CLINICAL TRIAL PROTOCOL DEVELOPMENT AND KEY COMPONENTS OF TRIAL PROTOCOL

CLINICAL TRIAL PROTOCOL DEVELOPMENT

Once a clinical question has been postulated, the first step in the conception of a clinical trial to answer that question is to develop a trial protocol. A well-designed protocol reflects the scientific and methodological integrity of a trial. Protocol development has evolved in a complex way over the last 20 years to reflect the care and attention given to undertaking clinical experiments with human volunteers, reflecting the high standards of safety and ethics involved as well as the complex statistical issues.

Questions addressed by a protocol:

• What is the clinical question being asked by the trial?
• How should it be answered, in compliance with the standard ethical and regulatory requirements?
• What analyses should be performed in order to produce meaningful results?
• How will the results be presented?

Qualities of a good protocol:

• Clear, comprehensive, easy to navigate, and unambiguous.
• Designed in accordance with the current principles of Good Clinical Practice and other regulatory requirements.
• Gives a sound scientific background of the trial.
• Clearly identifies the benefits and risks of being recruited into the trial.
• Plainly describes trial methodology and practicalities.
• Ensures that the rights, safety, and well-being of trial participants are not unduly compromised.
• Gives enough relevant information to make the trial and its results reproducible.
• Indicates all features that assure the quality of every aspect of the the trial.

CLINICAL TRIAL PROTOCOL

The contents of a trial protocol should generally include the following topics. However,  site specific information may be provided on separate protocol page(s), or addressed in a separate agreement, and some of the information listed below may be contained in other protocol referenced documents, such as an Investigator’s Brochure.

General Information:

• Protocol title, protocol identifying number, and date. Any amendment(s) should also bear the amendment number(s) and date(s).
• Name and address of the sponsor and monitor (if other than the sponsor).
• Name and title of the person(s) authorized to sign the protocol and the protocol amendment(s) for the sponsor.
• Name, title, address, and telephone number(s) of the sponsor's medical expert (or dentist when appropriate) for the trial.
• Name and title of the investigator(s) who is (are) responsible for conducting the trial, and the address and telephone number(s) of the trial site(s).
• Name, title, address, and telephone number(s) of the qualified physician (or dentist, if applicable), who is responsible for all trial-site related medical (or dental) decisions (if other than investigator).
• Name(s) and address(es) of the clinical laboratory(ies) and other medical and/or technical department(s) and/or institutions involved in the trial.

Background Information:

• Name and description of the investigational product(s).
• A summary of findings from nonclinical studies that potentially have clinical significance and from clinical trials that are relevant to the trial.
• Summary of the known and potential risks and benefits, if any, to human subjects.
• Description of and justification for the route of administration, dosage, dosage regimen, and treatment period(s).
• A statement that the trial will be conducted in compliance with the protocol, GCP and the applicable regulatory requirement(s).
• Description of the population to be studied.
• References to literature and data that are relevant to the trial, and that provide background for the trial.

Trial Objectives and Purpose:

• A detailed description of the objectives and the purpose of the trial.

Trial Design:
The scientific integrity of the trial and the credibility of the data from the trial depend
substantially on the trial design. A description of the trial design, should include:

• A specific statement of the primary endpoints and the secondary endpoints, if any, to be measured during the trial.
• A description of the type/design of trial to be conducted (e.g. double-blind, placebo-controlled, parallel design) and a schematic diagram of trial design, procedures and stages.
• A description of the measures taken to minimize/avoid bias, including:

                    (a) Randomization.
                    (b) Blinding.

• A description of the trial treatment(s) and the dosage and dosage regimen of the investigational product(s). Also include a description of the dosage form, packaging, and labelling of the investigational product(s).
• The expected duration of subject participation, and a description of the sequence and duration of all trial periods, including follow-up, if any.
• A description of the "stopping rules" or "discontinuation criteria" for individual subjects, parts of trial and entire trial.
• Accountability procedures for the investigational product(s), including the placebo(s) and comparator(s), if any.
• Maintenance of trial treatment randomization codes and procedures for breaking codes.
• 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 Subjects:

• Subject inclusion criteria.
• Subject exclusion criteria.
• Subject withdrawal criteria (i.e. terminating investigational product treatment/trial treatment) and procedures specifying:

1. When and how to withdraw subjects from the trial/ investigational product treatment.
2. The type and timing of the data to be collected for withdrawn subjects.
3. Whether and how subjects are to be replaced.
4. The follow-up for subjects withdrawn from investigational product treatment/trial treatment.

Treatment of Subjects:

• The treatment(s) 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 the follow-up period(s) for subjects for each investigational product treatment/trial treatment group/arm of the trial.
• Medication(s)/treatment(s) permitted (including rescue medication) and not permitted before and/or during the trial.
• Procedures for monitoring subject compliance. 

Assessment of Efficacy:

• Specification of the efficacy parameters.
• Methods and timing for assessing, recording, and analysing of efficacy parameters.

Assessment of Safety:

• Specification of safety parameters.
• The methods and timing for assessing, recording, and analyzing safety parameters.
• Procedures for eliciting reports of and for recording and reporting adverse event and intercurrent illnesses.
• The type and duration of the follow-up of subjects after adverse events. 

Statistics:

• A description of the statistical methods to be employed, including timing of any planned interim analysis(ses).
• The number of subjects planned to be enrolled. In multicentre trials, the numbers of enrolled subjects projected for each trial site should be specified. Reason for choice of sample size, including reflections on (or calculations of) the power of the trial and clinical justification.
• The level of significance to be used.
• Criteria for the termination of the trial.
• Procedure for accounting for missing, unused, and spurious data.
• 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 protocol and/or in the final report, as appropriate).
• The selection of subjects to be included in the analyses (e.g. all randomized subjects, all dosed subjects, all eligible subjects, evaluable subjects).

Direct Access to Source Data/Documents:

• The sponsor should ensure that it is specified in the protocol or other written agreement that the investigator(s)/institution(s) will permit trial-related monitoring, audits, IRB/IEC review, and regulatory inspection(s), providing direct access to source data/documents.

Quality Control and Quality Assurance:

Ethics:

• Description of ethical considerations relating to the trial.

Data Handling and Record Keeping:

Financing and Insurance:

• Financing and insurance if not addressed in a separate agreement. 

Publication Policy:

• Publication policy, if not addressed in a separate agreement. 

Supplements:
(NOTE: Since the protocol and the clinical trial/study report are closely related, further relevant information can be found in the ICH Guideline for Structure and Content of Clinical Study Reports.)

When considering the above items, special attention must be given to designing a protocol that eliminates bias and reduces variance.

Key components of a trial protocol

The trial protocol is a comprehensive document and the core structure of the protocol should be adapted according to the type of trial. ICH–GCP can be used as a reference document when developing a protocol for pharmaceutical clinical trials (Phase I to Phase IV) involving a pharmaceutical substance (the investigational medicinal product [IMP]). Most institutions and pharmaceutical companies use a standard set of rules to define the main protocol outline, structure, format, and naming/numbering methods for their trials. In this section, we briefly describe the main components of a typical protocol.


Protocol information page:

The front page gives the:

• trial title
• trial identification number
• protocol version number
• date prepared

The descriptive title of the protocol should be kept as short as possible, but at the same time it should reflect the design, type of population, and aim of the trial. ICH–GCP suggests that the title of a pharmaceutical trial should additionally include the medicinal product(s), the nature of the treatment (eg, treatment, prophylaxis, diagnosis, radiosensitizer), any comparator(s) and/or placebo(s), indication, and setting (outpatient or inpatient). The key investigational site, investigator, and sponsor should also be detailed on the title page.



Trial summary or synopsis:
A synopsis should provide the key aspects of the protocol in no more than two pages, and can be prepared in a table format. The main components of the protocol summary include:
full title

• principal investigator
• planned study dates
• objectives
• study design
• study population
• treatments
• procedures
• sample size
• outcome measures
• statistical methods