Medical Device Link.

COMMENTARY

Glen Paul Freiberg is vice president, regulatory, quality, and government affairs at Gen-Probe Inc. (San Diego) and is a member of IVD Technology’s editorial advisory board. He can be reached at glenf@gen-probe.com.

A previously published commentary (March 1997) suggested that the ethics of determining use for IVD tests should be outside FDA jurisdiction.¹ That was another way of saying that clinical utility determination should not be part of the FDA approval process. This recommendation and conclusion were limited to diagnostic products regulated by the Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD). Since the publication of that commentary, new technology IVD test availability in the United States has evolved into two classes of products. One class is regulated by FDA via the standard product approval processes; the other class, using the same technologies, via the Clinical Laboratory Improvement Amendments (CLIA) in which FDA approval for laboratory-developed tests is not needed.²

By contrast, the use of most IVD tests in the European Union (EU) and many other countries is regulated by a self-certification process in which no governmental approval of clinical utility prior to marketing is necessary. While there are some exceptions to the self-certification approach (e.g., self-testing), this commentary will address the bulk of traditional laboratory-use tests.

Lessening the Regulatory Burden

Even though IVD tests are considered medical devices under section 201(h) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), they are unique among devices because clinicians determine how to use the test results. Since diagnostics do not achieve true clinical utility or application without further interpretation, is it appropriate for FDA to continue regulating the utility of IVD tests for one segment of the market? In other words, why should the OIVD review process continue unchanged while laboratory-developed tests are not evaluated for clinical utility by OIVD?

Recognizing that the diagnostics playing field has been moving in different directions that are detrimental to traditional IVD manufacturers and distributors, members of the IVD industry have attempted to work with OIVD to lessen the regulatory burden. Some efforts have been successful. For example, in addition to the creation of the analyte specific reagent (ASR) product category, AdvaMed (Washington, DC) developed the initial ASR question-and-answer document.³ OIVD also issued its own abbreviated ASR guidance document.⁴ In December 2005, AdvaMed submitted an updated version of this document to OIVD for review. The organization hopes OIVD will release the document without concept editing as an official guidance soon.

The IVD industry has reaped other regulatory benefits such as the special 510(k) process and the replacement reagent and instrument family policy, which was issued through good guidance practices.^5,6 The special premarket notification 510(k) process has resulted in some improvements in OIVD review times for a small subset of product changes and improvements. The replacement reagent policy has resulted in major gains in speed to market for products that qualify. FDA created this policy to avoid submissions in which IVD manufacturers could validate the mixing and matching of previously cleared assays and assay test platforms. However, these incremental process improvements have not lessened the regulatory burden on manufacturers in the area of clinical utility determination.

In June 2003, Bradley Thompson, then of Baker & Daniels (Indianapolis), submitted to the FDA docket a draft guidance for a new regulatory category called in vitro analytical tests (IVAT).⁷ This proposal came after meeting with OIVD management and being encouraged to proceed. Three IVD industry representatives prepared this draft guidance to provide OIVD with a means of allowing the industry to determine a limit on their clearance claims, speed products to market, and reduce the need for laboratory-developed products. The goal was to introduce a new 510(k) category through a guidance allowing claims for analytical results only. Laboratories and physicians would be held responsible for clinical utility determinations based on knowledge, experience, and literature. However, after reviewing the draft guidance, OIVD concluded that while an FDA-determined IVAT option was already available for well-characterized products (e.g., electrolytes), only OIVD should determine applicability, not the IVD industry. OIVD rejected the overall goals of having analytical-only clearance and having the industry make IVAT determinations. Therefore, a great divide remains between the criteria for providing diagnostic information for laboratory-developed tests and traditional tests to clinicians.

Other Approaches

With more than 90% of innovative genetic tests, which are not nearly as well-characterized as electrolytes, being regulated under CLIA alone, understanding and accepting the government’s position of dual systems for IVD product regulation remains difficult. So, as a next step after OIVD rejected the IVAT proposal, AdvaMed sponsored a legal review of the FD&C Act to confirm whether or not OIVD’s claim of approval jurisdiction over clinical utility was valid. A legal brief in the IVD industry’s favor would have allowed an escalation of the IVAT discussion to the FDA commissioner’s office. However, the AdvaMed sponsored legal analysis confirmed that OIVD has approval jurisdiction over clinical utility.

Concurrent with this activity, AdvaMed members considered whether adding regulations to laboratory-developed tests would be more appropriate. Since such tests are not governed by any FDA protections, this approach was worth considering. However, with no evidence that such tests, most of which fall into CLIA’s high-complexity category, have been problematic, it remains clear that under the FDA current clearance practices, IVD products and labeling are overregulated. AdvaMed has also considered proposing two tiers of reimbursement that would put a dollar value on FDA clearance or approval such that FDA regulated tests could have a higher reimbursement rate. However, the bureaucracy that this system would create would be a great challenge, and the current reimbursement for IVDs is already a significant enough challenge.

Late last year, as the IVD industry was considering these and other approaches to deal with the ongoing overregulation of its product lines, OIVD published a draft guidance titled, “Nucleic acid–based IVDs for detection of microbial pathogens.”⁸ The draft guidance contains the customary least-burdensome language, but the text includes a restriction stating that the microbial product lines listed in the guidance are exempt from the reagent replacement policy. According to the draft guidance, “the interchanging of different reagents with different instrument systems would significantly affect the safety and effectiveness of the device.”

This OIVD draft guidance did not include any data to support or justify this proposed exemption from the reagent replacement policy (RRP), only an opinion. In fact, the guidance does not address why these Class II products are any different from others regulated by OIVD in the microbiology branch or the other diagnostics branches. In summary, this RRP exemption declaration contradicts the intent of least burdensome and ignores the objective of the policy, which is to validate and document such replacement products by proving that safety and effectiveness are not affected when applying cleared products to alternate platforms. Any such proposed exemption should be data driven, not opinion driven.

The OIVD opinion on the reagent replacement policy exclusion for the subject product lines appears to create a subset of Class II products. These microbial products using nucleic acid test technology are no longer at the same level of risk as others. Historically, the 510(k) process has generally ignored technology when determining substantial equivalence. In fact, the progression of polyclonal antibody tests to monoclonal to nucleic acid testing have all been traditional 510(k)s. The risk of putting a cleared nucleic acid test on other previously approved test platforms or open systems should fall under the validation requirements of the reagent replacement policy. The draft guidance that proposes this limit to the policy shows a worrisome direction at OIVD.

For consideration of the industry, the laboratory profession, and the government, laboratories and clinicians should exclusively determine the clinical utility of laboratory-developed products. That is, the time has come for the IVD industry to propose a different legislative approach to correct the overregulation of IVD products. Specifically, the FD&C Act should be changed to eliminate the clinical utility determination of all diagnostic products that OIVD currently regulates. With so many CLIA-regulated products of high complexity and potential or alleged risk not requiring OIVD regulation, it will be difficult for FDA to defend the status quo, which is justifying clinical utility as part of the review process for IVD manufacturers’ products but not for laboratory-developed products.

Other safeguards will remain in place: good manufacturing practices, or quality system regulations, recall requirements, medical device reporting, and factory inspections. In summary, an IVAT approach that proves what a test does analytically should be legislated as the appropriate diagnostic review limitation. As with current laboratory-developed tests, peer reviewed literature will determine success, usefulness, and laboratory adoption, with laboratories and physicians making the clinical utility determinations. For those tests in which customers and clinicians cannot determine utility, the market professionals will restrict the use of such products without the need for OIVD.

Conclusion

The opportunity to make the legislative changes to remove OIVD clinical utility determinations is timely since the FD&C Act required device user fees renewal. IVD manufacturers should participate in this process by making contact with AdvaMed, other trade groups, and Congress to include this stipulation in the planned legislative update. Focusing on the overregulation of IVDs and making changes to eliminate the clinical utility determination for currently regulated IVD products will level the playing field between laboratory-developed tests and IVD manufacturers, and within the existing framework for safety and use of such products. This change will improve the consistency of diagnostic test results since traditional kits manufactured under the quality system regulation will be accelerated to the market. And, these changes will reduce the need for labs to develop their own tests to meet the changing needs of the laboratory and clinical community.

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