Nonclinical protocol

It is very likely that incomplete or missing records would prevent the verification of data integrity. Source records should be complete to facilitate an understanding of actual study conduct for critical phases of method development, method validation, and subject sample analysis. The records should confirm whether the testing was conducted in an appropriate manner, with well-designed and optimally controlled experiments. The documentation of actual laboratory events should demonstrate that the quantitative measures are suitable to achieve the objectives of the clinical or nonclinical protocol. The records should confirm that the reported results accurately reflect the actual concentration of the analyte in the biological matrix. It should be noted that the failure to adequately document critical details of study conduct has resulted in rejection of bioanalytical data for regulatory purposes. 

Subpart G - Protocol for and Conduct of a Nonclinical Laboratory Study Sec. 58.120 Protocol. 

The formulations that are developed and used for preclinical studies are sometimes specific for the test species to be employed, but their development always starts with consideration of the route of exposure that is to be used clinically and, if possible, in accordance with a specified regimen of treatment (mirroring the intended clinical protocol, as much as possible). One aspect of both nonclinical and clinical formulation and testing which presents an important but often overlooked aspect of pharmaceutical safety assessment is the special field of excipients. These will be considered at the end of this chapter... 

Nonclinical laboratory studies must be conducted in accordance with the protocols. 

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... 

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). 

Maintain copies of all protocols pertaining to all (nonclinical laboratory) studies for which the unit is responsible. 

List of Required Items for a Protocol of a (Nonclinical Laboratory) Study (From... 

Tests to establish the identity, strength, and purity of the test and control articles need not comply strictly with GLP requirements (e.g., protocol, QAU inspection requirements), but good documentation of anal5dical test results (usually in a laboratory notebook) and retention of raw data for such tests is a good practice. As the development process proceeds and the same material is used in both nonclinical and clinical studies, CGMP principles wiU apply to the production and characterization processes. 

SUBPART G PROTOCOL FOR AND CONDUCT OF A NONCLINICAL LABORATORY STUDY... 

A protocol is required for each nonclinical laboratory study. Usually a single protocol will cover only one experiment with a single test article in a single type of test system. It is permissible, however, to conduct several experiments using the same test article under a single comprehensive protocol. It is also permissible to study several test articles concurrently using a single common procedure under one protocol. 

In nonclinical research, attention to detail is every bit as important as in clinical development. As Gad (2006) observed, the importance of nonclinical laboratory studies demands that they be conducted according to scientifically sound protocols and with meticulous attention to quality. ... 

Protocol for conduct of a nonclinical laboratory study (subpart G)... 

Statisticians to assist in designing clinical protocols and in evaluating generated results from both nonclinical and clinical studies... 

If a sponsor has conducted phase 1 trials outside of the United States and believes that there are adequate human safety studies already available, it may not be necessary to conduct any phase 1 trials in the United States. In such a case, the sponsor would prepare an IND and include in the initial IND submission a clinical protocol for phase 2 or 3. This IND, because it will involve exposure of more patients to the drug for the purposes of safety testing as well as efficacy evaluations, will require a greater level and depth of manufacturing and nonclinical data. The next section will describe the requirements for such an advanced-stage IND. 

Table 2 Nonclinical Study Protocol Items Commonly Included in a CRO-Conducted Research Study...

Every person who is responsible for any part of any GLP study must have the appropriate education, training, and experience, or combination thereof, to enable that person to perform the assigned functions. Each testing facility shall maintain up-to-date records of training, experience and job description for everyone involved in the conduct of a nonclinical laboratory study. There shall be adequate personnel to conduct the study according to the protocol who shall take appropriate precautions to avoid contamination of the test and control articles and the test systems. 

The final report and any amendments, all raw data, documentation, protocols and any amendments, and specimens (with the exception of specimens subject to degradation) generated as a result of a nonclinical laboratory study shall be retained in an archive. The archive facility needs to be set up for orderly storage and expedient retrieval. Conditions of storage shall minimize deterioration of the documents or specimens. The archives do not necessarily have to be an in-house facility the laboratory may contract with commercial archives to store materials in a GLP fashion. 

There are two types of guidelines that must be considered in initiating the nonclinical program. The first relates to the types of studies required the second relates to protocol requirements for the studies themselves. 

Prior to the initiation of initial studies in humans, it is important that all of the nonclinical information available is made into an integrated summary. This information must be included in the clinical investigators brochure so that the clinical protocol can be modified to include relevant biochemical or other markers to minimize human risk. The regulatory authority and ethics committees are... 

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