National Cancer Institute - NCI Division of Cancer Treatment and ...

Co-Development of Diagnostics
and Therapeutics: Using
Biomarkers for Personalization
of Treatment
During 2004, Dr. Simon published two
papers that demonstrated the vast
improvement in efficiency of randomized
phase III trials that can be achieved from
using a biomarker or genomic classifier
to select patients likely to respond to the
new treatment. In many cases, however,
such classifiers are not available at the
start of phase III trials. During 2005,
Drs. Freidlin and Simon published a
new phase III design that addressed this
limitation. The design does not limit entry
based on a biomarker but requires that
tumor specimens be collected at the time
of entry. At the end of the trial, outcomes
for all patients on the new treatment
are compared to those for all patients
on the control. If the difference is significant
at a level of 0.04 or better, results
are taken to support approval of the
new drug with a broad labeling indication.
If not, then the specimens from the first
half of patients randomized are used to
develop a classifier of which patients
appear to benefit from the new regimen.
That classifier is then applied to the
second half of the randomized patients,
and those predicted to be sensitive to
the new treatment are identified. If the
outcomes for patients in that subset
on the new treatment are significantly
better than for the control patients in
the subset and if the significance level
is 0.01 or less, then the data are taken to
support approval with a narrowed labeling
indication for the new treatment.
S C I E N T I F I C A D V A N C E S
Freidlin B, Simon R. Adaptive signature design:
an adaptive clinical trial design for generating
and prospectively testing a gene expression
signature for sensitive patients. Clin Cancer Res
2005:11;7872–8.
Dr. Simon has interacted with scientists
from industry and the Food and Drug
Administration (FDA) in numerous scientific
workshops and seminars to develop
effective approaches to the development
and evaluation of biomarker classifiers
that identify patients who respond to
particular therapeutics. In order to facilitate
the application of this approach,
Dr. Simon has established formal pharmacogenomic
agreements with Johnson
& Johnson Pharmaceutical Research &
Development and Centicor.
Simon R. Roadmap for developing and validating
therapeutically relevant genomic classifiers.
J Clin Oncol 2005:23;7332–41.
Simon R, Wang SJ. Use of genomic signatures
in therapeutics development in oncology and
other diseases. Pharmacogenomics J (In press).
Trepicchio WL, Essayan D, Hall ST, Schechter G,
Tezak Z, Wang SJ, Weinrich D, Simon R. Designing
prospective clinical pharmacogenomic trials.
Effective use of genomic biomarkers for use in
clinical decision making. Pharmacogenomics J
(In press).
Simon R. Validation of pharmacogenomic
biomarker classifiers for treatment selection.
Dis Markers (In press).
Simon R. A checklist for evaluating reports of
expression profiling for treatment selection.
Clin Adv Hematol Oncol (In press).
Simon R. Guidelines for the design of clinical
studies for development and validation of
therapeutically relevant biomarkers and
biomarker based classification systems. In:
Biomarkers in Breast Cancer: Molecular Diagnostics
for Predicting and Monitoring Therapeutic Effect.
Hayes DF, Gasparini G, eds. Totawa, NJ: Humana
Press; 2005.
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