A hot topic in genomics research today is the extension of next-generation sequencing from basic to applied research, especially clinical diagnostics. Over the past year, I have been investigating this from the perspective of information management in translational and clinical genomic labs. This has included direct discussions with people involved in many different aspects of the transition and researching applicable regulations. A major area of concern and misunderstanding is CLIA and other applicable standards. Here is a short, basic Q&A with links to more information.
What is CLIA?
The Centers for Medicare & Medicaid Services (CMS) regulates all laboratory testing (except research) performed on humans in the U.S. through the Clinical Laboratory Improvement Amendments (CLIA). Congress passed CLIA in 1988 establishing quality standards for all laboratory testing to ensure the accuracy, reliability and timeliness of patient test results regardless of where the test was performed. CLIA regulations are codified in the Code of Federal Regulations (CFR); Title 42, Public Health; Part 493, Laboratory Requirements—commonly denoted as 42 CFR Part 493. Approximately 225,000 labs are certified under CLIA, ranging from small physician office labs that perform less than 2,000 tests per year to large hospital-based and independent labs performing millions of tests each year. These encompass the simplest to the most complex tests, including a growing number of genetic tests.
For more information, see the CMS Overview of CLIA and current CLIA information from the CDC.
How do I know if I need CLIA Certification or FDA Approval?
In the United States, the Food and Drug Administration (FDA) regulates the development and marketing of commercial tests. Commercial tests are considered "medical devices" and, specifically, "in vitro diagnostic devices (IVD)." As such, they must be evaluated and approved by the FDA.
While most common laboratory tests are commercial tests, manufactured and marketed to several labs, some new tests are developed, evaluated, and validated within one particular laboratory. These tests, called "laboratory-developed tests" or "LDTs" are used solely within that laboratory and are not distributed or sold to any other labs or health care facilities. Many LDTs are genetic tests that are developed by specific labs for rare diseases. Because the laboratory-developed tests are not marketed to others, they do not require approval from the FDA. Instead, the federal government regulates development, evaluation, and use of lab-developed tests through CLIA.
In general, because the FDA does not evaluate LDTs, they must undergo a more lengthy and rigorous validation process by the individual laboratory wishing to implement the new method. The in-house procedure may involve numerous experiments, such as comparing the results from the new test method to those generated by a well-established test method.
For more information, Lab Tests Online® is an excellent public resource on clinical lab testing. The information on FDA approval of commercial tests and CLIA certification of laboratory-developed tests is condensed from a five-part post titled, Putting New Laboratory Tests into Practice.
What other standard is applicable to clinical genomics labs?
Another important standard for clinical genomics labs is ISO 15189:2007 – Medical laboratories: Particular requirements for quality and competence. ISO 15189:2007 is based on ISO/IEC 17025:2005 – General requirements for the competence of testing and calibration laboratories (the main ISO standard used by testing and calibration laboratories), and ISO 9001 – Quality Management Systems - Requirements, but it is specific to the quality management system requirements for medical laboratories.
ISO 15189:2007 is a fundamental requirement for many clinical labs outside the U.S. (in some countries it is the standard by which laboratories are reimbursed), with accreditation organizations in 44 countries. Within the U.S., the College of American Pathologists (CAP) offers a CAP 15189 Program that accredits medical laboratories in accordance with the ISO 15189:2007 Standard. CAP 15189 accreditation is not necessary for CLIA certification, nor is it a replacement for it. However, ISO 15189:2007 directly addresses electronic records and protection of laboratory information systems. Clinical genomics labs that use computer hardware and software to automate laboratory data/information management systems should consider an applicable ISO 15189:2007 accreditation program.
What about electronic signatures?
CLIA does not require electronic signatures. If your lab wants to use electronic records and electronic signatures for FDA submissions, it will need to meet applicable FDA regulatory requirements. The regulations are codified in the Code of Federal Regulations (CFR); Title 21, Food and Drugs; Part 11, Electronic Records; Electronic Signature—commonly denoted as 21 CFR Part 11.
The regulations in part 11 apply to records in electronic form that are created, modified, maintained, archived, retrieved, or transmitted, and set forth the criteria under which the agency considers electronic records, electronic signatures, and handwritten signatures executed to electronic records to be trustworthy, reliable, and generally equivalent to paper records and handwritten signatures executed on paper. The security and auditing requirements of 21 CFR Part 11 are similar to those specified in ISO 15189:2007, and can be summarized as follows:
Security – Control the authorization and authentication of personnel with access to sample and test data, and control the integrity (create, modify, maintain, and transmit) of sample and test data.
Auditing – Allow the lab to identify all individuals who have entered or modified data, files, or programs, and record time-sequenced development and modification of systems documentation.
Finally, another good source of overall laboratory standards information is the Clinical and Laboratory Standards Institute (CLSI).
