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FDA's New Draft IVDMIA Guidance Still Not Clear For Some Industry Stakeholders

Following overwhelming criticism from laboratory test developers that the US Food and Drug Administration’s initial draft guidance for in vitro diagnostic multivariate index assays would stifle innovation, the agency last week issued a new, vastly changed draft document attempting to allay some of these fears and clarify the scope of its oversight.
“The previous draft elicited a considerable number of comments (both written and at the public meeting [held in February]),” FDA’s Office of In Vitro Diagnostics Director Steven Gutman acknowledged in an e-mail to Pharmacogenomics Reporter last week. “FDA was anxious to respond to these comments and has re-issued the draft to see if we have been responsive to concerns about lack of clarity in the definition of IVDMIAs and concerns over chilling of technology.”
The new guidelines include a more detailed definition of what the agency considers an IVDMIA and exclude terms such as “test system” and “algorithm” that were criticized for being too ambiguous in the first version. Additionally, the guidelines clarify the agency’s risk-based approach, provide a transition period to test developers during which the agency will exercise enforcement discretion over certain requirements, and include provisions for orphan-disease testing.
The original draft guidance was issued last September, and in February the agency hosted a public meeting to discuss its intent to regulate IVDMIAs. At the meeting, the majority of speakers said that the guidelines, by imposing costly and time-consuming regulatory hurdles, may hobble innovation and make reimbursement even more difficult, particularly for diagnostics in niche markets. A minority view held that patient safety would be jeopardized without FDA oversight of IVDMIAs [see PGx Reporter 02-14-07].
In the new draft, the FDA emphasizes that although it is exercising enforcement discretion over standard laboratory-developed tests ─ an area typically under the purview of the Centers for Medicare & Medicaid Services’ CLIA guidelines ─ IVDMIAs are considered “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. Therefore, IVDMIAs should be regulated by the agency, the FDA concludes.
“With this draft guidance document, FDA seeks to identify IVDMIAs as a discrete category of device, and to clarify that, even when offered as LDTs, IVDMIAs must meet pre- and postmarket device requirements under the [Federal Food, Drug, and Cosmetic] Act and FDA regulations, including premarket review requirements in the case of most Class II and III devices,” the agency states in the new draft.
Paul Radensky, a lawyer representing the Coalition for 21st Century Medicine – an alliance formed in the wake of FDA’s first IVDMIA draft guidance – recognized FDA’s continued efforts to promulgate regulation with input from stakeholders.
Due to the significant concerns raised in numerous public comments to the September 2006 draft guidance “there would have been very serious concerns if FDA had finalized the guidance based upon the earlier draft because there would not have been adequate notice as to what the final policy would be,” Radensky told Pharmacogenomics Reporter this week.
However, the coalition members are of the opinion that FDA should strengthen existing CLIA guidelines before assuming oversight of IVDMIAs. And despite substantial changes in the new version of the guidance, coalition members maintain that the agency still hasn’t gotten it right. According to Radensky, the new definition of an IVDMIA remains “highly subjective” and therefore, FDA enforcement remains “unpredictable.”
Nevertheless, the agency did incorporate some suggestions from the community in the new draft. For example, several speakers during the February public meeting suggested FDA incentivize the development of diagnostics in rare disease markets by granting marketing exclusivity for “orphan diagnostics” or small-volume tests. The recommendation has found its way into the new draft IVDMIA guidance.
According to Caroline Popper, regulatory affairs senior advisor for Exagen, the changes in the new version show the agency “really listened at the public hearing in February.” Exagen submitted its breast cancer recurrence test, eXagenBC, for 510(k) clearance with the FDA in April [see PGx Reporter 04-11-2007].
The public will have 30 days to comment on this new version of the draft guidance. When asked when the agency expects to issue its final guidelines, Gutman quipped: “I stopped trying to predict future events or timelines about three years ago.”
In what may either be an attempt to scuttle a highly unpopular first draft or simply an effort to eliminate confusion between multiple draft versions, the FDA is only providing a link on its website for the new document. The September draft, which can be viewed here, is no longer accessible via The FDA would not say why the original version is no longer available on its website.
A Clearer Definition?
Originally, the FDA defined an IVDMIA as a “test system that employs data, derived in part from one or more in vitro assays, and an algorithm that usually, but not necessarily, runs on software, to generate a result that diagnoses a disease or condition or is used in the cure.”
In the new iteration, the FDA makes sure to emphasize the complexity of IVDMIAs and the added safety concerns associated with such products.
The agency no longer refers to an IVDMIA as a “test system,” but as a device that “(1) combines the values of multiple variables using an interpretation function to yield a single, patient-specific result (e.g., a ‘classification,’ ‘score,’ ‘index,’ etc.), that is intended for use in the diagnosis of disease or other conditions, or in the cure,
mitigation, treatment or prevention of disease; and (2) provides a result whose derivation is non-transparent and cannot be independently derived or verified by the end user.”
Presenters had taken issue with FDA’s characterization of IVDMIAs as “test systems” since the agency’s understanding of a test system did not match the definition under CMS’ Clinical Laboratory Improvement Amendments. How FDA oversight of IVDMIAs would dovetail with existing CLIA regs for laboratory-developed tests was a major question at the public hearing [see PGx Reporter 02-14-2007].  
Additionally, the agency no longer characterizes IVDMIAs as algorithm-based, another term that participants at the public hearing pointed out as too broad. In the current draft, FDA has stayed away from using the word “algorithm” to describe IVDMIAs since “it was not viewed as necessary or helpful in trying to define this class of device,” Gutman said. Instead, the FDA now characterizes IVDMIAs as using “an interpretation function” to yield a patient-specific result that cannot be verified by the doctor.
According to Exagen’s Popper, the fact that FDA deliberately dropped the word “algorithm” from the new version shows that the agency was really paying attention. “Frankly, I think that [the FDA] took good notes and it shows how thoughtful they’ve been,” she said.
In the current draft the FDA provides a list of “real or hypothetical” devices that the agency would consider IVDMIAs, including: a gene-expression profiling assay for breast cancer prognosis; a device combining quantitative results from several immunoassays to obtain a qualitative “score” that predicts a person’s risk for developing a disease; and a device integrating a person’s age, sex, and genotype of multiple genes to predict risk or diagnose a condition.
Devices the agency would not consider IVDMIAs include tests that interpret multiple variables but that healthcare providers could otherwise interpret themselves. Examples of products that FDA identified as being outside the scope of the draft guidance were devices that determine genotype and chromosomal copy number, conduct common clinical calculations, store clinical information, and calculate common, public demographic risk.
According to Radensky, FDA’s list of would-be IVDMIAs doesn’t clear up the definition of an IVDMIA. Radensky told Pharmacogenomics Reporter this week that FDA’s definition is still “highly subjective,” thus making FDA’s oversight over such tests “unpredictable.”
“Defining the whole test system as the device leaves unanswered several key questions about the interface between CLIA and the FDA – in particular, questions that were raised about conflicts between CLIA requirements for test reporting or clinical consultation, and FDA limitations on statements made outside labeling,” Radensky said. Additionally, the FDA “did not address the numerous comments it received urging the agency to proceed under more formal regulatory procedures, such as notice-and-comment rulemaking.”
Currently, if a lab is unsure about the status of its product, it can either conduct an internal assessment to determine if it should submit its product for FDA approval or request a meeting with the agency. “Manufacturers may consult with the Office of In Vitro Diagnostic Device Evaluation and Safety if they are unsure whether a device is an IVDMIA,” the agency suggests in the draft document.
Even though going straight to the agency may appear to provide more certainty for laboratories, the guidance provides no guarantees that the FDA won’t change its mind about the status of the test, Radensky suggested. “The agency could tell a laboratory that its test is not an IVDMIA but later come back and tell the laboratory that compliance with the medical device regulations is required.”
In contrast, Exagen’s Popper felt that the new draft “is one of the most clearly worded documents from the FDA on this topic.
“I think it’s a significant step forward, if not a leap forward, from where we were prior,” Popper said. “It appears to me to respond to a lot of the complaints about ambiguity, and does so in a very clear and lucid way.” Exagen’s breast cancer recurrence test, currently pending at FDA, is not considered an IVDMIA. Still, the company’s product will enter a market dominated by IVDMIAs manufactured by Agendia and Genomic Health.
Risk-based Approach
The current version of the guidelines highlights FDA’s risk-based approach and the increased risks associated with IVDMIAs as compared to other laboratory-developed tests.
“IVDMIAs raise significant issues of safety and effectiveness. These types of tests are developed based on observed correlations between multivariate data and clinical outcome, such that the clinical validity of the claims is not transparent to patients, laboratorians, and clinicians who order these tests,” the agency asserts in the guidance.

“We believe our business model and financial stability can sustain changes in regulation, and we will continue to work with the FDA to determine the appropriate regulatory pathway for Oncotype DX, as we have been doing for the past 18 months.”

“Additionally, IVDMIAs frequently have a high risk intended use. FDA is concerned that patients are relying upon IVDMIAs with high risk intended uses to make critical healthcare decisions when FDA has not ensured that the IVDMIA has been clinically validated and the healthcare practitioners are unable to clinically validate the test themselves,” the agency adds. “Therefore, there is a need for FDA to regulate these devices to ensure that the IVDMIA is safe and effective for its intended use.”
Medical devices may be designated to three risk-based classes – Class I having low risk, Class II being moderate risk, and Class III having high risk. Most IVDMIAs will be Class II or Class III devices, FDA has said. Class II devices require a 510(k) premarket notification submission, while Class III devices require premarket approval.
FDA’s risk-based approach toward IVDMIAs can be most readily observed through its handling of breast cancer recurrence tests.
In reviewing Agendia’s MammaPrint – the first FDA-approved IVDMIA for breast cancer recurrence – the agency lowered Mammaprint’s status from a Class III to a Class II device. Following the test’s approval, the agency issued a guidance that determined that MammaPrint — as well as future genomic breast cancer prognostics — can be considered as Class II devices if they comply with a set of “special controls.”
Although the special controls guidance grew out of the FDA’s review of Agendia’s product, the document conferred de facto Class II status to all breast cancer prognostic tests and absolved device makers from going through FDA’s more rigorous premarket approval process [see PGx Reporter 05-16-2007].
Meanwhile, Genomic Health’s Oncotype DX, a predictive and prognostic test, may have to be submitted for premarket approval. The FDA points out in the draft that “a device intended as an indicator of a patient’s risk of cancer recurrence may be a Class II device, while the same device intended to predict which patients should receive chemotherapy might require premarket approval.”
Genomic Health began selling Oncotype DX, which is performed in its own CLIA-approved lab, as a homebrew test without first seeking FDA approval. In a letter to the company last year, OIVD said it considers Oncotype DX a device under section 201(h) of the Federal Food, Drug, and Cosmetic Act. The status of the test is currently under discussion at the FDA [see PGx Reporter 02-01-2006].
In a statement to Pharmacogenomics Reporter this week, Genomic Health seemed for the first time to acknowledge the possibility that its test may have to undergo PMA. However, the company remained confident that its test would pass muster with the FDA.
“With multiple independent studies involving more than 2,600 patients, several peer-reviewed publications, clinical experience in over 27,000 patients and support from payor assessment groups such as Blue Cross Blue Shield TEC, we believe Oncotype DX should meet FDA approval standards,” Genomic Health said in a statement. “We believe our business model and financial stability can sustain changes in regulation, and we will continue to work with the FDA to determine the appropriate regulatory pathway for Oncotype DX, as we have been doing for the past 18 months.”
Transition Period and Orphan Dx’s
Genomic Health specifically said it was “pleased” the agency is allowing for an 18-month transition period that permits uninterrupted patient access to currently available tests. 
“For 12 months following publication of the final guidance document, FDA intends to exercise enforcement discretion with respect to all regulatory requirements for currently marketed, laboratory-developed IVDMIAs,” the agency says in the document. “FDA intends to exercise enforcement discretion for an additional six months for currently marketed, laboratory-developed IVDMIAs if the manufacturer submits a 510(k) or PMA within the initial 12-month period following publication of the final guidance.”
Radensky, however, felt a six-month approval period may be too short a time frame for FDA to sufficiently review applications. “The inclusion of a transition period is very helpful, but the timelines laid out may be insufficient,” he said. “If laboratories have 12 months to submit a 510(k) or PMA, but only 18 months for clearance or approval, this would imply a six-month period for approval of a PMA, which is shorter than average time-to-approval.”
Finally, addressing the concerns of laboratory test developers who during the February public hearing expressed concern about FDA oversight stifling innovation for tests in orphan disease settings, the agency has proposed an abbreviated regulatory pathway as an incentive to develop tests for conditions that affect fewer than 4,000 people in the US each year.
For drugs and biologics, a rare disease is one that impacts less than 200,000 people. In 1983 Congress passed the Orphan Drug Act, which gave financial incentives to drug and biologics manufacturers, including tax credits for clinical research cost, government grant funding, and a seven-year marketing exclusivity to sponsors of novel orphan-designated products.
“It’s an old concept newly applied to diagnostics,” Popper said. “So, I’m sure there is going to be tweaking as this experience develops.”

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