Biology Reference
In-Depth Information
Data are needed not only to understand the clinical properties of the biomarker, i.e., the
specific predictive properties of the biomarker to pre-select patients most likely to benefit
from the treatment. Substantial data are also required to understand the technical properties
of the biomarker, i.e., the accuracy, reproducibility and real-world reliability of all aspects of
the assay. Detailed information is needed on all the reagents, the equipment and laboratories
intended to run the assay, as well as the analytical methods that will generate a report and
how that report is to be interpreted. All of this must be done at risk early enough to trouble-
shoot and refine the processes, because the assay that is used for Phase III studies is expected
to be the intended product, or very close to it.
These high expectations mean that a pharmaceutical company may benefit from partner-
ing with an experienced diagnostic company. This scenario creates vulnerability for the phar-
maceutical company that is not entirely within its control: if any problems occur with the test
or timely access to test results, the test may become a barrier to prescribing the drug. Hence,
selection of a diagnostic partner is of great importance to the pharmaceutical company. There
are also considerations for competition from diagnostic labs that may try to launch compet-
ing assays. Though regulations in the US can create a high bar and should make it more
difficult for a competitor to launch an equivalently labeled test, enforcement against even
'home-brew' assays in oncology indications has been fairly scarce [78,79] . Hence the mutual
value proposition needs to be thoroughly assessed early in the partnership negotiation to set
reasonable expectations for both sides.
Because a companion diagnostic test will be used specifically to select treatments for
patients, these tests are often held to high standards for regulatory approval. In the United
States, the Food and Drug Administration's Center for Devices and Radiological Health
(FDA's CDRH) regulates the manufacturing, re-packaging, re-labeling and importation of
medical devices, which include not only the assay reagents and platform, but also the soft-
ware that analyzes the data and reports the results to treating practitioners. Devices are clas-
sified based upon the intended use and indications for use, with increasing requirements
needed for an increase in the level of potential for risk posed to the patients for whom they
are to be used. Unless the device meets a pre-specified exemption, Class I and II devices
require acknowledgment of a '510(k)' premarket notification (21 CFR Part 807 Subpart E)
before being commercially distributed. This mechanism might be acceptable for launch of a
new assay that has a pre-existing assay on the market already that measures something simi-
lar. However, if a test is intended to truly be used as a companion diagnostic, to select patients
for exposure to a new drug with an accompanying regulatory claim of benefit and indica-
tions for use, it will most likely need a premarket approval (PMA; 21 CFR Part 814) and will
be considered a 'Class III' device because of the potential that it may pose a significant risk
of harm to the patient. Furthermore if either a 510(k) or PMA will be needed, the developer
may need to formally notify the agency before using the investigational device in a clinical
study by submitting and seeking an investigational device exemption (IDE)(21 CFR Part 812),
or by requesting a pre-submission meeting to discuss the intended use and development plan
for the device. These meetings will typically involve not only the device division but also
attendance by the drug division that will be reviewing the companion treatment, and can be
quite informative about the expectations of the agency. For example if one intends to utilize
the investigational test results to select subjects that will be included or excluded from a drug
treatment study, a formal IDE may be needed to justify the design as being acceptably safe for
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