Thursday, March 24, 2016

Protocol Template for Clinical Trials

For any clinical trial, the study protocol is the most critical document and is the blue print of the entire study. There are clinical studies with very high quality of the study protocol. There are also clinical studies with sub-optimal quality of the study protocol. It would be nice if there is a protocol template so that all clinical trial protocols are written in a consistent way no matter whether the clinical trial sponsors are industry, academic, or government agencies.  

Usually, people follow the ICH E6 (Good Clinical Practice) as the guidance for developing the clinical study protocol. ICH E6 has a specific section about "Clinical Trial Protocol and Protocol Amendment(s)". The outline of the clinical trial protocol is listed as below in ICE E6:
CLINICAL TRIAL PROTOCOL AND PROTOCOL AMENDMENT(S)
1 General Information
2 Background Information
3 Trial Objectives and Purpose
4 Trial Design
5 Selection and Withdrawal of Subjects
6 Treatment of Subjects
7 Assessment of Efficacy
8 Assessment of Safety
9 Statistics
10 Direct Access to Source Data/Documents
11 Quality Control and Quality Assurance
12 Ethics
13 Data Handling and Record Keeping
14 Financing and Insurance
15 Publication Policy
16 Supplements
Another way people write the clinical study protocol is to follow the ICH E3 (Structure and Contents of Clinical Study Report). The idea is that the section 7 to 9 of the study report will describe the study protocol and delineate how the clinical study is conducted. Following the ICH E3, the clinical study protocol can be organized according to the outline below:
7. INTRODUCTION
8. STUDY OBJECTIVES
9. INVESTIGATIONAL PLAN
9.1 OVERALL STUDY DESIGN AND PLAN - DESCRIPTION
9.2 DISCUSSION OF STUDY DESIGN, INCLUDING THE CHOICE OF CONTROL GROUPS
9.3 SELECTION OF STUDY POPULATION
9.3.1 Inclusion Criteria
9.3.2 Exclusion Criteria
9.3.3 Removal of Patients from Therapy or Assessment
9.4 TREATMENTS
9.4.1 Treatments Administered
9.4.2 Identity of Investigational Product(s)
9.4.3 Method of Assigning Patients to Treatment Groups
9.4.4 Selection of Doses in the Study
9.4.5 Selection and Timing of Dose for each Patient
9.4.6 Blinding
9.4.7 Prior and Concomitant Therapy
9.4.8 Treatment Compliance
9.5 EFFICACY AND SAFETY VARIABLES
9.5.1 Efficacy and Safety Measurements Assessed and Flow Chart
9.5.2 Appropriateness of Measurements
9.5.3 Primary Efficacy Variable(s)
9.5.4 Drug Concentration Measurements
9.6 DATA QUALITY ASSURANCE
9.7 STATISTICAL METHODS PLANNED IN THE PROTOCOL AND DETERMINATION OF SAMPLE SIZE
9.7.1 Statistical and Analytical Plans
9.7.2 Determination of Sample Size
It will be desirable to have a protocol template so that all clinical trial protocols are written in a consistent way. While there is no universal protocol template across the industry, academic, and governmental agencies, for efficiency and consistency, there should be a protocol template within each company or organization.

In an effort to increase the efficiency of clinical trial protocol reviews, the National Institutes of Health (NIH) has released a draft protocol template developed in collaboration with the US Food and Drug Administration (FDA). As indicated in the preface of the draft protocol template,
"This Clinical Trial Protocol Template is a suggested format for Phase 2 or 3 clinical trials supported by the National Institutes of Health (NIH) that are being conducted under a Food and Drug Administration (FDA) Investigational New Drug Application (IND) or Investigational Device Exemption (IDE). Investigators for such trials are strongly encouraged to use this template when developing protocols for NIH supported clinical trial(s). However, others may also find this template beneficial for other clinical trials not named here.
This template is provided to aid the investigator in writing a comprehensive clinical trial protocol that meets the standard outlined in the International Conference on Harmonisation (ICH) Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance (ICH-E6). In order to facilitate review by NIH and FDA, investigators should retain the sections in the order provided."
In the meantime, FDA is also make the collaborative efforts to develop so-called the common protocol template developed by TransCelerate Biopharma to help ensure consistency for the medical product development community. CDISC is also making efforts to develop or modelize the clinical study protocol - The protocol representation model (PRM). The common protocol template and PRM (once developed and accepted by clinical research community) can also help with the downstream activities: standardized study protocol -> standardized data collection / case report forms -> standardized data structure -> standardized software -> standardized data presentations.

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