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Originally published January 1996

The special-purpose-reagents policy:

A solution to the 10-year-old IUO/RUO dilemma?

Christopher D. Zalesky

For more than 10 years, FDA and industry have struggled over issues related to commercialization of reagents labeled "For investigational use only" or "For research use only." Scientific advances, particularly in the area of genetic testing, threaten to generate a flood of new reagents, exacerbating this already difficult situation. This article discusses the current situation and summarizes a newly conceived policy proposal.

More than 1000 individual IVD tests are currently on the market, and more than 10,000 test-manufacturer combinations are currently subject to regulation by FDA. The number of tests is expanding and is expected to grow explosively when assays begin to spin off from research on the Human Genome Project. It is possible that in the not too distant future the number of assays will range in the tens of thousands, with the number of potential test-manufacturer combinations being vast.

Without a substantial increase in FDA's resources or a fundamental change in its approach to premarket regulation of small-volume esoteric reagents, the anticipated flood of new reagents could easily overwhelm the agency. Such a flood could result in extensive backlogs in all IVD reviews and further add to the long-standing problems with commercialization of products labeled "For investigational use only" (IUO) or "For research use only" (RUO).

It is likely that FDA now regulates more than 90% of all IVD tests in routine, high-volume use. It is also likely that this amount represents only about 10% of the universe of all available IVDs. The remaining 90% are used for esoteric, low- volume, or limited testing purposes. Many fall into a regulatory gray zone where they are not clearly subject to, or exempt from, active regulation by FDA.

What Is a Special-Purpose Reagent?

These esoteric, limited-use IVDs include what have recently been described as special-purpose reagents (SPRs). They include monoclonal and polyclonal antibodies, antigens, and genetic probes.

The common characteristics of SPRs are these: (1) They are key raw materials or components of IVD tests, and (2) they generally have a limited range of possible uses centered on the diagnosis of human diseases or conditions. SPRs cannot be used alone. They must be used in conjunction with additional special- or general-purpose reagents or must undergo further manufacturing steps and extensive qualification and validation using patient specimens.

Immunohistochemical (IHC) staining kits and serum tumor marker assays share some common technical and regulatory ground with SPRs. They are not SPRs, however, and it is important not to confuse the reclassification efforts under way for IHC stains and serum tumor markers with the SPR issue. Similarly, SPRs are not general-purpose reagents, such as laboratory acids, bases, and reagent chemicals. General-purpose reagents are exempt from most FDA regulations (see Figure 1).

Responsibility

Most often SPRs are used by IVD manufacturers developing and manufacturing IVD test systems (assays) or by clinical laboratories compounding "home brew" assays. Suppliers of SPRs have no control over how these materials will ultimately be evaluated or used. This responsibility resides with the reagent purchaser, not the reagent manufacturer.

Because SPRs are often key components of assays intended for the diagnosis or management of human diseases or other conditions, FDA has an interest in how they are made, sold, and used. Industry has an interest in seeking a clearer regulatory policy and in ensuring that a reasonable and appropriate level of regulation is applied to these materials. Both parties have as their mutual goal a regulatory approach that will not obstruct the continued availability of these materials and will not impede the advance of new technology.

While FDA believes that it has a responsibility to regulate SPRs, it also recognizes that application of the established PMA and 510(k) processes may be neither strictly necessary nor practical. Neither FDA nor SPR manufacturers play a central role in determining how these reagents are ultimately used in IVDs or home brew tests, what claims are made regarding their use or performance, or how the assay is validated.

IVD manufacturers who use SPRs to produce IVD test systems, which are ultimately subject to premarket clearance or premarket approval by FDA, have the central responsibility for validation of the test system. Clinical laboratories that use SPRs to produce home brew tests have the central responsibility for the use, validation, and claims that are made for the reagents. The primary regulatory oversight in the latter case belongs to the Health Care Financing Administration (HCFA) under its responsibility to inspect clinical laboratories for compliance with CLIA '88.

The established FDA 510(k) clearance process works well for a limited domain within the IVD test universe. Tests in this domain have clear predicates that are already cleared or approved and produce high or relatively high revenue. Such products have a very short return on investment (ROI) to recover clinical and regulatory cost outlays. This same process does not, however, provide a workable mechanism to address the much broader range of reagents in the IVD universe.

SPRs are low-revenue producers. Years of sales may be required to cover the costs of clinical trials and regulatory submission via the established 510(k) or PMA mechanisms. And even when companies have been willing to accept a long ROI, uncertainties regarding issues such as clinical utility have spelled the demise of many premarket submissions.

Exempt or Not?

IVD manufacturers and clinical laboratories have sought to address this situation through a variety of mechanisms, including sale of IVD reagents as components (customarily, though not universally, FDA has chosen not to regulate components), application of IUO/RUO exemptions, and development of home brew tests. In some instances, companies and laboratories have chosen to ignore the regulations altogether.

Uncertainty and lack of a definitive, workable FDA guidance have created a regulatory environment in which manufacturers and laboratories operate at some peril. Over the past 10 years, FDA has taken enforcement action against IVD manufacturers that, in its judgment, have inappropriately applied the investigational device exemption (IDE) regulations or the exemption for RUO-labeled products to products that are actually being used for clinical diagnostic procedures (see sidebar, "A brief history of the IUO/RUO debate").

Solutions based entirely on FDA compliance policies aimed at eliminating commercialization of SPRs have not been widely accepted, because many of the products these policies seek to eliminate have become the standard of care. FDA and the medical profession recognize that their elimination would have a serious negative impact on public health. Strict compliance-based solutions also ignore the underlying economic causes of unapproved commercialization of SPRs: most of them are low-volume, low-revenue products. The costs associated with premarket clinical studies and submission of extensive data in the form of a 510(k) or PMA application to FDA are often many times the annual expected revenues for the products.

In the absence of flexible alternatives to the 510(k) or PMA process, a strict compliance-based approach could result in a de facto ban on the commercialization of esoteric or limited-use IVD products. Seeking to resolve this dilemma, FDA, in cooperation with industry, is developing a draft policy--the special-purpose-reagents policy (SPRP)--to address this issue (see sidebar, "A common-sense proposal for regulation of special-purpose reagents"). The document is expected to be available for public comment early this year.

Benefits of the Proposal

Clearer and more appropriate regulation of SPRs provides benefits in a number of areas:

The Medical and Clinical Laboratory Communities. Clarification of the regulatory scheme for SPRs will give laboratories, physicians, and patients access to IVD tests for conditions and analytes for which tests could otherwise be unavailable. The policy will also assure users a greater choice of assays for conditions and analytes for which some tests already exist.

FDA. While retaining the full extent of its current discretion and authority, FDA would under the proposed SPRP be relieved of the responsibility of processing 510(k)s or PMAs for SPRs. As previously mentioned, the number of SPRs available may soon increase exponentially.

The SPRP will also resolve some long-standing confusion regarding regulation of IVDs labeled for IUO or RUO. With the SPRP in place, IVDs would fall clearly into one of the following three categories:

* Subject to premarket review (510(k) or PMA).

* For investigational use only or for research use only.

* Special-purpose reagent for further manufacturing use only.

Products that do not fall into one of these categories would be subject to enforcement action by FDA.

IVD Manufacturers. Industry would be relieved of the responsibility of filing premarket submissions for potentially enormous numbers of SPRs. The SPRP will also clarify and resolve issues regarding regulation of reagents sold for further manufacturing use.

This policy does not favor any one segment of the industry or any one manufacturer. All companies that currently sell or contemplate selling SPRs would benefit.

Christopher D. Zalesky is director, regulatory affairs, Centocor, Inc. (Malvern, PA).