics in Clinical Research
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
- Keywords
- COVID-19 pandemic, patient enrollment, drug development, contract research organizations, pharmaceutical companies
- MeSH terms
- Drug Development, Clinical Trial Protocols as Topic, COVID-19, SARS-CoV-2, Clinical Trials as Topic, Humans, Research Design, United States, Benchmarking, Pandemics
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