The Tiered Approach
A breakthrough towards the routine adoption of the tiered approach in bioanalysis
In the generation of data to support the development of new therapies, the bioanalytical community has always taken great care to ensure that science and quality go hand in hand.
The formalisation of this paradigm arose from dialogue between industry and regulators in the 1990s, leading to the preparation and widespread adoption of the US Food and Drug Administration (FDA) Guidance document. It is this and subsequent Guidance documents that have formed the basis of rugged bioanalytical practice for the past 15 years.
However, diverse development pipelines of innovator companies now require dramatically different bioanalytical workflows. When coupled with the astounding advances in detection technology that have been observed over the last decade it seems appropriate to now consider whether the validation paradigms based on late-stage development endpoints remain valid within the context of recent scientific advancement.
In its simplest terms a validation is carried out to ensure that the future application of a set of parameters will generate "valid" data. It is the understanding of what "valid" data looks like within the context of a given point in the drug development continuum that is driving industry dialogue around an alternative to regulatory validation for certain endpoints.
Owing to the significant number of stratified endpoints that the bioanalyst now supports it is clear that the one-size-fits-all approach described in the regulatory guidance documents may not be appropriate in all cases. In fact, there are number of areas where an alternative approach to the familiar regulatory validation has been successfully adopted. The analysis of metabolites in safety testing[3,4] is a good example of the application of scientific validation over regulatory validation in order to generate valid, phase-appropriate data. Similarly, it is common to carry out a limited scientific validation prior to analysis of samples for early exploratory purposes. These approaches have helped to expedite drug development and reduce time between critical go/no go decisions. It is therefore a logical progression to apply similar principles to the analytical activities in routine drug development and ask the question: Are there further opportunities where scientific validation may be more appropriate than regulatory validation?
The general consensus within the industry is "yes" but there remain the unanswered questions of when scientific validation is appropriate and specifically what should it look like. This is a matter of confidence in being able to define phase-appropriate scientific validation such that the potential benefits of the promised expedited drug development timelines can be realised without further regulatory hurdles incurred by incomplete submission.
Open to Interpretation
In assessing the potential of scientific validation as a replacement for regulatory validation from the perspective of a bioanalytical service provider there is a weakness that must first be addressed before widespread adoption is achieved. That is, the concept of regulatory validation is very well defined in bioanalytical culture such that a "validation study" is easily outsourced and both parties understand their role within the arrangement. But the introduction of scientific validation opens up the possibility of interpretation into which experiments are scientifically required to adequately define a procedure to support a given endpoint. The possibility for this subjectivity could therefore lead to confusion. Moreover, for a service provider engaged with multiple Sponsors it is entirely conceivable that the Sponsor-driven scientific validations carried out for two equivalent endpoints may be carried out to different standards. Scaling this scenario to the size of today's outsourcing landscape raises the potential for stratification of our understanding of bioanalysis and presents significant challenges to the outsourcing model.
It is with this need for clarity and specificity in mind that the industry welcomes the recent publication by Phillip Timmerman and colleagues on behalf of the European Bioanalysis Forum (EBF). This seminal paper takes significant steps towards defining the Tiered Approach and describing in some detail the content of scientific validation at various points in drug development. The EBF proposes five scenarios where a Tiered Approach may be taken: Quantification of metabolites in plasma in relation to ICH M3(R2), tissue (homogenate) analysis, urine analysis, clinical studies in early development and preclinical studies in early development. EBF provided rationale for scientific validation within these five scenarios and proposed specific scientific validation criteria to be applied in each instance. EBF also proposed terminology for clearer discussion of the tiered approach in order to minimise confusion in any communication with and between scientists or the regulators. This paper is very welcome and sorely needed as it marks the beginning of a practical realisation and harmonisation of the tiered approach in industry.
Charles River has long been involved in the application of a tiered approach in drug development having spoken and chaired conference sessions on the topic. The recent EBF publication takes the much-needed next step and provides an informative jumping-off point for strategic discussions with outsourcing partners. This is significant progress towards realising the full potential and wide-spread adoption of the tiered approach for bioanalytical support in drug development and Charles River looks forward to more integration of these approaches.
If you are interested in reading more about tiered approaches, check out this recent Eureka blog.
- Shah, VP, et al., Analytical methods validation: bioavailability, bioequivalence and pharmacokinetic studies, Pharm. Res., (1992) 9, 588-592
- U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Veterinary Medicine (CVM), Bioanalytical Method Validation, Guidance for Industry,May 2001
- Timmerman, PM, Gordon, B, et al., Best practices in a tiered approach to metabolite quantification: views and recommendations of the European Bioanalysis Forum, Bioanalysis, (2010) 2(7), 1185-1194, doi:10.4155/bio.10.90
- U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Pharmacology and Toxicology, Safety Testing of Drug Metabolites, Guidance for Industry, Feb. 2008.
- Timmerman, PM, et al., Tiered approach into practice: scientific validation for chromatography based assays in early development - a recommendation from the European Bioanalysis Forum, Bioanalysis, (2015) 7(18), 2387doi:10.4155/bio.15.168,
How to cite:
McGregor, Rona. The Tiered Approach. Eureka blog. Nov 5, 2015. Available: https://eureka.criver.com/the-tiered-approach/