HiFi DNA Tech has sued the US Food and Drug Administration for allegedly failing to respond in time to a petition to down-classify its PCR-based human papillomavirus genotyping test, leading the company to claim that the agency’s regulatory approach is out of step with current scientific thinking about the link between HPV and cervical cancer.
The suit, filed Oct. 12 in a US District Court in Connecticut, alleges that the FDA failed to respond in time to a petition the company filed in March to reclassify its PCR-based HPV DNA test from a class III device to a less burdensome class II device.
In its petition, the Trumbull, Conn.-based company, which makes reagents and has developed a PCR-based HPV genotyping methodology, argued that the agency needed to “bridge the gap between the scientific understanding [of the link between HPV and cervical cancer] and the regulatory control of the FDA … so that [diagnostic] manufacturers will be allowed to bring their safe and effective new technologies for HPV testing to the market timely through the 510(k) system in consistence with the least burdensome principles of the Food and Drug Administration Modernization Act of 1997.”
Under the Federal Food, Drug and Cosmetic Act, the agency must respond – either approve or deny such petitions – within 210 days. Oct. 12 marked the 220th day, leading HiFi DNA to file its suit against the FDA and the Department of Health and Human Services.
Before issuing its petition, the company last December submitted a 510(k) application for its HPV DNA PCR Detection Device and identified Digene’s HC2 High-Risk HPV DNA Test, which the FDA approved in March 2003, as a predicate device. However, in response to HiFi DNA’s submission, the FDA said its test would require premarket approval, citing the 1988 premarket approval of of Digene’s ViraPap, a filter hybridization test and the predecessor to the HC2 High-Risk HPV DNA test.
However, since PCR-based tests were developed after 1988, HiFi said it believes the FDA’s determination that such tests should require premarket approval is burdensome to test developers and makes it difficult for companies to launch more accurate HPV DNA tests.
“The need for an FDA-approved PCR-based HPV DNA detection device with provision to prepare positive clinical samples for genotyping is more urgent now after the Gardasil vaccine is made available to the populace,” HiFi argues in its petition to the agency, referring to Merck’s HPV vaccine that was approved in 2006.
The FDA approved the vaccine for females between the ages of nine and 26 to help prevent infection with HPV types 6, 11, 16, and 18. “To date, there are no FDA-approved PCR-based methods for HPV genotyping on the market in spite of the fact the PCR technology has been available for about 20 years,” HiFi DNA said in its petition.
With or without FDA approval of its HPV DNA PCR Detection Device, the company plans to launch the assay as a homebrew test within the next month, HiFi DNA President Sin Hang Lee told Pharmacogenomics Reporter this week. The reagents are currently available for research use.
“If the FDA approves the test, then we could sell the reagents as a kit with a uniform standard; everything will be optimized in a kit,” said Lee, who is also a Connecticut-based pathologist. “If the FDA does not approve it, then we have to sell the reagents individually, so every laboratory that is using our technology has to optimize their reagents.
“I believe the PCR-based HPV test is coming [on the market] with or without FDA approval,” Lee stated. “The current Digene [ViraPap] test is 20 years old, out of date, and was developed before PCR was introduced into medical practice.”
HiFi DNA claims that its test is “the nation’s first PCR/DNA sequencing-based clinical HPV genotyping methodology.”
“There is insufficient evidence to indicate whether a single WNL (within normal limits) Pap result with concurrent negative HPV Next PCR test confers low risk similar to consecutive annual, technically adequate WNL Pap results,” HiFi states in its petition to the FDA. “Positive results of [an] HPV PCR Test should be confirmed by genotyping with DNA sequencing, or be considered inconclusive if no genotyping results can be obtained by DNA sequencing.”
Digene, which was acquired by Qiagen in July, describes its test as a signal-amplified, nucleic acid test that assesses a “patient’s risk for cervical intraepithelial neoplasia and cancer.” The test determines the genetic makeup of 13 high-risk HPV strains.
Another company, Third Wave Technologies, has said it plans to submit for FDA approval two HPV products based on its PCR/fluorescent signal amplification-based Invader technology: a screening test to detect the presence of 14 high-risk HPV types and a genotyping test to detect two specific high-risk types of HPV, strains 16 and 18.
Third Wave and Digene are currently embroiled in a patent-infringement suit over an HPV nucleic acid hybridization probe. In September, the US District Court for the Western District of Wisconsin denied Digene’s motion to reconsider its July 2007 opinion that Third Wave does not infringe Digene’s patent.
Laboratory Corporation of America, which sells PCR-based HPV genotyping services, says on its website that its assay can detect the presence of more than 20 HPV types, but it can only provide HPV typing information for nine strains: HPV 6, 11, 16, 18, 31, 33, 35, 39, and 45.
But HiFi DNA’s Lee argues that the FDA’s decision to equate its PCR-based test to Digene’s 1988 product is burdensome to test developers. Furthermore, the company stressed that its HPV test is a vast improvement over Digene’s ViraPap test, and is unlike any test currently on the market.
“Everyone practicing pathology, who knows laboratory medicine, agrees that the  FDA-approved Digene test is outdated and cannot be used for genotyping,” Lee said. “PCR is a technology that amplifies the DNA you’re looking for, so it’s more specific.”
Recent studies have shown that the connection between HPV infection and a patient’s risk for developing cancer is “very remote,” Lee said.
“If someone gets an HPV infection, it doesn’t mean that they will have cancer. No, it’s not that simple,” he said. “Most of the HPV would disappear in 168 days, and only a small percentage of the women who have HPV infection would develop [a] persistent infection.”
Determining the type of HPV infection a patient has consecutively is not as clinically significant as determining persistent HPV infections, Lee claims. The molecular technology of PCR amplification of HPV DNA followed by nucleic acid-based genotyping gauges persistent HPV infection so that patients may be more accurately immunized with type-specific HPV vaccines, HiFi DNA said in its petition.
There is also a public health reason why the FDA should take the least burdensome approach in classifying PCR-based HPV tests, according to HiFi DNA. The company cited clinical trial data from Merck showing that women who are sero-positive and PCR-positive for the vaccine-relevant HPV genotypes and who receive the vaccine have a 44.6-percent increased risk of developing high-grade intraepithelial lesions.
In the June 7 issue of Infectious Agents and Cancer HiFi DNA published an article describing its test and reporting the product’s performance in a clinical trial.
“The aim of this study was to optimize a robust ‘low-temperature’ (LoTemp) PCR system to streamline the research protocols for HPV DNA nested PCR-amplification followed by genotyping with direct DNA sequencing,” the study authors report. While most thermocycling is conducted at 95°C, HiFi’s method lowers the temperature by 10°C at each step of thermocycling during in vitro DNA amplification, which yields more homogeneous PCR products, the company claims.
“With this protocol, template purification before enzymatic cycle primer extensions is no longer necessary.”
“The need for an FDA-approved PCR-based HPV DNA detection device with provision to prepare positive clinical samples for genotyping is more urgent now after [Merck’s HPV vaccine] Gardasil is made available to the populace.”
In the study, the LoTemp PCR polymerase reagents proved stable at room temperature for at least six weeks. HiFi’s assay detected 107 isolates of HPV in 513 cervicovaginal clinical samples, which were all validated by DNA sequencing. HPV-16 was the most prevalent genotype constituting 27.2 percent of positive cases, followed by HPV-56, which comprised 8.5 percent of positive cases.
“For comparison, Digene’s HC2 test detected 62.6 percent of the 107 HPV isolates and returned 11 (37.9 percent) of the 29 HPV-16 positive cases as ‘positive’ for high-risk HPV,” the study authors said.
HiFi’s test “is developed to facilitate the transfer of the molecular technology into the hospital clinical laboratories. Most hospitals cannot afford to do PCR [followed by] DNA sequencing for genotyping of HPV because the current technology of using PCR and sequencing is labor intensive, and costly,” Lee said. “Our technology is simple, the [LoTemp] enzyme is stable, and you can use less trained technicians to do the work, thus reducing the cost of doing the test.”
Although HiFi’s LoTemp PCR method might be more “efficient” than other marketed tests, its novelty might be the biggest reason why the FDA chose to brand it a Class III product rather than a Class II device.
“Most people are not familiar with LoTemp PCR because most people set their thermocycler at 95°C. We set ours to 85°C,” Lee said. “Most people have never heard of it. Therefore, they will need some training. A few minutes, a few hours will be enough to learn the rules of this new technology.”
Although HiFi’s suit accuses the FDA of using a 20-year-old approval order to maintain a stricter regulatory environment for PCR-based HPV tests and of blocking newer, more efficient HPV tests from entering the market, the agency has previously explained that its classification method for diagnostics is a risk-based system.
IVDMIA End Game?
HiFi’s hopes that its test will be down-classified to Class II status may be bolstered by the agency’s recent decision to regulate in vitro diagnostic multivariate index assays. The FDA has determined that this subset of laboratory-developed tests is for “high risk intended use” since they include elements that are more complex than standard LDTs and include “unique interpretation functions” that cannot be independently validated by clinicians [see PGx Reporter 08-01-2007].
FDA’s Office of In Vitro Diagnostic Device Evaluation and Safety Director Steven Gutman previously told Pharmacogenomics Reporter that Agendia’s MammaPrint test for breast cancer recurrence, the first FDA-approved IVDMIA, is an example of a genetic test that displays “the kind of novelty and complexity that our entire risk-based structure would flag as something that does have an impact on public health.”
Although the FDA felt that the MammaPrint was a novel and complex product, it down-classified it from Class III to Class II status after Agendia petitioned the agency regarding the test’s safety and effectiveness. Theoretically, HiFi’s situation can also go in this direction.
Furthermore, by issuing its guidance entitled “Class II Special Controls Guidance Document: Gene Expression Profiling Test System for Breast Cancer Prognosis” three months after it approved MammaPrint, the FDA determined that the test — as well as future genomic breast cancer prognostics — can be considered Class II devices if they comply with a set of “special controls” that are outlined in the guidance document.
In its petition, HiFi argues its test should be a Class II product by outlining a set of “special controls” it will follow to assure the test’s safety and effectiveness.
According to the company, the device is not intended as “a stand-alone diagnostic assay.”
“If HPV genomic DNA is detected, the nested PCR products resulting from the use of this device can provide materials suitable for HPV genotyping by direct automated DNA sequencing to determine by the ordering physician the need for referral to colposcopy,” the company said in its petition. “This information, together with the physician's assessment of cytology history, other risk factors, and professional guidelines, may be used to guide patient management. The use of the information is not intended to prevent women from proceeding to colposcopy.”