The optimal scope of FDA regulation of genetic tests: meeting challenges and keeping promises.

• Author: Han, Juliana

TABLE OF CONTENTS I. INTRODUCTION II. THE STATE OF THE ART A. Trends in Technology B. Current Oversight III. SOURCES OF FDA JURISDICTION A. Devices B. Interstate Commerce IV. THE PRACTICE OF MEDICINE LIMITATION A. The Example of Off-Label Prescribing B. A Guiding Principle for Genetic Test Regulation V. CONCLUSION I. INTRODUCTION

With the completion of the Human Genome Project and the advent of increasingly sophisticated genetic technologies, the promise that genetic advances will revolutionize medicine appears closer than ever. Soon, tests will function as medical crystal balls, forecasting risks of disease years into the future based on genetic variations. Medical care might soon benefit from tests that accurately predict the risk of common diseases with complex etiologies, such as cancers, Parkinson's disease, or Alzheimer's disease. (1)

Despite these hopes, fears have risen about the potential dangers of genetic testing. For instance, misleading and inaccurate tests can generate false diagnoses and lead to unnecessary treatment such as mastectomies for breast cancer patients. (2) Furthermore, without guarantees of privacy and confidentiality, both accurate and inaccurate genetic information might be used by employers (3) or insurers (4) to discriminate against patients. In response to some of these fears, many states have enacted legislation specifically to safeguard genetic information privacy (5) and to regulate the use of genetic information by health insurers. (6)

Given the risks associated with genetic testing, both the general public and the federal government have focused on perceived gaps in the regulatory oversight of genetic tests. (7) Most new genetic tests are developed and conducted in-house at a single clinical laboratory; these laboratory-developed tests are also known as "home brew" tests. (8) Tests may also be packaged as complete testing systems ("kits") and sold to multiple laboratories. (9) Although the Food and Drug Administration ("FDA") regulates kits, it does not regulate lab-developed tests. (10) This discrepancy drew the attention of federal oversight committees. (11) In recent months, the FDA has taken the first concrete step toward regulating lab-developed tests by issuing preliminary guidance for a subset of such tests known as In Vitro Diagnostic Multivariate Index Assays ("IVDMIAs"). (12)

Despite the FDA's initial efforts toward more sweeping regulation, questions remain about its legal authority and the proper boundaries of increased oversight. (13) This Note investigates the sources of the FDA's jurisdiction over lab-developed genetic tests and provides a guiding principle to ensure that expanded regulation does not nullify the benefits of genetic testing. Part II describes the trends in genetic tests and the current regulatory framework for such tests. Part III explores the constitutional and statutory sources of authority for FDA oversight of lab-developed genetic tests. Part IV argues that the FDA's long-standing policy against interfering with the "practice of medicine" should act as a limiting principle in the regulation of these tests. Part V suggests that such a principled approach will allow the FDA to ensure genetic test quality while avoiding the damaging effects of unbounded regulation on developing technologies.

2. THE STATE OF THE ART

   1. Trends in Technology

      Before exploring the proper scope of increased regulation, some understanding of the present state of genetic testing and the current regulatory framework may be helpful. Each person's DNA sequence is composed of billions of nucleotides, comprising a genetic code that programs the person's biological makeup. (14) Variations or mutations in the code affecting just a single nucleotide can correlate to a clinical outcome such as disease risk or drug response. (15) In their most basic form, genetic tests consist of two major steps: first, they identify key variations in a patient's DNA, and second, they correlate those variations to a clinical outcome to aid in medical care. (16) Thus, genetic tests can be used to diagnose a condition, predict risk, or aid in the selection of therapeutics or dosages of drugs. (17) This Note will focus on predictive testing, considered by some to require the most regulation due to its inherent uncertainty. (18)

      The latest generation of tests is the product of ongoing advances in both steps. First, the technology available to determine a person's genetic code is gaining speed and accuracy. Whereas the sequencing of a single composite human genome took the Human Genome Project thirteen years and billions of dollars, (19) scientists are developing sequencing technology that is far more efficient. (20)

      Second, manufacturers are looking beyond single-gene variations with high penetrance to the impact of multiple genes in complex diseases. Penetrance measures the causal link between the genetic variation and the health outcome, so a gene variant of high penetrance is one that correlates well with a disease outcome. (21) Traditionally, tests were developed to detect variants of a single gene with a well-established correlation to a disease. (22) Recent tests, however, start with a disease and identify multiple, often novel, genes of interest. (23) Such tests employ complex analytical methods to determine the impact of multiple genes. (24) This new approach is predicated on the idea that although any one gene may be weakly penetrant, considering combinations of multiple genes can boost predictive power. (25) Private companies are embracing this approach by creating their own data banks of gene-disease correlations. (26) The results of these efforts are genetic tests that can provide predictive data for complex and common diseases based on multi-gene analysis.

   2. Current Oversight

      The regulatory requirements for genetic tests differ considerably based on whether they are marketed as kits or lab-developed tests. Kits are complete test systems with all of the reagents, components, and instructions needed to conduct the test and are intended for sale to multiple laboratories. (27) Lab-developed tests are generally assembled and conducted in-house at a single lab. (28) Unlike kits, they are sold as services to individual health care providers and patients who request them. (29)

      Kits are regulated as medical devices by the FDA. (30) Medical devices are categorized from class I (lowest risk) to class III (highest risk) and regulated depending on the level of control necessary to assure safety and effectiveness. (31) The latest genetic tests are likely to be class III devices due to their complexity and use. (32) Class III device manufacturers must submit an application for premarket approval, (33) which requires that manufacturers submit data supporting any claims of analytical and clinical validity, (34) unless they can demonstrate that the device is "substantially equivalent" to a previously marketed device. (35) Of the hundreds of available genetic tests, only a few have been approved as kits because of the substantial cost and delay these requirements impose. (36)

      By contrast, lab-developed tests are largely unregulated and consequently constitute the majority of genetic tests marketed today. Unlike kits, lab-developed tests are not subject to any premarket requirements or external validation. (37) Although the FDA has asserted the authority to impose such regulations on lab-developed tests, it has historically exercised its "enforcement discretion" by declining to do so. (38) Therefore, laboratories have the freedom to decide whether a test is medically meaningful and whether it is supported by valid data. (39) In 1997, the FDA considered revoking the exception for lab-developed tests. (40) Ultimately, however, it decided to simply limit the exception by regulating the chemical components of lab-developed tests. These components, called analyte specific reagents ("ASRs"), (41) are regulated by the FDA if they move in commerce. (42) Current regulation of ASRs imposes only general quality controls, however, and does not address their eventual use in genetic tests. (43)

      In September 2006, the FDA issued preliminary guidance for a subset of lab-developed tests denoted as In Vitro Diagnostic Multivariate Index Assays. (44) IVDMIAs are defined as test systems that use data from in vitro assays and an algorithm to provide a medically useful, patient-specific test result. (45) The preliminary guidelines suggest that most IVDMIAs are likely to be class II or class III devices subject to premarket and postmarket safety and effectiveness requirements. (46) The FDA recently sent letters to certain manufacturers stating that their new tests may be subject to FDA approval requirements. (47) At least with regard to these new tests, the FDA has suggested that the technology warrants regulation because of its complexity and its potential role in diagnosing diseases or affecting treatment. (48)

      In light of the recent preliminary guidelines, it is important to determine the proper scope of FDA regulation of lab-developed tests. Any regulatory oversight must consider at least two key parameters: analytical validity and clinical validity. (49) Analytical validity indicates "how well a test measures the property or characteristic it is intended to measure. In a DNA-based test, an analytically valid test would be positive when the particular gene mutation is present (analytical sensitivity) and negative when the gene mutation is absent (analytical specificity)." (50) A test's clinical validity is the accuracy of the test in diagnosing or predicting risk for a health condition. (51) Clinical validity is measured by a test's predictive value for a given health condition. (52) For newer genetic tests, a test's clinical validity will depend on the quality of the clinical data on which it is based and the algorithms used to compute the test result. (53)

      While no uniform, comprehensive regulatory system...