Protocol Template for Clinical Trials

For any clinical trial, the study protocol is the most critical document and is the blueprint 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 sections 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 are no universal protocol templates 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 making 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.

Reference:

• Guide Notice for Clinical Trial Protocol Template for Phase 2 and 3 IND/IDE Studies
• NIH Clinical Trial Protocol Template
• NCI Protocol Template and Guidelines
• NIH Clinical Trials Protocol Template - NIH Office of Science Policy
• NIH/FDA Protocol Template
• Michael Mezher (2016) NIH, FDA Release Streamlined Clinical Trial Protocol Template 

Targeted or Selective Safety Data Collection in Late Pre-authorisation and Post-authorisation Clinical Trials.

Last month, FDA released its final guidance "Guidance for Industry: Determining the Extent of Safety Data Collection Needed in Late-Stage Premarket and postapproval Clinical Investigations. One thing we noticed is that in the final version, the FDA changed its terminology from "Targeted Safety Data Collection" to "Selective Safety Data Collection".

“This guidance provides recommendations on when to consider selective safety data collection and how to do so to maintain a balance between eliminating the collection of data that will not be useful and collecting sufficient data to allow adequate characterization of the safety profile of a drug,” FDA says,

The final guidance significantly revised and finalized guidance originally released in 2012. In response to public comments requesting more detail and examples, FDA says the draft guidance was revised and reorganized to clarify what types of safety data and what circumstances may be appropriate for the selective collection, in addition to more detail on the draft guidance topics and additional information on safety data reporting issues.

Following the release of the draft guidance, FDA conducted the webinar to explain the main points of this guidance. The webinar and the slides can be found here.

While FDA has the explicit guidance on the targeted/selective safety data collection, EMA's position is less clear. EMA’s clinical trial directive does not explicitly require a complete collection of all AEs and other non-critical safety data. The communications with EMA suggest that it allows sponsors to target the collection of nonserious AEs and other non-critical safety data when appropriate in post-authorization studies.

The US Food and Drug Administration (FDA) on Thursday significantly revised and finalized guidance originally released in 2012 that will help the industry understand what types of safety data needs to be collected in late-stage premarket and postapproval clinical investigations.

In response to public comments requesting more detail and examples, FDA says the draft guidance was revised and reorganized to clarify what types of safety data and what circumstances may be appropriate for the selective collection, in addition to more detail on the draft guidance topics and additional information on safety data reporting issues.

Combining with the FDA guidance "Oversight of Clinical Investigations —A Risk-Based Approach to Monitoring", we see an effort from FDA to ease the burden in conducting the clinical trial and cut the cost of drug development. Over the years, the clinical trial protocol has become so complicated, a lot of data collected during the trial has little or no value to the objective of the study, and on-site monitoring and 100% source data verification has limited improvement in data quality, but are always implemented.

Fully adopting this two guidance may be quick in the government and academic sponsored clinical trials, but it will take some time for the clinical trials sponsored by the industry for the licensure purpose.

References:

Zachary Brenan 2016 "FDA Finalizes Guidance on Safety Data Collection for Late-Stage and Postapproval Trials"

One-sided versus Two-sided test

For vast majority of clinical trials, two-sided tests are performed and two-sided p-values are presented. Once a while, we will see some study results presented with one-sided p-value. 

 

In a previous post "One-Sided Test in A Superiority Trial", an example from the RAPID study was given and the purpose of presenting the one-sided p-value seemed to be for looking better to the readers. Since then, the RAPID study results have been officially published in LANCET. However, in LANCET publication, the one-sided p-value was replaced with two-sided p-value. I can only guess that LANCET did not like the trick of presenting the one-sided p-value. Below is the comparison. Notice that for a one-sided p value of 0.017 (significance level is 0.025), the two sided p value is supposed to be 0.034 (significance level is 0.05).

In early presentation by the company	In official publication in LANCET
The annual rate of lung density loss was significantly less in augmentation-treated patients (-1.45 +/- 0.24 units vs. -2.19 +/-0.25 units; p = 0.017, one-sided).	However, the annual rate of lung density loss at TLC alone was significantly less in patients in the A1PI group (–1·45 g/L per year [SE 0·23]) than in the placebo group (–2·19 g/L per year [0·25]; difference 0·74 g/L per year [95% CI 0·06–1·42], p=0·03)

In a recent paper by Sitbon et al "Selexipag for the Treatment of Pulmonary Arterial Hypertension", ones-sided p-value was presented. Here is what the paper says:

•  Sample size calculation is based on at a one-sided type 1 error rate of 0.005.
• Because of the alpha spending for one interim analysis, The final analysis used a one-sided significance level of 0.00499 instead of 0.005.
• P values were calculated with the use of a one-sided log-rank test. 

 

Ironically, even though the one-side p-value was presented, when it came to the confidence interval, the two-sided confidence interval were presented.

 

FDA's statistical review has more details about how the statistical analyses were performed and the results were presented. In this study, one of the reasons for using the one-sided p-value could be the nature of the group sequential design. In group sequential design and the adaptive design, one-sided significant level is often used because it is easier for calculation.
 

In both cases, the statistical test was essentially the two-sided test even though the one-sided p-values were presented. The significance level was α/2 instead of α. I can only guess that the reason for presenting the one-sided p-value is to make the p-value look smaller (more impressive).