written by Michelle E. Roland, MD
published on HIVresistanceWeb: May 12, 1999
Most HIV/AIDS clinicians understand the pharmaceutical development, regulation and reimbursement process well. New drugs undergo FDA-approved clinical trials in a series of phases aimed to evaluate safety and efficacy. New Drug Applications (NDAs) are submitted for FDA review, and once a drug is approved, most third party payers will reimburse for the clinical use of the drug. Drugs may be prescribed, but not marketed, for off-label indications. Third party payers evaluate the standard of care in making decisions about reimbursement for off-label use. Several FDA regulations enable drugs to be used outside of the standard clinical trials mechanism prior to full approval for life threatening illnesses. The most common mechanism used for HIV related drugs is the Expanded Access Program, which serves to provide access to investigational drugs and to gather data on their use in larger patient populations.
The regulation, marketing and reimbursement of diagnostic tests are quite different. Most physicians who are not actively involved in laboratory medicine are unaware of these differences, and their implications in terms of clinical availability of new tests and technologies. As clinical trials of antiretroviral resistance assays are completed (e.g., GART and VIRADAPT; see summaries of trial results, and more information is presented and published regarding the associations of specific mutations and combinations of mutations with clinical outcomes, the clinical demand for these assays will increase. In addition, several companies involved in the development of these tests are poised to introduce them into the market and/or to seek FDA approval for their clinical use.
Some clinicians and patients have had access to either genotypic and/or phenotypic antiretroviral resistance assays through research studies. Others have had access to assays being developed in local university-based clinical laboratories. A few private labs have made "home brew" assays available to those who can pay for them, and some have succeeded in getting third party reimbursement. Most patients and clinicians, however, have no way of accessing these tests.
Fundamental questions regarding interpretation and the clinical utility of these tests remain. There have also been, and continue to be, many questions about the sensitivity and specificity of the different assays. Regardless of these unknowns, however, many clinicians and patients would like to have the opportunity to use these tests to assist in clinical decision making. The current state of knowledge and demand for access regarding resistance assays can be compared to the pharmaceutical expanded access situation.
Given the evolving scientific data in this area, the rapid progress in the technical development of many of these assays, the competition between involved companies, and the increasing desire of clinicians and patients to have access to these tests, there are likely to be rapid policy developments in the regulation, marketing and reimbursement of antiretroviral resistance assays over the next few months. We will present a series of articles examining these issues as they evolve. We also invite readers to share their experiences regarding access and reimbursement, and their questions, by sending us a note in the "Ask the Experts" area of this Web site.
Background
Diagnostic tests are regulated and monitored by a number of agencies, not just the FDA. Other agencies involved in this confusing area include the Health Care Financing Administration (HCFA), Centers for Disease Control and Prevention (CDC) and the College of American Pathologists (CAP). The roles of each of these agencies, and the interactions between them, are confusing and may be in flux. Briefly, HCFA is involved through regulations referred to as the Clinical Laboratory Improvement Amendments of 1988 (CLIA) that became effective in 1992. These regulations suggest a minimum standard required for the use of a non-FDA approved diagnostic test. One hundred and fifty samples should be run to determine the sensitivity, specificity, negative and positive predictive value, and reproducibility or precision of the assay. Once this validation has been completed and signed by the Medical Director of the Laboratory, billing can occur (as outlined below).
Currently, none of the resistance assays is available in a kit, which includes premixed, titrated reagents and controls that are subject to ongoing, centralized quality assurance. Therefore, each time a master batch of reagents is prepared for a non-kit based assay, the CLIA regulations suggest that 40 samples be run for quality assurance. Several companies are developing kits that they plan to submit to the FDA for approval. At this time, however, the FDA has reviewed the current status of antiretroviral resistance assays and is not regulating them. The role of the FDA in regulation and monitoring could change. To make things even more complicated, some states are "CLIA exempt," and therefore regulate labs themselves. These states have higher standards than those required by CLIA. California, for instance, has obtained this CLIA exempt status.
Clinical laboratories undergo mandated proficiency testing for many of the tests they perform. There are 10-20 proficiency providers (some are state specific). Currently, CAP and CDC are involved in proficiency testing of HIV-1 RNA assays. The results of these proficiency evaluations are provided to HCFA and to the involved labs in the form of reports. In some cases, CDC proficiency testing reports are published. Both CAP and CDC will be offering proficiency panels this year to laboratories performing resistance testing. Proficiency testing will be voluntary during the first year. This quality assurance tool will be very important as some assays available through private laboratories (known as home brews) have a poor reputation in terms of both sensitivity and specificity.
Diagnostic tests are reimbursed based on CPT (Current Procedural Terminology) codes. These codes are developed by the American Medical Association (AMA) with input from CAP. In some cases, a specific test will have its own code; in other cases a combination of codes for the different processes involved in conducting the test are used. Currently, the only RNA amplification-based assays with their own CPT code are the quantitative HIV-1 RNA assays. Prior to the development of this CPT code, a combination of codes were used. This is the strategy being used for billing of resistance assays. Each third party payer determines its own policies regarding reimbursement for diagnostic tests. Medicaid (with individual state policies), Medicare (also administered through HCFA), HMOs and private insurers must all be considered.
Common language included on the printed results for a university-based antiretroviral resistance assay read, "This test result or one or more of its components was developed and its performance characteristics determined by the XX Clinical Laboratories. It has not been cleared or approved by the U.S. Food and Drug Administration. The FDA has determined that such clearance or approval is not necessary." The laboratory then bills various units of a number of CPT codes, for example RNA extraction (1), reverse transcription and PCR (multiple), gel electrophoresis (multiple), sequence assembly (multiple) and interpretation (multiple).
The current status of reimbursement for these assays is a murky area. Medical, California’s Medicaid program, appears to be reimbursing for resistance test; it is difficult to track the amount of reimbursement each lab is receiving, however. At least one of the companies involved in this area has hired a consultant who is lobbying the California state legislature regarding these issues. In some cases, private insurers and HMOs are paying, in other cases they are not. For example, Northern California Kaiser has a contract with the Stanford University Clinical Laboratory to provide their assay. FDA approval of one or more resistance assay kits will likely result in more consistent third party payer reimbursement policies. No assays have yet been submitted to the FDA.
