BOSTON Now that Roche Molecular Diagnostics and Affymetrix have broken the proverbial dam by weathering a long clearance process with the US Food and Drug Administration to market the AmpliChip, will other drug-metabolism diagnostics start making their way into the clinic, as well?
Using the example provided by Roche's AmpliChip CYP450 microarray and Affy's GeneChip platform, the FDA has produced a guidance document to help companies usher their own drug-metabolism tests through the clearance process more quickly.
The new document appears tailor-made for products like the drug-metabolism SNP-genotyping assay under development by Eli Lilly and ParAllele, a partnership that the companies have been quietly working on for close to a year.
"It's great news for us. It provides a clear path forward," said Aaron Solomon, vice president of business development at ParAllele. "We were doing what's documented here it doesn't really change things, it just tells us we've been on the right path."
Lilly's upcoming product, tentatively named "Megallele D-Met," is scheduled for launch in August and September through contract research organizations, said Rick Hockett, medical fellow group leader of genomic medicine at Eli Lilly.
He said Lilly will distribute the assay to CROs, which will use it in Lilly's drug-discovery studies. However, the drug maker will not be involved in producing, marketing it, or pursuing FDA clearance yet, said Hockett.
Solomon said ParAllele plans to file the product with the FDA within the next 12 months with the aim of marketing it as an in vitro diagnostic.
The generality of the recently released Class II guidance, which is not specific for any particular class of drug-metabolizing enzymes, may also be advantageous to Parallele. The Megallele D-Met assay will interrogate a panel of approximately 1,500 SNPs, of which about 170 are "documented to have some effect on drug metabolism," Solomon said.
The assay has three general classes: the CYP450 enzymes, the non-cytochrome enzymes acetylases, transferases, etc. and transporters, according to Hockett. There are "roughly 29 genes" on the assay for which Lilly and ParAllele have identified an effect on metabolism, he added.
"For those 170 SNPs that have clinical relevance, we're going to validate this system for use in clinical trials. We're just going the extra step so the FDA can review those results," Hockett said.
The assay will initially be used by CLIA- and GLP-certified CROs to genotype patients in clinical trials for Lilly, said Solomon. ParAllele will develop a smaller assay when it pursues FDA clearance to market the device as a consumer testing product, Solomon said. Distribution might be handled by Affy, which distributes other ParAllele products, he added.
Moreover, the Parallele assay will run on Affy's GeneChip platform, so only the Megallele D-Met will require clearance, said Solomon.
Solomon estimates that the Megallele kit can be used in as many as 1 million genotyping assays in the United States annually, based on the number and size of clinical trials. Solomon said Parallele had not developed an estimate of the clinical market.
Hockett said he "is trying to convince ParAllele and the CROs that this has to be cost-effective. We're trying to force the retail price for this to be somewhere in the $500 to $700 range per test."
Lilly's current goal is to genotype every patient in the company's Phase I trials, he said. "Ultimately, I think in 20 to 25 years, everybody should have this done. The world's population is the market for this," he added.
The Class II Guidance
Entitled "Class II Special Controls Guidance Document: Drug Metabolizing Enzyme Genotyping System," the document was released on the FDA Center for Devices and Radiological Health's web site on March 9. The guidance is standard procedure, an FDA official told GenomeWeb News, Pharmacogenomics Reporter's sister publication. New devices lacking a "predicate" product to which the FDA can compare as was the case for the AmpliChip when it was being reviewed by the FDA must endure a laborious pre-market approval process. This process "takes a long time and requires clinical trials," the FDA official said.
For companies that wish to win FDA clearance for a genotyping-based drug-metabolism device and later market it as an in vitro diagnostic like the AmpliChip including Roche, should it decide to produce another the Class II guidance shows how they can "go by the [less stringent] 510(k) process and not have to do the pre-market approval," the FDA official said.
The Class II guidance outlines the content and format of the abbreviated 510(k) submission needed as an application for clearance, including a device description and specific issues that firms should address when seeking clearance. These issues stem from health risks presented by the technology, and are not among the requirements of the general controls of the Federal Food, Drug, and Cosmetic Act, according to the guidance.
Newness doesn't drive more stringent submission standards. Rather, "it's the risk associated with the application or device," Bob Becker director of the Division of Immunology and Hermatology Devices at the FDA's Office of In Vitro Diagnostic Evaluation and Safety, told Pharmacogenomics Reporter at the IBC Biomarker Pipeline conference, held in Boston this week. Those devices that are similar to pre-existing, cleared products such as the AmpliChip can be considered Class II or 510(k), he said.
The Class II guidance's "specific risks to health associated with [drug-metabolizing enzyme] genotyping systems" are related to the possibility of improper drug administration as a result of inaccurate testing or incorrect interpretation.
For both of these risks, the document recommends steps companies can take to satisfy questions about these risks: To ensure accurate testing, the document outlines steps to verify the system's performance characteristics, its comparability among different users (and methods, such as traditional DNA sequencing), and the reliability of its software; and to avoid incorrect interpretation of the device's output, the guidance makes specific recommendations for the device's labeling, including directions for use and the interpretation of results.
The guidance recommends avoiding the use of genotyping tests to estimate a patient's drug response when the patient carries an allele with unknown activity, and in situations in which the drug's metabolic pathway is not fully understood.
The document also recommends that manufacturers obtain a substantial-equivalence determination before marketing a drug-metabolizing-enzyme genotyping device.
Two more guidance documents are due to be released by the FDA soon: the much-anticipated voluntary submission guidance for pharmacogenomic data is scheduled for release on Friday, according to GenomeWeb News, and a draft of the so-called "theranostics" guidance was expected to be released in February (see GenomeWeb News ). However, only a "concept paper" will be available at an April FDA workshop.