Genetic and Genomic Diagnostic Tests

by Food and Drug Administration (FDA)

(Page 2 of 2)

"Diagnostic devices will lead to personalized medicine," says James C. Fuscoe, Ph.D., director of the Center for Functional Genomics at the FDA's National Center for Toxicological Research in Jefferson, Ark. For example, with these kinds of tests, it may be possible someday to tell, within a day or two and in some cases even faster, whether a drug is having the desired effect. This, Fuscoe says, is because the cellular changes that can be detected by an -omics test would occur before any treatment effect is evident in a patient. "If there is no drug response," he says, "the patient can be immediately put on another appropriate drug."

The CDRH is now reviewing both genomic and genetic diagnostic devices. Genomic tests, for example, may look at the activity of many or all genes at the same time, while genetic tests, a subset of genomic tests, look for abnormalities in a person's genetic code. A breast cancer microarray chip that provides a snapshot of which genes are active in a group of 70 genes, for example, might be a genomic testing device. A chip that looks at the genetic code for these 70 genes might be considered a genetic test.

Genetic tests such as the Tag-It Cystic Fibrosis Kit involve DNA taken from a person's blood, saliva, or other body fluid that is examined for an abnormality and that flags a disease or disorder. The genetic abnormality associated with certain hereditary diseases can be relatively large — a piece of chromosome, or even an entire chromosome that's missing or added. Sometimes, the abnormality is very small — such as one extra, missing, or altered chemical base within the DNA strand. Genes can have too many copies, can be too active or inactive, or can be lost altogether. Sometimes, pieces of chromosomes mutate or change and become switched, transposed, or discovered in an incorrect location. If the mutated sequence is present in a patient's genome, the probe will find it and bind to it, flagging the mutation. But tests like Tag-It detect only a limited number of the hundreds of mutations in the gene that causes cystic fibrosis, Fuscoe says, "so the test is not perfect."

In the case of treating HIV infections, the virus often becomes resistant to drugs. When this happens, the drugs are not helping a patient. In fact, because of the significant negative side effects of these drugs, they are probably hurting the patient. The TRUGENE HIV-1 Genotyping Test, made by Visible Genetics Inc. of Toronto and cleared by the FDA in 2002, is a genetic test that allows doctors to determine from a blood sample whether a patient carries drug-resistant strains of HIV-1. If so, the patient can be given a different drug.

Similarly, some drugs require the body to metabolize them at just the right rate — not too quickly and not too slowly — to achieve the desired effect. The AmpliChip Cytochrome P450 Genotyping Test, made by Roche Molecular Diagnostics, is the first genetic lab test cleared by the FDA that uses DNA extracted from a patient's blood to detect variations in a gene that affects how certain drugs, such as antidepressants, antipsychotics, and some chemotherapy medications, are broken down and cleared from the body. Doctors can then adjust a drug's dosage for an individual patient.

In August 2005, the FDA cleared for marketing a genetic blood test called UGT1A1 Molecular Assay, which, like the AmpliChip, can significantly reduce the risk of ineffective or harmful therapies by telling doctors how to individualize drug dosing. The test is made by Third Wave Technologies Inc. of Madison, Wis., and specifically tests the action of an enzyme present in a drug used to treat colon cancer.

Since genomic tests often look at many hundreds or thousands of genes, the result may be a pattern of gene activation that also is designed to be diagnostic or characteristic of a condition. Genomics-based devices have the potential to become essential tools to identify patients at risk for developing life-threatening reactions to certain products. This information could be used to help make choices related to exposure, or to develop predictive tests for adverse responses.

One project being studied by the FDA is the diagnostic gene expression microarray for allergy to the proteins in latex, a complex natural product derived from rubber trees, most commonly found in medical gloves. "In our FDA lab we are applying new genomic technologies to try to understand why people become allergic to latex," says Rosalie K. Elespuru, Ph.D., of the FDA's Genomics and Genetics Laboratory in the CDRH. "We are also using the information to try to predict who will become allergic before it happens."

Elespuru takes blood from people who are allergic to latex and from those who are not and cultures the white blood cells that generate immune responses. She then exposes them in the laboratory to the latex proteins to which people are allergic. Once all the samples are obtained, Elespuru assembles a small microarray of just the genes she finds to be important. These then, she says, will be used to test more samples from those who are allergic and from those who are not "to see if it is truly representative of a genomic profile for latex allergy."

Impact on the FDA

The expansion of microarray-based technologies will likely have a major impact on the regulatory practice of evaluating laboratory tests as diagnostic devices, according to the FDA.

Previous submissions for pre-marketing review of diagnostic devices by the CDRH have generally involved evaluating information on one or a few results per sample at a time. New -omics technologies will challenge the agency in that hundreds, thousands, or tens of thousands of results per sample will be generated. The FDA will need the necessary background for making regulatory decisions. The agency will also need to seek unique efficient and effective ways to evaluate the performance of diagnostic devices that use microarrays and other new technologies to ensure a seamless transition from laboratory study to product development, evaluation, and regulation and, ultimately, medical practice.

Projects like the latex allergy experiments provide a base for evaluating genomic and genetic device performance and for continuously updating the FDA's capability in new technologies as they evolve. Continually mastering genomic and genetic technologies involved in these projects will prepare the agency for possible future projects, such as those involving the rapid detection of bioterrorism agents and human responses to them.

The FDA has many ongoing activities to communicate with science and technology leaders to enhance its understanding of the new sciences, to gain experience, and to share knowledge in these important new, evolving areas of science. These activities include training initiatives, communications with everyone involved, in-house working groups, agency research, and improved pathogen detection, to name a few.

The FDA's mission is to ensure that safe and effective products are made available as soon as possible for consumer use, and to not become a barrier to product development. Although still early in its development, genome-based research shows promise that eventually it will enable medical science to develop highly effective diagnostic tools to better understand the health needs of people based on their individual genetic makeups.

About the Author

www.fda.gov
FDA is A United States government body that oversees medical devices, including contact lenses, intraocular lenses, excimer lasers and eyedrops. In the US, these products must be approved by the FDA before they can be marketed.