Medical Device Link.

COMMENTARY

Attila T. Lorincz, PhD, (left) is the senior vice president of research and development and chief scientific officer, and Mark del Vecchio is vice president of regulatory and clinical affairs at Digene Corp. (Gaithersburg, MD). The authors can be reached at attila.lorincz@digene.com and mark.delvecchio@digene.com, respectively.

Considering that an estimated 60 to 70% of healthcare decision making is based on IVD test results, IVDs represent a cornerstone of human health promotion and maintenance.¹ However, there is room for improvement in applying diagnostics to such decision making, given the problems at the regulatory, laboratory, and manufacturing levels. It is inarguable that if a disease is not diagnosed properly, then a drug or other treatment is unlikely to produce significant benefits and may be harmful.² Without IVD tests and procedures in which appropriate and consistent clinical usefulness and validity have been established, the outcomes of clinical treatment processes are likely to be suboptimal.

Consequently, failed treatments are linked to incorrect diagnoses. But patients are unaware of this linkage, and instead defer all consideration for disease determinations to the clinicians’ expertise. Unfortunately, some clinicians may not sufficiently challenge lab test results to confirm their accuracy. Such oversight may be due to the limited time that clinicians can spend either consulting their patients or researching and understanding new diagnostic tests. Another reason may be the deluge of emerging diagnostic tests that offer minimal or conflicting data on their clinical usefulness.

Challenges for the IVD Industry

Some of the more significant challenges for the IVD industry include promoting the value of diagnostic tests, and providing hard data and facts to demonstrate their accuracy, clinical relevance, and robustness. Unfortunately, the healthcare system sometimes blurs the line between misdiagnosis and inadequately validated tests. According to a report examining critical issues in the IVD industry, “low compliance with diagnostics-based quality measures for diabetes, cardiovascular disease, colorectal cancer, and breast cancer alone was linked to 56,200 avoidable adverse health events and up to 34,000 avoidable deaths.”¹

Another challenge for the industry is the rapid pace at which basic research identifies potentially useful disease biomarkers. While this rapid identification leads to an understandable desire to quickly provide associated tests to needy patients, it also introduces risks of cutting corners in quality.

The IVD industry has been slow in explaining the importance of accurate diagnosis to lawmakers, clinicians, and the public. However, some industry members have made significant efforts to demonstrate and improve the value of diagnostics.¹ Of particular concern is the inconsistent worldwide patchwork of regulations that seems inadequate to ensure the overall reliability and accuracy of test results as more tests are developed, and to foster a clear understanding of the clinical value of the results.³ Such confusion allows test results to be provided unknowingly to patients through their doctors, even though their performance and clinical usefulness have not been extensively evaluated.

For example, there has been a proliferation of laboratory-developed home- brew tests. While most home brews have some value, the means by which they are offered to the public, which is faster than FDA-approved tests, is their potential Achilles’ heel. Home brews are regulated by the Clinical Laboratory Improvement Amendments (CLIA), which do not require any demonstration of clinical accuracy, reliability, or utility prior to offering a new test. Since the clinical performance and utility of home brews are not subject to a level of scientific rigor as stringent as that which FDA applies to tests developed by IVD manufacturers, the true clinical value and consistent performance of many home brews remain unproven.

The complex CLIA regulations that govern home-brew tests and related analyte specific reagents (ASRs) also do not establish an effective standard for determining how the results obtained using them compare to those IVDs that have undergone the more rigorous 510(k) clearance or premarket approval processes. The European Union’s regulations also have very limited premarket requirements for most diagnostic tests, are largely risk-based, and are rooted in postmarketing surveillance.⁴

ASRs are the key reagents that are manufactured to quality standard regulations and good manufacturing practices, and used by labs to develop their home-brew tests. While ASR-based home brews may be more robust, they may not perform better than tests that are not made with ASRs if they are not properly validated by end-users. The problem does not stem from ASR products per se, but from several other factors.

For example, there are no regulatory checks for monitoring the negative impact of home-brew tests developed by clinical labs, which causes the uncertainty as to whether or not such tests may cause harm due to misdiagnosis. Both large and small IVD companies have interpreted and applied the ASR regulations broadly, thereby creating difficulties in understanding what an ASR really is. In addition, because the CLIA re-gulations were never intended to regulate the design, development, manufacture, and clinical utility of diagnostic tests, inspections that determine compli-ance with CLIA are inadequate in these regards.

At the core of this problem is one basic question: Why are tests developed by IVD manufacturers subject to a higher standard than are home-brew tests? The key to improving this situation lies not in lowering the standards bar, but rather in leveling the requirements and set-ting them to a better standard that can en-sure acceptable quality for all diagnos-tic tests.

A jarring report released by the Institute of Medicine (IOM; Washington, DC) in 2000 found that 44,000 to 98,000 deaths in the United States were due to medical errors, including a substantial proportion of diagnostic errors.⁵ This report should encourage the IVD industry to explore the causes of such a startling statistic. Whether such errors are related to inaccurate testing, misinformation regarding the value of test results, misunderstandings of the significance of multiple and perhaps conflicting test results, or other reasons (e.g., proper communication and awareness of the facts), the industry should embrace the challenge in addressing such issues. Even though the public does not recognize the risks and consequences that exist in receiving inaccurate test results, when patients experience bad clinical outcomes due to incorrect test results, the IVD industry’s reputation suffers regardless of whether the errors were in the test design or the conduct of the testing laboratories.

Towards a Better Regulatory Framework and Evidence-Based Medicine

A possible solution is to build a regulatory framework that is similar to how professional and medical societies establish medical practice guidelines and recommendations. Regardless of whether a test is produced by a laboratory as a home brew or developed by an IVD manufacturer, several levels that each define an increasing body of evidence would be established to support the clinical value and performance of specific diagnostic tests. Doctors would use such levels to understand the extent of data and information supporting a specific test. They would communicate such information to their patients when discussing the initial need for the tests and the results received.

When most patients get test results from their doctors, they usually have no idea (along with their doctors) as to what methods were used to obtain the results, and how the reliability, accuracy, and usefulness of the methods were demonstrated. In the end, patients should be told such information clearly and with some reasonable expectation that they understand the message. Society can expect no less in the interests of fair disclosure. By doing so, consumers would be encouraged to take an active role and seek out the best available tests to diagnose their symptoms or risks. At the same time, healthcare professionals should respect the needs of vulnerable patients who are expecting meaningful and reliable test results.

The IVD Industry’s Responsibilities

Members of the IVD industry need to work together effectively to increase the accuracy of testing and the quality standards that must be met to define and communicate the clinical meaningfulness of test results. Many labs cannot afford to purchase and run the most sophisticated IVD tests. This necessitates IVD manufacturers to implement cost reductions. Manufacturers will also need to increase the sophistication of the designs of their next-generation automated machines so that they are more flexible and can be operated reliably by one or a few moderately skilled technicians. In addition, the IVD industry should work tirelessly to ensure that patients receiving unfavorable test results will not be discriminated against by employers or insurance companies.

In a sense, the IVD industry is at a crossroads. The industry needs to decide if it wants to continue developing analytical tests for which someone else assumes the responsibility of demonstrating clinical validity and usefulness; or be more involved in producing value-added clinically accurate tests intended to be used in defined algorithms that convey a seal of quality and utility. Some industry members have suggested that there is a lack of evidence that a quality problem exists in labs.⁶ The IOM report, a College of American Pathology discussion, and recent articles published in the Los Angeles Times and New York Times indicate otherwise.^5,7–9

The medical community appears to be struggling to improve the healthcare system. Clinical expertise is more variable than ideal, and physicians with different levels of training may have unclear notions about the meaning of clinical validation and clinical utility of test results. Perhaps the IVD industry should not expect the medical community to try to raise the bar on its own. It is also difficult to envision rapid progress in solving this problem through innovative leadership from CMS and FDA. The IVD industry should remain persistent in implementing best practices to foster true quality, and should assist FDA and CMS in their important regulatory roles. In the long run, it will be innovation, robust quality, and proof of clinical utility that will be the foundations of a profitable and successful IVD industry.

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