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What is a protocol and how is it used in scientific research and review?

(Excerpted from “Designing your Research for Speedy IRB Approval
Paul W. Stewart, PhD, Professor of Biostatistics, UNC-CH)

  • A Master Protocol Document (‘MPD’ or ‘protocol’) is a repository for accumulated ideas, information, literature review, and references. It is a working document that specifies all the details, algorithms, procedures, strategies, and plans for study conduct, and serves as a master source of text used for reference and guidance. Beginning in the earliest stages of study planning, it is highly efficient to use a MPD template as a tool for collecting ideas, references, information, and evolving text for subsequent use in grant proposals, IRB applications, and publications.
  • Increasingly, funders, IRBs, and journals are requiring submission of a protocol as part of their review processes. For example: “The Good Clinical Practice (GCP) guidelines of the International Council for Harmonization (ICH E3 GCP 6) require a research protocol for any study that involves human participants. In addition, Title 21 Part 312 of the Code of Federal Regulations (21 CFR 312) describes both a research protocol and protocol amendments for studies conducted under an Investigational New Drug application.”NDAT GCP
  • All phases and sizes of studies should have a protocol that describes the essential elements of sound research practices – background/rationale, objectives, specific aims, study design, procedures, data collection/validity/quality, safety monitoring/management, a rationale for the chosen sample size choice, and a complete and adequately-detailed statistical analysis plan for each specific aim. The MPD should be as simple or as complex as the study it represents.
  • A grant proposal or IRB application cannot be substituted for an MPD because they do not provide comprehensive detail. A grant proposal is meant to convince funders of the need, relevance and innovation of a research concept as well as the suitability of the research setting and investigators. An IRB application is intended to describe the planned study procedures, related risks and benefits, how participants’ identities and data will be protected, the informed consent process, and other issues related to protection of human subjects. A study protocol details all these aspects of the research project, with special focus on clearly stated aims, specification of outcome measures and other variables of interest along with their units of measure (or the range of valid values if the variable is categorical), comprehensive description of the data to be collected, a rationale for the chosen sample size, and aim-specific statistical analysis strategies and methods to be used to analyze data.
  • In the MPD, the specific aims, study design, variables of interest, and aim-specific statistical analysis plans should be aligned; e.g., if assessing feasibility is a specific aim, then the protocol should specify outcome measures and plans for analysis of feasibility data.
  • Protocol reviewers are tasked with assuring that studies involving human subjects are founded on good science, are reasonable in terms of participant burden, and will yield valuable information to better understand, diagnose, treat or manage a disease, condition, or behavior. A comprehensive and carefully constructed MPD is a sign to others that the investigative team takes seriously their scientific and ethical responsibility to participants, funders, and their institution.
  • It is highly recommended that the research team includes a professional statistician as a co-investigator to collaborate on the development and execution of all aspects of the study protocol; e.g., study design, specific aims, measures of interest, statistical analysis strategies and methods, and justification of the choice of sample size in terms of anticipated precision of estimators and anticipated power levels of test procedures.
  • Statistical consultation through NC TraCS can be extremely helpful and is highly recommended; however, a brief statistical consultation does not necessarily guarantee that scientific review will be free of substantial concerns. In contrast to comprehensive scientific review, a brief statistical consultation has the potential to address only the delimited specific questions you ask.
  • It is recommended that UNC investigators use the HIPAA-compliant REDCap software system available from NC TraCS Institute. Use of REDCap and REDCap training sessions are available at no charge to UNC investigators. Fees are charged by TraCS only for assistance provided by the TraCS Biomedical Informatics Core. For collection and management of human research data, spreadsheet software such as MS Excel is not recommended. Advantages of using REDCap include:

    Reliability. REDCap is in use in over 1500 institutions worldwide. Developed at Vanderbilt University, REDCap is hosted and supported locally at UNC by NC TraCS Institute. UNC REDCap is hosted on sophisticated IT infrastructure and is backed up multiple times per day.

    Security. Users access REDCap online through a secure login page. Traffic between the web browser and the database is encrypted. Data storage complies with UNC’s encryption policy. User-rights management gives you full control authorizations. Audit trails provide accountability.

    Ease of Use. The user interface is intuitive, allowing simple studies to be built in minutes. Built-in training resources allow new users to learn as they go. NC TraCS Institute offers weekly tutorial training sessions in Brinkhous-Bullitt. Web-based data entry can take place almost anywhere.

    Data Quality. REDCap supports critically important data quality features such as: Structured data dictionary, Skip logic, Mandatory fields, Range checking, Form locking/unlocking. The data quality module provides customized data quality checks. Data resolution workflow allows for data queries to be raised and resolved. For data monitoring, limited reports/graphs can be generated by REDCap.

    Features. REDCap supports a broad range of project types from simple surveys through complex longitudinal clinical trials. Additionally, REDCap also includes support for: randomization and concealment, survey scheduling, data quality workflows, data coding (via Bioportal), and text and voice messaging.

    Data export. REDCap exports CSV files along with Stata/SAS/R/SPSS code easily used to create formatted datasets.

    For further information see the following:

  • Final checks prior to SRC submission should assure: information in the Synopsis is fully detailed in the protocol; text is internally consistent; boilerplate language has been replaced with study- and setting-specific details; version number and date are current; all acronyms have been included in a table of abbreviations; and pages have been numbered.
  • It is recommended to use a protocol template specific to study type/design, to insure that all elements are present and sufficiently described to facilitate scientific review. UNC-recommended templates are available below: