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Originally published May, 1998

Regulations and Standards

CLIA reform: Present and future

Bradley Merrill Thompson

The revolution now under way in the field of IVDs is bringing about rapid change in both the technologies used in diagnostic tests and the methods used for assessing their performance. Manufacturers have responded to the needs of physicians and other health-care providers by developing new generations of rapid, accurate, and simple-to-use diagnostics that can deliver results at the point of care.

Even more impressive are the revolutionary technologies that are still on the drawing board. For example, several companies are now developing tests that show great promise of being highly sensitive and specific to markers of acute myocardial infarction.¹ Such tests promise to provide essential diagnostic information virtually upon patient presentation, thus speeding the delivery of life-saving treatments.

But none of these advances will make any difference unless the intended users are able to gain access to them—an outcome that is being made very difficult by the procedures currently in place for administrating the Clinical Laboratory Improvement Amendments of 1988 (CLIA).

Last year, a coalition of concerned organizations was formed for the express purposes of facilitating public access to new IVD technologies and eliminating duplicative reviews and other administrative roadblocks to the adoption of those technologies. Members of the coalition include the Association of Medical Diagnostics Manufacturers, the Health Industry Manufacturers Association, the Indiana Medical Device Manufacturers Council, the Medical Device Manufacturers Association, and a number of diagnostics manufacturing companies.

As a starting point, the coalition last year supported adoption of the Ganske-Dingell provision (see below) as part of the FDA Modernization Act of 1997 (FDAMA).² Now, however, the coalition is seeking more-fundamental improvements in the administration of CLIA. The outcome of this effort could have profound consequences for future access to new IVD technologies.

Background

FDA has performed premarket reviews of new IVD technologies for more than 20 years. Although the agency's review process has not always been efficient, the low incidence of reported problems suggests that it has been effective.

In 1992, the Department of Health and Human Services devised a regulatory scheme to make use of FDA's expertise in product evaluations as part of the implementation of CLIA. During FDA's premarket review of commercial IVDs, the agency was to be required to categorize the complexity involved in performing each test. The complexity ranking assigned to a test would determine both its quality control requirements and the personnel qualifications to be imposed on its laboratory users.

Because FDA received no funding to carry out these tasks, however, it declined to categorize the complexity of the tests it reviewed. Despite the fact that the complexity reviews required by CLIA resembled the premarket reviews already being conducted by FDA, it was the Centers for Disease Control and Prevention (CDC) that eventually assumed responsibility for categorizing the complexity of laboratory tests.

Duplication and Conflict

Under the current regulatory scheme, FDA approval of new IVD products is based on rigorous scientific evidence supplied by manufacturers. Such evidence may include the results of field studies to demonstrate that the intended users of a test can obtain results comparable to those obtained by trained clinical laboratory professionals. As part of its approval, FDA also requires that the labeling of an IVD conform to specific regulations.

To help clinical laboratories and physicians determine whether they can legally use a newly approved IVD product, the manufacturer must petition CDC for a determination of the product's complexity. CDC then reviews again all of the manufacturer's evidence about the product, and may require the submission of different data for issues already considered by FDA. CDC also conducts a second review of the product labeling. Completion of this second round of reviews can be time consuming: petitions seeking waived status may take anywhere from several months to well over a year. In addition, the process may require manufacturers to conduct expensive new studies.

These two regulatory regimes—product approval by FDA and CLIA complexity categorization by CDC—often present device manufacturers with conflicting mandates. The time spent in meeting these requirements adds to product development costs and delays use of the latest and most effective—and potentially even lifesaving—diagnostic procedures.

At best, the technical reviews performed by CDC merely duplicate the extensive product evaluations already conducted by FDA. But all too often, CDC's regulatory regime significantly delays access to important diagnostic tools for medical practitioners and patients. Until recently, for instance, CDC was insisting on performing reviews of devices already cleared by FDA for home use by prescription. This practice—which CDC has since abandoned—created the absurd situation in which physicians and other medical professionals were effectively prevented from using such devices even though their patients could use them at home. Similarly, the burdens of the current CLIA system effectively prohibit point-of-care testing even in cases when it is the most effective method for managing patient care.

The Ganske-Dingell Provision

Congress did not intend for CLIA to create a duplicative or conflicting bureaucratic maze for IVD manufacturers, but it has taken some time for correction of this problem to get under way. Last year, Congress took a major step in this direction by including in FDAMA a provision to clarify the original intent of the CLIA legislation.² Authored by Congressmen Greg Ganske (R—IA) and John Dingell (D—MI), this provision and the accompanying report accomplish three needed corrections that will increase public access to important diagnostic devices.

FDA Home-Use Clearance Means Automatic Waiver. According to CLIA, when FDA approves a device for home use CDC must automatically grant the device waived complexity status. Over the years, however, CDC's interpretation of this provision has been inconsistent and at times contrary to a proper reading of the statute and congressional intent. Indeed, Congress has repeatedly criticized CDC for its wasteful and duplicative reviews and for its refusal to honor CLIA's home-use provision. Last July, the Senate's Labor and Human Resources Committee reported as follows:

Under CLIA, the FDA was provided the responsibility to categorize the complexity of new [IVD] devices. However, the FDA failed to undertake this task and the responsibility for regulating the complexity of these IVD products was assumed by the [CDC]. At the same time, FDA continues to conduct extensive evaluations of these IVD devices before clearing them for market under the [FD&C Act], including reviewing their instructions for use.

The committee is concerned that this dual responsibility has resulted in a process that causes confusion and unnecessary conflict for IVD device manufacturers. In many cases, this overlap has delayed the delivery of potentially lifesaving devices to market. Additionally, CDC's focus on the same safety and effectiveness issues as FDA highlights the wastefulness of this duplicative review. Therefore, the committee believes that FDA should reassert its exclusive role in the implementation of the complexity evaluations under the CLIA regulations.³

About three weeks later, the Senate labor appropriations subcommittee echoed this sentiment.

The Committee understands that under [CLIA], the FDA was given the responsibility to categorize the complexity of new [IVD] devices. However, the FDA failed to undertake this task and the responsibility for regulating the complexity of these IVD products is being carried out by the CDC. At the same time, FDA continues to conduct extensive evaluations of these IVD devices before clearing them for market under the [FD&C Act], including reviewing their instructions for use. The Committee concurs with the concern expressed by the authorizing committee that this dual responsibility has resulted in a process that causes confusion, unnecessary conflict, and duplication of effort. This Committee encourages the CDC to review with the FDA the prospect of returning to the FDA the role of categorizing the complexity evaluations under the CLIA and be prepared to report on the review during the fiscal year 1999 hearings.⁴

In FDAMA, Congress sought to eliminate once and for all any confusion about CDC's role in categorizing devices that FDA had already approved for home use. The House report accompanying FDAMA states:

Section 21(g) provides a technical correction to minimize any duplication between the [CDC] and the FDA determinations related to the accuracy of test systems. In re-writing Paragraph (3) of Section 353(d) of the Public Health Service Act, the Committee intends to clarify that approval of a test for a home use by the FDA is an automatic route to waived status under the [CLIA]. The Committee is aware that the CDC, because of a misunderstanding of the statutory language, has denied waived status for at least one test approved for home use by prescription. The bill clarifies that, when the FDA already has determined that a diagnostic product can be used safely and effectively by a layperson at home, such a product should not require additional review or action by the Secretary to determine whether CLIA requirements can be waived for this product. This is the case whether the product is available over the counter or by prescription.⁵

In short, FDAMA states that when FDA has determined that a device can be used in the home to produce results that are equivalent to the results obtained in the laboratory, the device qualifies for waived status under CLIA. Despite this clarification, however, CDC has continued to stand in the way of automatically granting waived status to FDA-approved home-use tests. Most recently, CDC has sought to limit such waivers by precluding the use of labeling written for professionals rather than for home-users. CDC's continued denial of waiver petitions for FDA-approved tests suggests that it needs to further clarify its interpretation of the waiver statute.

Inherent Sensitivity Is Outside CDC's Authority. According to the original version of CLIA, waived status should be granted to tests that "employ methodologies that are so simple and accurate as to render the likelihood of erroneous results negligible."⁶ CDC has in some cases interpreted this language so as to require an evaluation of the inherent sensitivity and specificity of a test system—that is, the degree to which a test result, once obtained, provides a valid clinical measure of the disease state. But the controls created by CLIA do not meaningfully affect a product's inherent sensitivity and specificity profile.

The Ganske-Dingell provision makes it clear that the inherent sensitivity and specificity of an FDA-approved product is not the proper focus of a CDC review. As modified by FDAMA, the CLIA definition of waived tests now includes those that "employ methodologies that are so simple and accurate as to render the likelihood of erroneous results by the user negligible." CDC's review, in other words, should focus on the potential for error "by the user." The process for granting waived status using this criterion is now more clearly consistent with the overall purposes of CLIA, which emphasizes the use of quality controls, proficiency testing, and personnel requirements to ensure that users can operate a test system consistently and reliably.

Separate and Independent Routes to Waived Status. Under CLIA, the general criteria for waived status are that the test should be "simple" and pose "insignificant risk of an erroneous result."⁷ CLIA also offers a list of three ways that a test can satisfy these general criteria.

Unfortunately, CDC's 1995 proposed rule on the process and criteria for granting waived status and the agency's decisions to date suggest that CDC has misinterpreted the statute.⁸ CDC interprets the list of routes to waived status as merely examples of factors that it may (or may not) take into account when deciding whether a test satisfies the general criteria. For example, CDC considers the criterion of "posing no reasonable risk of harm if the test is performed incorrectly" to be only one of several factors that may lead to waived status—and not as itself being dispositive of waived status.

To reaffirm Congress's original intent regarding these waiver criteria, FDAMA created two amended and newly designated subparagraphs (A) and (B). The House report makes it clear that those two subparagraphs and the home-use criterion are each independent and sufficient routes to obtaining waived status.

CDC's Current Review Procedures

The FDAMA amendments to CLIA will certainly serve to clarify the law, reaffirm the original intent of Congress, and increase public access to diagnostic procedures. Even so, they represent merely incremental improvements to a system that is badly in need of fundamental reform.

Since it was first created in 1992, the process for obtaining waived status for a new diagnostic test has evolved into another, and thoroughly redundant, level of regulation over the approval of medical technology. This second governmental gatekeeper between IVD manufacturers and patients requires a painfully long time to perform its tasks (see Tables I—IV). According to CDC, the review of a petition for waived status typically takes about 42 weeks; but it can take as long as 90.⁹ And much of this time is additional to whatever time a manufacturer has already spent getting its product reviewed and cleared by FDA.

One factor that has contributed to the lengthy review of waiver petitions is the virtual absence of written CDC policies or procedures to guide manufacturers. In this regard, the regulated community has become accustomed to the practices of FDA, whose general administrative procedures are the subject of an extensive set of regulations.¹⁰ FDA also offers a wide range of guidance documents that detail its regulatory expectations for specific products, and it has adopted procedures that govern its interactions with industry to produce further guidance materials. The review procedures followed by the Center for Devices and Radiological Health are the subject of an even more specific set of blue book memoranda, which cover such topics as the following.

• When supplements are required.

• When panel review is appropriate.

• The FDA decision-making process for 510(k)s.

• Ensuring consistency of reviews.

• Methods for requesting additional information.

• Required elements for device labeling.

• Ensuring the integrity of the review process.

• Sign-off procedures.

By contrast, CDC has issued nothing even remotely comparable that would describe the procedures it follows in reviewing waiver petitions. This absence of documented administrative procedures fosters industry misunderstanding of the process, contributes to lengthy delays and wide disparities in review times, and permits inconsistencies to develop in the way the agency handles petitions from different sponsors. Guidance from CDC would help to resolve all these issues. In addition, such guidance would also help CDC anticipate its workload and identify areas where efficiencies can be achieved.

Areas in Need of Reform

To resolve many of the problems that now exist in the administration of CLIA, certain members of the coalition have identified several key areas in need of reform.

Eliminate Duplication. One priority for reform is to identify and eliminate areas of duplication and conflict between the regulatory schemes of FDA and CDC. In most cases this can be accomplished by adopting new rules that clarify which of the two agencies has responsibility for each of the regulatory tasks that must be performed. However, in some cases it may be appropriate to add provisions to the current statute, following the model of FDAMA's statutory amendment of CLIA's home-use provision.

Table II. Average CDC review times for all waived status applications, as of May 1997.

Table III. Fastest and slowest times of CDC initial determination for all waived status applications, as of May 1997.

Table IV. Fastest and slowest times of total CDC review for all waived status applications, as of May 1997.

Clarify the Criteria for Waived Status. Manufacturers should be free to develop alternative ways of demonstrating that their products satisfy CLIA's general criteria for waived status. Along these lines, the waiver criteria could be improved by making certain that they are not prescriptive in nature. This is particularly true for certain restrictive concepts in CDC's 1995 proposed regulations, such as the requirements that devices be demonstrated to be "fail safe" and that manufacturers must use direct, unprocessed specimens in their clinical trials. Since some of these issues were raised in comments on the 1995 proposal, CDC is presumably working on at least some of them.

Define the Process for Categorization Reviews. CDC can remedy many of the problems discussed above by developing procedures to govern its review process and by establishing mechanisms for appeal and reconsideration of its decisions. At a minimum, CDC should establish written policies and procedures that spell out the following.

• How submissions are docketed and tracked during the review process.

• How the review of petitions is prioritized (e.g., is the rule first-in, first-out, or are other factors considered?).

• What information is required in order to obtain expedited review of a categorization petition.

• What procedures apply to communications between CDC reviewing staff and the applicant.

• What procedures exist to protect the confidentiality of information provided to CDC.

• When review by the Clinical Laboratory Improvement Advisory Committee (CLIAC) or another advisory committee is required.

• How long review of a typical categorization should take, and how much time is required for the various steps in the review process.

• A detailed model for categorization petitions, including how to present summaries of analyses, studies, and other evidence relevant to CDC's decision.

By defining and publicizing the process for CLIA categorization review and the criteria for waived status, CDC will help improve compliance by the regulated community.

Define Guidance Procedures. It is imperative that CDC establish and reveal its basic approach to working with the public to develop policy.

Although a general regulation should be used to address most of the issues discussed in this article, there will undoubtedly be many more-specific issues requiring CDC interpretation. Most of these will not rise to the level of requiring formal notice-and-comment rule making. For such issues CDC should consider following the principles for FDA guidance development mandated by FDAMA, and the more specific good guidance practices policy adopted by FDA in 1997.

In general, CDC should adopt procedures to ensure that the public is involved in the development of its interpretive rules and policy statements. Since the creation of such policies often requires detailed scientific, medical, or technical information, CDC should ensure that its procedures provide adequate opportunity to obtain input from experts in these fields. It should also work to ensure that public participation does not impede the efficient, timely, and inexpensive formulation of needed policies.

One way that CDC could accomplish many of these goals is to heighten the role of public involvement in CLIAC meetings used for policy development. CDC should go beyond the requirements of the Federal Advisory Committee Act to diversify the composition of CLIAC, provide more specific and advanced notice of topics to be considered at CLIAC meetings, and improve the organization of the meetings to create a more logical flow of information and facilitate productive involvement by the public.

The Future

In light of all the problems that currently exist in the administration of CLIA, many members of the coalition believe that CDC's 1995 proposed rule on the categorization of waived tests should not be permitted to proceed to a finalized status. Instead, they recommend that the agency first propose and solicit comments on a revised version of that rule.

Although it is a radical reversal to begin rule making again from scratch, in this case the reasons for doing so are compelling. CDC's proposed rule could not have anticipated the current rapid pace of technological advances in device instrumentation; nor could it have accounted for structural changes in the health-care system that have greatly changed the character of the intended users of new diagnostic tests. In addition, there is a practical need to bring the rule into line with FDAMA's statutory amendments to CLIA, and to improve the categorization process by expanding the range of topics addressed in the rule.

Sometime in the near future, members of the coalition may ask CDC and the Health Care Financing Administration (HCFA) to initiate negotiated rule making to develop a revised version of the waived-status rule. To form the rule-making committee, CDC and HCFA could invite participation by representatives of various laboratory groups, medical professional societies, patient groups, and manufacturing associations, among other interested parties. The revised version of the rule should accomplish the following objectives.

• Take into account recent substantial technological advancements in device instrumentation.

• Account for the structural changes in the U.S. health-care system that relate to the role of diagnostic testing.

• Bring the rule into conformity with the requirements of CLIA, as amended by FDAMA.

• Establish administrative review procedures, including an appeals mechanism for CDC decisions regarding petitions for waived test status.

Conclusion

The need of health-care providers for rapid, accurate, and easy-to-use tests is driving the IVD industry to focus on the point-of-care market. At the same time, technological advances are occurring to make such testing possible, and the pace of technological change for IVDs is continuing to quicken. These changes may also affect the substantive criteria that are appropriate for determining waived status. CDC should adopt new rules that take these market and technological forces into account.

For the last several years, the attention of health-care professionals, the health industry, and patients has been focused on FDA as the gatekeeper controlling patient access to new medical technologies. With the great progress currently being made by that agency, many of those same people may now turn their attention to the issues surrounding the CLIA process for complexity categorization. In that area, there are certainly improvements still to be made.

References

1. Freiherr G, "Cardiac Markers: Developers Enter a New Era of Progress," IVD Technol, 4(3):32—36, 1998.

2. Food and Drug Administration Modernization Act of 1997 [FDAMA], Publ. L. no. 105-115, 111 Stat. 2296, 2324 (codified as amended 42 USC section 263(a)(1997)), section 123(h).

3. Report of the Senate Labor and Human Resources Committee, S. Rep. 105-43, p 32, July 1, 1997.

4. Report of the Senate Labor Appropriations Subcommittee, S. Rep. 105-58, p 66, July 24, 1997.

5. "Prescription Drug User Fee Reauthorization and Drug Regulatory Modernization Act of 1997, H.R. 1411," H.R. Rep. 105-310, p 76, October 7, 1997.

6. Clinical Laboratory Improvement Amendments of 1988 [CLIA], 42 USC section 353(d)(1)(3)(B).

7. CLIA, 42 USC section 353(d)(1)(3).

8. "Public Health Service; CLIA Program; Categorization of Waived Tests," proposed rule, in FR 60(177):47534—47543, September 13, 1995.

9. Centers for Disease Control and Prevention, written responses to Senate Labor and Human Resources Committee, October 19, 1997.

10. 21 CFR 10.

Bradley Merrill Thompson directs the food, drug, and medical device practice at the law firm of Baker & Daniels (Indianapolis), and serves as general counsel of the Indiana Medical Device Manufacturers Council.