Public Health at Risk: Failures in Oversight of Genetic Testing Laboratories - Part One

Executive Summary

The Human Genome Project unleashed a torrent of information about the human genome and the role of genetic variation in human health. As a result, genetic testing is now among the fastest-growing areas of laboratory medicine. Today, genetic tests for about 1,000 diseases are clinically available, with hundreds more available in a research setting.

Making sure that laboratories can accurately and reliably perform genetic tests is a fundamental requirement for the success of genetic medicine, and the government has a key role to play in overseeing laboratory quality. Congress has provided federal agencies a broad mandate to ensure the accuracy and reliability of genetic testing, but inattention and delay have meant that this mandate has gone unheeded.

This report describes the role of the Clinical Laboratories Improvement Amendments of 1988 (CLIA) in ensuring laboratory quality, and documents the repeated failure of the Centers for Medicare and Medicaid Services (CMS) to implement this law with respect to genetic testing laboratories. It identifies the lack of transparency regarding laboratory quality as a key impediment to sound healthcare decision making by healthcare providers and patients.



The report also summarizes data from the Genetics and Public Policy Center's recent survey of genetic testing laboratory directors. Survey findings indicate a clear correlation between participation in proficiency testing, which is not currently required under CLIA for genetic testing, and test quality. The findings also show that nearly three-quarters of laboratory directors surveyed support more oversight of genetic testing under CLIA, and more than 90 percent found proficiency testing to be useful in improving genetic testing quality.

The report concludes that implementation of CLIA with respect to genetic testing laboratories through the creation of a genetic testing specialty is necessary to ensure the quality of genetic testing, to fulfill the promise of genetic medicine, and to protect the public's health.

Introduction

The Clinical Laboratories Improvement Amendments of 1988 (CLIA) (1) is a little heralded statute with an important mission. Congress enacted the law out of concern over the poor quality of services being offered by clinical laboratories. Congress wanted to make sure that the millions of tests performed on patients every year provided accurate and reliable results.

Authority for implementing CLIA was delegated to the Centers for Medicare and Medicaid Services (CMS). Thus, while much better known for its role in administering the Medicare and Medicaid programs, CMS also is responsible for monitoring the quality of nearly 200,000 clinical laboratories in the United States (2), which together perform more than 10 billion tests each year (3).

At the time CLIA was enacted, few human genes had been identified and genetic testing was a nascent field largely confined to esoteric research laboratories or prenatal testing for chromosomal disorders. Not surprisingly, in implementing CLIA CMS focused first on those testing areas that were mature and most in need of strengthened oversight. As a result, CLIA has improved the overall quality of clinical laboratory testing in the United States.

However, in the 18 years since CLIA was enacted and with the completion of the Human Genome Project, genetic testing has moved from the sidelines into mainstream medicine (4). Today there are about 1,000 diseases for which genetic tests are available clinically, and several hundreds more are available in a research setting (5) (Figure 1). While initial research focused on rare diseases caused by a mutation in a single gene, more recent research has focused on the identification of genetic contributions to complex, multifactorial conditions such as cancer, diabetes, and heart disease (6, 7).



Identifying the genetic underpinnings for variation in response to drugs has sparked interest in targeted drug design and in identifying those genetic variants that may predispose an individual to an adverse drug reaction, or, conversely, to a particularly good therapeutic response (8).

The common denominator in all of these current and future applications of genetic research to human health is the genetic test used to identify genetic variants. These involve testing DNA or RNA (molecular genetic tests), proteins or other metabolites (biochemical genetic tests), or chromosomes (cytogenetic tests). A genetic test can be performed on a wide variety of tissue samples and across the human lifespan. Accurate genetic test results are critical to diagnosis, prognosis, safe and effective treatment, and disease prevention. Genetic tests can lead to profound life-altering decisions, such as the decision to undergo surgery, undertake chemotherapy, discontinue a medication, or to become pregnant or continue a pregnancy. An accurate test result also can help patients make informed decisions about their health and healthcare.

During the 1990s, in anticipation of the "genetic revolution," several government advisory bodies considered what regulatory changes would ensure the smooth transition of genetic testing from research to practice (9-11, 48). Key among the recommendations of these advisory committees was that CMS create regulations under CLIA that focused specifically on genetic tests through the creation of a new "specialty." These expert bodies recognized that laboratory quality is a fundamental requirement of genetic testing quality and that current regulations were insufficient to ensure that quality.

Yet despite these recommendations, CMS has not acted. In 2000 the agency announced it would develop a genetic testing specialty (13). Dedicated personnel within the Centers for Disease Control (CDC), which advises CMS on CLIA implementation, spent years working to develop the content for a genetic testing specialty and to solicit public input. Based on this work, in April 2006 the Department of Health and Human Services (HHS) placed the issuance of a genetic testing specialty on its regulatory agenda, with a target date of November 2006 (14).

However, in July 2006, CMS — with no notice to the public — abruptly reversed course, deciding not to issue a regulation for a genetic testing specialty. Despite the fact that genetic testing appears to be among the most rapidly expanding areas of laboratory medicine, CMS officials now assert that creating a specialty lacks sufficient "criticality" to warrant rulemaking and that existing regulations are adequate (15).

The government's assessment is mistaken, and creation of a genetic testing specialty is critical to the public's health. While admittedly only one component of a system needed for genetic testing quality, a CLIA specialty is central to the goal of ensuring the accuracy and reliability of genetic tests that are used to make important, indeed profound, life decisions. Conversely, an inaccurate test result can lead to ill-informed decisions with tragic consequences, and to wasted healthcare resources.

CLIA: Intent and Implementation

The federal government, through the Department of Health and Human Services

(HHS), has been engaged in clinical laboratory oversight for nearly 50 years. Congress enacted the Clinical Laboratories Improvement Act of 1967 in response to reports of high error rates in laboratory testing (16). But the Act was limited in scope, and during the early 1980s Congress again became concerned about laboratory quality. In particular, Congressional hearings revealed that high numbers of false negative results were being reported by laboratories performing Pap smears to screen women for cervical cancer (17). Women with abnormal, possibly cancerous, cells were being incorrectly informed that their Pap smears were normal, leading to needless illness and death.

Congress enacted the Clinical Laboratory Improvement Amendments of 1988, referred to as CLIA, in order to address deficiencies in the original law, and to "strengthen federal oversight of clinical laboratories to assure that the tests results are accurate and reliable."(17) Congress found that laboratory testing played a critical role in the delivery of health services and in maintaining good health, and that patients both "expect such testing to be done properly" and "assume, quite reasonably, that their interests and the public health are being protected by appropriate government agencies."(17)

Among the problems uncovered by Congress were a "seriously flawed system" for ensuring laboratory compliance and an "ineffective proficiency-testing system for evaluating the performance of laboratories." With respect to compliance, Congress found that the government's reliance on private accrediting bodies had created weaknesses in the administration of quality standards, noting that while the government had delegated enforcement to these entities, "these bodies have made plain their preference and capacity is for education, not enforcement."(17)

Congress noted that proficiency testing "should be the central element in determining a laboratory's competence since it purports to measure actual test outcomes rather than merely gauging the potential for accurate outcomes."(17) Proficiency testing requires a laboratory to demonstrate that it can obtain the correct answer when performing a test on a tissue sample; thus it serves as a "method of externally validating the level of a laboratory's performance."(17) But Congress identified serious defects including "lax federal oversight and direction, lack of proficiency testing for many analytes, inconsistent criteria for acceptable laboratory performance, and improprieties by laboratories in handling specimen samples."(17) Congress intended CLIA to remedy these shortcomings through new, more rigorous laboratory standards (17).

Congressional intent was clear: HHS — of which CMS is an agency — was to require laboratories to participate in proficiency testing for each type of clinical test they performed, unless the secretary of HHS determined that "an appropriate proficiency test could not reasonably be developed and implemented."(17) Congress did not intend for the secretary "to exempt analytes from proficiency testing merely because such testing is not currently available or because it is difficult to obtain consensus on the best method of proficiency testing."(17) Additionally, Congress intended for laboratory performance on proficiency tests to be transparent. Under CLIA, the secretary "would be required to set up a system for compiling the results of proficiency testing and making them available on request to anyone interested [in] reviewing or comparing laboratory performance," along with "some appropriate explanatory information that would assist the requester in understanding the meaning and validity of the information released."(17)

Under CLIA, HHS is responsible for developing standards for quality assurance and quality control, record keeping, equipment and facilities, personnel and proficiency testing, as well as other standards "necessary to protect the health and safety of patients."(1) This authority was delegated to CMS.

Regulations implementing CLIA first went into effect in 1992 (18). The regulations categorize laboratory tests by complexity and specify different requirements depending on the complexity of a test. Tests either may be waived, moderate complexity, or high complexity. Tests are categorized based on specified criteria, which include the knowledge needed to perform the test, the training and experience required, the complexity of reagent and materials preparation, and degree of interpretation and judgment required (19). Waived tests are those that "are so simple and accurate as to render the likelihood of erroneous results negligible," or which pose "no reasonable risk of harm to the patient if the test is performed incorrectly."(20) Laboratories performing only waived tests are subject to only minimal regulation. They need to obtain a certificate of waiver from CMS, and must agree to permit inspection of their facilities.

Laboratories performing tests of moderate and/or high complexity must, in addition to general laboratory registration and inspection requirements, comply with applicable proficiency testing, patient test management, quality control, personnel, and quality assurance provisions. Also, they must be certified in each applicable testing specialty or subspecialty established in CLIA regulations.

Several specialty and subspecialty areas have been established pursuant to CLIA, each with its own requirements related to personnel, quality control, and proficiency testing, among others. Laboratories performing moderate or high-complexity tests must enroll in an approved proficiency-testing program for each specialty or subspecialty for which certification is sought (21). Requirements for proficiency testing programs have been established for most specialties and subspecialties under CLIA. The regulations specify a minimum proficiency test score that laboratories must receive for each specialty and subspecialty.

Proficiency testing is mandated for microbiology (including the subspecialties of bacteriology, mycobacteriology, mycology, parasitology, and virology), diagnostic immunology (including the subspecialties of syphilis serology and general immunology), chemistry (including the subspecialties of routine chemistry, endocrinology, and toxicology), hematology (including routine hematology and coagulation), cytology (gynecologic examinations), and immunohematology.

If a specialty or subspecialty has not been established in the regulations, then the laboratory must "establish and maintain the accuracy of its testing procedures" and verify the accuracy of its test results at least twice a year (22).

Consistent with Congressional intent that results of proficiency testing be made available to the public, the law directs HHS to "establish a system to make the results of the proficiency-testing programs ... available, on a reasonable basis, upon request of any person. The Secretary shall include with results made available ... such explanatory information as may be appropriate to assist in the interpretation of such results."(1) However, no such system appears to have been established under CLIA regulations. With the exception of cytology, no information regarding laboratory performance on proficiency testing is available on CMS's Web site, nor is information provided to the public or healthcare providers regarding how to request such information.

Next Week: Part II

References

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12. Clinical Laboratory Improvement Advisory Committee Meeting Summary Reports February 7-8, 2001, January 30-12, 2002, September 11-12, 2002, September 17-18, 2003, February 11-12, 2004, September 22-23, 2004, February 16-17, 2005, September 7-8, 2005, and February 8-9, 2006.
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13. Federal Register 65 (May 2000): 25928.
    
    
14. Federal Register 71 (April 2006): 22595.
    
    
15. Meeting between representatives of the Genetics and Public Policy Center and representatives of the Centers for Medicare and Medicaid Services, August 3, 2006.
    
    
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18. Code of Federal Regulations, title 42, sec. 493.
    
    
19. Code of Federal Regulations, title 42, sec. 493.17.
    
    
20. Code of Federal Regulations, title 42, sec. 493.15.
    
    
21. Code of Federal Regulations, title 42, sec. 493.801.
    
    
22. Code of Federal Regulations, title 42, sec. 493.801(a)(2)(ii).