Originally Published IVD Technology April 2005
Anniversary Essays
7. U.S. regulatory issues
Recent FDA reforms in the regulation of IVDs have sometimes helped and
sometimes hindered manufacturers’ efforts to meet market demands.
Thomas M. Tsakeris
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Thomas M. Tsakeris is a former director of FDA’s Division of Clinical Laboratory Devices. He is now president of Devices and Diagnostics Consulting Group Inc. (Rockville, MD) and a member of the IVD Technology editorial advisory board. He can be reached at ddcgi@comcast.net. |
Many IVD industry observers would assert that FDA’s regulation of IVDs has changed dramatically over the past 10 years. Others might argue that, despite some changes, an atmosphere of business as usual has prevailed. The perception differs depending upon point of view; that is, the position the observer occupies within an IVD company or within the industry. But it is generally agreed that the measure of net change is largely the difference in the length of time required to obtain FDA marketing authorization for new IVD products.
Most observers would agree, as well, that, while a decade of changes in FDA regulations, policies, and administrative procedures has formed new opportunities for IVD manufacturers in some areas, those changes have raised new regulatory issues in others. Indeed, the interaction between industry and FDA seemed to involve its own laws of motion, where action and reaction between the two entities would sometimes result in predictable and sometimes in unpredictable outcomes.
This article addresses several key areas that have presented challenges to IVD manufacturers and FDA during the period of interest. It examines the ways that changes introduced by both industry and the regulators have affected the regulatory equilibrium over the years.
FDA in Transition
When IVD Technology first appeared in 1995, FDA was in the middle of a self-imposed so-called era of reformation inspired by anticipation of the enactment of what became the FDA Modernization Act of 1997 (FDAMA). In the aftermath of the generic drug scandal of the late 1980s, congressional oversight in the early 1990s had focused intensely on FDA’s regulation of medical devices. Congress was concerned that the traditionally fast-track approach to medical device approvals taken by the Center for Devices and Radiological Health (CDRH)—faster than that used for new drug approvals—may have been compromised by insufficient clinical validation requirements, particularly for premarket approval (PMA)–type devices. Its heightened oversight of FDA led to management conservatism within the agency and thus to a painful slowdown in new medical device approvals.
This slowdown created alarm and consternation in the medical device industry. Subsequent outcries from that quarter directed at Congress led to the legislature intensifying its oversight of FDA, but this time sending the agency in the direction of, in the words of FDAMA, “least burdensome” regulation. As a result, FDA, with a good deal of industry urging, embarked on a series of initiatives designed to facilitate the review and approval of new medical devices, including, of course, IVDs. Those involved reclassification of tumor markers and immunohistochemistry (IHC) reagents, new regulations for analyte specific reagents (ASRs), and reconsideration of the waiver provision of the Clinical Laboratory Improvement Amendments of 1988 (CLIA).
Helpful Product Reclassifications
In December 1995, FDA’s immunology devices advisory panel recommended that tumor-associated antigen immunoassays for monitoring disease treatment or recurrence be reclassified from Class III devices to Class II devices subject to 510(k) provisions. The agency acted accordingly.1
Although the reclassification action covered only a modest number of IVDs (screening and diagnostic tumor tests were excluded), it was remarkable in that FDA had previously considered all cancer tests to have the highest public health profile. Also, it had been generally assumed that the ultraconservative immunology devices panel would reject the reclassification petition that had been filed by Centocor Diagnostics. FDA staff, however, had assured the panel that reclassification of this narrow band of tumor tests would not compromise their evaluation as safe and effective.
The reclassification action was also important in that it tended to set the regulatory risk of other high-profile nonscreening, nondiagnostic IVDs (e.g., other monitoring tests and tests for risk assessment) at a lower level. This became particularly significant following implementation of the FDAMA automatic reclassification provision, more commonly known as de novo classification. Under the provision, new tests could follow a 510(k) pathway even though no clear-cut predicate test existed, so long as FDA considered the test less risky than PMA-type tests.2
A reclassification action that affected a considerably larger number of products got under way in October 1994. At that time, FDA’s hematology and pathology devices advisory panel recommended that most IHC reagents be grouped into Class I, making them exempt from 510(k) review but, importantly, not from good manufacturing practices (GMPs), and selected certain others for placement in Class II or Class III. FDA concurred, and formally classified IHC reagents in June 1998.3
Up to that time, the widespread off-label use of IHC reagents, which had been broadly commercialized for research use only, had presented FDA with an enforcement and a premarket review dilemma. Many IHC reagents are unique individual primary-antibody reagents that must be integrated by the clinical laboratory into a particular immunological method for the microscopic examination of tissue or cells by a pathologist, often to assist in the detection and characterization of tumor cells.
Because of the multitude of IHC reagents in existence, requiring their premarket review would have placed an extraordinary burden on FDA resources. Moreover, since many of these reagents were widely commercialized, well understood, and reliable for their intended uses, any FDA enforcement measures taken to prohibit or limit their use might have created a serious public health concern.
The IHC classification action is a good example of the prudent application of regulatory resources guided by input from both industry and the public.
The ASR Regulation
Of even broader scope and significance than classification of IHC reagents was FDA’s 1997 promulgation of the ASR regulation. This classified a newly created broad category of distinct IVD reagents as Class I products and placed a smaller group of specialized ASRs, as with the immunohistochemistry reagents, into Class II and Class III.4 FDA calls ASRs the “building blocks of in-house tests” and designates them “restricted devices,” as they must be used only by clinical laboratories certified under CLIA to perform high-complexity testing. Also, the agency permits no clinical utility or performance claims to appear in product labeling or advertising. A draft compliance policy guide that addresses unapproved research-use and investigational IVDs was disseminated in conjunction with the ASR regulation.5
The ASR regulation was to a large extent an evolutionary end point in FDA’s attempt to obtain control over the commercial distribution of unapproved IVDs that had existed for decades. Although the regulation attempted to subject clinical laboratories to incremental regulation by requiring them to report ASR-based tests as not having been cleared or approved by FDA, it seemed to affirm FDA’s long-standing policy of staying at arm’s length from active regulation of clinical laboratories and in-house-developed—so-called home-brew—tests. The agency has preferred to defer regulation of those labs and tests to the Centers for Medicare and Medicaid Services (CMS; Baltimore) as part of that organization’s responsibilities under the CLIA regulations.
Many IVD industry observers believed at the time that the ASR regulation would have little impact on IVD marketing. Observers generally assumed that most new IVDs could be marketable only in the form of complete test kits or systems carrying clinical utility and performance claims cleared or approved by FDA. In actuality, the regulation fostered conditions for innovation and collaboration among traditionally competing IVD test producers; that is, IVD manufacturers and the reference clinical laboratories that produce home-brew tests.
The promulgation of the ASR regulation enabled IVD manufacturers to provide clinical laboratories with proprietary reagents that were produced under GMPs in accordance with the FDA quality system regulation and that utilized new technologies. These reagents could be offered for routine use when integrated into complete test systems and validated by the labs within the context of CLIA quality standard requirements. That is, the labs could offer innovative tests and services much more rapidly and make claims of clinical utility and performance for ASR-based tests without direct FDA oversight. Thus, the ASR regulation was, and remains, an alternative means by which new biotechnology-based IVDs for testing for a wide variety of diseases and conditions could be offered to the public relatively quickly, without having to go through an arduous and time-consuming FDA premarket review process.
Unfortunately, while the ASR route to market seemed worth doing, it seemed worth overdoing to some IVD manufacturers that have abused it. For example, some ASR providers have stretched the definition of analyte specific reagent to include test platforms employing multiple ASRs. Some more blatantly represent complete test systems as ASRs, with labeling claims going beyond what the ASR regulation permits.
FDA’s slow response to these abuses did not help. However, the agency did issue clarifying ASR guidance in February 2003.6 It is interesting that this guidance exceeded the explicit stipulations of the regulation in specifically prohibiting inclusion of user instructions with the ASR. Recently, FDA has acted in response to concerns about overzealous claims by both ASR suppliers and clinical labs, particularly in the area of genetic testing. Also in February 2003, it issued draft guidance for multiplex tests for DNA and protein markers, including array-based tests.7
FDA has indicated that it will disseminate a revised version of the multiplex guidance and new ASR guidance in the near future. In the meantime, compliance enforcement seems to be mainly a matter of sending to selected IVD companies and clinical laboratories engaged in questionable ASR commercialization and promotion activities letters of invitation to meet with FDA to discuss the merits of their commercialization practices.8-12
The CLIA Waiver
FDA’s role in implementing CLIA—namely, complexity categorization—may itself be characterized as complex. Although the CLIA implementing regulations of 1992 initially assigned complexity categorization responsibility to FDA, early budget shortfalls in the collection of the CLIA user fees that were to fund FDA resulted in this activity being assigned to the Centers for Disease Control and Prevention (CDC) during the 1990s.
The main concern among IVD manufacturers has been with the waiver provision of CLIA. CLIA had been enacted by Congress in the belief that the testing conducted in physicians’ offices was of inadequate quality and should be held to the same standards as tests performed in other clinical testing facilities. Nevertheless, the CLIA waiver provision allowed standards for certain tests to be waived if the tests could be shown to have appropriate simplicity and accuracy and to offer failure safeguards.
Physician office laboratories (POLs) like waived tests very much because they do not have to meet most CLIA quality-standard requirements nor incur the associated cost of compliance, which is significant. Manufacturers of POL-type IVDs thus are compelled to go through two separate regulatory gates: FDA’s premarket review process, then the CLIA waiver review process. However, successfully demonstrating to FDA that a device is safe and effective for POL use does not mean that the device is automatically waived under CLIA. The standard of waiver there is much higher.
The problem has been that the waiver criteria specified in a 1995 proposed rule are both nebulous and demanding.13 The waiver review process has been further complicated by the involvement of several different federal agencies (CDC, CMS, and FDA) with differing perspectives on how waiver criteria should be applied.
To the credit of FDA, which took over the complexity categorization program in 2002, it issued proposed alternative guidance for obtaining waived status in 2001. This guidance was fairly well received by the IVD industry, but because of political pressure from sister agencies within the Department of Health and Human Services (HHS), FDA quickly withdrew it. As a result, only a few new types of IVD device have obtained CLIA-waived status over the years. Many of these were waived because they were cleared or approved for home use, which imparts automatic waived status.14 FDA has promised to publish new guidance soon.
The waiver review process represents a significant HHS management failure that may be ameliorated only through legislative reform of CLIA. If those original congressional concerns regarding POL testing quality still exist—and they may, given the results of several CMS surveys that reveal persistent shortcomings in overall quality control—then either the waived category should be eliminated or CLIA should be amended to allow FDA-approved POL-type devices to be deemed as meeting CLIA waiver requirements when used in accordance with FDA cleared/approved product labeling. It does not make sense that a stifling, layered regulatory burden be imposed in an area of IVD product development—specifically, point-of-care IVDs—where the application of new technology can reap large benefits for public health and society generally.
The Creation of OIVD
At the end of 2002, CDRH elevated the Division of Clinical Laboratory Devices within the Office of Device Evaluation (ODE) to a higher level in the center’s organization. The Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD) that was created now stands on an equal administrative footing with ODE. OIVD’s stated mission is to apply a total product life-cycle approach to the regulation of IVDs through the integration and consolidation of premarket (product review) and postmarket (compliance) functions. Among its goals are “to shift resources from premarket to postmarket assessment by exploiting the current methods of defining IVD performance and actualiz- ing the spirit of the least-burdensome provisions of FDAMA” and “to improve the timeliness of decision making and staff interaction while maintaining or improving current output.”15
The new office is still flexing its muscles, so it is difficult to determine how successful it has been in meeting these goals. Product review timeliness has no doubt been influenced by review-throughput timelines imposed by the Medical Device User Fee and Modernization Act of 2002; OIVD has done fairly well in keeping review cycle times within stated goals.16 The question is whether OIVD staff have taken seriously a least-burdensome approach to the review processes. The record is mixed but trending in a positive direction.
Several OIVD initiatives are notable. For example, the office has employed the de novo reclassification process liberally.
Under de novo procedures, FDA has cleared tests using tandem mass spectrometry for certain types of newborn screening, an endotoxin assay for risk assessment of severe sepsis, a new fungal test for deep-seated mycoses and fungemia, immunomagnetic tests for circulating cancer cells, a test for the detection of Factor V Leiden DNA mutations, and a test for allergy to the immunosuppressive drug Sirolimus. FDA has also cleared a novel cardiac marker test under existing classification regulations. The de novo process allows accelerated product clearance with fewer follow-up restrictions. It seems advisable for OIVD to consider further expansion of it.
Additionally, since August 1, 2003, FDA has made available on its Web-accessible 510(k) database more-detailed and more-useful standardized summaries of 510(k) clearances granted. FDA has also indicated that it plans to implement early in 2005 a so-called Turbo 510(k), or e-510(k), pilot procedure whereby IVD sponsors may submit 510(k) applications on-line. Finally, the agency issued guidance on the use of symbols on labels and labeling in November 2004.17
Conclusion
FDA and the IVD industry have both undergone remarkable changes over the past 10 years. IVD manufacturers have seen product life cycles continue to shorten, which places heavy demands on them to get new products to market more quickly than ever. Whether the new OIVD total product life-cycle approach can keep pace with this acceleration in the IVD industry in a least-burdensome manner is yet to be determined. However, if the recent past is any indication of future progress, then the outlook for the IVD industry is encouraging.
References
1. Federal Register, 62 FR:66003, December 17, 1997.
2. “New Section 513(f)(2)—Evaluation of Automatic Class III Designation, Guidance for Industry and FDA Staff” (Rockville, MD: FDA, Office of Device Evaluation, 1998 [accessed 28 December 2004]); available from Internet: www.fda.gov/cdrh/modact/classiii.html.
3. Federal Register, 63 FR:30132, June 3, 1998.
4. Federal Register, 62 FR:62243, November 21, 1997.
5. “Commercialization of In Vitro Diagnostic Devices (IVDs) Labeled for Research Use Only or Investigational Use Only,” draft compliance policy guide (Rockville, MD: FDA, Center for Devices and Radiological Health, 1998); available from Internet: www.fda.gov/cdrh/comp/ivddrfg.html.
6. “Analyte Specific Reagents; Small Entity Compliance Guidance; Guidance for Industry” (Rockville, MD: FDA, Office of In Vitro Diagnostic Device Evaluation and Safety, 2003 [accessed 28 December 2004]); available from Internet: www.fda.gov/cdrh/oivd/guidance/1205.html.
7. “Multiplex Tests for Heritable DNA Markers, Mutations, and Expression Patterns,” draft guidance for industry and FDA reviewers (Rockville, MD: FDA, Office of In Vitro Diagnostic Device Evaluation and Safety, 2003 [accessed 28 December 2004]); available from Internet: www.fda.gov/cdrh/oivd/
guidance/1210.html.
8. “Letter from OIVD to Roche Molecular Diagnostics Re: AmpliChip,” October 29, 2003 (Rockville, MD: FDA, Office of In Vitro Diagnostic Device Evaluation and Safety, 2003 [accessed 28 December 2004]); available from Internet: www.fda.gov/cdrh/oivd/amplichip.html.
9. “Letter to Correlogic Systems Inc.,” February 18, 2004 (Rockville, MD: FDA, Office of In Vitro Diagnostic Device Evaluation and Safety, 2004 [accessed 28 December 2004]); available from Internet: www.fda.gov/cdrh/oivd/letters/021804-correlogic.html.
10. “Letter to Quest Diagnostics,” March 2, 2004 (Rockville, MD: FDA, Office of In Vitro Diagnostic Device Evaluation and Safety, 2004 [accessed 28 December 2004]); available from Internet: www.fda.gov/cdrh/oivd/letters/030204-quest.html.
11. “Letter to Laboratory Corporation of America,” March 2, 2004 (Rockville, MD: FDA, Office of In Vitro Diagnostic Device Evaluation and Safety, 2004 [accessed 28 December 2004]); available from Internet: www.fda.gov/cdrh/oivd/letters/030204-labcorp.html.
12. “Letter to Ventana Medical Systems Inc.,” March 18, 2004 (Rockville, MD: FDA, Office of In Vitro Diagnostic Device Evaluation and Safety, 2004 [accessed 28 December 2004]); available from Internet: www.fda.gov/cdrh/oivd/letters/031804-Ventana.html.
13. Federal Register, 60 FR:47534, September 13, 1995.
14. “Information on CLIA Waivers” (Rockville, MD: FDA, Center for Devices and Radiological Health, 2001 [accessed 28 December 2004]); available from Internet: www.fda.gov/cdrh/clia/cliawaived.html.
15. “Overview of OIVD, Goals of OIVD” (Rockville, MD: FDA, Office of In Vitro Diagnostic Evaluation and Safety, 2005 [accessed 28 December 2004]); available from Internet: http://www.fda.gov/cdrh/oivd/overview.html#3.
16. “Explanation of New Goal for Reducing Device Approval Times” (Rockville, MD: FDA, Center for Devices and Radiological Health, 2003 [accessed 28 December 2004]); available from Internet: www.fda.gov/cdrh/mdufma/goalpma.html.
17. “Guidance for Industry and FDA Staff, Use of Symbols on Labels and in Labeling of In Vitro Diagnostic Devices Intended for Professional Use” (Rockville, MD: FDA, Center for Devices and Radiological Health, 2004 [accessed 28 December 2004]); available from Internet: www.fda.gov/cdrh/ocd/guidance/4444.html.
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