Following on from this the next page of the trial should consist of a table of contents with the following headings which have all been thoroughly examined further on in the essay. An example of this is shown below:5
Table of Contents
1 BACKGROUND
1.1 Investigational Agent
1.2 Preclinical Data
1.3 Risk/Benefits
1.4 Dose Rationale
1.5 Trial Conduct
1.6 Population
1.7 Literature
2 TRIAL OBJECTIVES
3 TRIAL DESIGN
3.1 Primary Study Endpoints/Secondary Endpoints
3.2 Study Design/Type
3.3 Randomization
3.4 Maintenance
3.5 Trial Treatment
3.6 Duration
3.7 Discontinuation
3.8 Product Accountability
3.9 Data Identification
4 SELECTION AND WITHDRAWAL OF SUBJECTS
4.1 Inclusion Criteria
4.2 Exclusion Criteria
4.3 Subject Withdrawal
4.4 Treatment of Subjects
4.5 Medication
4.6 Monitoring for subject compliance
5 ASSESSMENT OF EFFICACY
5.1 Efficacy Parameters
5.2 Method and Timing
6 ASSESSMENT OF SAFETY
6.1 Safety Parameters
6.2 Method and Timing
6.3 Adverse Event Reporting
6.4 Definitions
6.5 Adverse Event Follow-up
7 STATISTICAL PLAN
7.1 Statistical Methods
7.2 Subject Population(s) for Analysis
7.3 Significance
7.4 Termination Criteria
7.5 Accountability Procedure
7.6 Deviation Reporting
8 DIRECT ACCESS TO SOURCE DATA/DOCUMENTATION
9 QUALITY CONTROL AND QUALITY ASSURANCE
10 ETHICAL CONSIDERATIONS
11 DATA HANDLING AND RECORD KEEPING
12 FINANCE AND INSURANCE
13 PUBLICATION PLAN
14 SUPPLEMENTS
The table of contents then should be followed by another page which should contain a list of abbreviations in the protocol so that any person reading will be able to refer to what they all mean. An example listed is shown below:6
List of Abbreviations
CFR Code of Federal Regulations
ICH International Conference on Harmonisation
CRF Case Report Form
FDA Food and Drug Administration
GCP Good Clinical Practice
IRB Institutional Review Board
Consequently following on from this will be the constituted protocol. Each of the subheadings examined in the table of contents have been explained thoroughly stating exactly what should be included in a clinical trial protocol for a novel drug. 5
1 Background5
Investigational Agent
The name of the investigational product(s) is inserted here i.e. Zopilol.
Preclinical Data
A summary of the findings from non-clinical studies that are potentially found to have clinical significance and from clinical trials that are relevant to the trial are inserted here.
Risk/Benefits
A summary of all the known and potential risks as well as benefits to the human subjects are inserted here i.e. zopilol is beta-adrenoreceptor blocker drug and is principally used in the treatment of hypertension as well as for angina and arrhythmias.
Dose Rationale
A description of and justification for the route of administration, dosage, dosage regimen, and treatment period(s) are inserted here. In the case of zopilol it would ideally be administered orally although it would also be available as an infusion. The treatment dose would normally be a 50mg tablet to be taken daily.
Trial Conduct
The insertion of a statement that the trial will be conducted in compliance with: the protocol, GCP and the applicable regulatory requirement(s). For example: This study will be conducted in compliance with the protocol approved by the Institutional Review Board, and according to Good Clinical Practice standards. No deviation from the protocol will be implemented without the prior review and approval of the IRB except where it may be necessary to eliminate an immediate hazard to a research subject. In such case, the deviation will be reported to the IRB as soon as possible.
Population
A description of the population to be studied will be inserted i.e. 500 people.
Literature
The reference to any literature and data that are relevant to the trial and that provide background for the trial would be included here.
Trial Objectives5
A detailed description of the objectives and the purpose of the trial would be inserted here.
Trial Design5
The scientific integrity of the trial and the credibility of the data from it depend substantially on the design. A description of the trial design includes the following:
Primary Study Endpoints/Secondary Endpoints
A specific statement of either primary or secondary endpoints if any is to be measured during the trial.
Study Design/Type
A description of the type/design of trial to be conducted (e.g. double-blind, placebo controlled, parallel design) as well as a schematic diagram of trial design, procedures and stages would be inserted here.
Randomization
A description of the measures taken to minimize/avoid bias, including (for example):
- Randomization (include a description of the method)
- Blinding
As bias is any process or effect at any stage of a study from its design to its execution to the application of information from the study that produces results or conclusions that differ systematically from the truth. Bias can be reduced only by proper study design and execution and not by increasing sample size. Almost all studies have bias, but to varying degrees. The critical question is whether or not the results could be due in large part to bias, thus making the conclusions invalid. Observational study designs are inherently more susceptible to bias than are experimental study designs. Stratification is one such technique that is commonly used in “comparative studies in order to avoid bias.”7
Maintenance
Insert a description of the maintenance of the randomization codes and the procedure for breaking codes.
Trial Treatment
Insert a description of the trial treatment(s) and a description of the dosage form, packaging, and labelling of the investigational product(s). So in the case of this novel drug the label for zopilol would be as shown below:
Duration
Insert the expected duration of subject participation and a description of the sequence and duration of all trial periods, including follow-up if any.
Discontinuation
Insert a description of the stopping rules or discontinuation criteria for individual subjects, parts of the trial, and entire trial.
Product Accountability
Insert accountability procedures for the investigational product(s), including the placebo(s) and comparator(s) if there are any.
Data Identification
Insert the identification of any data to be recorded directly on the CRFs (i.e. no prior written or electronic record of data), and to be considered to be source data.
Selection and Withdrawal of Subjects5
Inclusion Criteria
Subject inclusion criteria are inserted here so defining who is eligible for the study.
Exclusion Criteria
Subject exclusion criteria are inserted here. Contra-indications to trial treatments are considered here along with mismatched concurrent treatments. As well as the latest participation in other research.
Subject Withdrawal
Insert subject withdrawal criteria (i.e. terminating investigational product treatment/trial treatment) and procedures specifying:
- When and how to withdraw subjects from the trial/investigational product treatment.
- The type and timing of the data to be collected for withdrawal of subjects.
- Whether and how subjects are to be replaced.
- The follow-up for subjects withdrawn from investigational treatment/trial treatment.
Treatment of Subjects
Insert how the treatment(s) is(are) to be administered, including the name(s) of all the product(s), the dose(s), the dosing schedule(s), the route/mode(s) of administration, and the treatment period(s), including follow-up period(s) for subjects for each investigational product treatment/trial treatment group/arm of the trial.
Medication
Insert medication(s)/treatment(s) permitted (including rescue medication) and not permitted before and/or during the trial.
Monitoring for subject compliance
Insert the procedures for monitoring subject compliance.
Assessment of Efficacy5
Efficacy Parameters
The specifications of the efficacy parameters are inserted here.
Method and Timing
The methods and timing for assessing, recording and analyzing efficacy parameters are inserted here.
Assessment of Safety6
Safety Parameters
Insert specifications for safety parameters.
Method and Timing
Insert the methods and timing for assessing, recording and analyzing safety parameters.
Adverse Event Reporting
A statement about compliance with the local IRB requirements and the requirements of other regulatory authorities that may apply are inserted here. Procedures for eliciting reports of and for recording and reporting adverse event and intercurrent illnesses should be described in this section.
Definitions
Definitions of how you will apply the terms “unanticipated”, “serious”, and “related” to problems that arise during the study should be inserted here.
Adverse Event Follow-up
The type and duration of the follow-up of subjects after adverse events are inserted here.
Statistical Plan5
Statistical Methods
Insert a description of the statistical methods to be employed including timing of any planned interim analysis.
Subject Population(s) for Analysis
Insert the number of subjects planned to be enrolled. In multi-center trials, the number of enrolled subjects projected for each trial site should be specified. Provide a reason for choice of sample size, including reflection on (or calculations of) the power of the trial and clinical justification. Also inclusion of how you will select the group of subjects for analysis (e.g., all randomized subjects, all dosed subjects, all eligible subjects, and only evaluable subjects).
Significance
The level of significance to be used should be inserted here.
Termination Criteria
The criteria for the termination of the trial should be inserted here.
Accountability Procedure
Insert the procedure for accounting for missing, unused and false data.
Deviation Reporting
Insert the procedures for reporting any deviation(s) from the original statistical plan. Any deviation(s) from the original statistical plan should be described and justified in the protocol and/or in the final report.
Direct Access to Source Data/Documentation6
It should be specified in the protocol or other written agreement the investigator(s)/institution(s) will permit trial-related monitoring, audits, IRB/IEC(s) review and regulatory inspection(s) by providing direct access to the source data or documentation.
Quality Control and Quality Assurance6
Insert how you will ensure that this study is conducted – and that data are generated, documented (recorded), and reported - in compliance with this protocol, with GCP, and any other applicable regulatory requirements.
Ethical Considerations6
Describe the ethical considerations relating to this study. The following language is an example:
This study will be conducted according to US and international standards of Good Clinical Practice (FDA regulations 21 CFR 312 for IND studies and FDA guidance E6) for all studies. Applicable government regulations and Liverpool John Moores University research policies and procedures will also be followed.
Data Handling and Record Keeping5
A description of who, what, where and why should be inserted here.
Finance and Insurance5
Insert financing and insurance statements if not addressed in a separate agreement. Who will be responsible for paying for research related costs? Who will be responsible for paying for injuries in case of accident?
Publication Plan5
Where ownership of the data is not in question – this section may be omitted. Otherwise, insert a publication policy, if not addressed in a separate agreement (most commonly a contract).
Supplements5
Insert any other documentation for the trial.
Once a draft of the protocol has been produced then it should be distributed for critical review and “comment to all those who have had input.”8 Their will be numerous drafts of the protocol before it is finalised. The protocol will be reviewed by a committee of individuals and then it is usually followed by a final sign-off procedure takes place. It should be noted that the review process can be lengthy because the reviewers don’t have prior knowledge to any earlier discussions in regards to the protocol.8 Spending time on the protocol in order to ensure an excellent protocol is worthwhile as it saves time and ultimately very few amendments would have to be made. However, the “world is unpredictable and situations can change during the lifetime of a clinical trial, protocol amendments often become necessary.”8
REFERENCES
-
.
-
Ignazio Di Giovanna, Gareth Hayes, Principles of clinical research (2001), 1st Edition, Institute of clinical research, Chapter 8 on: The clinical trial protocol, Pg 181 -182.
-
.
-
accessed on 02/03/2007.
-
.
-
accessed on 02/03/2207.
-
Ignazio Di Giovanna, Gareth Hayes, Principles of clinical research (2001), 1st Edition, Institute of clinical research, Chapter 8 on: The clinical trial protocol, Pg 189 -190.
-
Ignazio Di Giovanna, Gareth Hayes, Principles of clinical research (2001), 1st Edition, Institute of clinical research, Chapter 8 on: The clinical trial protocol, Pg 195.
