Navigating GCP Bioanalysis: Ensuring Accuracy, Compliance, and Patient-Centricity
A clinical trial involves a myriad of activities all of which require detailed and careful planning. The safety and consent of patients are of the greatest importance and at the heart of a clinical trial. The clinical trial regulations are necessarily extensive as the multiple aspects of a trial require suitable management and control. A clinical trial protocol requires collaborative input from many areas, including, clinical and medical teams, contract research organisations for analytical design of pharmacokinetics (PK) and pharmacodynamics (PD) studies, routine clinical chemistry and many other components.
Analysis of the exposure of a drug is determined by the levels of drug administered and availability in the body. Quantitative assessment of exposure is achieved by bioanalytical techniques and the associated PK parameters. Bioanalysis can be performed by many analytical techniques, but two types of bioanalytical methodology prevail. These are LC-MS/MS assays and ligand binding assays (LBA). LC-MS/MS is used predominantly for small molecules but is increasingly used for larger molecules such as peptides and proteins. Bioanalysis using LBA is usually delivered by immunoassay technology and is primarily used for larger molecules such as proteins. Hybrid methodology is also used where immunoassay techniques can select analytes which can subsequently be processed to be quantitatively analysed by LC-MS/MS. In recent years there has been a significant development of new drug modalities, notably in cell and gene therapy. These drug models also need quantitative assessment and analytical techniques such as hybridization assays, qPCR, dd PCR are common for DNA/RNA entities.
How Does Bioanalysis fit into GCP?
As with GLP and other regulatory studies involving bioanalysis, a fundamental requirement is to demonstrate that the method used for the analysis is accurate, precise, and reliable. These and other characteristics such as dilutional linearity and selectivity are first assessed in method development to ensure that the quantitative measurement of drug levels is robust and can measure analyte concentrations at levels that are clinically relevant and informative.
The basic requirement according to GCP regulations is that bioanalytical methods are validated and that they are fit for the intended purpose. In a similar way to GLP studies, bioanalytical assays require a fully validated method that can operate within recommended performance guidelines. The main difference between GLP and GCP studies is the clinical aspect. GCP itself does not contain separate analytical guidelines for bioanalysis, however there is a short guide on ‘good clinical laboratory practice’ published by the World Health Organisation, which mirrors the GLP guidelines.
The ICH M10 is a set of guidelines that have been effective since January 2023, they provide recommendations for the bioanalytical validation and sample analysis in regulatory studies that are subject to GCP.
Aside from the analytical procedures, a key component in GCP, that is specific to clinical work, is patient consent to the proposed procedures within the trial. This includes all analytical interventions described in the clinical protocol. The consent must detail the specific analyses proposed, both for primary endpoints such as PK studies which will be pivotal to dose selection in dose defining studies and other analytical investigations such as biomarker analysis.
Biomarker analysis is not within the scope of the M10 validation guidance, but many white papers such as the document form the Critical Path Institute on context of use and the fit for purpose model for biomarker validation are used, in addition to earlier white papers such as that from the Crystal City VI conference. The criticality of informed consent is that if it is identified during the clinical study that additional analysis may be of use or significant interest, the ability to perform the test must be part of the original consent, if not, further consent from trial subjects must be obtained prior to analysis. Biomarker analysis is an area that often forms a key area of a clinical trial. These analyses are often included to monitor PD effects and can be informative on development decisions and dose selection. In contrast, biomarkers are often analysed in an investigatory manner, known as exploratory endpoints, in other words, to investigate the impact of a drug on what may or may not be critical biomarkers.
Bioanalytical Method Lifecycle
Clinical trials are conducted over several phases. From phase 1 early safety studies through phase 2 efficacy and analysis of dose to phase 3 and often to phase 4 post marketing studies. From phase 1 onwards fully validated methods are required for bioanalysis. The time frame from phase 1 to phase 3 and beyond is often several years. The question arises as to whether the assay initially validated for phase 1 analysis is still suitable for phase 3? During the clinical phases further validation may be executed and is referred to as ‘in study’ validation. The first validated method may change over the drug development period, potentially prompted from experience of the clinical trial analyses and optimisation of range and robustness, this forms part of the ongoing validation and assay lifecycle.
Regulatory bioanalysis has detailed requirements for validation, and in GCP, additional requirements are centred on the conduct, consent and contractual agreements. All aspects from sample collection to the analytical method used must be planned, developed and validated to the required degree for successful GCP bioanalysis.