At least three large pharmaceutical and biotechnology companies support the US Food and Drug Administration’s plan for regulating predictive laboratory-developed tests, but they also asked the agency to clarify how it would regulate the tests, according to publicly available comments on the draft guidance.
Given the high cost of diagnostics development, some laboratory test makers are concerned that increased oversight and lengthy FDA reviews, particularly with regard to IVDMIAs, will hamper innovation and hurt Dx shops [see PGx Reporter 02-14-07].
Yet others have noted that FDA approval of genetic tests may give big pharma and biotech firms added confidence regarding the accuracy of the diagnostics, which in turn may encourage them to use the tests to develop pharmacogenomics-based targeted drugs [see PGx Reporter 05-30-07].
Genentech, Roche, and Pfizer seemed to share this sentiment in their comments to the FDA’s IVDMIA draft guidance. The drugmakers largely favored FDA oversight for laboratory-developed tests that may potentially be used to determine whether patients should or should not use their drugs.
Genentech said that FDA oversight could help avoid “unacceptable scenarios” such as a patient being deprived of life-saving medication based on a negative test result from an assay, a patient being prescribed a medication unnecessarily, and the use of an assay that has not undergone appropriate clinical validation.
In its comments to the FDA, Genentech described one such “unacceptable scenario” in its own experience with “a laboratory-developed diagnostic intended for use with one of [its] products.”
According to Genentech, the test made what the company “consider[ed] misleading and inaccurate claims about its accuracy and clinical utility, claims that are not supported by either the analytical data or the clinical data cited.” Although the test was not an IVDMIA, “the same issues apply to IVDMIAs that are not regulated,” Genentech said.
Genentech would not disclose the name of the test or its manufacturer.
The company also expressed concern about the possibility of false positive or negative results with IVDMIAs that are not approved by the FDA. “A false result could directly affect a patient treatment decision, potentially excluding patients from receiving life-saving therapy or putting patients at risk by receiving unnecessary treatments,” Genentech wrote.
Genentech’s concern may rise out of the company’s experience with Dako’s HercepTest. Ironically, although HercepTest is FDA approved, a number of studies have reported greater false-positive results when using the product to profile HER2/neu amplification and overproduction in breast cancer. In fact, several journal articles recommend that Dako’s test should not be used to determine HER2 status unless the status is confirmed by FISH.
Although Genentech did not mention Dako or the HercepTest in its comments to the FDA, the company did state that it “support[s] regulatory oversight of IVDMIAs that are used as predictive diagnostics.”
The FDA in May issued a special controls guidance assigning Class II status to gene-expression tests that provide breast cancer prognosis information, but are not used to make treatment decisions. The guidance, Class II Special Controls Guidance Document: Gene Expression Profiling Test System for Breast Cancer Prognosis, begins to shed some light on how the agency thinks about the regulatory status of IVDMIAs, because it was issued in reference to Agendia’s application for the clearance of the MammaPrint test, a prognostic breast cancer recurrence IVDMIA [see PGx Reporter 05-16-2007].
Ultimately, the special control document confers de facto Class II status to all gene expression-based breast cancer prognostic tests and absolves device makers from having to go through FDA’s more rigorous premarket approval process.
In the IVDMIA draft guidance it seems the FDA intends to regulate such devices based on their risk level. Low-risk Class I devices will generally be exempt from premarket review, while higher-risk Class II and Class III devices will typically require a 510(k) premarket notification and an application for premarket approval, respectively. Most IVDMIAs will likely be Class II or Class III, OIVD said in the draft.
“We applaud the tolerability of risk approach to regulation outlined in the IVDMIA draft guidance, whereby regulatory stringency (Class I versus Class II devices) is related to the purpose, risk, and potential harm of an incorrect result,” Pfizer said in its comments to the FDA. However, the draft document in its current form is still unclear about how this risk-based approach would be implemented.
“Because the results of this test could form the basis for treatment decisions and the claims could lead to inappropriate treatment of patients, this is highly concerning … We support regulatory oversight of IVDMIAs that are used as predictive diagnostics.”
“The agency needs either a large number of examples, or some specific definition of harm from the failure of the test, such as ‘likely to result in death or significant harm to individuals,’” the company suggested.
In one case, however, Pfizer differs with its peers at Genentech and Roche in that it believes the FDA should allow companies to market IVDMIAs without FDA approval or with the lower submission requirements of a Class II device as long as the product is initially commercialized as “second line” treatment – as a kind of supplement to physician’s judgment or other tests.
The drugmaker, which uses multivariate index assays in many of its 200 ongoing drug-research programs, said that such a strategy “would not restrict innovation or the ability to accumulate large volumes of data at low cost such as could be needed for qualification of highly dimensional tests.”
From the companies’ comments it was also evident that the FDA needs to do more work to clarify its regulatory stance on IVDMIAs.
At the agency’s public hearing in February there was much confusion regarding how FDA oversight would dovetail with existing guidelines under the Centers for Medicare and Medicaid Services’ Clinical Laboratory Improvement Amendments.
Roche, in its comments, said that perhaps the FDA’s previous use of enforcement discretion toward analyte-specific reagents had formed the misleading notion among laboratory test developers that the agency doesn’t have the power to regulate IVDMIAs.
“We are pleased that the agency is making clear its regulatory authority in the draft guidance document,” Roche said.
Pfizer, however, outlined areas in which the FDA can still do more to clarify its position on IVDMIAs. According to the firm, the definition of IVDMIAs is “overly broad and the parameters of FDA’s intended oversight is not clear.”
The FDA has said that IVDMIAs, which are algorithm-based tests, are more complex and thus require more federal oversight in order to ensure public health. Pfizer, however, notes that while the mathematical component confers additional risks when interpreting test results in the real world, “it is hard to believe that all IVDMIA tests would require complex interpretations.”
In Pfizer’s view, FDA should only regulate those IVDMIAs that are so complex that “a person reasonably skilled in the field would be unable to interpret the pattern of results without using an algorithm.
“Such a definition would put the focus on the interpretation of the assay, rather than on the mere use of an algorithm,” Pfizer wrote. The company did not define in its comments what kind of credentials a “reasonably skilled” person in the field would hold.
FDA’s Office of In Vitro Diagnostics Director Steven Gutman previously told Pharmacogenomics Reporter that the complexity of a diagnostic is only one factor determining the level of FDA oversight [see PGx Reporter 05-23-2007]. According to Gutman, FDA regulates tests based on their intended use. While the complexity of a device is a factor in the agency’s determinations, that aspect alone may or may not impact the level of FDA oversight on the product, he said.