Protocol amendments

Item 31: Plans for communicating important protocol modifications to relevant parties

Example

“The Sponsor is authorized to amend the protocol. All important protocol modifications will be first discussed within the Steering committee and then communicated to the relevant parties (local investigators, EC [ethics committee], trial registry) by the Sponsor. Substantial amendments will only be implemented after approval by the EC, whereas non-substantial amendments are communicated by the Sponsor to the EC within the annual safety report. … Amended protocols will be sent to the study sites for filling in the Investigator Site File, and training on new documents will be documented on site [473]. 

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Explanation

The trial protocol that is initially approved by the Research Ethics Committee undergoes subsequent modification in 34% to 59% of trials [35, 217, 250, 474, 475]. Numerous studies have revealed substantive changes between pre-specified methods (e.g., as stated in approved protocols, registries, or regulatory agency submissions) and those reported in trial publications, including changes to primary outcomes, [255, 257, 258, 476] sample size calculations [201] eligibility criteria [216, 217, 477] and interventions, [478] as well as methods of allocation concealment, [330] blinding, [5] and statistical analysis [201, 479, 480]. These substantive modifications are rarely acknowledged in the final trial reports [201, 250, 251, 481]. 

While some amendments may be unavoidable, reviews of pharmaceutical industry trials found that a third to half of amendments could have been avoided with greater attention to key issues in the protocol [35, 475]. Substantive amendments can generate challenges to data analysis and interpretation if they occur part way through the trial (e.g., changes in eligibility criteria) [482] and can introduce bias if the changes are made based on the trial data [257, 258, 476]. The implementation and communication of amendments is also burdensome and potentially costly.

It is important that substantive protocol amendments are reviewed by an independent party, such as the Research Ethics Committee, and transparently described in trial reports. The notion of “substantive” is variably defined by authorities, but in general refers to a protocol amendment that can affect the safety of trial participants or the scientific validity, scope, or ethical rigour of the trial [483, 484]. 

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In a sample of trial protocols approved in 2016, 66% to 77% reported how amendments would be handled [9, 10]. 

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The protocol should describe the process for making amendments, including who will be responsible for the decision to amend the protocol and how substantive changes will be communicated to relevant parties (e.g., Research Ethics Committee, trial registries, regulatory agencies). Early consideration of extenuating circumstances that might be encountered during a trial can help ensure that appropriate mitigating strategies are approved in advance [73]. 

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Version control using protocol identifiers and dates (Item 2), as well as a list of amendments, can help to track the history of amendments and identify the most recent protocol version.

Summary of key elements to address

• Process for making protocol amendments, including:

  • Decision-making authority for protocol amendments

  • How substantive changes will be communicated to relevant parties (e.g., Research Ethics Committees/Institutional Review Boards, trial registries, regulatory agencies)