Clinical Laboratory Improvement Amendments

In accord with the CLIA, the CLIA Program sets standards and issues certificates for clinical laboratory testing.^[2] CLIA defines a clinical laboratory as any facility which performs laboratory testing on specimens derived from humans for the purpose of providing information for:^{[citation needed]}

• diagnosis, prevention, or treatment of disease or impairment
• health assessments

An objective of the CLIA is to ensure the accuracy, reliability and timeliness of test results regardless of where the test was performed. Most Laboratory Developed Tests have been regulated under this program.^[3] In 2014 the FDA started a public discussion about regulating some LDTs.^[4]

Per CLIA, each specific laboratory system, assay, examination is graded for level of complexity by assigning scores of 1, 2, or 3 for each of the following seven criteria. A score of 1 is the lowest level of complexity, and a score of 3 indicates the highest level. Score 2 is assigned when the characteristics for a particular test are intermediate between the descriptions listed for scores of 1 and 3.^[5]

Criteria for categorization:

1. Knowledge
2. Training and experience
3. Reagents and materials preparation
4. Characteristics of operational steps
5. Calibration, quality control, and proficiency testing materials
6. Test system troubleshooting and equipment maintenance
7. Interpretation and judgment

Centers for Medicare and Medicaid Services (CMS) has the primary responsibility for the operation of the CLIA Program. Within CMS, the program is implemented by the Center for Medicaid and State Operations, Survey and Certification Group, and the Division of Laboratory Services.

List of CLIA test complexity categorizations:

• Waived
• Moderate
• Provider-performed Microscopy (PPM)
• High
  • Laboratory Developed Test (LDT)s

Complementary and alternative medicine tests, such as Live blood analysis (LBA), Biological Terrain Assessment (BTA), dental sensitivity testing, and cytotoxic testing have not been categorized by the CDC, and are thus treated as high complexity laboratory developed tests.^[6][7] CAM tests are often ordered by chiropractors, naturopaths, and nutritionists and accompanied by non-validated clinical interpretations which are used to recommend or justify costly, unnecessary, and potentially damaging treatments.^[8][9] A 2001 OIG report found that the majority of laboratories performing CAM tests were not enrolled in CLIA and that CAM laboratory personnel did not meet the high complexity qualifications.^[10] For laboratories enrolled in CLIA, they had their certificates revoked or were sent deficiency notices for failing to adhere to CLIA regulations.^[10] No CLIA laboratory has been able to validate their LBA CAM tests per standards.^[10] CAM tests are not covered by health insurance.^[6] The number of CAM laboratories is unknown and the sales of supplemental remedies based on the results of these tests is unknown.^[11] Since CLIA does not regulate the clinical validity/usefulness of a test, it is possible for a CLIA laboratory to offer tests that have no clinical utility.^[8][12]

Getting laboratories that conduct CAM testing to enroll in CLIA is itself a challenge. Medical laboratories enroll in CLIA to qualify for Medicare/Medicaid reimbursement, nearly all providers bill patients directly for CAM laboratory tests.^[10] Additionally, CAM providers are concerned by the closure of other CAM laboratories under CLIA, and have sought to avoid detection.^[10] Some CAM providers and laboratory personnel have not had exposure to laboratory curriculum and are unaware of CLIA requirements.^[10] CLIA is largely reliant on laboratories to self-identify themselves for enrollment.^[10]

Providers of CAM laboratories have opposed oversight by CLIA and have suggested they should regulated by their peers or under a CAM specific division.^[13][10] CAM providers have stated that they should be exempt from CLIA since CAM laboratories do not participate in health insurance.^[10] Others claim that they are exempt from CLIA because the tests are performed solely for research purposes and not used in patient care and treatment decisions.^[11] Several pathologists have stated that CAM testing falls within the scope of their medical license and should not be regulated under CLIA.^[10]

CLIA provisions are geared towards CLIA certified laboratories, but not for those that have not enrolled. When a CAM laboratory is found to be operating without a CLIA certificate, they are sent a cease and desist letter to stop testing until the laboratory is CLIA certified.^[10] There are no administrative remedies available to CMS when a laboratory refuses to enroll in CLIA and refuses to cease testing.^[10] CMS cannot impose monetary or other administrative penalties on laboratories that defy the law, but can only refer cases to other Federal or State agencies.^[10] CMS plays the primary role in federal oversight of laboratories under CLIA and there are limited regulations at the state level that restrict CAM laboratories.^[10]

CLIA applies to sperm analysis and the postcoital test, but does not apply to andrology nor embryology laboratories, nor testing performed as part of an assisted reproductive technology (ART), nor reproductive tissue banks. There are no federal personnel requirements.^{[14][15][16][17]}

The lack of CLIA applicability has been criticized noting how semen analysis is categorized as a high complexity test whereas the analysis of oocytes and embryos is unregulated, despite similar equipment and techniques in use.^[18] There are accreditation programs such the CAP/ASRM Reproductive Laboratory Accreditation Program (RLAP), and TJC and CAP offer specialty accreditations, but these are voluntary in nature.^[18][15]

In the summer of 1991, HHS notified the American Society of Reproductive Medicine (ASRM) and the Society for Assisted Reproductive Technology(SART) that in vitro fertilisation(IVF) and Gamete intrafallopian transfer(GIFT) laboratories were to be covered under CLIA '88.^[14] However, when CLIA '88 was published on February 28, 1992, it did not explicitly mention andrology and embryology laboratories creating uncertainty in regulatory oversight.^[14] In 1992, Senator Ron Wyden (D-OR) introduced the Fertility Clinic Success Rate and Certification Act (FCRCA), colloquially called the "Wyden bill", requiring the Disease Control and Prevention (CDC) to develop a model program for the certification of embryo laboratories, to be carried out voluntarily by interested states.^[15][19][14] This created initial confusion as to whether CLIA was applicable.^[14] In 1994, HCFA stated that in vitro fertilization was categorized as the therapeutic procedure, not a diagnostic procedure and therefore not covered under CLIA.^[14] As such, AAB/ABB took the position that IVF laboratories test are covered under CLIA, while ASRM and SART took the opposing position.^[14] On September 16, 1998, the Clinical Laboratory Improvement Advisory Committee (CLIAC) made a non-binding recommendation that CLIA coverage apply to embryology laboratories and suggested the College of American Pathologists (CAP) and ASRM accreditation checklist.^[14] However, the United States Secretary of Health and Human Services Donna Shalala did not implement the recommendation prompting the AAB to sue HHS to force a decision On March 16, 1999.^[15][14] In response, ASRM filed an amicus brief opposing AAB's lawsuit.^[14] On March 8, 2000, the lawsuit was dismissed by Thomas F. Hogan due to lack of standing.^[14]

In 1994, the American Board of Bioanalysis (ABB) created the first CLIA-approved HCLD board exam for andrologists and embryologists.^[14]

The CLIA Program is funded by user fees collected from approximately 200,000 laboratories, most located in the United States.^[3]

Under CLIA, tests and test systems that meet risk, error, and complexity requirements are issued a CLIA certificate of waiver.^[20] In November 2007, the CLIA waiver provisions were revised by the United States Congress to make it clear that tests approved by the FDA for home use automatically qualify for CLIA waiver,^[21] although many waived tests are not done according to designed protocols – more than 50% of such tests are done incorrectly – and result in medical errors, some with fatal consequences.^[22]

CLIA^[23] and the College of American Pathologists (CAP)^[24] have written policies for the minimum period of that laboratories should keep laboratory records and materials, with some examples as follows:

During the retention period, specimens are considered to be part of the medical record and must be kept under a CLIA accredited laboratory to ensure compliant handling and storage conditions.^[25][26] If a specimen is sent-out to a non-CLIA biorepository and recalled, the additional testing would not be in compliance.^[25] There is an effort to make more biobanks CLIA equivalent as specimen recalls become more common due to expanded testing.^[25]

Though CLIA does specify minimum retention periods, it does not explicitly specify which entity maintains ownership of the specimen while it is being retained and after the retention period has passed.The US currently does not have well-defined federal regulations regarding the ownership and utilization of physical human tissue specimens, their derivatives, as well as the biological information they contain.^{[27][28][29][30][31][32]} The current standing by bioethicists is that patients who have consented to have their diagnostic specimens collected have also abandoned them, and thus have no ownership rights.^[29][33] The Common Rule permits the use of biospecimens that would otherwise be discarded provided that the donor can not be identified, though utilization of the materials for research may require Institutional review board (IRB) approval.^[29] The Association of American Medical Colleges (AAMC) has taken the stance that it "unambiguously rejects the concept that individuals retain any property interest in their excised tissues."^[34]

Proponents of patient ownership rights advocate that patients must own their samples so that they can make informed decisions about how the tissues will be used, such as in bioweapons development, stem cell research, and for-profit ventures.^[31] The 21st Century Cures Act enacted in December 2016 allows researchers to waive the requirement for informed consent when clinical testing "poses no more than minimal risk" and "includes appropriate safeguards to protect the rights, safety, and welfare of the human subject."

The probability that a patient may sue researchers who utilize tissues that would typically be discarded is low, but as genetics research becomes more prevalent, this likelihood may increase.^[29] Ideally, researchers should obtain informed consent from individuals, and aim for transparency in their intended use for the human tissue while protecting the privacy of the donor.^[29]

CAP and other laboratory accreditation organizations (AO) have additional requirements and protocols for repurposing biospecimens that would otherwise be discarded.^[31]

In July 2011, an Advance Notice of Proposed Rule Making (ANPRM), entitled "Human Subjects Research Protections: Enhancing Protections for Research Subjects and Reducing Burden, Delay, and Ambiguity for Investigators" was published in the Federal Register.^[35]

The rise in direct-to-consumer (DTC) genetic testing has created concerns for secondary use of both patient samples and their data.^[36]

In the US, newborn screening (NBS) is mandated in all states, though parents may decline the screening process based on religious beliefs or philosophical reasons in some states.^[37] Few parents opt of the program due to health concerns, and a lack of awareness of the ability to opt-out.^[37] After the initial testing is complete, the residual dried blood spots (DBS) on newborn screening cards may be used for secondary purposes including shared with law enforcement and sold for research.^[38] The decreasing costs of whole genome sequencing have also raised concerns that blood spots may be sequenced in the future, limiting any de-identificaiton procedures.^[39][40][41] While CLIA does specify minimum retention requirements, it does not specify a federal maximum retention period. Retention periods for NBS cards vary by state with several states storing the cards long-term such as New Jersey with 23 years, or Texas which may keep the cards indefinitely.^[42][43] The absence of parental awareness and consent for these activities, and a lack of transparency and federal regulations, has led to significant public concern and apprehension.^{[44][45][46][47]}

The CDC Good laboratory practice guidelines for newborn screening recommends that "laboratory specimen retention procedures should be consistent with patient decisions."^[49] Researchers have described the NBS samples as a gold mine representing a patient population that would otherwise be impossible to get.^[46] The American Civil Liberties Union (ACLU), Council for Responsible Genetics(CRG), and the International Association of Privacy Professionals(IAPP) oppose the long term storage of identifiable NBS blood spots.^[50]

In 2009, the Texas NBS program had to destroy millions of stored blood spots that were stored for decades without consent.^[51] In Michigan, a 2022 lawsuit found that the NBS program long term storage and sales to third-parties was found to violate state statues noting how "post-testing conduct is not necessary to effectuate that interest because 'the health of the child is no longer at stake.'"^[52] In New Jersey, the Institute for Justice filed a class-action lawsuit in 2022 under the 4th amendment seeking to limit the retention period of NBS cards after they were found to be used in warrantless law enforcement investigations without consent.^[48][53][54]

The origins of CLIA can be traced back to the late 1960s, when cytology laboratories faced issues due to overworked personnel and a high incidence of errors in reading PAP smears. In response to these concerns, the Clinical Laboratory Improvement Amendment was introduced in 1967, which laid down the first set of regulations for laboratory standards, focusing mainly on independent and hospital laboratories.^[55]

The Clinical Laboratory Improvement Act of 1988 (CLIA 88) was passed in the USA subsequent to the publication of an article in November 1987 in The Wall Street Journal entitled "Lax Laboratories: The Pap Test Misses Much Cervical Cancer Through Labs Errors", which alerted the public to the fact that a pap smear may be falsely negative. The article implied that false negative tests resulted largely from the carelessness of doctors. Subsequent to this, claims involving pap smears showed an alarming growth. The Act aimed at a comprehensive regulation of gynecologic cytology laboratories.^[56]

For CLIA laboratories licensed under a Certificate of Accreditation (CoA), bi-annual inspections are conducted by an third-party accreditation organization (AO) that meets or exceeds the CLIA requirements.

Though Foundation for the Accreditation of Cellular Therapy (FACT) (formerly Foundation for Accreditation of Hematopoietic Cell Transplantation) does not have deeming status under CLIA, most laboratories involved in cell therapies are accredited by FACT.^[58]

In Dec 2022, TJC announced they would no longer recognize Commission on Office Laboratory Accreditation (COLA) for lab accreditation at TJC hospitals as of Jan 1, 2023 and facilities would have until Dec 31, 2024 to transition accredidation.^[59][60] With the COVID-driven inspection backlog and a lack of inspectors, the move was criticized as being purely a financially driven attempt to capture additional market share.^[61][62] No reason for the change was given by CLIA, COLA., or TJC TJC had originally begun recognizing COLA accreditation in 1997.^[63][64]

Clinical laboratories in the US that perform high complexity testing require a high complexity laboratory director (HCLD) that has earned doctoral degree in a chemical, physical, biological or clinical laboratory science from an accredited institution and be certified and continue to be certified by a board approved by HHS. The current approved boards are the following:

• Medical laboratory scientist
• Individualized Quality Control Plan

• Clinical Laboratory Improvement Amendments (CLIA),Centers for Medicare & Medicaid Services (CMS)
• CLIA Regulations Assessment Workgroup, CDC Clinical Laboratory Improvement Advisory Committee (CLIAC)
• CLIA Laboratory Lookup, CMS S&C's Quality, Certification and Oversight Reports (QCOR)