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U.S. Department of Health and Human Services

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Emerging Issues 2000: Genetic Technologies

The revolution in human genetics and the sequencing of the human genome will create new opportunities for public health and new challenges for FDA. CDRH is preparing for the capability of assessing and regulating genetic testing devices within the near future. OST organized meetings with ODE senior staff to assess the role of genetic testing in CDRH. Staff presented grand rounds and updates on emerging science issues. The FDA Science Forum was organized. OST scientists served as members of scientific advisory committees for other FDA Centers, and taught courses on biocompatibility to update review staff. Information sessions, including presentations by developers of genetic and genomic technologies, have been organized by ODE’s Division of Clinical Laboratory Devices. Scientists in OST’s Division of Life Sciences have aided the recruitment of speakers and contributed actively to the discussions. OST is also involved in the FDA Genomics/Proteomics working group, organized by the Commissioner’s Office. This group is developing priorities for action related to FDA readiness in assessing new genetic technologies.

OST scientists are developing laboratory projects to develop hands-on readiness for the emerging technologies. These projects will provide a base for keeping up with the technologies as they evolve. It is also expected that they will demonstrate some of the ways in which new genetic approaches can enhance human health. There are two quite different types of devices representing the new technology expected to come to CDRH for review: genomic or genetic testing devices.

Laboratory projects in genetics testing and genomics are developed to enhance the reviewer readiness for emerging technologies involving the genome revolution. Models derived from these studies are useful to derive standards related to identification of genotoxic components of medical devices (including dyes in sutures, surgical sealants, etc.) and assessment of genetic testing components.

The genomic type involves gene expression, often in comparison to a reference population. This involves analyzing many hundreds or thousands of genes that are up-regulated or down-regulated in response to a stimulus. The result is a pattern of gene expression that is designed to be diagnostic or characteristic of a particular subset of the population. For this type of device, data organization and assessment, i.e., bioinformatics, are important. Examples would be a pattern of gene expression related to toxic responses and other adverse events.

The second type of assessment is a genetic test to determine the presence or absence of a particular DNA sequence already known to be related to a health outcome. In practice, this is a yes or no question, independent of signal size. Examples are mutations in the cystic fibrosis gene (human genetic disease), in a drug metabolizing gene (adverse event from a particular class of drug), in the p53 gene of a tumor (diagnostic for cancer), or in genes related to susceptibility to cardiovascular disease. Pharmaceutical companies are planning to submit genetic testing devices along with drugs in order to stratify a clinical trial population, or to include or exclude a certain segment of the population, resulting in a customized therapy. The goal is to identify a smaller and more appropriate clinical trial population.

The technological issues in insuring the safety and efficacy of these two different types of genetic testing devices are different. It is important to address both sets of issues.

OST has developed projects in each area that can be used as a basis for investigations into the issues affecting the safety and efficacy of genetic and genomic devices.

Genomic devices. A project to develop a gene expression pattern characteristic of latex sensitivity is being developed in collaboration with the CDRH Offices ODE and OSB, with CBER, and with a small biotech company. This project allows OST to gain data and experience. OST scientists expect to establish gene chip technology in the future. The gene expression model could be used to develop methods for evaluating new biomaterials, such as those resulting from tissue engineering. With an in-house system, OST could offer to partner with ODE in identifying technological sources of error in chip devices (e.g., reproducibility of oligonucleotide sequence and quantity deposited). These issues could then be addressed in standards and guidelines for approval of these devices. Collaboration between OST’s Division of Life Sciences and Division of Electronics and Computer Science could be established in the area of data management, bioinformatics, and pattern recognition.

Genetic devices. Genetic testing and genetic susceptibility testing involve the resolution of single-base pair differences in DNA, usually by hybridization to specific oligonucleotides. OST has a project in this area utilizing the human p53 gene. The project involves assessing sequence changes in the p53 gene using both conventional and microarray technologies. This project serves as a model for genetic testing related to diagnosis, prognosis, and therapy of many types of cancer. It may also be used as a model for standards development related to identification of genotoxic components of medical devices. These include dyes in sutures and other products, components of surgical sealants, and some types of breast implants.

Development of an In Vitro P53 Human Gene Mutation Assay for Cancer Risk Studies 
Key words: p53, cancer risk, mutation, genetic testing, genetic devices

There is a great need for more relevant tests for evaluating the cancer risk of medical devices and low frequency radiation. This includes assessing the genotoxic constituents of medical device materials, e.g., those in surgical sealants and bone cement (t-butylhydroperoxide and hydroquinone), as well as implants (toluenediamines). Dyes associated with medical devices can be genotoxic. Assessing the long-term risk of devices emitting low frequency radiation, including cellular phones, is also problematic. Recent findings in cancer research have shown that a substantial proportion of human tumors has mutations in the p53 tumor suppressor gene, 50% on average, but varying by tumor type. These mutations cause loss of genome integrity and cellular growth control; evidence is accumulating that these mutations are directly related to cancer development in humans. Among the most compelling data are the cases in which p53 signature mutations, characteristic of the environmental agents to which a population has been exposed, are found in their tumors.

In assessing human cancer risk, therefore, one important question is whether a biomaterial, breakdown product, impurity, or other relevant substance or device has the capability of causing mutations in critical regions of the p53 gene. There are no currently available practical means of determining this. Therefore, OST has worked to develop a standardized screening assay for measurement of mutation induction in the p53 gene. Until recently, it has not been technically feasible to easily identify and select p53 mutations. However, several laboratories have developed methods for identifying p53 mutations introduced into yeast. A recently constructed version of the yeast, created at MIT, carries a plasmid carrying p53 cDNA and two genes that are transactivated by wild-type p53 protein. The strain is engineered such that p53 mutants have a double mutant phenotype allowing mutant identification by color and mutant growth advantage on selective media. OST acquired this strain and have made progress in developing a p53 mutagenicity assay for routine screening purposes. By varying conditions of culture growth, temperature, media components, concentration (the chemical used in the p53 mutation assay), age of plates, and incubation time, scientists established conditions for optimum selection of yeast having p53 mutations. In a reconstruction experiment, OST scientists demonstrated the recovery of 10 mutants in a background of 105 or 106 non-mutants. Scientists determined that several variables are critical in reproducible selection of mutants (temperature, plate age). By selecting for linked markers, OST developed simple tests to monitor for loss of the two plasmids. Other experiments have studied the role of media, temperature, growth stage, and expression time on mutation generation and recovery. Initial experiments with UV radiation were successful in generating p53 mutants, although the doses have not been optimized. OST explored ways of accomplishing mutant expression and selection on one plate, to make the assay as functionally simple as the Ames Salmonella plate assay; but this has not yet been achieved. There has been good progress in developing a more relevant tool for assessing cancer risk.