Sometimes it is necessary to make changes to a study after NCI approval and prior to activation (opening the study to patient accrual). The changes could be editorial/administrative, or the Chairs and HQ Team may need to make scientific and/or treatment-related changes to the approved study; for the latter, a pre-activation revision of the study is submitted to NCI for review. If the Study Chair submits the approved study to his/her site IRB and the study subsequently has to be changed, the site IRB would have to re-review the study. To eliminate this burden on the site IRB, the Study Chair should not submit the study to his/her IRB until RTOG Headquarters activates the study.

When the protocol is submitted to NCI, the Protocol Associate (PA) simultaneously circulates it to the following RTOG reviewers:

• The Research Strategy Committee
• The full member PIs
• The Disease Site Committee
• The appropriate Modality Chairs (e.g., Medical Oncology, Surgical Oncology, Pathology, etc.)

Reviewers e-mail or fax their feedback concerning the study to the PA. The PA sends these comments to the Study Chair with the NCI review. The Study Chair decides whether or not to revise the protocol based on the reviewers' comments and communicates decisions about the comments to the PA, who documents the Study Chair's responses.

CAEPR is the "Comprehensive Adverse Event and Potential Risks List" issued by NCI for investigational agents provided under an NCI IND in a clinical trial.

The CAEPR incorporates all adverse events for an agent formerly found in the Pharmaceutical Data Sheet (PDS), Agent-Specific Adverse Events list (ASAEL), Investigator's Brochure (IB), and Adverse Events Expedited Reporting System (AdEERS).

NCI mandates that the CAEPR be included in the Drug Therapy section of the protocol for these agents and requires that the risks described in the sample consent correspond to the CAEPR.

It is the Study Chair's responsibility to write the consent using the NCI Consent Template, which is provided in Appendix I of the protocol template. The Study Co-Chairs and the Protocol Associate can assist the Study Chair as needed.

Exceptions to eligibility are not permitted. Questions from institutions concerning eligibility criteria should be referred to the Headquarters Disease Site Team Data Manager(s).

If the Study Chair feels that eligibility criteria for an active study should be amended (for example, based on changes in science/treatment, for patient safety, or due to a significant impact on study accrual), the Chair should contact the Disease Site Team Protocol Associate (PA). The PA will circulate the Study Chair's recommended change(s) to the Site Chair, Study Co-Chairs, and the Team for review and feedback and will submit the amendment to NCI for approval.

The level of detail necessary for treatment can't be included in one page, and sites shouldn't use an overview or summary to treat. The Study Chair should keep the Schema page as simple as possible, conveying the relationships and temporal sequence of the treatment components. The Schema page can refer institutions to Sections 6, 7, and 8 for treatment details.

Submitting another version of the protocol while the protocol associate (PA) is in the process of editing the previous version slows down the development process. The PA will circulate the edited first draft of the protocol to the Study Chairs and Disease Site Team for their review. At that time, the Chairs and Team can send further changes to the PA, who will make the changes and circulate the next draft for review. This process ensures that the Chairs and Team see all changes to the protocol and are on "the same page". The Chair can e-mail the PA at any time in the process for the current version of the developing protocol.

The PA will be receiving changes to the protocol from several Chairs and multiple Disease Site team members. Changes to the current version of the protocol should be indicated clearly so that the PA can find the changes quickly and make them. Changes can be tracked, underlined, bolded, or highlighted. Sending changes that are not clearly indicated slows down the development of the protocol.

• The RTOG Protocol Concept Form, available on the RTOG web site, is the first step in presenting a research study for development by RTOG. The RTOG protocol concept form is submitted to the RTOG Protocol Associate (PA) designated for the disease site.
• An LOI is a Letter of Intent submitted by the PA to obtain drug from the NCI for Phase I and II studies.
• An NCI Phase III Protocol Concept Form is submitted to NCI by the PA for all Phase III studies. It must be approved by NCI prior to submitting a full protocol.
• After the RTOG Protocol Concept is approved for development by RTOG Research Strategy, an LOI or NCI Phase III Protocol Concept Form may apply. An LOI is not used with an NCI Phase III Concept Form.

Electronic submission (e-mailing) of the protocol text and all subsequent changes to the Protocol Associate (PA) facilitates the development of your study. It is the most time efficient method; RTOG Headquarters in Philadelphia may be closed, but Study Chairs can e-mail comments and/or changes 24/7, which the PA can address in the next business day. Changes to text are not taken over the phone. Faxed, handwritten text is frequently illegible. Electronic submission is less likely to create unintended errors, and also provides documentation of the development of and changes to the protocol.

The RTOG protocol template is a tool to assist Study Chairs in authoring a protocol. It includes prompts to and guidelines for Study Chairs and standard language to assure consistency across RTOG studies and ensure quality assurance. In response to NCI mandates, new treatment techniques/regimens, and changing research demands, a multi-disciplinary group at RTOG Headquarters has rewritten and redesigned the prior RTOG protocol template. The current template is available to all Study/Site Chairs via the Protocol Associate (PA).

A Protocol Associate (PA) is a medical editor and a member of a Headquarters Disease Site Team. The PA edits the Study Chair’s original draft to RTOG standard (according to the current protocol template) and tracks outstanding issues during protocol development. The Study Chair's timely response to the PA’s requests for information expedites the protocol development process. The PA maintains the “master” protocol document, making all changes received from the Study/Site Chairs and HQ Disease Site Team to the protocol, and working with the team, the PA ensures that the protocol includes the components necessary for NCI review. When all issues have been resolved, the PA submits the protocol to NCI.