Protocols, clinical trials

Figure 5.3 A typical clinical trial protocol template (in this case as required by the Irish Medicines Board www.imb.ie Irish Medicines Board).

The clinical trial protocol is a detailed written plan that outlines how the study procedures are to be carried out and how the data are to be collected and analyzed. It insures the quality and integrity of the trial, particularly when multiple research sites are participating in data collection (Chow and Liu, 1998). The purposes of the protocol are to outline ... 

Further information and advice related to the use of the clinical trial design can be found in a variety of sources including textbooks, manuscripts, organizations and Internet sites. In addition to the chapter reference list which cites helpful sources of information related to clinical trial protocol development, design and analysis, the following sources are also recommended. 

Uses of Specific Laboratory Tests to Discover, Confirm, and/or Exclude a Disease. Some tests can confirm the diagnosis of a disease (e.g., tissue histology from a broncho scopic biopsy to confirm lung cancer), but cannot be used to exclude the disease or discover the disease in routine screening. Other tests can be used both to confirm and to exclude the diagnosis of a disease (e.g., glucose tolerance test for diabetes mellitus), but are too inconvenient to be used to discover the disease in routine screening. The uses of each laboratory test to discover, confirm, or exclude a disease should be considered before a test is simply added to a clinical trial protocol. This ensures that the test is appropriate in the context of the planned clinical trial. 

Clinical Trial Protocol and Protocol Amendments Investigator s Brochure... 

Name and description of the clinical trial protocol Summary of results from nonclinical studies Potential risks and benefits to human subjects Description and justification for route of administration, dosage, and treatment plan Compliance to GCP... 

Clinical trials are conducted according to GCP. There should be a protocol that states the reason for the clinical trial, how it is to be conducted, the number of people to be included, eligibility criteria, medical tests and observations to be made, and information to be collected. Clinical trial protocol must be approved by the IRB/IEC before commencement. 

Statistics analysis is an integral part of a clinical trial. A clinical trial protocol includes information on statistical parameters that the trial is expected to be based on and methods for the analysis of data. 

A Sponsor submits a clinical trial application to the Competent Authority in each member state where the trials are to be conducted. The Competent Authority has 60 days to review and approve or reject the application. Application is in prescribed forms and covers the proposed clinical trial protocol, manufacturing, and quality controls on the drug, and supporting data, such as (1) chemical, pharmaceutical, and biological data, (2) nonclinical pharmacological and toxicological data, and (3) clinical data and previous human experience. The supporting data are submitted in the Common Technical Document (CTD) format (see Section 7.11). 

In view of the regulatory delay that was caused by the need to apply for a CTC, a Statutory Order (SI 1974/498) was made during 1974, to provide an exemption from the need to hold a CTC in such cases, subject to certain conditions. This order applied to trials conducted by doctors and dentists on their own responsibility (DDX). The basis of the clinical trial exemption (CTX) scheme, introduced in 1981, to include studies initiated by the pharmaceutical industry, was that together with a detailed clinical trial protocol and summaries of chemical, pharmaceutical, pharmacological, pharmacokinetic, toxicological and human volunteer studies, a clinical trial in patients may proceed without the need for the additional details normally required for a CTC or Product Licence application. This exemption scheme was based on the requirements that ... 

The government had required that the sponsors should have their own in-house study review board to review the ethical aspects of clinical trial protocols. Such a requirement was based on the former Japanese GCP, which stipulates that the company should organise an internal formal body or mechanism that reviews and authorises its planned studies before submitting to either study centres or the MHW for clinical trial plan notification. 

In 2003 there were 2378 CTN scheme notifications. It should be noted, however, that this does not indicate the number of different clinical trial protocols, which was approximately 560 in 2003-4. This contrasts with two CTX 50 working day applications in the same period and zero 30 working day applications. 

Table 2.8. Typical issues addressed when designing a clinical trial protocol. The trial objectives should clearly define what questions the trial should answer. The study design section should contain comprehensive information detailing trial size, criteria used to choose the study population, and enrolment procedures. Description of intervention section should give the background to the intervention itself, its therapeutic rationale and how it is to be administered. Measurement of response should detail the data to be collected, how it will be collected and analysed. The organization and administration section should give full details of all the investigators, where the trial is being run, and its project management details...

IRBs approve the clinical trial protocols, which describe the type of people who may participate in the clinical trial, the schedule of tests and procedures, the medications and dosages to be studied, the length of the study, the study s objectives, and other details. IRBs make sure the study is acceptable, that participants have given consent and are fully informed of their risks, and that researchers take appropriate steps to protect patients from harm. 

Preparation, approval and amendment of clinical trial protocols... 

Clinical Trials Data Bank We have established a clinical trials data bank to collect information on your clinical trials protocols. Please list your protocols for serious and life-threatening conditions [Food and Drug Administration Modernization Act of 1997 section 113]. When finalized, you should list your protocols in accordance with our Draft Guidance for Industry—Information Program on Clinical Trials for Serious or Life-Threatening Diseases Implementation Plan, June 2001. 

New compounds, while in principle more promising, pose a considerable problem in all aspects of the clinical trial. The example of VCDP shows the problems of acute toxicity (which is considerable), of late phototoxicity of the skin (which has not been analyzed), the administration of the compound (which needs to be optimized) and the availability of the compound (which is difficult to prepare in large quantities). Whereas these problems are not insurmountable for any new compound, ethical and practical questions must be answered satisfactorily before a clinical trial protocol can be prepared. 

CSOs assisting clients with clinical trial design need to be an extension of the client s project team and have access to all the data to assist in developing a realistic clinical trial package to determine the safety and efficacy of a drug candidate. In addition to assisting clients with clinical development plans and preparing clinical trial protocols, many of these CSOs also offer... 

The clinical trial protocol should contain data on the trial site and methodology, a list of the neunes, address, position, bacl round and clinical experience of each investigator. The individual data for each patient should be included in the report. 

Clinical Trial Protocol signed by both the Chief Investigator and the Firm s Medical Director, in 2 copies... 

Department established in April 1997. Pharmaceutical companies have started to consult this department on their development plans, clinical trial protocols, necessary studies, etc., with fees (See Table 2). 

Clinical Trial Protocol Notification. The sponsor is obligated to submit the clinical trial protocol notification of the test drug. The following drugs are required to submit the notification of the clinical trial (The article 66-6 of the Enforcement Regulations of PAL. Notification No. 421 of the PAB in 1997) ... 

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