For every clinical trial, study protocol is the centerpiece and study protocol dictates how the study should be conducted, what data will be collected, and how the data will be analyzed. Usually, after the IND (Investigational New Drug) including the study protocol is filed and FDA does not provide any comments (or put it on clinical hold) within 30 days, the sponsor will consider the study protocol is granted approval to proceed. However, it is very common that during the study conduct, some aspects of the study protocol needs to be changed or amended.
Protocol amendment is guided by the Code of Federal Register (CFR) section 312.30 Protocol amendments. CFR states the followings regarding the protocol amendments:
(b) Changes in a protocol. (1) A sponsor shall submit a protocol amendment describing any change in a Phase 1 protocol that significantly affects the safety of subjects or any change in a Phase 2 or 3 protocol that significantly affects the safety of subjects, the scope of the investigation, or the scientific quality of the study. Examples of changes requiring an amendment under this paragraph include:
(i) Any increase in drug dosage or duration of exposure of individual subjects to the drug beyond that in the current protocol, or any significant increase in the number of subjects under study.
(ii) Any significant change in the design of a protocol (such as the addition or dropping of a control group).
(iii) The addition of a new test or procedure that is intended to improve monitoring for, or reduce the risk of, a side effect or adverse event; or the dropping of a test intended to monitor safety.
One question that is often asked is whether or not the protocol needs to be amended if the only changes to the protocol are about the statistical analyses or the sample size. The changes in statistical analysis or the sample size can be considered as changes “that significantly affects the scope of the investigation, or scientific quality of the study”, therefore subject to the protocol amendment. Notice the word ‘significantly’, which implies that some changes may be allowed without amending the protocol, for example small increase (usually less than 10% of total subjects) in sample size, and changes in the statistical analysis methods for secondary or exploratory endpoints,
In the latest issue of “Therapeutic Innovation and Regulatory Science”, Getz et al published a paper “the impact of protocol amendment on clinical trial performance and cost”. They 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. My experiences with clinical trials in rare diseases indicates even a high percentage (almost every protocol) of protocols with amendments and a high number of protocol amendments.
The protocol amendments has great impact on the conduct of the clinical trials:
- Significant impact on the cost
- Significant impact on the timeline
- Significant impact on the resources
- May have significant impact on the credibility of the study results
- May result in more protocol deviations
“Unplanned delays, disruptions, and costs associated with implementing protocol amendments have long challenged drug development companies and their contract research partners. Despite a rigorous and extensive internal review and approval process, the majority of finalized protocols are amended multiple times – particularly those directing later-stage phase III studies.
The frequency of protocol amendments varies by therapeutic area and is highly correlated with more scientifically and operationally complex protocols. Increased amendment frequency per protocol is associated with protocols that have a higher relative number of protocol procedures and eligibility criteria, and more investigative sites dispersed across more countries.
Amendments are implemented for a wide variety of reasons, including the introduction of new standards of care, changes to medications permitted before and during the clinical trial, the availability of new safety data, and requests from regulatory agencies and other oversight organizations (eg, ethical review boards). The top reason for amending a protocol is to modify study volunteer eligibility criteria due to changes in study design strategy and difficulties recruiting patients. “
Some large pharmaceutical companies start to look at the impact of the protocol amendment on the overall cost and the timeline. I even heard (unconfirmed) that GSK used the number of protocol amendment as one of the performance evaluation criteria. The less number of the protocol amendments, the better the performance is.
The number of protocol amendments may be the results of a specific study design. A recent discussion about the phase I dose cohort expansion study results in unlimited number of protocol amendments. This specific design has been discussed in my previous posting. As an example, a dose cohort expansion study by Merck has 50 protocol amendments and still counting.
Adaptive design has been a hot topic in clinical trial field for last ten years. The enthusiasm about the adaptive design has died down a little bit except in oncology area. One of the key advantages for adaptive design is to implement the changes based on pre-specified criteria and therefore avoid the protocol amendment. For example, if all criteria for pruning the treatment arms or for increasing the sample size are pre-specified, when the criteria are met, there is no need for protocol amendment to implement the changes. This could be good in saving the time/cost, but may be bad due to the loss in learning opportunities.
For traditional study designs, it is always desirable to minimize the number of the protocol amendments. In reality, the protocol amendments are ubiquitous. The reason for protocol amendments may include the followings (it is not intended to be an exclusive list).
- Lack of internal expertise in the therapeutics area
- Lack of consultation from external experts
- Lack of Engagement with steering committee
- Lack of engagement with CRO who may have the first hand experiences about the sites.
- Lack of experience from other countries – standard care may be very different in other countries
- Too late in engaging the statisticians – statistician should engage in the study design including endpoint selection, not just calculating the sample size.
- Sign off the final protocol too early, for example the protocol was signed off before pre-IND meeting with FDA
- Submitting the final protocol when the concept protocol, protocol synopsis, or draft protocol suffice
- Inadequate or unrealistic inclusion/exclusion criteria
- Lack of quality control in protocol review / approval process.
- Protocol amendment after FDA pre-IND meeting
- Protocol amendment per external committees requests – such as Data Monitoring Committee (DMC), Steering Committee
- Protocol amendment after the investigator meeting
- Protocol amendment after FDA’s IND comments
- Protocol amendment due to the difficulties in patient enrollment
- Protocol amendment after blinded interim analysis
- Protocol amendment due to expansion in the number of countries
It is not a good idea to have a country specific protocol amendment with significant deviation to an IND study protocol. For example, I used to work on a randomized, placebo controlled study where the regulatory authority in one of the targeted countries did not approve the inclusion of the placebo arm in the study. I was asked if a country-specific protocol could be used so that the placebo arm could be dropped from the protocol for this specific country. In this case, the deviation to the IND study protocol seems to be too big. The country-specific protocol is not a good solution and this specific country may need to be excluded from the study participation.
A small tip for CRF/eCRF revision due to the protocol amendment :
When inclusion/exclusion criteria are revised in protocol amendment, to avoid the potential impact on the CRF data collection and the downstream activities, it is better to:
- Keep the inclusion / exclusion number intact (i.e., skip the number) if one or more of them are removed, for example if the inclusion criteria #3 is removed, the amended protocol will have inclusion criteria 1, 2, 4, 5 (i.e., #3 is skipped).
- Add additional inclusion/exclusion criteria after the last existing inclusion or exclusion riterion if additional inclusion/exclusion criteria need to be added,