Clinical Trial Protocol amendments: approve them, implement them

5 June 2017

Clinical Trial Protocol amendments: approve them, implement them

To a clinical trial sponsor, a protocol amendment incurs extra costs and delays in the trial schedule. This opinion is supported by the statistics of Tufts Center for the Study of Drug Development (Tufts CSDD), published in 2016. Having analyzed more than 800 protocols, Tufts CSDD defined the most common reasons for amendments, their impact on trial progress and possible ways to facilitate their implementation.

According to the study, 23% of amendments were completely avoidable. However, most of the amendments were acknowledged as unavoidable, because there were changes in the trial strategy and structure. New data on the drug safety, changes in the manufacturing technologies and in requirements of the regulatory authorities are also named among the reasons behind the amendments.

Sometimes protocol design allows modifications to the study, for example, in dose cohort expansion studies. In one of the oncological trials by Merck the protocol was amended 50 times, and as the trial is ongoing, no one can state there will not be any more amendments.

Electronic Case Report Form (eCRF) is the main tool for collecting and structuring clinical data. It ensures consistency and completeness of the collected data.

Anna Polikarova, Operations Director at Data Management 365 company (DM 365), explains how to implement protocol amendments into eCRF effectively:

“Before the start of a clinical trial we perform thorough analysis of the protocol and its supporting documentation for practical reasons: efficient eCRF design will ensure collection of necessary and sufficient data in the format convenient for export and following statistical analysis.

Cooperation among a medical writer, a medical monitor, a data manager and a biostatistician at the protocol development stage allows to create such a trial design that makes the probability of amendments as low as possible.

Protocols amendments can be either substantial, or non-substantial. Non-substantial amendments are rather easy to implement and usually do not affect data collection process significantly. However, one should not underestimate them. For example, even a minor change in Visual Analogue Scale Assessment wording may affect the results.

It is much more difficult to implement unforeseen substantial amendments, such as the following changes in: trial design, informed consent procedure, screening procedure, subjects’ allowable age range and other inclusion/exclusion criteria, duration of treatment, drug dosage, assessment of the results of previous studies or risk/benefit evaluation, assessment of drugs interaction; principal investigator replacement or contracting a new site in a new country, etc.

Capabilities of the EDC (electronic data capture) system used in the trial are of great importance in such scenarios. Having tested and compared several EDC platforms, we have chosen the electronic system developed by our partner Flex Databases. One of the main advantages of this system is its flexibility, which allows to implement several protocol amendments either sequentially or simultaneously.

For example, if the changes affect previously filled forms, the system allows investigator to enter new data without re-populating the whole eCRF. EDC helps to avoid mistakes and switch to the new protocol version as quickly as possible without losing already collected data.

In the EDC we use, it is possible to configure individual routes for subjects who undergo procedures per different protocol versions or its amendments. These routes have unique sets of forms, which allows to manage the data separately. Online reports, including analytical ones, adjust automatically without re-configuration.

We came upon various challenges during amendments implementation and databases update, and we always found an effective solution for that. For example, in one of the ongoing trials inclusion/exclusion criteria changed several times, so our team customized the system so that the investigator could choose the applicable protocol version to evaluate whether a Subject matches the conditions for the participation in the trial. Depending on the investigator’s choice, the system offers the right form for inclusion/exclusion criteria evaluation and a corresponding set of linked forms.

Protocol amendments are routine practice for clinical trials. And you don’t have to be afraid of them, because professional and well-timed approach helps to solve any problem.”