The True Cost of Protocol Amendments

A single substantial amendment costs a median $141,000 in a phase II trial and $535,000 in a phase III trial, based on direct cost data from 52 protocols (Getz et al., 2016). Those figures cover paperwork and contracts. They do not include the months a trial spends running two versions of the same protocol at once.

Where the money actually goes

An earlier Tufts CSDD study put the average direct cost per amendment at $453,932, and found investigative site fees, increased grants, and contract changes made up 58% of that total (Getz et al., 2011). Most of the money went to sites already running the trial, not to any new science.

Those figures are also the smaller number. Getz et al. (2016) estimate that indirect costs, staff time, delays, and lost opportunity around a substantial phase III amendment, run three to four times higher than the direct cost figure. On a $535,000 median direct cost, that puts the true toll closer to $1.6 million to $2.1 million per amendment.

By 2022, the industry could not even produce that estimate. Getz et al. (2024) tried to collect indirect cost data for their benchmarking study, and no participating company could supply it, so the most recent study reports no cost trends at all.

The time cost is the bigger one

Cost is only half the story regardless. Getz et al. (2016) found protocols with a substantial amendment ran 3 months longer in conduct than protocols without one, 580 days against 490 (p = .0003). The gap between first patient and last patient first visit nearly doubled, 403 days against 238 (p < .0001).

The earliest Tufts CSDD study measured the cycle time to implement a single amendment at a median of 65 days, nearly half of it spent simply deciding what to change, with an average of 2.3 amendments adding 4 months to an amended protocol overall (Getz et al., 2011).

That timeline has since stretched further. Getz et al. (2024) measured an average of 260 days from identifying the need to amend to final oversight approval, with investigative sites running on two different versions of the same protocol for a mean of 215 days, about seven months. The time between internal approval and re-consenting the first patient rose 154% since 2010.

The cycle time to implement one amendment has moved from a median of 65 days in the earliest benchmark to an average of 260 days roughly a decade later, close to four times as long. The direct cost figures above come from studies run in different years and are not inflation-adjusted, so the 3 to 4 times multiplier likely understates today's indirect toll.

None of these figures include the cost of running a multi-site trial where some sites operate under the old protocol and some under the new one at the same time, a period during which two groups of patients are, technically, in two different studies. That gap, more than the invoice for the amendment itself, is where an amendment's real cost tends to hide.

References

Getz, K., Zuckerman, R., Cropp, A., Hindle, A., Krauss, R., & Kaitin, K. (2011). Measuring the incidence, causes, and repercussions of protocol amendments. Drug Information Journal, 45, 265–275. https://doi.org/10.1177/009286151104500307

Getz, K. A., Stergiopoulos, S., Short, M., Surgeon, L., Krauss, R., Pretorius, S., Desmond, J., & Dunn, D. (2016). The impact of protocol amendments on clinical trial performance and cost. Therapeutic Innovation & Regulatory Science, 50(4), 436–441. https://doi.org/10.1177/2168479016632271

Getz, K., Smith, Z., Botto, E., Murphy, E., & Dauchy, A. (2024). New benchmarks on protocol amendment practices, trends and their impact on clinical trial performance. Therapeutic Innovation & Regulatory Science, 58(3), 539–548. https://doi.org/10.1007/s43441-024-00622-9