Laboratory Regulations

US clinical genetic laboratories operate under a layered regulatory structure. CLIA sets the federal floor for any lab testing human specimens for diagnostic or health-assessment purposes. CAP offers more rigorous voluntary accreditation with deemed status. The FDA governs the diagnostic devices themselves (IVDs vs LDTs). State agencies (most notably New York CLEP) layer additional requirements. CLSI publishes the consensus technical standards labs cite in their SOPs. Professional society guidelines (ACMG/AMP) define how variants are classified and reported.

• CLIA (Clinical Laboratory Improvement Amendments, 1988):
  • Federal law administered by CMS; applies to all US labs testing human specimens for diagnosis, prevention, treatment, or health assessment.
  • Stratifies tests by complexity: waived, moderate complexity, and high complexity (PPM is a moderate-complexity subset). Genetic testing is high complexity.
  • High-complexity labs must employ a qualified laboratory director (MD/PhD/DO with board certification or equivalent) plus technical supervisor, clinical consultant, general supervisor, and qualified testing personnel.
  • Inspection cycle: every two years, by CMS or a CMS-deemed accreditor.
  • Required: SOPs, validation/verification, QC, proficiency testing, personnel competency, document control.
• CAP (College of American Pathologists):
  • Voluntary accreditation, deemed-status with CMS.
  • Inspection every two years on a peer-review model using detailed checklists (All Common, Molecular, Cytogenetics, Biochemical Genetics, etc.).
  • Generally more rigorous than CLIA minima, with more granular molecular and genetics requirements.
• FDA:
  • IVDs (in vitro diagnostic devices): manufactured kits subject to FDA premarket review (510(k), De Novo, or PMA) and labeled for specific clinical indications.
  • LDTs (laboratory-developed tests): tests designed, manufactured, and used within a single CLIA-certified high-complexity lab. Historically held under FDA enforcement discretion, leaving oversight largely to CLIA/CAP.
  • 2024 final rule: FDA finalized phase-out of blanket enforcement discretion, bringing LDTs under the medical device framework over a multi-year staged transition (registration, adverse event reporting, and eventually premarket review for higher-risk LDTs). This shift is actively being litigated and implemented; the conceptual change matters more than specific dates.
  • Companion diagnostics are FDA-approved IVDs tied to a specific therapeutic decision (e.g., EGFR testing for tyrosine kinase inhibitor selection).
• ACMG/AMP guidelines: 2015 joint standards for sequence variant interpretation (Pathogenic, Likely Pathogenic, VUS, Likely Benign, Benign) using PVS1/PS/PM/PP and BA/BS/BP evidence codes. Subsequent ClinGen Variant Curation Expert Panel (VCEP) gene-specific specifications refine the framework. ACMG also issues reporting recommendations including the Secondary Findings list (currently SF v3.x).
• State-level oversight - NY CLEP (Clinical Laboratory Evaluation Program): any lab receiving specimens from New York residents must hold a NY permit. CLEP review is test-specific and notably stringent; many out-of-state labs hold or specifically waive NY permits, which can affect specimen acceptance.
• CLSI (Clinical and Laboratory Standards Institute): publishes consensus technical guidelines (e.g., MM01 molecular methods, MM09 NGS, EP05 precision, EP17 detection capability). CLSI documents are not law but are routinely cited as the standard of practice in SOPs and during inspections.
• HIPAA and GINA: HIPAA governs protected health information; GINA (Genetic Information Nondiscrimination Act, 2008) prohibits genetic discrimination in health insurance and most employment but does not cover life, disability, or long-term care insurance.

• A new in-house NGS gene panel is an LDT and historically required only CLIA/CAP-level validation; under the FDA final rule, LDTs face progressively stricter device-style oversight.
• A lab cannot accept New York specimens without a NY CLEP permit covering that specific test category.
• Genetic counselors should know that a "PCR-based test cleared by FDA" is an IVD with manufacturer-defined indications, while "send-out NGS panel from Lab X" is typically an LDT validated by that lab.
• ACMG Secondary Findings disclosure is a reporting policy choice tied to ACMG/CAP/professional standards, not directly to CLIA.