Chapter 4 Essential Documentations

4.1 Introduction to Essential Documentation in a Randomized Clinical Trial

4.1.1 Module goal

This module provides guidance for the development and management of essential documentation before, during, and at the close of a randomized clinical trial (RCT).

4.1.2 General considerations

Documentation provides validation that research is conducted maintaining the highest ethical and clinical standards as established by the World Health Organization and the International Conference on Harmonization (ICH) guidelines for Clinical Good Practice (GCP)

Documentation requirements will vary according to several factors, such as intervention (e.g., drug, device, behavior), sponsor (e.g., NIH, drug company), and regulatory authorities (e.g., FDA). Thus, you should verify that your documentation plan complies with the specific your RCT.

The ICH GCP, section 8, “Essential Documents for the Conduct of a Clinical Trial” provides a full listing of documents that are generally deemed essential. These documents demonstrate that the trial conduct complies with the standards of GCP and all regulatory requirements. This module focuses on describing the following Essential Documents:

4.1.3 Resources

4.2 Protocol

4.2.1 What

A study protocol describes the objective(s), design, methodology, statistical considerations, and organization of an RCT. It is the core document required for all parties who have responsibility for approval, conduct, oversight, and analysis of the RCT. Key sections typically include (also see template examples at the end of this module):

  • Background/rationale
  • Objectives and purpose
  • Study design
  • Statement of qualifications
  • Criteria for inclusion, exclusion, and withdrawal of study subjects
  • Treatment /intervention
  • Methods and timing for assessing, recording and analyzing data
  • Methods for obtaining safety information and safety monitoring (Safety Monitoring Plan?)
  • Statistical methods
  • Ethical considerations
  • Statement related to permitting RCT-related monitoring, audits, and inspection by the sponsor, IEC/IRB, and regulators, including direct access to source data/documents (Site monitoring plan?)
  • Quality Control and Quality Assurance
  • Data handling and record keeping (Data Management Plan?)
  • Financing and Insurance
  • Informed consent procedures

4.2.2 Why

The detailed rationale and approach to clinical research documented and maintained in the study protocol assures that the RCTs design and implementation adhere to the integrity of the science and ensure the validity of its findings. It is produced to:

  • Ensure feasibility of study design and objectives
  • Ensure that study design will result in the collection of crucial information
  • Clarify study requirements and methodology for all partners
  • Ensure approval of study by ethical committee(s)

Over-seeing regulatory bodies, such as Internal Review Board (IRB), Data Safety and Monitoring Board (DSMB), and National Institutes for Health (NIH) will request to review the study protocol for approval prior to starting the RCT, and may request the updated protocol at any point in the RCT. Top tier journals will also request access to the protocol prior to publication of the study’s findings.

4.2.3 How

The protocol must be completely written before the study begins. The initial draft often requires input from several team members, but the PI(s) should take responsibility for its final editing. It is a tedious but necessary process. Any changes to the study conduct (i.e., Protocol Amendments) must be meticulously documented and dated in a timely manner in the protocol and in clinical trials.com as required. The final protocol at the study’s end should reflect exactly what transpired during the study’s conduct. The Project Director can serve as the main organizer for maintaining the protocol and its updates under the PIs supervision.

4.2.4 Special considerations for older subjects

None

4.2.5 Common pitfalls

Common pitfalls include: incomplete or unclear initial protocols, inadequate documentation of protocol amendments, and inconsistency with other study key documents (e.g. manual of operations and IRB applications).

4.2.6 Resources

Site contains helpful templates

4.3 Manual of Operational Procedures

4.3.1 What

The Manual of Operational Procedures (MOP) is a handbook of instructions designed to guide the research team to successfully carry out all aspects of a particular research project according to that study’s research protocol. It clearly spells out the “who, what, where, when and how” of the RCT’s conduct. In general, the MOP transforms the protocol into a description of the exact procedures involved to implement every aspect of the RCT. Typically, each section of a MOP contains: steps required for task completion, person responsible, and resources required. Key sections typically include:

  • Introduction
  • Protocol (embedded in to MOP)
  • Study organization and responsibilities
  • Human Subjects Protection
  • Training plan
  • Communications plan
  • Study flow
  • Eligibility and Recruitment
  • Randomization
  • Blinding and Unblinding
  • Site Quality Management/Assurance
  • Site Preparation
  • Protocol Implementation
  • Procedures for managing trial progress
  • Test article
  • Safety Assessment and Reporting
  • Data Collection and Management
  • Specimen and Laboratory Management
  • Laboratory Quality Assurance
  • Site Monitoring
  • Regulatory Binder Maintenance
  • Study completion and Close-out Procedures
  • Appendices including:
  • Study definitions
  • List of abbreviations
  • Adherence monitoring forms
  • Data Collection Forms
  • Copies of DSMB charter and report templates
  • Statistical programming for key elements

4.3.2 Why

The MOP is intended to serve as a study “cookbook”. The MOP facilitates adherence to study protocol, organizes the conduct of the study, and ensures consistency in research efforts throughout the study and across study sites. In theory, another investigator should be able to replicate the RCT’s conduct exactly as it was originally conducted by using the MOP.

4.3.3 How

The MOP must be completely written before the study begins. The initial draft requires input from several team members, particularly those closest to the research component being operationalized in each section. It is a tedious but necessary process. Any changes to the study procedures must be meticulously documented and dated in a timely manner in the MOP. The final MOP should reflect exactly what transpired during the study’s conduct. A project director can serve as the main organizer for maintaining the MOP and its updates under the PIs supervision. Copies of the MOP should be available at study sites and in the main study file system.

4.3.4 Special considerations for older subjects

None

4.3.5 Common pitfalls

Common pitfalls for MOP development include: lack of adequate formatting or tracking, lack of required appendices, and finding the right balance of necessary detail to include.

4.3.6 Resources

Site contains helpful templates

4.4 Statistical Analytic Protocol

As the Statistical Analytical Plan (SAP) is an essential document, it just briefly mentioned here. The details about developing and maintaining a SAP are covered in the Experimental Design and Statistical Considerations Module.

4.4.1 What

A SAP is a document that contains a technical and detailed explanation of the principal features of the analysis described in the study protocol. It includes detailed procedures for executing the statistical analysis of the primary and secondary variables and other data.

4.4.2 Why

Guidance on data ascertainment, management, storage, analysis and interpretation are critical to preserve the validity of the design and soundness of scientific conclusions.

4.4.3 How

Most often, the SAP and MOP are maintained as separate documents, but sometimes the SAP is embedded into the MOP. The SAP must be assembled prior to enrollment. It should be authored by the project statistician in concert with investigative team. Any changes to the statistical analytic plan related to the main outcomes must be clearly documented and dated in a timely manner in the SAP. These changes must be conceived and documented prior to the active phase of data analyses.

4.5 Data Safety and Monitoring Documents

These are documents related to Data Safety Monitoring Board (DSMB), or similar bodies such as a Data Safety Advisory Council (DSAC), activities within an RCT. Two main documents are required; the DSMB charter and interim data reports.

4.5.1 DSMB/DSAC charter

4.5.1.1 What

The Charter describes the responsibilities of the DSMB. The charter also defines the relationships between the DSMB and other parties responsible for study oversight, including the sponsor, clinical research organizations, steering committee, study investigators, IRBs/ECs, appropriate regulatory agencies, and the DSMB management organization (when applicable). Sections generally included in the charter:

  • Role of DSMB
  • DSMB Responsibilities
  • Membership
  • Board Process
  • Meeting format
  • Meeting materials/ reports
  • DSMB meeting minutes/reports

4.5.1.2 Why

The purpose of the charter is to define the responsibilities of the DSMB, detail membership requirements, describe the data to be reviewed, delineate the meeting process, and outline the considerations and policies of the DSMB.

4.5.1.3 How

The charter should be developed and approved by all parties responsible for study oversight, including the PI, the DSMB members and the sponsor (e.g., NIH Project Officer). If your trial is funded by the NIH, talk with your Project Officer about his/her preference for who should take the lead in developing the charter. There are general guidelines and many templates available (see Resources below). If funded by the NIH, the Project Officer may recommend a preferred format or template.

4.5.1.4 Special considerations for older Subjects

None

4.5.1.5 Common pitfalls

Common pitfalls for DSMB charter development include a lack of adequate planning or corroboration with DSMB members and sponsor and insufficient information inclusion.

4.5.1.6 Resources

4.5.2 Interim data reports

4.5.2.1 What

Interim data reports provide members of the DSMB with information to allow them to evaluate safety, study conduct, scientific validity and integrity of the trial. The reports convey data of relevant study activities and outcomes as agreed upon at the outset as in the purview of the DSMB. There are two types of the interim reports produced; one for the open session of the DSMB, and one for the closed session. Sections generally included in these reports are listed below. Those marked by an asterisk are usually only included in the open report and not repeated in the closed reports:

  • Report Summary
  • Protocol Synopsis
  • Organizational chart
  • DSMB Roster
  • Brief statement of trial purpose
  • Primary Trial Outcome
  • Projected timetable and schedule
  • List of participating clinics, data centers, resource centers
  • Study status
  • Facility recruitment and subject accrual status
  • Data quality
  • Safety assessments (e.g., adverse events)
  • Protocol Deviations
  • Outcomes (may or may not be included)
4.5.2.1.1 Open session report

The open session report provides information on study conduct, including: recruitment and demographic data, subject/facility characteristics, protocol compliance, site performance, quality control, adverse event data, and outcome data when appropriate aggregated for both arms of the RCT (i.e. all subjects).

4.5.2.1.2 Closed session report

The closed session report contains data similar to that presented in the open session report but is presented separately for each study arm in a semi-blinded fashion. For example, the arms are NOT identified by control or intervention, but as group 1 and group 2. If a study has an interim analysis with a pre-determined stopping rule, outcomes with statistical comparisons are also presented in the closed session.

4.5.2.2 Why

To provide a clear representation of trial activity to ensure participant safety and data integrity and to inform DSMB recommendations related to study continuation.

4.5.2.3 How

Prior to starting the study, the PI, and Statistician should work with the DSMB members and the Project Officer to draft a report outline using recommended guidelines or templates. Once approved by all parties, additions or modifications to these reports may be directed by the DSMB as the study progresses.

The research team prepares the data for the DSMB reports which should be sent to DSMB members 1 to 2 weeks prior to the meeting to allow sufficient time for review. There are software applications such as that can be automated to fill in the recurring data needed for these reports (see Data Management Module).

The Closed Session Report is confidential. Printed copies of this report should be destroyed after the meeting. Procedures for securing and eliminating closed reports distributed to telephone and video conference participants should be specified in advance of the meeting.

4.5.2.4 Special considerations for older subjects

None

4.5.2.5 Common pitfalls

Common pitfalls for DSMB charter development include a lack of adequate planning or corroboration with DSMB members and sponsor and insufficient or ineffectual information inclusion.

4.5.2.6 Resources

4.6 Regulatory Binder

4.6.1 What

The Regulatory Binder is an indexed collection of essential documents relevant to the RCT. While frequently referred to as a regulatory binder, it may also be called: Study Files, Investigator Files or Investigator Binder. ICH Good Clinical Practice Guidelines (GCP) list documents generally considered essential for inclusion in the regulatory binder. The basic sections of a regulatory binder include:

  • IRB Information/Protocol Review Correspondence
  • Study Protocol and Supporting Documents
  • Informed Consent Forms and Supporting Documents
  • Source Documents
  • Case Report Forms (CRFs) / Data Collection Tools
  • Study Participant logs
  • Adverse Events & Unanticipated Problems
  • Monitoring/Auditing
  • Correspondence and Meeting Minutes
  • Study-related SOPs/MOPs
  • Study Staff documentation (resume/CV and required certifications and conflict of interest)
  • Laboratory
  • Drug/Device Accountability
  • Regulatory Submissions

4.6.2 Why

A complete regulatory binder allows ready access to all materials that reflect regulatory compliance and adherence to the ethical standards for Good Clinical Practice. The regulatory binder is often the first thing reviewed during audits and inspections.

4.6.3 How

The PI and Project Director (PD) should compile a list of all essential documents specific to the RCT as indicated by the sponsors and regulatory authorities. Many sponsors supply investigators with binders and organization strategies (see Resources). Additionally NIH provides a regulatory binder checklist. Harvard Catalyst provides a template for a regulatory binder.

The Project Director should be responsible for the creation and maintenance of the binder under the PI’s supervision. It is helpful to include a section in the MOP about the regulatory binder/file management addressing the following:

  • Creation/required documents
  • Location of various components when study is on-going
  • Updating frequency and responsibility
  • Management/storage of outdated documents and retention requirements

The regulatory binder may take the form of one or more physical binders, located in one or more physical locations. It may also take the form of an indexed collection of electronic documents maintained on a study website or shared file. Physical binders should be labeled (cover and spine) with the protocol number, PI name, and study site. Use multiple binders or master binders to maintain documentation as needed.

Access to the various sections of the binder may be controlled based on role in the study and status related to study blinding.

4.6.4 Special considerations for older subjects

None

4.6.5 Common Pitfalls

Lack of adequate organization or management plan.

4.6.6 Resources