The Impact of Protocol Amendments on Clinical Trial Performance and Cost
Abstract
Background Tufts Center for the Study of Drug Development (Tufts CSDD), in collaboration with 15 pharmaceutical companies and contract research organizations, gathered data on substantial global protocol amendments to better understand how to manage and to reduce the significant unplanned expense and delays associated with major changes to finalized protocol designs.Methods Data from 836 phase I-IIB/IV protocols were analyzed to understand amendment prevalence. Impact assessments were based on data from 136 randomly selected amendments. Data from 52 protocols were analyzed to derive estimates of the direct cost to implement amendments.Results Tufts CSDD found that 57% of protocols had at least one substantial amendment, and nearly half (45%) of these amendments were deemed "avoidable." Phase II and III protocols had a mean number of 2.2 and 2.3 global amendments, respectively. Protocols with one or more global amendments tended to be larger in scope, with longer patient recruitment durations and overall study durations compared with those without a global amendment. Protocols with at least one substantial amendment had fewer actual screened and enrolled patients relative to the original baseline plan than did those protocols without an amendment. The median direct cost to implement a substantial amendment was US$141,000 for a phase II protocol and $535,000 for a phase III protocol.Conclusions The study findings provide insights into optimizing development planning, protocol design, and clinical trial management practices.
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Pharmaceutical companies and CROs can address some issues that prevent efficient execution of clinical trial feasibility and site selection, as cited in a Tufts study.
“In this way, pharmaceutical companies and contract research organizations can address some of the issues cited in a study by the Tufts Center for the Study of Drug Development that prevent the efficient execution of clinical trial feasibility and site selection and often waste the time of HCOs in the process, with protocols with little to no chance of success.17”
From A global federated real-world data and analytics platform for research (2023) · cites this paper as [17]
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 [35]
The trial protocol that is initially approved by the research ethics committee undergoes subsequent modification in 34% to 59% of trials.
“The trial protocol that is initially approved by the research ethics committee undergoes subsequent modification in 34% to 59% of trials.35 216 249 473 474”
From SPIRIT 2025 explanation and elaboration: updated guideline for protocols of randomised trials (2025) · cites this paper as [35]
Reviews of pharmaceutical industry trials found that a third to a half of amendments could have been avoided with greater attention to key problems in the protocol.
“While some amendments may be unavoidable, reviews of pharmaceutical industry trials found that a third to a half of amendments could have been avoided with greater attention to key problems in the protocol.35 474”
From SPIRIT 2025 explanation and elaboration: updated guideline for protocols of randomised trials (2025) · cites this paper as [35]
CONSERVE was developed between June 2020 and February 2021 following a process adapted from the reporting guideline development procedure of Moher et al, modified to replace face-to-face meetings with virtual meetings and emphasizing rapid completion given the unprecedented disruption of trials in the context of the COVID-19 pandemic.
“CONSERVE was developed between June 2020 and February 2021 following a process adapted from the reporting guideline development procedure of Moher et al, 11 modified to replace face-to-face meetings with virtual meetings and emphasizing rapid completion given the unprecedented disruption of trials in the context of the COVID-19 pandemic.”
Cites
Measuring the Incidence, Causes, and Repercussions of Protocol Amendments
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Self-citationNew Governance Mechanisms to Optimize Protocol Design
Getz, K. A., Kim, J. S., Stergiopoulos, S., et al. (2013) · Therapeutic Innovation & Regulatory Science · doi:10.1177/2168479013494386 · Cited by 12 · see citing works
Self-citationScale-up of continuous reactors using phenomenological-based models
Monsalve-Bravo, G. M., Moscoso-Vásquez, M., & Álvarez, H. (2014) · CONICET Digital (CONICET) · Cited by 4 · see citing works
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A global federated real-world data and analytics platform for research
Palchuk, M. B., London, J. W., Perez-Rey, D., Drebert, Z. J., Winer-Jones, J. P., Thompson, C. N., Esposito, J., & Claerhout, B. (2023) · JAMIA Open · doi:10.1093/jamiaopen/ooad035 · Cited by 831 · see citing works
“In this way, pharmaceutical companies and contract research organizations can address some of the issues cited in a study by the Tufts Center for the Study of Drug Development that prevent the efficient execution of clinical trial feasibility and site selection and often waste the time of HCOs in the process, with pro…”
BackgroundSPIRIT 2025 statement: updated guideline for protocols of randomised trials
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
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Self-citationSPIRIT 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
Speich, B., von Niederhäusern, B., Schur, N., Hemkens, L. G., Fürst, T., Bhatnagar, N., Alturki, R., Agarwal, A., Kasenda, B., Pauli-Magnus, C., et al. (2018) · Journal of Clinical Epidemiology · doi:10.1016/j.jclinepi.2017.12.018 · Cited by 146 · see citing works
Promoting public access to clinical trial protocols: challenges and recommendations
Chan, A.-W., & Hróbjartsson, A. (2018) · Trials · doi:10.1186/s13063-018-2510-1 · Cited by 84 · see citing works
Gryaznov, D., von Niederhäusern, B., Speich, B., Kasenda, B., Ojeda-Ruiz, E., Blümle, A., Schandelmaier, S., Mertz, D., Odutayo, A., Tomonaga, Y., et al. (2022) · BMJ Open · doi:10.1136/bmjopen-2021-053417 · Cited by 22 · see citing works
Getz, K., Smith, Z., Botto, E., Murphy, E., & Dauchy, A. (2024) · Therapeutic Innovation & Regulatory Science · doi:10.1007/s43441-024-00622-9 · Cited by 21 · see citing works
“Pro-tocols Pro-tocols with amendments, however, resulted in fewer actual screened and enrolled patients relative to original plan than protocols without amendments [1].”
Self-citationSpeich, B., Odutayo, A., Peckham, N., Ooms, A., Stokes, J. R., Saccilotto, R., Gryaznov, D., von Niederhäusern, B., Copsey, B., Altman, D. G., et al. (2022) · Trials · doi:10.1186/s13063-022-06516-1 · Cited by 21 · see citing works
- Authors
- Getz, K. A., Stergiopoulos, S., Short, M., Surgeon, L., Krauss, R., Pretorius, S., Desmond, J., & Dunn, D.
- Affiliations
- Tufts University (US)
- Eli Lilly (United States) (US)
- Medidata (United States) (US)
- Alexion Pharmaceuticals (United States) (US)
- PAREXEL International (United States) (US)
- Amgen (United States) (US)
- Biogen (United States) (US)
- Corresponding author
- Getz, Kenneth A.
- Venue
- Therapeutic Innovation & Regulatory Science
- Published
- 2016-07
- Volume
- 50
- Issue
- 4
- Pages
- 436-441
- ISSN
- 2168-4790 (ISSN-L)
- 2168-4804
- OpenAlex
- W2300808610
- Cited by
- 72
- References
- 3
- Citations by year
- 2026: 16 · 2025: 11 · 2024: 9 · 2023: 8 · 2022: 8 · 2021: 7 · 2020: 3 · 2019: 2 · 2018: 4 · 2017: 4
- FWCI
- 3.38
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Therapeutic Innovation & Regulatory Science (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Clinical Trials
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
- Social Sciences › Economics, Econometrics and Finance › Economics and Econometrics › Pharmaceutical Economics and Policy
- Keywords
- protocol modification, clinical trial costs, patient recruitment, trial duration, clinical trial management, protocol design
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