Medical Device Link.

Originally Published IVD Technology March 2004

Commentary

In June 2003, a group of IVD manufacturers proposed to FDA the adoption of a new regulatory category called in vitro analytical tests (IVAT). Such test kits are defined as those IVD tests for which analytical utility is established, but clinical utility has not yet been proven. In this context, analytical utility is the ability of a test to measure the characteristics it is designed to measure with a known degree of specificity and certainty. The proposal was contained in the form of a draft guidance for a new type of 510(k) that was submitted to FDA’s docket.

This proposal was principally made so that labs, physicians, and ultimately patients can get access to needed tests more quickly, without waiting until lengthy clinical trials are completed. The trade-off is that IVD manufacturers would not be able to make clinical claims unless they obtained traditional FDA clearance based on clinical data. 

The IVD Lag

Most people have heard of the drug lag, the long delay in getting new drugs into the hands of patients who need them. However, few people realize that the traditional process of obtaining regulatory approval for IVD tests also can be, and has been, a barrier to patient access to innovative, potentially lifesaving diagnostic technologies. Today, due to the incredible amount of time it takes to demonstrate an IVD test’s clinical utility after its analytical validity is already established, a number of cutting-edge IVD technologies continue to sit and collect dust on manufacturers’ shelves. Gathering the necessary clinical data for FDA clearance can take many years. 

One example of a cutting-edge diagnostic technology that sat on the shelf for a long time, inaccessible to clinical laboratories, is the fluorescent in situ hybridization (FISH) method, which is now used in numerous labs. The FISH technology is an invaluable tool for applying DNA probes to identify chromosomes. Nonetheless, this technology was substantially delayed by the clinical utility requirement. Realizing the importance of getting this technology to market, and recognizing the significant delays involved in the approval process, FDA finally cleared the test for use. The path was long and arduous, taking more than three years for approval. 

Another test that suffered long-delayed approval is the prostate specific antigen (PSA) blood test. FDA first approved this test in 1986 to aid in the care of men already diagnosed with prostate cancer. However, despite knowing that the PSA test was useful in diagnosing prostate cancer as early as 1991, FDA did not approve PSA as a diagnostic tool until 1994, after requiring the manufacturer to conduct extensive clinical trials. The PSA test has been recognized as one of the top 15 medical innovations during the past 25 years.

As a result of the lengthy process required to establish clinical utility and gain clearance, many potentially lifesaving IVD technologies may remain inaccessible to the healthcare community. This is even the case when the need for a test is stirred by a public health crisis. Indeed, despite the urgency of such public health disasters as anthrax, West Nile Virus, or other infectious diseases that have peppered the headlines during the past few years, the public must still wait.

Filling the Void

So what is filling this public health void? It’s not investigational-use-only or research-use-only products. FDA has made it clear that those regulatory pathways are not intended for commercializing tests. It’s also not analyte specific reagents (ASR). IVD manufacturers are finding there is no market for single reagents that do not offer complete solutions for a testing need.

Rather, it’s home-brew tests. To fill the public health void, clinical laboratories have been making these tests in their own back rooms, without any FDA oversight. Clinicians have been forced to rely on these products even though they lack FDA clearance, are not made under good manufacturing practices (GMP), and are sold without the regulatory scrutiny that IVD manufactured products receive. Only the Centers for Medicare and Medicaid Services under the Clinical Laboratory Improvement Amendments (CLIA) regulate laboratory activities. Moreover, that regulatory scheme is focused on the quality of testing, not on IVD test manufacturing.

The concept of using home brews instead of ASRs to create an in-house test kit presents an interesting paradox. If a lab uses a regulated IVD manufacturer’s ASR in a home-brew test, it must disclose on its reports that it used a product lacking FDA approval. However, if a lab uses only internally manufactured reagents, it is not required to disclose that an FDA-cleared test was not used in producing the results. Physicians may then incorrectly assume that the lab report contains results obtained from FDA-approved products.

The result is that home brews are being used in increasing numbers to diagnose patients. According to FDA, in 2000, at least 301 clinical or research genetic tests were available in the United States, and 158 laboratories offered clinical genetic tests commercially. However, FDA had cleared only six specific gene tests.1 More-recent statistics suggest that genetic testing is available for more than 1020 diseases or conditions in more than 580 laboratories across the United States2 Most of these tests are indeed home brews. When home brews for infectious diseases, cancer, paternity, predisposition, and prenatal testing are added to these totals, the number of home brews that patients are exposed to is staggering.

As one might predict after considering the economics, an interesting result of this dynamic is that IVD manufacturers are starting to buy and partner with clinical laboratories. What else could be expected with such a gaping loophole? Nonetheless, this can hardly be what the policymakers wanted. 

Moreover, this situation may well represent a ticking time bomb if it turns out that unapproved home brews are hurting patients. The proposed IVAT guidance offers a potential solution. Because this solution conforms to existing statutes and regulations, it is believed that the solution could be implemented quickly.

Benefits to Manufacturers and Labs

The proposed IVAT guidance would benefit IVD manufacturers and clinical laboratories in a number of ways. 

First, the proposed guidance would fill a largely unmet need among clinical laboratories for diagnostic technologies that can help solve today’s health problems. In this uncertain world plagued by bioterrorism, previously unknown infectious diseases, and other urgent threats to the public health, laboratories need a broader array of IVD tools at their disposal quickly. The IVAT guidance would fill this need by ensuring that if a diagnostic technology is developed and analytically valid, it will be accessible to clinical laboratories promptly. 

Second, the guidance would place IVD manufacturers and clinical laboratories at the forefront of solving problems affecting the public health. As IVATs receive analytical clearance for use in clinical laboratories, the laboratories would work with physicians and their patients to put these diagnostic technologies into practice. Through this partnership, the manufacturers and laboratories would introduce to the public more-relevant diagnostic tests that would enhance the practice of medicine, and ultimately, the quality of healthcare. Moreover, earlier availability of IVATs would leave clinical laboratories free to concentrate their development resources where they can make the biggest impact on public health, that is, on developing specialized tests for those rare diseases and conditions for which commercially marketed diagnostic technologies likely will never be available.

Third, the proposed IVAT guidance would lead to the development of better diagnostic products for use in clinical laboratories. IVD device innovation would be enhanced by a process of incremental refinement and change, a “dialogue of innovation” that occurs between the health professionals who use the diagnostic technologies and the innovators who develop them. Using diagnostic tests in day-to-day clinical practice earlier in the development process would start this dialogue at a critical stage, encouraging more-meaningful exchanges of information and data. Such exchanges could be vital to prompting IVD product improvements, before applications for clearance of the clinical claims. Furthermore, this open exchange of expert feedback from lab professionals, without the regulatory hurdle of a clinical trial, can spur greater diagnostic product refinement throughout the development process.

Finally, because clinical laboratories would be using IVAT kits that are produced under GMP, results can be compared from lab to lab. This reproducibility would create consistency in clinical research, as well as among public health databases. Perhaps most importantly, physicians would be able to provide more-consistent care to patients who might be tested by multiple labs, and therefore have multiple results that need to be compared and analyzed.

Key Features of the Proposed Guidance

As stated above, an IVAT is an IVD test for which analytical validity has been established, but not clinical utility. An IVAT may be any type of Class I or II IVD test or test kit, as long as it meets these criteria and the manufacturer obtains 510(k) clearance under 21 CFR Part 807.
Through the regulatory clearance process and GMPs, the proposed IVAT guidance will assure laboratories that IVATs would effectively measure analytes and provide reproducible results from lab to lab. The only significant difference from current 510(k)s is that sponsors of an IVAT will not be required to submit a description of clinical uses or any supporting clinical data, as establishing clinical utility would not be required.

The proposed IVAT guidance would also complement CLIA and its regulation of clinical laboratories. The guidance would not prohibit home-brew tests, but rather provide laboratories with other alternatives. Clinical laboratories would still remain subject to CLIA validation requirements as they are now for all their tests. 

Because IVD manufacturers would not be seeking clearance for any of their clinical claims in an IVAT submission, laboratories would not be able to rely on clinical information from the manufacturers. This means that the labeling would not provide cutoff values or normal ranges. While manufacturers would be expected to claim validated analytical limits of detection or quantitation, laboratories would need to establish and validate the clinical cutoff values as they would for a test the lab developed itself. 

Similarly, because a normal range would not be established by the manufacturer under FDA standards, laboratories would be responsible for developing their own normal ranges, as they would for a home brew. The improved quality of materials and instructions for use should provide better consistency of these individually established ranges and enable comparison of results from lab to lab.

Conclusion

So far, FDA does not agree that there is an IVD lag problem that is worth the time and effort to solve it; or at least the agency is not acknowledging that FDA can and should play a role in solving this problem. The agency needs to hear from stakeholders that the IVD lag is potentially hurting patients, and that a process that encourages manufacturers to avoid regulation by joining with the clinical laboratory business to channel their innovations into home brews is not in society’s best interest.

Whether the problem gets solved by FDA, Congress, or the courts is yet to be seen. Nonetheless, the current system of regulation that keeps manufactured tests with analytical utility on the shelf while under-regulated home brews continue to fill the gap is badly in need of reform.
The proposed IVAT guidance can be accessed through FDA’s Web site at www.fda.gov/ohrms/dockets/dailys/03/jul03/072403/03d-0334-gdl0001-vol1.pdf. 

References

1. DW Feigal Jr. “Future Trends” (Washington, DC: Center for Devices and Radiological Health, 2000) presented at the AdvaMed Submissions Workshop, Washington DC, 18 July, 2000.

2. GeneTests (Seattle: University of Washington. [accessed 21 January 2004]); available from Internet: www.genetests.org. 

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