Medical Device Link.

REGULATIONS & STANDARDS

Jeffrey N. Gibbs, JD, is a director at Hyman, Phelps & McNamara, a Washington, DC–based law firm, and is a member of IVD Technology’s editorial advisory board. He can be reached at jng@hpm.com.

A day that both laboratories and IVD manufacturers will remember for a long time is September 7, 2006. On that date, FDA issued two documents: the draft guidance for analyte specific reagents (ASRs) and the new draft guidance for in vitro diagnostic multivariate index assays (IVDMIAs).

Collectively, these two documents may significantly affect not only the laboratories’ abilities to develop and offer new tests, but also existing lab-developed tests. If these documents are finalized as proposed, the ASR draft guidance would reduce the numbers and types of ASRs available to laboratories, and certain lab-developed tests would be subject to FDA regulation under the IVDMIA draft guidance.

History and Background

In 1976, Congress enacted the Medical Device Amendments to the Federal Food, Drug, and Cosmetic Act. This legislation was prompted by the growth of the medical device industry and several well-publicized problems with manufactured devices. Nothing in the amendments referred specifically to laboratories.

In 1988, Congress enacted the Clinical Laboratory Improvement Amendments (CLIA). This legislation broadened existing federal regulatory requirements for clinical labs and has been supplemented by very detailed regulations. CMS is now responsible for implementing and enforcing CLIA.

FDA first publicly suggested that lab-developed tests were subject to the Food, Drug, and Cosmetic Act (FD&C Act) as medical devices in a draft compliance policy guide released in 1992.¹ A citizen petition was filed challenging FDA’s interpretation.² Six years later, FDA responded that while the agency has the authority to regulate lab-developed tests, it would not do so at that time.³

That response to the petition was presaged by the 1997 ASR regulations. FDA established these regulations to ensure that labs had access to high-quality building blocks for their tests. In the preamble to the ASR final rule,

FDA reiterated its position that while lab-developed tests are medical devices, it would exercise its enforcement discretion and not regulate such tests as devices.

The release of the ASR and IVDMIA draft guidances indicates that the policy of enforcement discretion by FDA is changing. Even before the IVDMIA draft guidance was issued, the Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD) had contacted a number of laboratories to discuss the regulatory status of their tests and had sent warning letters to several ASR manufacturers.

Defining ASRs

Under the ASR regulations, manufacturers are authorized to provide ASRs to laboratories for developing tests. However, the regulations placed many limitations on the sale and distribution of ASRs. One restriction is that ASRs can be sold only to certain organizations and laboratories certified by CLIA as high-complexity clinical labs.⁴ ASR manufacturers cannot make any claims about the analytical or clinical performance of an ASR.⁵ ASRs also cannot be marketed for diagnosing or screening any specific disease or condition. In addition, ASR manufacturers cannot promote an ASR as a complete assay, kit, or part of a closed system.

Although lengthy, the ASR regulations were not free of ambiguity.⁶ In order to address some of the confusion, OIVD took a document of frequently asked questions about ASRs drafted by AdvaMed (Washington, DC) and used them to develop the ASR draft guidance. While this draft guidance clarifies some aspects of the ASR regulations, it differs in some significant respects from the AdvaMed document.

The preamble to the rule creating the ASR regulations described ASRs as “the active ingredients of tests that are used to identify one specific disease or condition.”⁷ However, the draft guidance states that ASRs have certain characteristics: “a single moiety”; “a single endpoint”; “no instructions or performance claims”; and “not promoted for use on specific instruments or in specific tests or test systems.”⁷ This position that an ASR must be a single moiety that identifies a single endpoint was not explicitly stated in the ASR regulations.

While the ASR draft guidance does not define single moiety or single endpoint, it does state that a “single antibody,” “single nucleotide primer,” and “single purified protein or peptide” are examples of “molecules” considered to be ASRs.⁷ FDA lists the following products not considered to be ASRs: reagents that are extensively processed (e.g., arrayed on beads), reagents that are offered with software for interpretation of results, and microarrays.

This list also includes “multiple moieties (e.g., antibodies, probes, primers) bundled together in a preconfigured or optimized manner so that they are intended to identify and quantify more than one chemical substance or ligand.”⁷ According to FDA, a vial offered by an ASR manufacturer that contains a primer and probe, or more than one primer or probe, does not qualify as an ASR. FDA’s view is that a primer–probe combination, or a pair of primers, is not an ASR.

The preamble to the final rule classifying ASRs explicitly included genetic testing in the scope of ASRs;⁸ such genetic tests and components of genetic tests consist of multiple nucleic acid sequences and probes. But according to the ASR draft guidance, since an ASR is limited to a single moiety, most products offered as ASRs for genetic tests can no longer be identified as ASRs.

Many products currently sold as ASRs, particularly those used in molecular biology, would not qualify under FDA’s new definition. Forcing manufacturers to sell each probe or primer separately, even when technically feasible, would increase the number of steps required by laboratories to create and run an assay, along with a corresponding increase in the chance of error.

Marketing and Promoting ASRs

The ASR draft guidance addresses manufacturer marketing practices. FDA asserts that ASRs and general-purpose reagents (GPRs) cannot be promoted together for developing tests by laboratories.⁷ On Web sites and in cataloges or other promotional materials, manufacturers and distributors should not list together ASRs, GPRs, and controls that can be combined into a test. FDA recommends that all products (ASRs, GPRs, and controls) should be listed in sales or promotional material “in a fashion that is not associated with use in a particular test (e.g., alphabetically, or by reagent type [primers together, buffers together]).”⁷ Although manufacturers can provide labs with both ASRs and quality control materials, according to the ASR draft guidance, quality control materials must also be promoted independently of ASRs.

The ASR draft guidance states that manufacturers are prohibited from providing laboratories with instructions for developing a test from an ASR, and from making claims regarding the ASR’s analytical or clinical performance. The name of an ASR itself can serve as a prohibited performance claim. According to the agency, “manufacturers should take care to avoid names for their ASRs that describe a specific clinical use.”⁷ For example, a “cystic fibrosis ASR describes a specific clinical use for the product,” and would not be considered an ASR by FDA.⁷ This can lead to narrow semantic distinctions.

The type of information that manufacturers can provide with ASRs to laboratories is limited to the “characteristics of the ASR itself.”⁷ While such information can include peer-reviewed, published, and presented literature, it cannot describe the ASR’s clinical utility, its clinical performance, promotion with a test system, or specific instructions for use. Manufacturers also cannot provide labs with information or instructions regarding the validation of a test developed with an ASR.

The ASR draft guidance emphasizes that manufacturers cannot promote closed-system laboratory instruments in conjunction with ASRs. FDA describes a closed-system laboratory instrument as a device in which the “user does not have the ability to modify instrument settings, or the design of the instrument allows only a specific proprietary reagent technology or assay method to be used.”⁷ An ASR that is promoted to be used with such an instrument becomes part of the test system. Promotion by a manufacturer of an ASR and software (either software with claims relating to a specific ASR, or an ASR with instructions for use with particular software) is prohibited by FDA, since this also constitutes a closed system. In labeling or promotional materials, an ASR manufacturer cannot reference other instruments, software, or reagents with its ASR.

Many companies thought they were selling ASRs and providing only the basic building blocks, since the laboratories needed to do a substantial amount of work to run an assay (e.g., source other reagents, identify an appropriate instrument, develop the test methodology, and validate under CLIA). But in FDA’s view, this is not enough to make a product an ASR. Even though the materials supplied by the manufacturers may fall far short of being a kit, it is still not an ASR. However, this regulatory framework creates a large gap. If a primer–probe pair is not an ASR under the draft guidance, it is not a diagnostic test either. The inability to offer for sale such basic building blocks as ASRs, even if they are not single moieties, could profoundly affect the laboratories’ abilities to develop new tests.

The ASR draft guidance appears to preclude the sale of many products currently sold as ASRs. With molecular diagnostics playing an increasingly important role in diagnostics, it is critical that measures taken to address legitimate concerns about the misuse of ASRs should not inhibit the introduction of new tests, many of which are first developed using ASRs.⁹

The IVDMIA Draft Guidance

The preamble to the rule creating the ASR regulations states that “clinical laboratories that develop [in-house] tests are acting as manufacturers of medical devices and are subject to FDA jurisdiction.”¹⁰ However, FDA “chose not to extend the rule to such tests, and it has generally exercised enforcement discretion over laboratory-developed ASRs and laboratory-developed tests that use commercially available and laboratory-developed ASRs.”¹⁰ FDA had used enforcement discretion because it was confident of the high-complexity laboratories’ abilities to use ASRs. FDA is now asserting that IVDMIAs are outside the scope of lab-developed tests because they “raise safety and effectiveness concerns.”¹⁰ The IVDMIA draft guidance does not set a minimum risk threshold for tests subject to regulation as IVDMIAs.

According to the IVDMIA draft guidance, FDA defines IVDMIAs not as lab-developed tests, but as test systems that “employ 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, mitigation, treatment, or prevention of disease.”¹⁰ This definition is not found in the FD&C Act, or any FDA regulations, and was not developed through the notice-and-comment rule making process. As FDA has acknowledged, the definition of an IVDMIA has not created bright lines. FDA has stated it is seeking attractive text that would provide greater clarity.

Under the current definition for IVDMIAs, if a laboratory develops a test using multivariate data to calculate a patient-specific result (e.g., a classification, score, or index) that FDA believes the clinicians cannot understand based on their prior knowledge, the lab has manufactured a test system that is subject to FDA regulations as a medical device. (Using data plus some computation to generate patient-specific results is ubiquitous.) While FDA has said it intends to apply the IVDMIA definition narrowly, some critics have asserted that the literal scope is broad, or at least ill-defined. Scores of potential IVDMIAs have been identified. According to the agency, most IVDMIAs will be Class II and Class III medical devices, which will require clearance through either the 510(k) premarket notification process, or the premarket approval (PMA) process.¹⁰

Consequently, laboratories that employ IVDMIAs subject to FDA regulation become medical device manufacturers. As medical device manufacturers, such labs are subject to the requirements of FDA’s quality system regulation (QSR), the medical device reporting (MDR) rule, and restrictions on labeling.

However, laboratories are already subject to CLIA and therefore have extensive quality-related documentation requirements. While the goals of the two regulatory systems are similar, their execution and implementation are different and achieving compliance may not be quick or easy.

The IVDMIA draft guidance has raised a host of other practical questions. For example, what exactly is the medical device in a laboratory being regulated? What transition period will be offered to laboratories offering IVDMIAs? While the draft guidance refers to the test system, it is not clear what that term encompasses. Another question is: How do labs continue to modify and upgrade lab-developed tests if the 510(k) or PMA restrictions on product changes apply? Legal questions also abound: In enacting the Medical Device Amendments, did Congress intend to make all lab-developed tests subject to the FD&C Act?

Conclusion

The ASR and IVDMIA draft guidance documents are undeniably important. It is equally undeniable that they are controversial. The Washington Legal Foundation has already challenged the legal basis for the IVDMIA draft guidance, and criticized FDA’s failure to go through the rule making process under the Administrative Procedure Act. Many comments on these draft guidances are expected to be submitted, both supportive and critical, along with proposed alternative language and approaches.

On February 8th, 2007, FDA held an all-day public meeting to discuss IVDMIAs. Although the speakers presented different views on the merits of the draft guidance and its impact on patients and innovation, there was agreement that much greater clarity was needed. In their closing remarks, the FDA representatives acknowledged the consensus for increased specificity.

Equally undeniable is the breadth of FDA’s position that all lab-developed tests are medical devices. While FDA has reassured the laboratory industry that it is seeking to regulate only a small portion of these tests, the agency’s view is that every lab-developed test is a device subject to FDA regulation. FDA officials have also indicated that in the future, the agency could seek to regulate other lab-developed tests.

Whatever the fate of these draft guidance documents, FDA said at the February 8 meeting that the status quo ante will be restored. FDA’s draft guidance documents have precipitated a discussion that is almost certain to lead to some changes in the regulation of lab-developed tests and ASRs. Perhaps such developments will catalyze a general discussion on how FDA should review diagnostic tests.

While many ASR manufacturers would prefer to sell kits, they are deterred by the time, costs, and uncertainties of the regulatory process, particularly for small-volume tests. The same factors deter some laboratories from submitting applications. Conversely, OIVD would have difficulty mobilizing the necessary resources to handle applications for every IVDMIA and all the assays that use materials no longer deemed to be ASRs.

The existence of lab-developed tests and the availability of high-quality ASRs have facilitated the introduction of important new laboratory tests. Any regulatory or legislative changes should take into account not only the potential benefits of increased regulatory scrutiny but also the impact on access.

OIVD has invited comments on these draft guidances which offer constructive alternative approaches. Given the importance of these issues, the industry needs to accept FDA’s invitation.

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