Biomedical Engineering Reference
In-Depth Information
3.4 Conclusions and Future Direcions
It is now widely accepted that there must be a paradigm shift in
the development of cancer therapies in the 21
st
century, and that
incorporations of biomarkers, in addition to the traditional clinical
trial endpoints, is critical for all stages of drug development. Early
clinical trials should not only focus on PK and safety, but also seek
to define the drug effects at the molecular levels, including target
modulation, feedback loops and pathway switching. Early drug
development should also be viewed as a crucial stage to test and
begin to qualify potential predictive markers in preparation for
larger confirmatory studies.
The strategy of incorporating PD and predictive/enrichment
markers early in development has proven to be critical to the
development of a few new MTAs including PARP inhibitor, Crizotinib
and Vemurafenib. However, it is also recognized that many of the
potentially useful targeted agents do not have a known predictive
markers or strong candidates of predictive markers. Furthermore,
the majority of tumors in patients are driven by multiple gene
alterations and epigenetic changes. In order to allow efficient and
reliable testing of the drug candidates and to optimize therapy for
individual patients, a few essential tasks have been identified to fill
the knowledge and technical gaps:
∑
Establishment of comprehensive and molecularly character-
ized preclinical models, to recapitulate the molecular signa-
tures and heterogeneity of tumors in patients
∑
In-depth studies on the biology of individual targets and
pharmacology of the agents, to better define the molecular
contexts predictive of sensitivity or resistance, to examine the
molecular interactions of the target with other pathways and
to develop and test hypothesis of combination strategies.
∑
Systematic efforts in biomarkers discovery, assay development,
and clinical qualification. Given the time, cost and expertise
that would be required in the process, the effort should start
as early as possible in the drug development.
∑
Collaborative efforts between public, industry and academic
partners to establish publically accessible assay protocols and
platforms for key targets and pathways.
