Protocol development is a cyclical process of review and modification, requiring input from all the investigators, collaborators and typically a number of sub-specialists. It can be helpful to assign a single coordinator the responsibility for incorporating comments and changes received from contributors into the document and resolving any issues identified with all the necessary people. Version control is really important in this process, so using footers with the version and date can help.

All contributors to the protocol should review the final draft and approve any changes. A procedure for collecting sign-off on the final draft protocol should be established.

Following all relevant reviews and incorporation of comments, the final version of the protocol can be produced and can be signed by the investigators and the sponsor if needed.

This final version is then submitted to the regulatory review committees. Here another round of changes may be required as review committees ask for changes or additions. Again, having a single person coordinating this is helpful. Each new version should be re-named and circulated to the investigators and any other committees in which the protocol is awaiting review. Ethics and regulatory review committees appreciate seeing the comments and outcomes from other committees. They also need the latest version, so typically it is best practice to submit new versions as they arise rather than wait until all the committee responses are in.

Once all the committees have approved the protocol and all the required changes have been made, the final version for implementation can be released.

After the study has begun any changes to the protocol become protocol AMMENDMENTS or MODIFICATIONS. The definition of amendment is anything that changes the design, data or any processes for the participant. Amendments also include significant changes to the management of the study, such as changes in sponsor, investigators or the addition of extra research sites. Examples might include changing the sample size, or changes to the inclusion criteria. Amendments must be approved by the ethics committees before implementation, unless there is a safety requirement for the changes. In this case they can be notified as soon as possible.

Modification, sometimes called minor or non-significant amendments, are minor changes that do not impact the conduct of the study or have any impact on the participants or the design. These might include changes such as changes in sample transportation logistics or corrections and clarifications within the protocol. Modifications or minor amendments need to be sent to the ethics committee in writing as notifications.

The SPIRIT group have also developed an invaluable checklist for protocol writing. http://www.spirit-statement.org/