Tissue engineering - Orthopaedic Biomaterials in Research and Practice - page 236

also be artificially synthesized. The gene to be inserted must be com-
bined with other genetic elements for it to work properly.
Genes may also be modified for better expression or effectiveness.
The most common form of genetic engineering involves inserting new
genetic material within the host genome at a random or specific location.
When inserted at a specific location, the effect is to generate mutations at
desired genomic loci capable of knocking out endogenous genes.
Although genetic engineering opens the door to many opportunities,
the efficacy of these methods is still unclear. In addition, there are ethical
concerns that the technology may be used for more than just treatment
of diseases, namely, for enhancement or modification of non-medically
related characteristics, such as appearances or behavior.

regulatory pathway and regulations

Because tissue-engineered constructs involve the use of biological ele-
ments such as cells or tissue, the regulatory process for these products is
more complex than for a “standard” synthetic product, such as a hip pros-
thesis. In a typical medical device, the indication, application, construc-
tion, and behavior are relatively more predictable. Tissue-engineered
products may be regulated by the FDA under several different pathways
because they often contain components from different product categories
of tissue, device, and biologics. For example, tissue-engineered prod-
ucts that fall under the medical devices category are often classified as a
Class III device and reach the market via the premarket approval process
in the United States. Conversely, pharmaceuticals typically require an
investigational new drug application/biologic license application in the
United States.
The FDA's regulation of tissue-engineered products has been con-
tinuously evolving. Detailed discussion of the regulatory history is
included in Chapter 10. In brief, the jurisdiction of combination products
is based on the determination of the primary mode of action (PMOA),
through which the product achieves its therapeutic effect. In products
where the mode of action is derived through multiple methods, the single
PMOA that provides the most important therapeutic action or provides
the greatest contribution to the overall therapeutic effect is scientifically
identified. The following sections discuss segments of potential regula-
tory requirements of a tissue-engineered product.

regulation After the initial toxicity, pharmacology, and pharmacokinetic studies,

the IND application may include chronic toxicity, carcinogenicity, spe-
cial toxicity, and drug metabolism studies. Special toxicity evaluations
include assessment of mutagenicity and reproductive and development
toxicity. After in vitro assessment, clinical trials are conducted in a
series of steps or phases (Figure 9.2). These are conducted in phases
because each is designed to answer separate research questions. During
Phase I, researchers test the product in a small group of people for
the first time to evaluate its safety, determine a safe dosage range, and