The clinical trial protocol is the single most important quality control tool for the trial, and specifies the research plan for the trial. Although sponsors know that protocol amendments during an ongoing clinical trial are costly and burdensome, they remain common.
A 2017 article out of Tufts Center for the Study of Drug Development (CSDD) introduced some stark statistics about the occurrence of protocol amendments:
- 59% of clinical trials have at least one protocol amendment
- Phase II studies average 2.7 amendments per protocol at an average cost of $141,000 per amendment
- Phase III studies average 3.6 amendments per protocol at an average cost of $535,000 per amendment
- Critically, Tufts CSDD found that up to 45% of amendments are avoidable
What causes protocol amendments?
The causes of amendments vary, but nearly half are necessary to modify study volunteer eligibility criteria or demographics. Without amendments, the trial may require too many visits or extensive procedures to attract enough volunteers. If the criteria are too tight or demanding, the study may fail to meet enrollment targets.
When the trial design changes, for example, because of a safety assessment or shift in volunteer demographics, amendments may be necessary to make the protocols fit the new strategy. The study may produce results that require the volunteer eligibility criteria to change as well, and that leads to amendments.
In addition, over-complex protocols might need adjustment because they require too many procedures or study volunteer visits and compliance is proving difficult. Not all changes are avoidable, though. If the regulatory updates mean the study design is no longer in compliance, then protocols must change.
What are the ramifications of rolling out one or more amendments?
Of course, the two biggest concerns surrounding amended protocols are cost and timelines. According to Ken Getz of Tufts, a single amendment usually takes about three months to implement, at a cost of half a million US dollars in direct costs. Just one amendment has the potential to double the planned duration of a trial.
Another concern is that any protocol changes will cause disruption in the study process for patients and investigators. As well as having a confirmed audit trail to show the amendment has been received and understood by the investigator, it may also require certain visits and procedures to be redone, resulting in duplication of effort.
What are some solutions for avoiding or reducing amendments?
Since about 40% of all amendments occur before the first patient has received their first dose (Tufts CSDD), it’s easy to see how complex trials present unprecedented executional challenges for sites and study managers alike. So how can sponsors take steps to reduce or mitigate the impact of a protocol amendment? Here are some recommendations:
- Take more time with the trial design upfront. Separating the study design and protocol development allows researchers to focus on the design initially and then author the protocols only after that design is complete.
- Challenge each protocol by taking it through a first and second stage review process. Reviewing in stages allows researchers to see what problems, like excessively burdensome visit requirements for patients, might occur down the road. They can then redesign the protocol to ensure the visit schedule is reasonable and practical for patients and sites.
- Seek patient input on the protocol design. Involving patients or patient advocacy groups in the proposed study design, and identifying and incorporating their feedback, can help ensure the design is workable.
- Leverage the latest clinical trial technology. Automated programs that highlight common protocol concerns – such as software that generates a first draft for protocols and checks regulatory submissions – will catch many errors.
- Build a centralized database of sites that can be queried during study feasibility. Determining if the sites have the necessary capabilities to carry out the study, and/or if they have a patient population that will meet the study’s eligibility criteria, could provide leading indicators to help drug developers avoid future amendments.
Although sponsors may be eager to get sites signed up and to start studies as soon as possible, the data shows that taking time to design a study protocol pays dividends in the long-run. Careful planning and efficient review, both manual and automated, of clinical trial designs are the keys to avoiding disruptive amendments.
By creating efficient protocols upfront, it’s possible to avoid costly and time-consuming amendments down the road and to ensure a successful study outcome.