Biomedical Engineering Reference
In-Depth Information
CDRH requirements. Some specific combinations may have
unique guidance documents such as drug-eluting stents.
When using existing drugs in a combination device, the com-
bination product drug should be compared with existing toxicity
data and previous therapeutic uses of the drug. If the device pro-
vides targeted delivery of the drug, then local exposure is usually
more of a consideration than systemic exposure. For well-
characterized drugs, the safety profile for systemic exposure may
be sufficient to assess risk, and no additional systemic toxicity
evaluations may be needed. However, if the drug has not been
previously evaluated for safety in the target location (e.g., eye),
then tissue-specific toxicity testing may be required to assess any
local effects.
Using an existing device in a combination product could
require limited testing if indications for use are unchanged from
the original device. Additional testing could be required if there are
any interactions between the drug and the device which could
create a new chemical entity; if the manufacturing process has the
potential to introduce unknown chemicals in the finished product;
or if the drug alters a local or systemic biological response to the
device.
There are additional considerations for biocompatibility testing
of a combination product device. The combination product is likely
to be extracted for testing, and potential adverse effects of extrac-
tion on any product components need to be taken into account. If a
drug is a component, multiple dose levels may need to be tested in
some assays with the device to characterize the drug toxicity.
Depending on the assay, the drug component may need to be
excluded from testing because of its method of action. For example,
drugs that affect cell division or have antimicrobial properties are
inappropriate for cytotoxicity or bacterial mutagenicity assays.
Lastly, the use of appropriate controls is important to provide a
comparator of the anticipated response in the assays.
Testing requirements for a new device and an existing drug
combination product may be similar to testing just the device.
Safety evaluation may be required for the device alone so there is
no possibly of toxicity being masked by the drug in the combina-
tion product. Functional studies will be needed to support the
claims made by the combination product.
Combination ocular products which have drugs as a compo-
nent may require an evaluation of drug exposure or a toxicokinetic
profile over the conditions of clinical use [
10
]. Considerations for
measuring drug exposure include the drug dose in the final
product, how well the drug has been previously characterized,
and the route and duration of drug exposure. If the drug compo-
nent is used commercially via a variety of routes and has been well
characterized (e.g., triamcinolone), a risk assessment is likely to
demonstrate that low doses do not pose a safety concern and as
