# Presentation: 633536

## The Role of CLIA in the Oversight of Genetic Testing 

- D. Joe Boone, Ph.D
- Office of Genetic Testing
- CDC
- Atlanta, GA
- http://www.phppo.cdc.gov/dls/genetics

##  Background

**CLIA enacted – 1988**
**NIH/DOE Task Force Report - 1997**
**CLIAC recommends changes to CLIA – 1998**
**SACGT recommends increased oversight – 1999**
**CDC Notice of Intent - May 2000**
**Notice of Proposed Rule Making - 2002 ?**

**Notes:**
Genetic testing is in the news everywhere.
However, when CLIA was enacted in 1988 most testing was for relatively rare conditions.  Now, we are talking about applying genetic testing to predict conditions or diseases that can affect everyone.
The 1997 NIH/DOE Task Force Report focused on gaps in the oversight of genetic testing.  These gaps have raised concerns about future testing.
In 1997 CLIAC began reviewing CLIA to see what changes might be necessary to address genetic testing and in 1998 they provided a set of recommendations.
In 1999, the CLIAC recommendations were reviewed by the Secretary’s Committee on Genetic Testing, who encouraged rapid implementation.
Finally, a Notice of Intent to solicit public comment about the CLIAC recommendations has been prepared.

## What topics should be addressed by 

**What topics should be addressed by **
**a CLIA Genetics Specialty? **

**  ****Definition – What is included and excluded?**
**  ****General requirements**
**  ****-  Documentation of clinical validity**
**  ****-  Person authorized to order a genetic test**
**  ****-  Informed consent**
**  ****-  Confidentiality**
**  ****-  Genetic counseling **
**  ****Requirements for specific testing phases**
**  ****-  Pre-analytic phase**
**  ****-  Analytic phase**
**  ****-  Post-analytic phase**

## Goals of Oversight

**Achieve Balanced Rules:   Access = Burden/Protection**
**Achieve Timely Rules:   Need Broad Public Input**
**Achieve Long-lasting Rules**
**Achieve Effective Implementation of Oversight**

**Notes:**
1) What part of CDC deals with CLIA matters?
The Division of Laboratory Systems is the operational unit at CDC that handles CLIA-related activities.
Names that you will also hear mentioned are Dr. Satcher, Director of CDC and Dr. Baker, Director of the Public Health Practice Program Office.
2) The Director of the Division of Laboratory Systems is a pathologist, Dr. Carlyn Collins.
Within the Division, there are three branches
3) The LPSB is the branch that has the primary responsibility for most CLIA matters including development of regulations, test categorization, and the wavier process.  I am the Acting Branch Chief of LPSB.  Other key personnel include Ms. Rhonda Whalen and Ms. Rosemary Bakes-Martin.
4)  The LPTB develops training products and provides laboratory training opportunities through the National Laboratory Training Network. 
Dr. Katherine Kelley is the Branch Chief.
5)  The LPAB is responsible for conducting CLIA-related research.
Dr. Thomas Hearn is the Branch Chief.   

##                Notice of Intent

_**Issues receiving the most comments:**_

**1.**  **Definition and categories for genetic testing**

**2**. ** Documenting clinical validity**

**3.**  **Who should be authorized to order a genetic test**

**4.**  **Documentation of informed consent**

**5.**  **Laboratory providing consultation/ counseling**

**6.**  **Pre- and post- analytical phase requirements **

**7.**  **Personnel qualifications/ responsibilities**

**Notes:**
Definition and categories:
	Definition: 
	Several organizations (CAP, AMP, ACLPS, ACLA) believe it’s too broad;
	HLA testing professionals: should disease association testing be included?
	AABB: asks that parentage testing stays exempt;
	Orchid, Inc: asks pharmacogenetic testing be excluded;
	Abbott: distinguishing in-house tests from those performed with FDA-	approved devices.
	Subspecialties:
	Suggest creating 3 separate subspecialties: cyto-, molecular, biochemical.
	Molecular: somatic/acquired vs. germline
	Biochemical: how to distinguish genetic from others; need to include maternal serum screening.
2. Clinical validity:
	Outside lab’s purview, role of individual lab/lab director, criteria
3. Authorized persons: patient ordering, restrict predictive tests?
4. Informed consent: outside lab’s purview, types of tests, should lab assist
5. Counseling: role of lab in providing consultation to physicians, role in counseling patients.
6. Preanalytic: compliance and content of clin info, suggest follow-up tests? sample reuse.
7. Personnel: lab director, tech supervisor, clin consultant are controversial

## Genetic Testing: Specialty & Subspecialties

_**CLIAC Recommends **_
**Three separate subspecialties**
**	****-  molecular genetics **
**	****-  cytogenetics**
**	****-  biochemical genetics**
**Testing for acquired/somatic mutations should be included in each genetic testing subspecialty**** **
**  **

## Definition: Biochemical Genetic Testing

**The analysis of human proteins and certain metabolites, which is predominantly used to detect inborn errors of metabolism, heritable genotypes, or gene products of genetic variations or mutations for clinical purposes. **
**Such purposes would include predicting risk of disease, identifying carriers, and establishing prenatal or clinical diagnoses or prognoses in individuals, families, or populations. [Tests that are used primarily for other purposes, but may contribute to diagnosing a genetic disease (e.g. blood smear, certain serum chemistries), would not be covered by this definition.]**

**Notes:**
The additional phrase “gene products of genetic variations or mutations” will cover detection of somatic mutations and proteomics under this subspecialty.  The workgroup thinks that as technology progresses to gene product analysis, proteomics has to be addressed and major issues will be in the pre- and post-analytic phases. However, the workgroup is concerned about the regulatory process and recommends providing guidance rather than changing lab structure. 

## Definition: Cytogenetic Testing

**An analysis performed on human chromosomes to detect heritable or acquired disease-related genotypes, mutations, phenotypes, or karyotypes for clinical purposes. **

## Definition: Molecular Genetic Testing

**An analysis performed on human DNA or**** ****RNA to detect heritable or acquired disease-related genotypes, mutations, or**** ****phenotypes or karyotypes for clinical purposes.**

## Steps to Establish “Clinical Validity”

**Reason for introduction of a new test**
**Review available scientific studies (internal and external work)**
**Select methodology**
**Establish analytical validity**
**Use the test in an appropriate test population**
**The Laboratory Director must be able to interpret the test result and its implications for a given individual or family.  The limitations of the test must be defined and reported**
**NOTE: Director can delegate responsibility, but retains   ultimate responsibility for ensuring clinical validity**

- _Six steps recommended:_

**Notes:**
The group discussed how a lab should establish analytic validity (Step 4) and felt that a lab cannot do a clinical test until its analytic validity is established. When a test is being developed or validated IRB approval is needed for using archival clinical samples. The group also considered the SACGT test review algorithm in which clinical validity is a continuation of analytic validity. Therefore analytic validity cannot exist without clinical validity.  The group agreed that this is a generic issue and should apply to all clinical tests. 
Steps 5 and 6 are to facilitate and accommodate evolving knowledge of a test. When data are limited, establishing clinical validity relies much on literature. The lab need to communicate the limits of a test and clarify the state of art.  

## Person Authorized to Order a Genetic Test

**Current CLIA defers to state laws; there should not be a federal requirement superseding state regulations. **
**Self-referral is acceptable, providing the laboratory medical director(s) is (are) willing to accept ordering and informed consent requirements and the state law allows such ordering**
**Interstate referrals are dependent upon individual state requirements (NY, CA, FL, etc) **

- _CLIAC recommendations:_

## Informed Consent

**Premise:  Informed consent is required for all tests**
**The individual ordering testing must be able to obtain the appropriate level of informed consent**
**The level of informed consent is dependent on predictive or diagnostic use of test **
**Determination of level of IC may be derived from**** ****established professional standards (guidelines)**
**The requisition should include an area for attestation from the person ordering the test that the appropriate consent was obtained**

- _CLIAC recommendations:_

## Genetic Counseling

**Genetic counseling (GC) needs to be available as appropriate**
**The laboratory should facilitate access to genetic services, when appropriate **
**The laboratory should not be required to have a documented relationship with genetic counseling resources because the laboratory cannot direct patient care **
**4.  The laboratory should be required to recommend genetic counseling for family members, when indicated**

- _CLIAC recommendations:_

**Notes:**
It was clarified that providing consultation regarding a test being ordered and/or its results is part of the laboratory director and clinical consultant’s responsibilities.  
The group then considered the extent to which a lab should assist in providing genetic counseling, specifically whether the laboratory should be required to act as referral source to provide health care providers with resources to locate genetic professionals and specialists who can provide the appropriate genetic counseling and education. The group made recommendations as shown.

## Clinical Consultant Qualifications

**Be an M.D., D.O., and have two years experience in genetic testing; or hold a Ph.D. in a relevant discipline, be Board certified, and have two years experience in genetic testing; or hold an MS in Genetic Counseling, be Board certified, and have two years experience in genetic testing (prospective).**

- _CLIAC recommendations:_

**Notes:**
-         The workgroup recommended that clinical consultants have experience in the intended testing area in order to interpret the clinical relevance of a test. Appropriate board certification should be required but using the same model as for tech supervisor is recommended.  
-         Clinical consultants should not be required to assist clients in test ordering, but need to be available for such assistance. 
	The group debated whether board-certified genetic counselors should qualify as clinical consultants, and recommended that a lab can hire CGC but an individual with a doctoral degree should be the clinical consultant. In addition, the scope of CLIA regulations does not embody genetic counseling.          

## Test Requisition and Clinical Information

**              **_**Information required on requisitions:**_
***    ******Patient name***
**    ****Date of birth**
***    ******Time and date of collection***
**    ****Gender **
**    ****Race/ethnicity (if applicable)**** **
***    ******Unique identifier on specimen container***
***    ******Specimen type (blood, amniotic fluid, etc.) ***
***    *****Reason for the test; Relevant clinical and laboratory ****	****information**** **
**    ****Pedigree (where applicable, required for linkage analysis)**
**   ***** ******Referring health professional or authorized person***
***    ******Check-off box to indicate if appropriate level of informed ******	******consent has been obtained (when required by law or regulation) ***
***    ******Check-off box to indicate if patient has declined having his/her ******	******samples used anonymously for QA/QC purposes*****   **

## Re-use of Tested Specimens

**Use the informed consent process to establish prior approval for subsequent use of sample(s) for “genetic” testing QA/QC**
**-  if not approved, discard sample**
**-  if approved, use anonymously for QA/QC**
**-  if subsequently desired for research testing under IRB, then new consent needed**
**-  Panel and reflex testing needs to be clearly identified when originally ordered**

## Result Reporting

_**The test report should include:**_
**    *****Name of the individual***
***    ******Date of birth ***
***    ******Specimen collection time/date ***
***    ******Time/date of receipt in the laboratory ***
***    ******Specimen accession number or case number***
**    ****Race/ethnicity (where applicable) **
**    *****Indication for testing ***
**    ****Test performed, including mutation(s) tested (may    ****	****be listed individually, or referenced to an easily ****	****obtainable reference) **
**    *****Test result***
***Predictive values (PV):  When applicable. Test limitations should always be reported***
**	****	****	****	****	****	****	****(Cont.)**** **

**Notes:**
The workgroup recommended that it is not necessary to list all mutations tested but it is necessary to list the test panel and references. This would allow lab flexibility in providing test results specific enough for physicians to understand. However, the group noted that interstate referrals may have problems if not all mutations are listed. In addition, problems may come from common kits and reagents.  

## Result Reporting

**A statement interpreting the test result that includes (as indicated), clinical implications, follow-up test recommendations, and/or genetic counseling indications **
***Documentation if a preliminary report has been       issued ***
***Notation of any deviations from the laboratory’s standard practice (when applicable)***** **
**Signature of the Laboratory Director *****and***** *****other authorized individual ***
**A means to contact the Laboratory Director, or appropriate designee **
***Date of report***

**Result Reporting**

**Notes:**
The phrase “documentation if a preliminary report has been issued” was recommended and accepted by the workgroup during the general discussion session.  The underlined “and” indicates the requirement for tech supervisor’s signature. The workgroup assumes that all genetic tests for now will be high complexity and tech supervisor is always needed. 
The workgroup noted that the paradigm of test categorization under CLIA, i.e., waived, moderate and high complexity, may no longer be the preferred model. For genetic tests, in addition to the analytic phase of testing, the pre- and post-analytic phases need to be considered.  The group agreed that recommendations on the waiver process are needed from professional groups. 

## Retention of Specimens

**Need to determine how long a specimen should be retained when an individual refuses to allow a sample to be used for QA/QC**
**Two options were outlined:**
**	****1.   Set a time limit (specifics to be defined)**
**	****2.   Set a policy making the Laboratory Director ****	****responsible for choosing a timeframe (to be defined ****	****in consensus document(s) developed by one or ****	****more professional and/or private groups**
**This requirement also applies to both heritable and acquired genetic disorders **

**Retention of Specimens**

**Notes:**
During discussion several issues regarding sample retention were raised for further consideration: 
1) Sample stability differs among different types. Some analytes degrade rapidly while others are relatively stable.
2) The timeframe for “opt-out” samples need to be defined.
3) Overriding conditions for record and sample retention need to be defined.
4) Lab director cannot set the timeframe on his/her own.

## Retention of Records

**It was agreed that the retention time will have to be a compromise between optimum retention and clinical practicality.  The time frame recommended as a compromise was a minimum of 10 years **
**Both positive and negative results need to be retained**
**This requirement applies to testing for both heritable and acquired genetic disorders **

**Notes:**
During discussion, several group members pointed out that the optimal timeframe for record retention may be disease-dependent. For example, records for cancer cases may require a minimum of 5 years, whereas those for newborn screening may need to be retained until the individual reaches majority. The the group then accepted the term “as legally defined”.

## Issues Requiring Further Discussion 

**Mechanism for distinguishing genetic tests**
**Criteria for clinical validity**
**Level of informed consent:  Intended use level? **
**Practicality of "opt-out”**
**Sample retention: Timeframe and format **

**Issues Requiring Further Discussion **

## Future Needs

- Private/public collaboration on guidance for genetic tests and testing
- Awareness of global lessons learned
- Innovative methods for delivery of educational materials
- “State-of-the-Art” production of materials containing known genetic mutations