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Biochemical Markers as Tools to Increase Efficiency in Drug Development
are in a markedly larger range compared with the imprecision of
Figure 2: The Critical Path and Biochemical Markers
the assay (<8–10%). For biomarkers, a decrease of 50–80% or an
increase of 100–200% is typically observed shortly (days to
Basic Prototype Preclinical
weeks) after initiation of the medication with antiresorptive or
Clinical development
FDA filing
research discovery development approval
anabolic drugs, respectively.
13
The respective changes in bone mass
range from 6–7% after two years of bisphosphonate treatment
14
to
2–3% or less for selective oestrogen-receptor modulators (SORMs)
The Critical Path
and calcitonin,
15,16
which is fairly small compared with the precision
error of 1–2% for bone mineral density measurements. Similarly,
Translational research
annual changes in joint space width of non-treated women are in the
range of 0.1–0.2mm,
12
which is also close to the range of the precision
Critical path research
error of repetitive measurements. Thus, biochemical markers have a
more suitable signal-to-noise ratio, which may prove particularly
useful in phase II studies expected to define the optimal dose of
Where biochemical markers may assist
the drug. In this context, studies indicate that three- to
six-month changes in biomarkers are highly correlated with two-year
Figure shows the idealised critical path, modified from ‘Challenge and Opportunity on the Critical Path to New
Medical Products’, published by the US Food and Drug Administration (FDA) in 2004.
1
It provides an outline of
changes in bone mineral density, suggesting that phase II
the different components of the FDA critical path. Starting with ‘basic research’, it illustrates biomarkers
development could be considerably shortened by the exclusive use
assisting in drug development as ideas become testable concepts for new products and are evaluated along the
critical path, ending in the selection of candidates for development. New products undergo a series of
of biomarkers.
6,13,17–19
evaluation steps as they move along the path, from basic research to ‘clinical trials’, in which biomarkers may
assist in both efficacy and safety evaluations.
Combinations of different types of markers, for example dynamic
markers of turnover (typically biochemical markers) and assessment of in an appropriate animal model mimicking the disease of interest may
current status (bone mineral density by X-ray), as described in then offer a method of assessment to determine whether the test can
Figure 1,
20
have provided complementary information and thereby be used as a surrogate marker for product efficacy. In clinical settings,
superior identification of progressors for clinical trial design. As a appropriate validated biomarkers may also be used to investigate
simple analogy, prediction of when a bathtub will run dry would the appropriate dose in humans in a classic phase II dose-finding
naturally be based on measurements of both the current state study, although on a much shorter time-frame due to the more
(volume) and the current change (flow in/out). dynamic nature of these markers. Biomarkers may even give
indications of efficacy in humans prior to phase II studies, as
US Food and Drug Administration Critical Path Initiative demonstrated in short-term studies with calcitonin and bone
In March 2004 the FDA released a report entitled ‘Innovation or resorption.
21
Most importantly, the efficacy marker from one study
Stagnation: Challenge and Opportunity on the Critical Path to New may be the safety marker of another study.
Medical Products’. The report identified reasons why, from a scientific
point of view, there has been a decrease in the number of innovative The combination of better animal models and tissue-specific
medical products submitted for approval. It was concluded that there biomarkers is important to predict the clinical outcome of drugs that
is a need to modernise the scientific tools used to predict medical are intended for use in human disease. Surrogate markers are needed
product development. to predict effectiveness with quantitative measures in order to guide
product development. Being aware of this unmet need, development
The critical path spans from first testable hypothesis to final approval of cell cultures, cartilage explants and animal models has become a
by the FDA of a new chemical entity (NCE). In the phase of pre-clinical rapidly growing field of the OA research.
6
In addition, numerous
development it is important to have tools for both product efficacy candidate assays targeting different degradation products of the
and product safety to build a bridge between results from disease extracellular matrix are already under intensive pre-clinical and clinical
testing for their ability to reflect structural changes of articular
cartilage.
6
Assays validated for such abilities are expected to facilitate
and accelerate the otherwise difficult, time-consuming and ultimately
Owing to their dynamic changes in
expensive process of developing candidate drugs with currently used
response to treatment, biological
imaging techniques (X-ray).
markers may provide relevant
In order to shorten time and save on cost there is demand for
information more rapidly than
innovative and efficient trial designs as well as improved clinical
end-points. Particularly in slowly progressing diseases such as OP and
imaging techniques.
OA, tissue-specific biomarkers can be very useful to predict the
response in a much shorter time compared with traditional methods,
where years of investigation are often necessary. To use specific
models and human experience. Tissue-specific tools such as biomarkers in such a translational approach may shorten the
biomarkers that detect relevant neo-epitopes and can be used to evaluation time significantly, improve predictability and efficiency and
investigate the mode of action of a substance on the target tissue in save on costs. Therefore, biomarkers are a useful evaluation tool in
vitro or ex vivo are useful. The assessment of the same neo-epitope certain steps of the critical pathway.
EUROPEAN MUSCULOSKELETAL REVIEW 19
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