Early phase clinical trials analysis

The preclinical stage of drug development focuses on activities necessary for filing an IND/CTA. The completed IND/CTA contains information that details the drug s composition and the synthetic processes used for its production. The IND/CTA also contains animal toxicity data, protocols for early phase clinical trials, and an outline of specific details and plans for evaluation. Process research, formulation, metabolism, and toxicity are the major areas of responsibility in this development stage. Analysis activities that feature LC/MS primarily focus on the identification of impurities, de-gradants, and metabolites. 

However, compared with the traditional analytical methods, the adoption of chromatographic methods represented a signihcant improvement in pharmaceutical analysis. This was because chromatographic methods had the advantages of method specihcity, the ability to separate and detect low-level impurities. Specihcity is especially important for methods intended for early-phase drug development when the chemical and physical properties of the active pharmaceutical ingredient (API) are not fully understood and the synthetic processes are not fully developed. Therefore the assurance of safety in clinical trials of an API relies heavily on the ability of analytical methods to detect and quantitate unknown impurities that may pose safety concerns. This task was not easily performed or simply could not be carried out by classic wet chemistry methods. Therefore, slowly, HPLC and GC established their places as the mainstream analytical methods in pharmaceutical analysis. 

WeU accepted Provides rich and high quahty data Can establish a causal link between altered pharmacokinetics and the variable of interest Early results from specific studies enable expansion of patient population in Phase 3 studies not usually difficult to perform Relatively straightforward and simple data analysis Not usually useful for screening Frequent sampling is very difficult in patients in large clinical trials or in children Relationship between altered pharmacokinetics and clinical response may not be established Study sample usually does not represent the target population Small sample may fail to elicit extremes of altered kinetics... 

Jill Myers (Biogen) discussed preapproval and postapproval process changes. She showed how the process used to produce AVONEX (Interferon beta-la) that was used in the pivotal phase 3 clinical trial differed from the commercial, approved process. The differences included the use of a different cell line and also the employment of different bioreactor and purification methods and production in different facilities located in different countries. The comparability of the two products was verified by extensive analysis and validation. Some of the key points of this talk were that (1) efficient change is possible even late in process implementation, (2) early characterization can light the pathway to change (i.e., know the protein), (3) it is important to maintain process identity during transfers, and (4) it is also important to validate process changes. 

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