Protocols

Outline of a protocol

The following is an excerpt from Section 4.6.3 of the book Clinical Trials: A Methodologic Perspective, written by Steven Piantadosi (New York, New York: John Wiley & Sons, Inc., 1997). This section describes the structure of protocols. It would be useful for all investigators to review this to make sure their protocols are in the proper format and contain the required sections, minimizing the time needed to edit the protocols before submission.

Brief Outline

  • Title Page (essential for all protocols).
  • Contents or Index (optional).
  • Protocol Synopsis (optional).
  • Schema (essential for complex safety and efficacy and comparitive treatment efficacy protocols).
  • Objectives of the Study (essential for all protocols).
  • Introduction and Background (essential for all protocols).
  • Drug Information (essential for studies employing drugs).
  • Staging Criteria (essential for all studies).
  • Patient Eligibility Criteria (essential for all protocols).
  • Registration or Randomization Procedures and Stratification (essential for all protocols).
  • Treatment Program (essential for all protocols).
  • Dosage Modification/Side Effects (essential for all protocols).
  • Agent Information (essential for all agents).
  • Treatment Evaluation (essential for all protocols).
  • Serial Measurements/Study Calendar (essential for safety and efficacy and comparitive treatment efficacy studies).
  • Statistical Considerations (essential for dose-finding, safety and efficacy, and comparitive treatment efficacy studies, optional for treatment mechanism studies).
  • External Collaborations or Reviews (essential for all multi-institutional studies).
  • Data Recording, Management, and Monitoring (essential for all protocols).
  • Special Instructions.
  • Communication and Publication of Data (essential for all studies which involve collaborations, especially data management, outside of the institution, particularly pharmaceutical company sponsored studies).
  • Peer Review (this section is optional).
  • Patient Consent (essential for all protocols).
  • References (essential for all protocols).
  • Data (Case Report) Forms (optional).
  • Protocol Amendments (essential for all protocols if any amendments exist).
  • Other Appendices (optional).
  • Glossary (optional)

Detailed Outline

This outline and brief discussion is intended to assist investigators in drafting, reviewing, and improving the quality of their own clinical trials. The emphasis of this outline is on comparative trials performed in a collaborative setting. However, almost all studies would benefit from having their protocols address most of the topics below. The headings presuppose a pharmacologic therapy, but there should be little difficulty in adapting it to trials using other treatment modalities. The total length of a protocol will usually be 20 typed pages or more, written in a structured formal style with page numbers and references, and containing most of the following sections.

  • Title Page (essential for all protocols). The title page should include: a) study title, b) date of last revision, c) principal investigator and phone number, d) other study collaborators, and e) administrative office and phone number. When developing protocols in a collaborative setting, the revision date can prevent much confusion. Some sponsors, such as pharmaceutical companies, omit naming a principal investigator. This diffusion of responsibility is unacceptable.
  • Contents or Index (optional).
  • Protocol Synopsis (optional). A one-page description of complicated and lengthy protocols can be a great help.
  • Schema (essential for complex safety and efficacy and comparitive treatment efficacy protocols). Patient flow with major relevant landmarks such as study entry, evaluations and treatments, and randomization are presented in diagrammatic form. The basic architecture of the study design will be evident from the schema alone. Doses, schedules, and other details regarding therapy should be deleted from the schema to prevent using it for treatment without consulting the full protocol.
  • Objectives of the Study (essential for all protocols). The objectives pose important scientific questions addressed by the trial. The objectives should be stated clearly, concisely, and quantitatively, and correspond with the hypotheses to be tested by the study. It is also helpful to indicate the relevant endpoints. This section is usually quite brief and is formatted as an outline with details.
  • Introduction and Background (essential for all protocols). This section provides the introduction and scientific background/rationale for the study and should be an adequate introduction to the subject for other investigators and reviewers. Summaries of similar or background studies will provide justification for the stated objectives. If a new treatment is being tested in safety and efficacy or comparitive treatment efficacy trials, pilot data may be required to justify the larger study. Keep in mind that some readers and potential critics of the protocol will not be as expert in the science as the authors. References must be included and it should be written in a narrative style. Supporting or recent historical data that justify the design of the study need to be included.
  • Drug Information (essential for studies employing drugs). All drugs used in the study need to be described in alphabetical order with respect to human toxicity, pharmaceutical data, administration, storage and stability, and supplier. The investigator should list the National Service Center (NSC) number, Investigational New Drug (IND) number, if relevant, and any other standard names for the drug.
  • Staging Criteria (essential for all studies). This section lists the criteria or system by which extent of disease will be established. In cancer studies, extent of disease may be determined by stage, the assessment of which is often standardized. For some other diseases, extent of disease may be less standardized, or even controversial. Therefore, the criteria used to establish extent may need to be listed explicitly.
  • Patient Eligibility Criteria (essential for all protocols). This section is a detailed, specific, and quantitative description of eligibility requirements and exclusions. For example, eligibility criteria may depend on sub-category of disease, prior therapy, measurability of disease extent or response, performance status or disease severity, and required organ function. Exclusionary criteria should also be outlined in the same way. Criteria for exclusions should be named on the basis of knowledge obtained prior to the assessment of response or study outcome. Exclusions should not be permitted on the basis of information that only becomes known after the initiation of treatment. Any competing studies of factors that will interfere with accrual should be listed here or in a separate section.
  • Registration or Randomization Procedures and Stratification (essential for all protocols). Phone numbers and contacts for placing a patient on the study are provided. This should include information required for central eligibility checks. In many cases, the individuals responsible for the mechanistic parts of placing a patient on study are not physicians or persons otherwise knowledgeable about the subtleties of the study. They may require detailed procedural specifications here to avoid confusion or entry of ineligible patients later. Stratification factors may affect the randomized assignment or treatment and need to be available at the time a treatment assignment or registration is requested.
  • Treatment Program (essential for all protocols). This includes details of required therapy such as chemotherapy dosage, biopsies, and masking procedures. For treatment mechanism studies, the dose escalation will be detailed. For studies employing more than one treatment modality, details of each need to be provided in separate sections. Within the treatment specification, secondary registrations or randomizations should be indicated. This section should also list criteria for discontinuing protocol treatment, e.g., completion of therapy, disease progression, unacceptable side effects, or patient preferenc
  • Dosage Modification/Side Effects (essential for all protocols). This includes details of required dose modifications and reductions when toxicities or side effects are encountered. The side effects or toxicities to be monitored should be listed. Dose modifications should address the following concerns: baseline conditions that necessitate changes in the initial dose; criteria for multiple courses of treatment; dose decrements or increments to be employed; criteria for substituting treatment delays for dose reductions; an investigator to contact concerning dose modification questions; and reporting requirements for unexpected side effects.
  • Agent Information (essential for all agents). This section explains details of drug preparation, storage, dilution, and stability. For experimental agents, availability and drug-specific background data should be given. The drug brochure for investigational agents should accompany the protocol.
  • Treatment Evaluation (essential for all protocols). This section provides the details for the methods of evaluation and for determining endpoints and toxicities. In studies like safety and efficacy trials of cytotoxic agents in oncology, the methods for assessing tumor response are critical to the evaluation and generalizability of the trial. Scoring, intensity, or other evaluation criteria should be listed.
  • Serial Measurements/Study Calendar (essential for safety and efficacy and comparitive treatment efficacy studies). This lists the study parameters and milestones and the time at which they are to be determined while the patient is on protocol treatment. This should include a listing of baseline measurements. In addition, this section specifies the actions to be taken in response to specific study complications, such as steps for removing a patient from the treatment protocol because of side effects or toxicity. This section should cross reference the data forms and their submission schedule.
  • Statistical Considerations (essential for dose-finding, safety and efficacy, and comparitive treatment efficacy studies, optional for treatment mechanism studies). This section addresses the following relevant points: recap of study objectives, required sample size, power, and the way it was estimated, precision of the design for determining major study endpoints, projected accrual rate and duration of the study, and analysis methods. Also, plans for interim analyses and guidelines for early stopping must be included. The statistical section should also outline the quantitative properties of the study with respect to secondary objectives. A sketch of the final analysis is also useful. In some cases, the analysis plan may need to be specified in considerable detail.
  • External Collaborations or Reviews (essential for all multi-institutional studies). This section describes arrangements and procedures with investigators outside of the parent institution. For example, the details of how to obtain pathological specimen or imaging review should be given. Names, addresses, and phone numbers should be listed for outside investigators if not given on the title page. In the event that extensive or critical portions of the study depend on collaborations outside the parent institution, supplementary protocols may need to be submitted (e.g., extensive pathologic review).
  • Data Recording, Management, and Monitoring (essential for all protocols). This section provides details for the collection and review of data while the study is in progress. It includes the contact person with names and addresses for submission of data forms or related collection instruments. This will include addresses and phone numbers for questions, emergencies, and the reporting of fatal, life-threatening, or unexpected reactions. The submission schedule for data forms must be outlined. In addition, the membership of a safety monitoring committee should be outlined.
  • Special Instructions. This section contains instructions to study managers for obtaining and mailing specimens for special laboratory tests or analyses. Any special data or data forms required by the study sponsor should be listed with instructions on how they should be handled.
  • Communication and Publication of Data (essential for all studies which involve collaborations, especially data management, outside of the institution, particularly pharmaceutical company sponsored studies). This section outlines agreements regarding the communication and publication of study data. Any limitation or restrictions of investigator access to the study data must be detailed. This section should also specify prior approvals, if required, for publishing the data. The format of this section is narrative.
  • Peer Review (this section is optional). This section outlines the peer review procedures that the protocol may have already passed. For example, for cooperative group protocols, peer review may include the group mechanism and NIH.
  • Patient Consent (essential for all protocols). This section may be submitted as an appendix with patient consent forms. The reading level of the patient consent document should be eighth grade or lower. An appropriate language should be used if there is a plan to enroll patients whose primary language is not English, and "back-translation" or other method should be used to be certain that important concepts are translated properly.
  • References (essential for all protocols). Include publications based on the trial (if any) and copies of important references from the protocol.
  • Data (Case Report) Forms (optional). Investigators are encouraged to submit proposed data forms for the study. Ideally, the forms should be self-coding for computer entry. The forms will be reviewed for capturing of items required to meet study objectives. Data forms may be submitted as an appendix.
  • Protocol Amendments (essential for all protocols if any amendments exist). This section includes a summary of all protocol modifications that affect patient treatment arranged in chronological order. A brief explanation of each amendment is also useful.
  • Other Appendices (optional). These may include ethics review documentation, toxicity criteria, flow sheets, etc.
  • Glossary (optional). Include definitions of special or unfamiliar terms. This section might be useful for psychosocial research terminology, new drugs, etc.