Biomedical Engineering Reference
In-Depth Information
categorized based on contact duration (short term, prolonged contact, permanent). The
basic tests include cytotoxicity, sensitization, irritation or intracutaneous reactivity, acute
systemic toxicity, subacute systemic toxicity, genotoxicity, implantation, hemocompatibil-
ity, chronic toxicity, and carcinogenicity. The preferred test sample is the intact medical
device that has been processed and sterilized in the same manner as the medical device that
will be used in humans. However, it is not always practical to use the intact medical device
due to the constraints of the biological tests. Therefore, an extract of the leachable compo-
nents or the degradation components of the implant are often tested first in the in vitro
assays (cytotoxicity) and also in the preliminary in vivo tests (sensitization and both sys-
temic toxicity tests). Completion of the preclinical tests described in the standards ASTM
F-748 and ISO 10993 typically takes up to two years, even if a qualified and experienced
facility is conducting the testing.
It is difficult to correlate in vitro testing to in vivo testing because the in vivo system is
much more complex and involves many more variables. Typically, cell culture assays are
more sensitive than in vivo tests; however, demonstration of cytotoxicity in vitro may not
necessarily mean that the material cannot be used in vivo. Both false negatives and false
positives can be obtained by cell culture testing; therefore, animal testing is a required
step in understanding safety and biocompatibility and also for an initial evaluation of the
product's performance and effectiveness. There are, however, variations in response to bio-
materials and drugs between species of animals. The guinea pig has been found to be the
most sensitive animal for assessing delayed immune hypersensitivity (the sensitization
test). The rabbit has been found to be the most sensitive animal model for detecting pyro-
gens in vivo. Although animal testing does provide a useful screen for restricting the
implantation of most toxic components in humans, the final and ultimate biocompatibility
and safety testing occurs during human clinical trials. In some cases, products that demon-
strate efficacy in a mouse or dog model may not always perform as well in humans, partic-
ularly in the case of a new drug. The effective dose sometimes varies greatly between species,
as well as between two humans. Therefore, dose escalation schemes are incorporated into
biocompatibility and safety and efficacy testing, and large numbers of patients must be used
in clinical trials.
5.6.3 The Regulatory Process
Regulatory approval by the Food and Drug Administration (FDA) is required in the
United States prior to administering a new drug or biologic or implanting a new medical
device in a human and also prior to marketing the new product. The FDA is currently
divided into six individual centers that regulate devices and radiological health (CDRH),
drugs (CDER), biologics (CBER), food and cosmetics, veterinary medicine, and toxicology.
An assessment must be made as to which mode of action—drug, device, or biological—
contributes the most to the therapeutic benefits of the overall product. Based on this criterion,
the FDA decides which center will take the lead on the regulatory review. Each FDA center
has different procedures and requirements that must be completed and met to gain FDA
approval. Some products are a combination of a biologic and a device or a drug and a device,
and, therefore, FDA requirements for two or more centers must be met before the product is
granted approval. Tissue-engineered medical products are examples of combination products.
