In the fifteen years since the founding of IVD Technology, the IVD industry—and its regulation by FDA—have both changed. The diagnostic capabilities of IVDs have improved dramatically during that period. Some of the advances, such as high-speed, lower-cost genomic sequencing, seemed like the stuff of science fiction when IVD Technology was first published. The number of diagnostic uses has mushroomed during that same period, and IVDs are playing an increasingly important clinical role. Even after discounting the hyperbole, IVDs may help reshape some areas of medicine, such as oncology, by enabling individualized therapy.

There have also been notable regulatory changes. For example, the data submitted in 1995 to support 510(k) premarket notifications would rarely—if ever—suffice today. The Office of In Vitro Diagnostics Device Evaluation & Safety (OIVD) did not exist fifteen years ago. Nor did user fees, de novo classification, or mandatory clinical data registries.

Yet even though it is self-evident that the regulation of IVDs has changed significantly since 1995, on closer examination it is not so obvious that the formal regulatory structure has changed that much. Put another way, an IVD regulatory affairs (RA) professional from 1995 could look through the current Federal Food, Drug, and Cosmetic Act (FD&C Act), and Code of Federal Regulations (CFR) for IVD-related provisions and feel right at home.

Perhaps the single biggest change in the CFR was the adoption of the analyte specific reagent (ASR) classification regulation. This regulation created a larger new class of in vitro diagnostic devices, and established multiple special requirements applicable only to these products. Yet as a result of the 2007 ASR Guideline narrowly interpreting what products fall within under the ASR classification, this regulation now has much less impact than originally envisioned. Some other diagnostic provisions in the CFR have changed, but most of its contents would be easily recognizable to the 1995 RA expert. This is also true for most other sections of the CFR that affect IVDs.

At the statutory level, the 1995 RA professional would have relatively little trouble adapting to the modern FD&C Act. The FD&C Act has been amended multiple times, but the changes are not IVD specific. Nor are they truly transformative. While Congress has, for example, added user fees, clarified that 510(k)s may need clinical data, created “510(k)s with limitations” for when CDRH believes there is a significant likelihood of off-label use posing potential risks, mandated the posting of clinical trials data, and made other changes, these amendments didn’t fundamentally alter the regulatory regime for devices, including IVDs.

Perhaps the amendment that would seem most far-reaching to the 1995 RA professional is the creation of the de novo process. This provision allows companies and FDA to avoid having to stretch for creative predicate devices. It also eliminated the perverse outcome that moderate risk devices needed to go through the premarket approval application (PMA) process for lack of a predicate device. To OIVD’s credit, the de novo process has been used for IVDs far more often than for any other type of device. Even so, given that de novo IVDs have averaged two clearances per year, it is difficult to say that this provision has revolutionized the IVD regulatory regime.

While the formal regulatory world of statutes and regulations has changed comparatively little, the informal world of guidelines and guidance documents has undergone much more of a shake-up. Numerous guidelines have been issued in the past 15 years, and many of the most important developments have occurred in this arena. For example, the 2008 guidance document titled “Recommendations for Clinical Laboratory Improvement Amendments of 1988 (CLIA) Waiver Applications for Manufacturers of In Vitro Diagnostic Devices” has significantly affected the waiver process, including making it more difficult to obtain CLIA-waived status. In the past five years, there have been numerous new IVD guidelines, and more are on their way.

Thus, although there have been many changes at the less-formal level, one would be hard-pressed to say that the formal regulatory structure for IVDs—the FD&C Act and CFR—has been fundamentally altered since 1995. Equally striking, some of the major regulatory topics covered by IVD Technology haven’t changed much either.

Looking Back: Some Issues Don’t Go Away

Consider an article by Tom Tsakeris that commented on the “tension between IVD producers and clinical laboratories with regard to making cutting-edge IVD technologies available to the public.”  The article further notes that “clinical labs have discovered that they can often compete successfully against manufacturers that must satisfy the heavier burden of FDA regulation.” The theme of this article—that the different regulatory regimes for IVDs and laboratory-developed tests (LDTs) present important challenges—is just as pertinent today as it was when Tsakeris wrote it in 1997.

Or consider a 1996 article by Christopher Zalesky regarding what was then called “special-purpose reagents,” and later named ASRs. This article referenced “the long-standing problems with commercialization of products labeled . . . ‘For research use only’ (RUO).”  The author hypothesized that adoption of an ASR policy would “resolve some long-standing confusion regarding regulation of IVDs labeled for . . . RUO[s].” While adoption of the ASR regulation did mitigate issues involving the sale of RUOs for diagnostics, the subsequent restriction of the ASR definition prompted a resurgence of RUO products. OIVD is reportedly now working on a new draft policy to address RUO issues, which Zalesky termed—in 1996—a “10-year-old . . . dilemma.”

Another early IVD Technology article triggering a sense of déjà vu is one by Tom Tsakeris from 1995. In this article, Tsakeris bemoaned the “paucity of IVDs available for over-the-counter (OTC) purchase.”  Tsakeris noted the lack of clear guidance from FDA, citing the agency’s “mixed messages.” Fifteen years later, addressing a similar theme, Tsakeris criticized “a highly uncertain waiver review end point” for assays seeking a CLIA waiver for physician office laboratory (POL) IVDs.  The stringency of FDA’s requirements that enable IVDs to be used outside of the laboratory—whether for OTC or POL use—has persisted as an issue for 15 years.

Perusing old issues of IVD Technology shows some other recurring regulatory themes. A 1997 article discussed problems with glucose meters. Because of user problems, FDA had “called for an investigation into the morbidity and mortality associated with home use of a new generation of glucose meters.”  While meter technology has greatly improved, glucose meters still present user issues. Another article touted the advent of electronic 510(k)s and their possible benefits. While there are many more electronic submissions to FDA, electronic submissions of 510(k)s have neither superseded paper applications nor revolutionized the regulatory process.

One current issue is determining what role FDA should play in assessing clinical utility. This question directly affects the intended uses of IVDs and the kinds of clinical data needed to support a marketing application. This issue, too, is not novel. In a provocative article proposing that FDA play a limited role in assessing clinical utility that foreshadowed later debates, Glen Freiberg declared, “Ethics of IVD use are outside FDA jurisdiction.”  He added, “Government should be relieved of the task of making value judgments that affect product clearances.”

The Present: IVD Regulation Has Changed Dramatically

Thus, an RA professional from 1995 might feel well-prepared to tackle the regulatory issues of 2010. After all, neither the FD&C Act nor the regulations have been dramatically altered, and despite the plethora of guidance documents, many regulatory policy issues are similar to—or the same as—those of 1995.

Appearances can be deceiving. The 1995 RA expert would quickly learn that the regulatory world has changed profoundly, and that many other alterations are underway. While the visible, outer regulatory scaffolding of statutes and regulations has changed comparatively little, the inner workings of the IVD regulatory regime have undergone major modifications.

One of the more obvious changes is the formation of OIVD itself. The creation of a separate office dedicated to IVDs is, among other things, a testament to the unique regulatory, clinical, and scientific issues that IVDs can present. The creation of this separate group to regulate all aspects of IVDs (and now radiological products) has had a variety of impacts on industry, including the greater autonomy from CDRH and the much tighter relationship between the product review and enforcement functions. The expansion of OIVD and its greater clinical rigor have had profound effects on IVD reviews.

Other changes stem from technology. Entire new disciplines—such as proteomics and metabolimics—have sprung up that were almost unimaginable in 1995. These scientific changes have had a direct impact on the regulatory world. Many of the hardest regulatory decisions stem from these new technologies. What do you do for a predicate device when you have a novel instrument? How do you evaluate its safety and effectiveness when there is no product like it? How can you establish clinical truth? What novel regulatory, analytical, and clinical risks do you need to manage because of the new technology, and how do you do so? What are the regulatory implications of providing laboratories with complex investments and assays whose functioning is less well understood by the laboratorians than an ELISA test? What issues are raised by the burgeoning discipline of bioinformatics—a field taken for granted now but not in 1995?

The 1995 RA professional would find the basic regulatory tools largely unchanged. Applying those tools to technologies that are fundamentally different, though, would prove highly challenging.

The advances in technology have given rise to a particularly vexing set of strategic decisions for RA professionals and companies: What is the intended use of the IVD?  This issue, of course, would have been familiar to an RA professional in 1995. The regulatory route for a prostate-specific antigen test—510(k) versus premarket approval application—turned on whether the company sought a monitoring or screening claim.

Modern technology, however, has led to many products for which crafting the intended use is far more difficult. A test for a single antigen or antibody could support only a relatively small number of biologically plausible claims. With new technologies, those limitations have largely been destroyed. Researchers can search for and then create assays based on 5 or 15 or 50 biomarkers and an algorithm for numerous kinds of tests, be they tests for a predisposition to cardiac risks or to psychiatric disorders. New assays often do not build on prior predicate devices, and there is often no intuitive relationship between a set of disparate biomarkers tied together through a complex algorithm, and a disease. This untethering of new assays from both prior diagnostic tools and established biomarker-disease relationships has had profound effects on regulatory, clinical, and business strategies. OIVD itself has evolved its expectations to address these products, but many of these adaptations are not reflected in formal documents. Using the regulatory paradigm of 1995 would not serve an RA professional well who was working on one of these products.

Another powerful example of how the stability of the formal regulatory structure masks profound regulatory changes comes from the area of LDTs. As of 1995, FDA had asserted regulatory jurisdiction over laboratories in the most tentative of fashions: a passing statement in a draft policy document regarding RUOs. FDA’s belief that it can regulate LDTs as medical devices has now achieved the status of dogma, and the agency is on the verge of sweeping regulation of LDTs.

Not long ago, a laboratory that asked about FDA regulation for a new LDT could have simply been told the following: FDA has claimed jurisdiction over laboratories, but it has not exercised that power. When describing the regulatory landscape, there was no need to go beyond that simple statement. Today, advising a laboratory about the nature and scope of FDA regulation is far more complex and nuanced, and the potential FDA role far greater.

The 1995 RA professional probably could not have envisioned that laboratories would, in effect, receive a 510(k) clearance for a single site. FDA has already cleared four of these 510(k)s, and other companies are seeking similar types of clearances. Another unanticipated change is the heavy use of pre-IDEs. Driven in part by technological innovation and by regulatory flux, the number of pre-IDEs has skyrocketed. While pre-IDEs may not be mandatory, they have become the norm for non-routine IVDs. In fact, OIVD has welcomed and encouraged the submission of pre-IDEs. While the non-binding nature of pre-IDE reviews has created some problems when OIVD subsequently raises issues that the sponsor thought had been settled, there is no question that the early identification of concerns by ODE reviewers is helpful. The 1995 RA professional who simply submitted a 510(k) for a novel analyte or a PMA would be out of step in 2010.

All of these changes would have greatly surprised the 1995 RA professional. And none of these developments stem from changes in the formal regulatory structure.

The Future: Fearless Forecasts

This retrospective review leads to an intriguing prospective question: How will IVD regulation in 2025 differ from that of 2010? Reflecting on the changes between 1995 and 2010 shows how difficult it would be to make even moderately accurate predictions.  Predicting some of the developments of the past fifteen years would have required an act of clairvoyance.

The perils of prediction notwithstanding, I have set out below five areas that I expect to be covered in IVD Technology in 2025.

1. The pace of technological change will accelerate, but the formal regulatory structure will lag far behind, creating more ad hoc, unpredictable regulatory reviews. The current system will not accommodate the pace of innovation. The failure to develop new approaches will accelerate negative trends, such as disadvantaging U.S.-based companies and patients compared to Europe, with its very different regulatory model. The pressures resulting from this “IVD lag” ultimately will result in the creation of a new, more flexible regulatory framework that can better accommodate the proliferation of new IVDs.

2. FDA’s greater role will increase the pressures for a more flexible and nimble regulatory regime for all diagnostics, including rare diseases, emerging diseases, and product modifications. FDA regulation of LDTs also will change FDA regulation of IVDs.

3. There will be a novel regulatory mechanism to deal with new intended uses. Much more so than other types of devices, IVD submissions are seeking clearance for entirely unprecedented intended uses. An innovative regulatory mechanism will be created to accommodate this proliferation of new uses.

4. Some problems will remain, such as user errors and too few OTC tests.

5. IVD Technology will devote even more space to regulatory issues. In 1995, the magazine  didn’t even have a regulatory column. In 2025, the complexities of FDA regulation will require even more coverage. I look forward to reading those articles.

References

1. T Tsakeris, “The Clinical lab: Manufacturers’ friend or foe?”, IVD Technology (July 1997).

2. C Zalensky, “The special-purpose reagents policy,” IVD Technology. (January 1996).

3. T Tsakeris, “OTC IVDs and Drugs: Weighing the risks and benefits of their availability,” MDDI’s IVDTechnology, p. 26 (Sept. 1995).

4. T  Tsakeris, “CLIA waived tests. Is there another way?” IVD Technology, p. 50 (March/April 2010).

5. A Scheck, “FDA eyes adverse events for glucose monitors,” IVD Technology (July 1997).

6. G Freiberg, “Ethics of IVD use are outside FDA Jurisdiction,” IVD Technology (March 1997).

Jeffrey N. Gibbs is a director at Hyman, Phelps & McNamara, P.C. (Washington, D.C.). He can be reached via e-mail at jgibbs@hpm.com.