Questions and Answers
Good Laboratory Practices for Molecular Genetic Testing for Heritable Diseases and Conditions -
MMWR R&R Vol. 58 / No. RR–6, June 12, 2009
Section 1: General questions and answers
Section 2: Information for laboratories
Section 3: Information for healthcare providers
Section 4: Information for patients and consumers
SECTION 1: GENERAL QUESTIONS AND ANSWERS
What is the purpose of providing the good laboratory practice (GLP) recommendations in the MMWR Recommendations and Reports document?
The MMWR report provides recommendations for good laboratory practices for ensuring the quality of molecular genetic testing for heritable diseases and conditions. These recommendations are intended for laboratories that perform molecular genetic testing for heritable diseases and conditions and for medical and public health professionals who evaluate laboratory practices and policies to improve the quality of molecular genetic laboratory services. This report also is intended to be a resource for users of laboratory services to aid in their use of molecular genetic testing and test results in health assessment and care. (Note: refer to MMWR PDF page 1, summary paragraph)
Who provided the recommendations included in the MMWR document?
The recommendations were developed by the Clinical Laboratory Improvement Advisory Committee (CLIAC). In formulating the recommendations, CLIAC considered the input from the CLIAC Genetic Testing Good Laboratory Practices Workgroup, which was composed of experts in genetic testing and clinical laboratory practices. (Note: refer to MMWR PDF page 1, summary paragraph; page 6, right column, Methods, Development of CLIAC Recommendations for Good Laboratory Practices in Molecular Genetic Testing)
Were professional guidelines considered in developing the recommendations?
In developing input for consideration by CLIAC, the CLIAC Genetic Testing Good Laboratory Practices Workgroup evaluated professional guidelines, regulatory and voluntary standards, accreditation checklists, international standards and guidelines, and other documents providing general or specific quality standards applicable to molecular genetic testing for heritable diseases or conditions. The workgroup report was presented to CLIAC at its September 2008 meeting. The CLIAC recommendations were formed on the basis of the workgroup report. (Note: refer to MMWR PDF page 2, left column, 2nd paragraph; page 6, right column, Methods, Information Collection and Assessment)
For which audience is the MMWR document intended?
To improve the quality and utilization of genetic laboratory services, the MMWR document is intended to be used by the following:
- Laboratories performing molecular genetic testing for heritable diseases and conditions;
- Users of the laboratory services, including (but not limited to) healthcare professionals, patients, referring or referral laboratories, and payers of laboratory services; and
- Medical and public health professionals who evaluate laboratory practices and policies. (Note: refer to MMWR PDF page 1, summary paragraph)
What issues are addressed in the MMWR document?
The MMWR document highlights areas of molecular genetic testing that have been recognized by CLIAC as needing specific guidelines for compliance with existing Clinical Laboratory Improvement Amendments of 1988 (CLIA) requirements or needing quality assurance measures in addition to CLIA requirements, and provides recommendations for good laboratory practices to ensure the quality of molecular genetic testing for heritable diseases and conditions. The recommended good laboratory practices address the total testing process, including the preanalytic phase (providing information to users of laboratory services, informed consent, test request, specimen submission and handling, test referral, and preanalytic systems assessment), the analytic phase (establishment and verification of performance specifications, quality control procedures, proficiency testing, and alternative performance assessment), and the postanalytic phase (test report, retention of records and reports, and specimen retention) of molecular genetic testing. The recommendations also address the laboratory’s responsibility regarding persons authorized to order and receive test results, confidentiality of patient information and test results, personnel competency, issues to consider before introducing molecular genetic testing or offering new molecular genetic tests, and the potential benefits of the quality management system approach in molecular genetic testing. (Note: refer to MMWR PDF page 1, summary paragraph; page 2, right column, mid-page; page 7, left column, Recommended Good Laboratory Practices)
How would this document improve the quality of genetic testing?
Implementation of these recommendations in laboratories performing molecular genetic testing for heritable diseases and conditions and an understanding of these recommendations by users of laboratory services are expected to improve the quality and utilization of molecular genetic laboratory services, leading to better health outcomes for patients, and in many instances, better health outcomes for families of patients. (Note: refer to MMWR PDF page 2, right column, lower section)
Will the recommendations change the current practices in laboratories performing molecular genetic testing?
Molecular genetic testing has been a growing area of laboratory testing, and the recommendations in the MMWR document are intended to address many of the laboratory practice issues that have been recognized as the development and clinical use of molecular genetic tests continue to expand. Overall, we expect that there will be a positive impact on laboratories that perform clinical genetic testing and that the positive impact will increase over time.
How will this document help to enhance the oversight for genetic testing?
The oversight responsibilities for genetic testing are shared by multiple entities, including federal and state government agencies, healthcare payers, and professional associations, which contribute to the oversight framework through a combination of functions such as standard-setting and compliance mechanisms. The MMWR document provides good laboratory practice guidelines for areas of molecular genetic testing that need specific guidance for meeting the CLIA requirements or need quality assurance measures in addition to the CLIA requirements. The recommendations are intended for a broad user audience, including laboratories performing molecular genetic testing for heritable diseases and conditions to improve the quality of their testing, users of laboratory services to improve understanding of good laboratory practices, and medical and public health professionals, such as laboratory surveyors and inspectors, to evaluate laboratory practices and policies. Therefore, we expect this document will help to enhance the oversight for genetic testing under the current regulatory framework. (Note: refer to MMWR PDF page 3, CLIA Oversight for Molecular Genetic Testing)
What role will CDC take in implementing these recommendations?
We plan to take the following steps to help with the application of the recommendations:
- Promote awareness. CDC will work with stakeholders, including other federal agencies, professional organizations, standard-setting organizations, CLIAC, and other advisory committees, to disseminate the report and relevant educational materials to the intended users.
- Work with CMS to provide the report and necessary training to surveyors.
- Develop informational and educational materials for specific user groups.
- Monitor the responses from the community in order to evaluate the effectiveness and utility of the recommendations and the need for update.
How will CDC help healthcare professionals and other users of laboratory services use the recommendations? Will a resource for addressing specific questions regarding the application of these guidelines be available?
Yes. CDC plans to develop informational and educational materials, such as fact sheets and Q & A’s for specific user groups, including laboratories, healthcare providers, patients, and general public.
SECTION 2: INFORMATION FOR LABORATORIES
Are the guidelines in the MMWR document regulatory requirements?
In some cases, the CLIA requirements are stated within the text of the MMWR and are indicated as CLIA requirements. However, additional recommendations in the MMWR report are voluntary guidelines. (Note: refer to MMWR PDF page 2, left column; page 7, left column, Recommended Good Laboratory Practices)
How are these good laboratory practice guidelines related to the CLIA regulations?
The recommendations provide good laboratory practice guidelines to enhance the oversight for genetic testing under the CLIA framework by addressing the following needs in molecular genetic testing:
- Providing clarification for areas that need specific guidance for meeting the CLIA requirements; and
- Providing guidance for areas that need quality assurance measures in addition to the CLIA requirements. (Note: refer to MMWR PDF page 2, left column; page 3, CLIA Oversight for Molecular Genetic Testing; page 7, left column, Recommended Good Laboratory Practices)
What recommendations are provided regarding the laboratory’s responsibility for improving the appropriateness of test selection and ordering?
The MMWR report emphasizes the responsibilities of laboratories for providing information regarding the molecular genetic tests they perform to users of their services, which may include (but are not limited to) persons authorized to order and receive test results under applicable state law, healthcare professionals, patients, referring or referral laboratories, and payers of laboratory services. Each laboratory performing molecular genetic testing should provide the following information to its users to facilitate appropriate test selection and request, specimen handling and submission, and patient care management:
- Information necessary for selecting appropriate testing, to include:
- A list of the molecular genetic tests the laboratory performs.
- For each molecular genetic test, the following information:
- Intended use, to include the nucleic acid target (for example: genes, sequences, mutations, or polymorphisms the test intends to analyze), the purpose of testing and appropriate use of the test, and the recommended patient population(s);
- Indications for testing;
- Test method to be used, which should be presented in user-friendly language in relation to the performance specifications and the limitations of the test;
- Current Procedural Terminology (CPT) codes may be included when appropriate;
- Specifications of applicable performance characteristics, to include information on both analytic validity and clinical validity of the test; and
- Whether testing is performed with a test system cleared or approved by FDA, with a laboratory-developed test or test system, or with an investigational test under the FDA’s oversight. A disclaimer may be necessary if there has not been FDA review or oversight.
- Information on appropriate collection, handling, transport, and submission of specimens.
- Patient information necessary for performing the testing and interpreting test results. The patient information may include relevant clinical or laboratory information, and when applicable, the patient’s racial or ethnic information, family history, pedigree, and patient consent information in compliance with federal, state, and local requirements.
- A statement indicating that test results may have implications for the patient’s relatives or family members.
- Availability of consultation from the laboratory regarding test selection and ordering, specimen submission, result interpretation, and the implications of test results.
- When possible and practical, laboratories should provide users with information on the charges for molecular genetic tests being performed. Estimating the expenses that a patient may incur with a particular genetic test or third party payer may not be readily available to some laboratories and providers because fee schedules of individual laboratories can vary depending on the health-care payment policy selections of each patient. However, advising the patient and family members of the financial implications of the tests, whenever possible, will help facilitate informed decision-making. (Note: refer to MMWR PDF page 7, right column, The Preanalytic Testing Phase, Test Information to Provide to Users of Laboratory Services)
Why should laboratories performing genetic testing provide this much information to users of their services? They are already required to provide instructions for specimen submission.
Under CLIA, laboratories are required to develop and follow written policies and procedures for specimen submission and handling, specimen referral, and test requests (42 CFR §§493.1241 and 1242). Laboratories must ensure positive identification and optimum integrity of specimens from the time of collection or receipt through the completion of testing and reporting of test results (42 CFR §493.1232). In addition, laboratories that perform nonwaived testing must ensure that a qualified clinical consultant is available to assist laboratory clients with ordering tests appropriate for meeting clinical expectations (42 CFR §493.1457[b]). The recommended laboratory practices in this report describe laboratory responsibilities for ensuring appropriate test requests and specimen submission for the molecular genetic tests they perform, in addition to laboratory responsibilities for meeting the CLIA requirements. The recommendations emphasize the role of laboratories to provide specific information to users who must make decisions regarding test selection and ordering, based on consideration of several factors.
- First, molecular genetic tests for heritable diseases and conditions are increasingly used in health-care settings. Users of laboratory services need the ability to easily access information regarding the intended use, performance specifications, and limitations of the molecular genetic tests from a laboratory in order to determine appropriate testing for specific patient conditions.
- Second, many molecular genetic tests are performed using laboratory-developed tests or test systems. The performance specifications and limitations of the testing may vary among laboratories, even for the same disease or condition, depending on the specific procedures used. Users of laboratory services who are not provided information related to the appropriateness of the tests being considered might select tests that are not indicated or cannot meet clinical expectations.
- Third, for many heritable diseases and conditions, test performance and interpretation of test results require information regarding patient race/ethnicity, family history, and other pertinent clinical and laboratory information. Informing users, before tests are ordered, of the specific patient information required by the laboratory should facilitate test requests and allow prompt initiation of appropriate testing procedures and accurate interpretation of test results.
- Finally, providing information to users about performance specifications and limitations of tests before test selection and ordering prepares users of laboratory services for understanding test results and implications. The CLIA test report requirements (42 CFR §493.1291[e]) indicate that laboratories are required to provide users of their services, upon request, with information about laboratory test methods and the performance specifications the laboratory has established or verified for the tests. However, for molecular genetic tests for heritable diseases and conditions, laboratories should provide test performance information to users before test selection and ordering, rather than waiting for a request after the test has been performed. The information provided in the preanalytic phase must be consistent with information included within the test reports.
Providing molecular genetic testing information to users before tests are selected and ordered should improve test requests and specimen submission and might reduce unnecessary or unwarranted testing. The recommended practices also might increase informed decision-making, improve interpretation of results, and improve patient outcome. (Note: refer to MMWR PDF pages 8-9)
What recommendations are provided regarding the laboratory’s role regarding informed consent for genetic tests?
Informed consent for genetic testing or specific types of genetic tests is required by law in certain states. Professional organizations recommend that informed consent be obtained for testing of many inherited genetic conditions. The CLIA regulations have no requirements for laboratory documentation of informed consent for requested tests. Regardless of whether informed consent is required, laboratories that perform molecular genetic tests for heritable diseases and conditions should be responsible for providing users with the information necessary to make informed decisions.
Informed consent is in the purview of the practice of medicine; the persons authorized to order the tests are responsible for obtaining the appropriate level of informed consent. Unless mandated by state or local requirements, obtaining informed consent before performing a test generally is not considered a laboratory responsibility. For molecular genetic testing for heritable diseases and conditions, not all tests require written patient consent before testing. However, when informed consent for patient testing is recommended or required by law or other applicable requirements as a method for documenting the process and outcome of informed decision-making, laboratories should ensure that certain practices are followed:
- Be available to assist users of laboratory services with determining the appropriate level of informed consent by providing useful and necessary information; and
- Include appropriate methods for documenting informed consent on test request forms, and determine whether the consent information is provided with the test request before initiating testing. Laboratories may determine situations in which a patient specimen can be stabilized until informed consent is obtained, following the practices for specimen retention recommended in these guidelines.
Laboratories should refer to professional guidelines for additional information regarding informed consent for molecular genetic tests and should consider available models when developing the content, format, and procedures for documentation of patient consent. (Note: refer to MMWR PDF page 9, left column, Informed Consent)
What recommendations are provided for establishment of test performance specifications?
When establishing performance specifications for molecular genetic tests, laboratories should consider the intended use, target gene(s), sequence(s), mutation(s), testing purpose, targeted patient population, methodology, and samples to be included. The MMWR recommendations include the following general principles for establishing performance specifications of each new molecular genetic test:
- Ensure a review is conducted of available scientific studies and pertinent references;
- Select appropriate test methodology for the disease or condition being evaluated;
- Establish analytic performance specifications and determine quality control procedures using appropriate number, type, and variety of samples;
- Define appropriate patient populations for which the test should be performed; and
- Ensure test results and their implications can be interpreted for a given individual or family, and the limitations of the test are defined and reported.
The MMWR report provides recommendations for samples to be used for establishment of performance specifications. The number, type, and variety of samples needed for establishing performance specifications should be adequate and as comprehensive as possible to ensure that test results can be interpreted for specific patient conditions and the limitations of the testing and test results are known. Samples used should reflect the following considerations:
- Determine appropriate samples based on the prevalence of the disease being evaluated and the prevalence of the mutation(s) or variant(s) to be detected. This consideration is not meant for laboratories to set a lower standard for rare diseases or rare mutations, but to ensure samples to be used are adequate and appropriate for establishing the test’s performance specifications and defining the limitations;
- Include an adequate number of samples representative of each type of patient specimen expected for the assay (for example, blood, buccal swabs, dried blood spots, fresh/frozen tissue, paraffin-embedded tissue, prenatal specimens, and other sample types);
- Include samples that represent each of the possible reportable results (or genotypes). For a multiplex genetic test or a test detecting multiple nucleic acid targets using targeted detection methods, it is good practice to include all the mutations or variants to be detected when establishing the test performance characteristics. For rare diseases that are not associated with common mutations, or for rare mutations or variants for which naturally occurring samples containing the target genotype(s) are difficult to obtain, alternative control samples or alternative control procedures may be expected and these control samples or procedures should also be included in the establishment of performance specifications;
- Verify control materials, calibration materials, and other reference materials required for the test procedures are specified and available. (Note: refer to MMWR PDF page 11, The Analytic Testing Phase, Establishment and Verification of Performance Specifications)
What specific quality control (QC) practices are recommended?
Laboratories per-forming molecular genetic testing must meet the applicable general CLIA requirements for control procedures at 42 CFR §493.1256. The MMWR guideline recommends the following specific QC practices for monitoring and ensuring the quality of the molecular genetic testing process:
- Perform control procedures each time patient specimens are tested.
- Include QC samples that are similar to patient specimens.
- Include an extraction control for any test that has a nucleic acid extraction step.
- Validate and monitor sampling instruments to ensure no carryover contamination occurs between sample testing.
- Ensure that the type and variety of the control materials included in tests are as comprehensive as possible, representing the genotypes expected for the patient population according to the prevalence of the disease and frequency of the mutations or variants. (Note: Refer to MMWR PDF page 14, Control Procedures)
My laboratory performs a number of molecular genetic testing for rare diseases. What QC practices are recommended when control samples for some of the rare mutations are not available?
If control materials are not available, the laboratory must meet the CLIA alternative control procedure requirements at 42 CFR §493.1256(h) to detect immediate errors and monitor test system performance over time. The following are examples of accepted alternative control procedures:
- Inclusion of a normal control is important for sequencing procedures. A normal control could be a tested, well-characterized patient sample that contains the reference sequence or a sample that contains subcloned reference sequence.
- A positive control capable of monitoring the ability of a test system to detect the nucleic acid targets should be tested periodically and carried through the extraction step to monitor and verify the performance of the test system.
- If a positive control is not available for each variant or mutation:
- include direct sequencing or testing of the patient sample by a reference laboratory to confirm the finding before reporting the test result, or
- include bidirectional sequencing using a separately extracted nucleic acid sample.
- If the inclusion of positive controls for each variant or mutation is impractical in testing that detects multiple mutations, rotate positive controls within a time frame that is reasonable and effective.
- If a commercial test system provides some but not all of the controls needed for testing, determine the additional control procedures (including the number and types of control materials and the frequency of testing them) necessary for monitoring and ensuring the quality of test performance.
- If purified DNA is used as a control in a method or procedure which contains an extraction step, have an alternative mechanism capable of monitoring DNA extraction and the preceding analytic steps. (Note: Refer to MMWR PDF page 15, Alternative control procedures)
CLIA requires a unidirectional workflow for amplification procedures that are not contained in closed systems. What is considered a "closed system"?
A closed system is a test system designed to be fully integrated and automated to purify, concentrate, amplify, detect, and identify targeted nucleic acid sequences. A closed system generates test results directly from unprocessed samples without manipulation or handling by the user, and does not pose a risk for cross-contamination because amplicon-containing tubes and compartments remain completely closed during and after the testing process. (Note: Refer to MMWR PDF page 16, Unidirectional workflow for molecular amplification procedures)
What specific recommendations are made regarding unidirectional workflow in molecular genetic testing?
CLIA requires laboratories to have procedures in place to monitor and minimize contamination during the testing process and to ensure a unidirectional workflow for amplification procedures that are not contained in closed systems (42 CFR §493.1101). The MMWR guideline provides the following specific recommendations for molecular genetic tests using amplification procedures that are not in a closed system:
- Control samples should be regularly tested to monitor cross-contamination
- Include at least one no-template control (NTC) sample in the entire testing procedure, if possible, each time patient specimens are assayed.
- If multiple units (e.g., multiple 96-well plates) are used in a run of patient specimen testing, an NTC sample should be included in each unit of the test run if the test system allows it.
- Ensure that specific procedures are in place to prevent cross-contamination for tests using successive amplification procedures (e.g., nested PCR). Additives that destroy amplicons from previous PCR reactions may be used.
- There should be a separate workflow for the processing and storage of control materials from patient testing processing and storage. (Note: Refer to MMWR PDF page 16, Unidirectional workflow for molecular amplification procedures)
What recommendations are provided for proficiency testing (PT)?
PT is a key component of a laboratory’s quality system and an important tool for assessing laboratory competence, evaluating the laboratory’s testing process, and providing education for the laboratory personnel. Currently, the CLIA regulations do not have PT requirements specific to molecular genetic testing. Laboratories performing genetic testing must comply with the general requirements at 42 CFR §493.1236(c), of at least twice annually verifying the accuracy of any genetic test or procedure they perform. Laboratories can meet this requirement by participating in a PT program for the genetic tests they perform. The MMWR report recommends more specific and stringent measures than the current CLIA requirements for performance assessment applicable to molecular genetic testing. Laboratories performing molecular genetic testing should consider the following practices to monitor and evaluate the ongoing quality of the testing they perform:
- Participate in PT, at a minimum twice per year, for each molecular genetic test the laboratory performs. Currently PT is available only for a limited number of molecular genetic tests, such as testing for fragile X syndrome, factor V Leiden, cystic fibrosis, and other common genetic conditions. These available PT programs are important external mechanisms for evaluating laboratory performance of molecular genetic testing. Laboratories performing molecular genetic testing should regularly review information on the development of additional PT programs and ensure participation as new programs become available.
- Test analyte- or disease-specific PT challenges with the laboratory’s regular patient testing workload by personnel who routinely perform the testing in the laboratory, as required by CLIA for testing of PT samples.
- Evaluate PT results reported by the PT program and perform investigative and corrective actions for disparate results. The corrective actions to be taken after disparate PT results should include re-evaluation of previous patient test results and, if necessary, retesting of patient specimens.
The MMWR report also recommends PT samples resemble patient specimens whenever possible. For the most common genetic tests, “real” samples or samples mimicking patient specimens should be used for PT challenges. Currently, many PT challenges are provided using purified DNA samples, thus not requiring participants to perform the pre-analytic steps of the testing process. Such practical limitations should be recognized in assessing test performance. Laboratories are encouraged to enroll in PT programs that examine the entire testing process, encompassing the preanalytic, analytic, and postanalytic phases of testing.
The MMWR report provides a list of resources for proficiency testing, external quality assessment, and for facilitating interlaboratory sample exchanges (Appendix C) to assist laboratories in meeting the proficiency testing and alternative performance assessment needs of their molecular genetic testing. (Note: refer to MMWR PDF page 17-18, Proficiency Testing and Alternative Performance Assessment; page 35, Appendix C)
What if there is no available PT program for the molecular genetic tests that my laboratory performs? What recommendations are provided for alternative performance assessment?
For molecular genetic tests for which no PT program is available, alternative performance assessment needs to be performed at least twice per year to meet the applicable requirements of CLIA, state programs, and accrediting agencies. The following recommendations should be considered in conducting alternative performance assessment:
- While data are currently unavailable on whether alternative performance assessments are as robust or effective as PT, professional guidelines, such as those developed by Clinical and Laboratory Standards Institute (CLSI), provide guidance on what would be considered acceptable alternative performance assessment approaches. Laboratories performing molecular genetic testing for which no PT program is available should adhere to these guidelines.
- For alternative assessments, laboratories need to ensure that the challenges reflect the technology involved in performing the testing, and the number of samples in each event is adequate for verifying the accuracy and reliability of test results.
- Alternative assessments may be performed by interlaboratory exchange or using externally derived materials, since external quality assessment may be able to detect errors or problems that internal assessment cannot.
- In circumstances in which interlaboratory exchange or externally derived materials are not practical or feasible, such as testing for rare diseases, testing performed by only one laboratory, patented testing, or unstable analytes (for example, RNA or enzymes), laboratories may consider options such as repeat testing of blinded samples, blind testing of materials with known values, exchange with either a research facility or a laboratory in another country, splitting samples for analysis with another instrument or method, or interlaboratory data comparison. (Note: refer to MMWR PDF pages 17-18, Proficiency Testing and Alternative Performance Assessment; page 35, Appendix C)
What recommendations are provided on retention of test reports?
Reports of molecular genetic tests for heritable diseases and conditions should be retained for at least 25 years after the date the results are reported. Laboratories may consider retaining test reports electronically, on microfilms, or by other methods but must ensure that all of the information on the original reports is retained and that copies (whether electronic or hard copies) of the original reports can be retrieved. The laboratory policies and procedures for test report retention must comply with applicable state laws and other requirements (e.g., of accrediting organizations if the laboratory is accredited) and should follow practice guidelines developed by recognized professional or standard-setting organizations. If state regulations require retention of genetic test reports for more than 25 years after the date of results reporting, laboratories must comply. Retention of molecular genetic test reports for heritable diseases and conditions longer than 25 years may be necessary to accommodate patient testing needs, to assist with providing health care for family members, and for ongoing quality assessment activities. (Note: refer to MMWR PDF pages 19 - 20, Retention of Reports, Records, and Tested Specimens)
Why should test reports for molecular genetic testing for heritable diseases and conditions be retained for at least 25 years?
Retaining molecular genetic test reports for an extended time frame is recommended because the results can have long-term, often lifetime, implications for patients and their families. Future generations may need this information to make health-related decisions. In addition, advances in testing technology and increased knowledge of disease processes could change the interpretation of the original test results, enable improved interpretation of test results, or permit future retesting with greater sensitivity and accuracy. Laboratories need the ability to retrieve previous test reports, which are valuable resources for conducting quality assessment activities, helping patients and family members make health decisions, and managing the health care of the patient and family members. As laboratories that perform molecular genetic testing for heritable diseases and conditions review and update policies and procedures for report retention, they should consider the financial ramifications of the policies, as well as technology and laboratory facility concerns. (Note: refer to MMWR PDF page 19, right column, Reports)
What recommendations are provided regarding retention of tested specimens?
The CLIA regulations require laboratories to establish and follow written policies and procedures that ensure positive identification and optimum integrity of patient specimens from the time of collection or receipt in the laboratory through completion of testing and reporting of test results (42 CFR §493.1232 Standard: Specimen identification and integrity). Depending on sample stability, technology, space, and cost, tested specimens should be retained as long as possible after the completion of testing and reporting of results. Stable specimens, such as extracted DNA samples or representative cDNA samples, should be retained until the next PT event or the next alternative performance assessment, to allow for identification of problems in patient testing and for corrective actions to be taken. Tested specimens may also be needed for testing of additional or future family members, and for more definitive diagnosis as technology and knowledge evolve. The laboratory’s specimen retention policy should consider the following factors:
- The type of specimens to be retained (for example: whole blood or DNA samples);
- The analyte(s) tested (for example: DNA, RNA, or both);
- Test results or the genotypes detected;
- Test volume; and
- New technologies that may not produce residual specimens.
The laboratory director is responsible for ensuring the laboratory’s policies and procedures for specimen retention are in compliance with applicable federal, state, and local requirements (including requirements for laboratory accreditation) and are consistent with the laboratory’s quality assurance and quality assessment activities. In circumstances where patient consent is required for testing but is not provided with the test requisition, the laboratory should determine the need to notify the test requestor regarding the informed consent requirement and the timeframe after which the test request may be rejected and the specimen discarded due to specimen degradation or deterioration. Laboratories should ensure that their specimen retention procedures are consistent with patient decisions, when applicable. (Note: refer to MMWR PDF page 20, left column, Tested Specimens)
How should we follow the recommended personnel qualifications? Currently we do not have a technical supervisor in our laboratory who meets the recommended qualifications in the MMWR report. Hiring someone to meet those qualifications would be costly and could circumvent our current technical supervisor.
The recommended technical supervisor qualifications are based on the complexity of molecular genetic testing for heritable diseases and conditions and the training, experience, and expertise needed to provide technical supervision for laboratories that perform these tests. Certain laboratories that perform molecular genetic testing for heritable diseases and conditions may have technical supervisors who meet the applicable CLIA qualification requirements for high-complexity testing, but do not meet the recommended qualifications in this section of the MMWR. These recommended qualifications are not regulatory requirements and are not intended to restrict access to certain molecular genetic tests; rather, they should be considered part of recommended laboratory practices for ensuring the quality of molecular genetic testing for heritable diseases and conditions. However, because the CLIA qualification requirements are intended to be minimum standards, laboratories should assess the tests they perform to determine whether additional qualifications are needed for their technical supervisors to ensure quality throughout the testing process. (Note: refer to MMWR PDF page 21, Personnel Qualification, Responsibilities, and Competency Assessments; p22, left column, Technical Supervisor Qualifications and Responsibilities)
Which recommendations will assist a laboratory that is considering adding new genetic tests to its services?
All recommended good laboratory practices provided in this document should be considered in the planning and preparation for introducing molecular genetic testing or offering new molecular genetic tests, together with appropriate professional guidelines and recommendations. The following scenarios should be considered in this planning stage:
- Introducing a new molecular genetic test that has not been offered in any laboratory;
- Introducing a genetic test to be performed in-house that has previously been referred to another laboratory; and
- Introducing an additional genetic test that can complement a molecular genetic test already being used for patient testing.
These scenarios present different planning issues, including the needs and requirements for training and competency of laboratory personnel, laboratory facilities and equipment, selection of test methodology, development of procedure manuals, establishment or verification of performance specifications, and personnel responsibilities. In addition, the following issues should be considered:
- The needs and demands for the procedure should be assessed in considering introduction of a new test. This may be accomplished by consulting with ordering physicians and other potential users of laboratory services, and by conducting market analyses;
- Certain genetic tests may be subject to restricted use due to intellectual property issues. Laboratories should conduct an analysis of the intellectual property and licensing issues associated with the test they intend to introduce, and make decisions accordingly. (Note: refer to MMWR PDF page 25, Considerations Before Introducing Molecular Genetic Testing or Offering New Molecular Genetic Tests)
SECTION 3: INFORMATION FOR HEALTHCARE PROVIDERS
What information in this MMWR document is relevant to me?
All the recommended good laboratory practices are intended to ensure the quality of molecular genetic laboratory services, which ultimately impacts the quality of test information and test results to be used in patient care and health management. This report is intended to not only provide guidelines for ensuring quality test performance, but also as a resource for health professionals in their use of molecular genetic test results for health assessment and care.
The MMWR report serves to inform healthcare professionals about the responsibilities and practices to be expected of laboratories in providing molecular genetic testing services. Issues directly relevant to healthcare professionals include the following:
- The laboratory’s responsibility for providing information necessary for test selection, test request, and specimen submission;
- The laboratory’s responsibility for documenting informed consent for the test being requested, when required by state and local requirements;
- Information that the laboratory needs to solicit on test request forms (requisitions);
- Information that the laboratory needs to provide regarding specimen submission, handling, and referral;
- Information that the laboratory needs to provide on test reports;
- The recommended retention timeframe for test reports and specimens in order to facilitate follow-up testing, testing of family members, and the possibility of retesting;
- The laboratory’s responsibility regarding persons authorized to order and receive test results; and
- The laboratory’s policies for ensuring confidentiality of patient information. (Note: refer to MMWR PDF page 9, Informed Consent; page 9, Test Requests; page 10, Specimen Submission, Handling, and Referral; page 18, Molecular Genetic Test Reports; page 19, Retention of Reports, Records, and Tested Specimens; page 21, Ensuring Confidentiality of Patient Information)
I have a patient with a familial cancer condition and I am considering requesting a mutation analysis, but I have not previously submitted a clinical specimen to this laboratory. What information should I expect the laboratory to provide to help me with specimen submission?
The laboratory or laboratory director should provide the following information to you to facilitate in selecting the appropriate test, completing the test requisition form, and submitting the specimen:
- Information necessary for selecting appropriate testing, to include:
- A list of the molecular genetic tests the laboratory performs;
- For each molecular genetic test, the following information:
- Intended use, to include the nucleic acid target (for example, genes, sequences, mutations, or polymorphisms the test intends to analyze), the purpose of testing and appropriate use of the test, and the recommended patient population(s);
- Indications for testing;
- Test methodology to be used, which should be presented in user-friendly language in relation to the performance specifications and the limitations of the test;
- Current Procedural Terminology (CPT) codes may be included when appropriate;
- Specifications of applicable performance characteristics, to include information on both analytic validity and clinical validity of the test;
- Limitations of the test; and
- Whether testing is performed with a test system cleared or approved by FDA, with a laboratory-developed test or test system, or with an investigational test under the FDA’s oversight;
- Information on appropriate collection, handling, transport, and submission of specimens;
- Patient information necessary for performing the testing and interpreting test results. The patient information may include relevant clinical or laboratory information, and when applicable, the patient’s racial or ethnic information, family history, pedigree, and patient consent information in compliance with federal, state, and local requirements;
- A statement indicating that test results may have implications for the patient’s relatives or family members; and
- Availability of consultation from the laboratory regarding test selection and ordering, specimen submission, result interpretation, and the implications of test results.
When possible and practical, laboratories should provide users with information on the charges for molecular genetic tests being performed. Estimating the expenses that a patient might incur from a particular genetic test might be difficult for certain laboratories and healthcare providers because fee schedules of individual laboratories can vary depending on the health-care payment policy selections of each patient. However, advising the patient and family members of the financial implications of the tests, whenever possible, facilitates informed decision-making. (Note: refer to MMWR PDF page 7, Test Information to Provide to Users of Laboratory Services)
What guidelines are provided regarding the laboratory’s role in providing consultative services for the molecular genetic tests they perform?
The CLIA regulations require clinical consultants for high complexity tests to be responsible for providing consultation to laboratory clients regarding the appropriateness of the testing ordered and the interpretation of test results (42 CFR §493.1457). Persons providing clinical consultation for molecular genetic testing must meet the following CLIA requirements:
- Be available to provide consultation to laboratory clients, which includes assisting clients with ordering appropriate tests to meet clinical expectations and discussing the quality of test results and interpretation of result; and
- Ensure that test reports include pertinent information required for interpretation of specific patient conditions.
The MMWR report recommends laboratories performing molecular genetic testing for heritable diseases and conditions to:
- Inform users of their services regarding the availability of consultation from the laboratory, regarding test selection and ordering, specimen submission, result interpretation, and the implications of test results; and
- When appropriate, include in the test report a recommendation for genetic consultation. A genetic consultation may encompass genetic services provided by trained, qualified genetics professionals (e.g., genetic counselors, clinical geneticists, or other qualified professionals) for healthcare providers, patients, or family members at risk for the condition. (Note: refer to MMWR PDF page 7, Test Selection, Test Performance, and Specimen Submission; pages 18-19, Molecular Genetic Test Reports; page 23, Clinical Consultant Qualifications and Responsibilities)
I am caring for a patient who shared with me that her sister “just tested positive for a BRCA1 mutation”. May I contact the laboratory that did the testing for my patient’s sister to get the test results in order to help with care management for my patient?
When a healthcare provider requests the genetic test information of a patient to assist with providing care for a family member, the following practices are recommended:
- Requests should be handled following established laboratory procedures regarding release and transfer of confidential patient information;
- Laboratories may release patient test information only to the authorized person ordering the test, the persons responsible for using the test results (e.g., healthcare providers of the patient designated by the authorized person to receive test results), and the laboratory that initially requested the test. The individual who was tested may be required to provide specific permission to the lab to release the findings to another health care provider. If a healthcare provider who provides care for a family member of the patient is authorized to request patient test information, the laboratory should request the patient’s authorization before releasing their genetic test results;
- When patient consent is required for testing, the consent form should include the laboratory confidentiality policies and procedures and describe situations in which test results may be requested by healthcare providers caring for family members of the patient; and
- Laboratory directors should be responsible for determining and approving circumstances in which access to confidential patient information is appropriate, as well as when, how, and to whom information is to be released, in compliance with federal, state, and local requirements.
The Health Insurance Portability and Accountability Act (HIPAA) Privacy Rule and the CLIA regulations are federal regulations intended to provide minimum standards for ensuring confidentiality of patient information; states or localities may have higher standards. Although the HIPAA Privacy Rule allows healthcare providers that are covered entities (i.e., healthcare providers that conduct certain transactions in electronic form, healthcare clearinghouses, and health plans) to use or disclose protected health information for treatment purposes without patient authorization and to share protected health information to consult with other providers to treat a different patient or to refer a patient, the regulation indicates that states or institutions may implement stricter standards to protect the privacy of patients and the confidentiality of patient information. Laboratories must comply with applicable requirements and follow professional practice guidelines in establishing policies and procedures to ensure confidentiality of patient information, including molecular genetic testing information and test results. (Note: refer to MMWR PDF page 21, left column, Ensuring Confidentiality of Patient Information, Information Regarding Family Members, Requests for Test Results to Assist with Providing Health Care for a Family Member)
What information should I expect on a molecular genetic test report?
A molecular genetic test report must comply with these general test report requirements as specified under the CLIA regulation 42 CFR §493.1291(c), to include the following information:
- The patient's name and identification number, or a unique patient identifier and identification number;
- The name and address of the laboratory location where the test was performed
- The test report date;
- The test performed;
- Specimen source, when appropriate;
- The test result and, if applicable, the units of measurement or interpretation, or both; and
- Any information regarding the condition and disposition of specimens that do not meet the laboratory's criteria for acceptability.
In addition, test reports of molecular genetic testing for heritable conditions should include the following additional or more specific information to assure accurate result interpretation, patient management, and, when warranted, the ordering of additional testing by individuals receiving and/or utilizing the test results:
- Patient’s date of birth;
- Indication for testing;
- The date and, if appropriate, time of specimen collection and arrival in the laboratory;
- Name of the referring physician or authorized individual who ordered the test;
- Test method, including the nucleic acid target(s) the test is intended to detect
- Performance specifications and limitations of the test;
- Test results in current recommended standard nomenclature;
- Result interpretation;
- References to applicable literature;
- Recommendation for consultation with a genetic professional, when appropriate and indicated;
- When appropriate, implications of test results for relatives or family members who may benefit from the information; and
- A statement indicating that the result and interpretation given is based on current knowledge and technology.
For any in-house developed test using an analyte-specific reagent (ASR), the test report must include the following disclaimer statement required by the FDA regulation 21 CFR 809.30(e): “This test was developed and its performance characteristics determined by (Laboratory Name). It has not been cleared or approved by the U.S. Food and Drug Administration.” (Note: refer to MMWR PDF page 18, Molecular Genetic Test Reports, Content)
If knowledge or technology advances result in improved result interpretation for a test the laboratory performed previously, should I expect the laboratory to provide an updated report to me?
Yes. The CLIA regulations require laboratories to provide pertinent updates on testing information to clients whenever changes occur that affect the test results or interpretation of test results, as specified under 42 CFR §493.1291(e). In light of the rapidly evolving field of molecular genetic testing, laboratories should consider the following responsibilities in meeting this CLIA requirement:
- Keep an up-to-date database of the molecular genetic tests performed in the laboratory, and provide updates to users when knowledge advancement affects the performance specifications and/or interpretation of test results; and
- Issue a revised or updated test report if the interpretation of the original analytic result changes due to advances in knowledge or technology. Indications for providing revised or updated test reports should include:
- A better interpretation is available on a variant found; or
- The interpretation of previous test results is changed (for example, a previously determined mutation is later recognized as a benign variant or polymorphism, or vice versa). (Note: refer to MMWR PDF page 19, left column, Updates and Revisions)
SECTION 4: INFORMATION FOR PATIENTS AND CONSUMERS
What information in the MMWR document is useful for patients and their families?
The MMWR document provides a resource for users of laboratory services, including patients and their families, as well as the general public, about the quality practices that they should expect from a laboratory performing molecular genetic testing. Among the recommendations in the MMWR document, the following issues are directly relevant to patients and their families:
- The laboratory should provide information about its molecular genetic test services through easily accessible sources such as websites, service directories, information pamphlets or brochures, newsletters, instructions for specimen submission, and test request forms. The information should tell you and your healthcare provider(s) which molecular genetic tests are offered by the laboratory, how well each test works, how specimens should be collected and sent to the laboratory for testing, and what information is needed by the laboratory to perform testing and report test results appropriately.
- The laboratory should be available to assist your healthcare provider(s) with selecting and ordering appropriate testing for you, and with interpreting your test results to include any implications for you and your family members.
- If your state requires informed consent for genetic testing, your healthcare provider or other authorized individuals are responsible for obtaining informed consent from you. The laboratory should provide information about the molecular genetic test to be ordered to your healthcare provider to assist with the informed consent process, and should include appropriate means for documenting informed consent on test request forms (e.g., check-off box, statement, separate form, or other methods).
- The cost of a genetic test for a particular patient may depend on your healthcare plan and payment policy selection. When possible, the laboratory should provide information to advise you of the financial implications of the molecular genetic tests being performed and cost estimates.
- Quality testing for many genetic diseases will require collection of your race/ethnicity, family history, and other pertinent clinical and laboratory information. The laboratory is expected to request this information when the test is ordered to ensure appropriate testing and result reporting. The laboratory is required to protect confidentiality of all patient information under its control.
- Your genetic test report must include all the components required by federal regulations (http://wwwn.cdc.gov/clia/regs/subpart_k.aspx#493.1291) and should provide additional information needed for your healthcare provider to understand the test results for managing your clinical care. Such additional information includes the test method used; accuracy, analytic sensitivity, other performance specifications, and limitations of the test; interpretation of the test results, and implications for family members. When appropriate, the test reports should also suggest genetic counseling or consultation for the patient and family members.
- The laboratory should keep your genetic testing results on file for at least 25 years; and
- The laboratory must keep your information and test results confidential, and may only give your test results to authorized people. If your state does not allow the laboratory to send test reports directly to patients, you can ask your healthcare provider to give you a copy of your laboratory report. Your healthcare provider should explain what the test results mean to you or may refer you to a qualified genetics professional for consultation. (Note: refer to MMWR PDF page 7, Test Information to Provide to Users of Laboratory Services; page 9, Informed Consent; page 9, Test Requests; page 10, Specimen Submission, Handling, and Referral; page 18, Molecular Genetic Test Reports; page 19, Retention of Reports, Records, and Tested Specimens; page 21, Ensuring Confidentiality of Patient Information)
I received an advertisement from a company offering genetic (DNA) profiling. They say I can order the test myself. What information should they provide to help me understand the test and decide if is right for me?
Laboratories that offer molecular genetic testing directly to consumers, or direct-to-consumer (DTC) genetic testing laboratories, should also adhere to the MMWR recommendations. These laboratories may not be meeting the same standards as certified clinical laboratories delivering healthcare information. DTC laboratory test findings are more similar to research observation, rather than proven clinical correlations. The MMWR guideline addresses many key concerns about DTC testing, including the laboratory’s responsibility to ensure its tests are valid, and to truthfully provide the test information, including analytic and clinical validity, limitations, costs, and other information needed for you to make an informed decision about the tests and the implications of test results for you. When you encounter information about DTC testing, it should be helpful to use the MMWR recommendations to check whether adequate test information is provided and ask questions about the laboratory’s practices to help you consider the quality and usefulness of these tests. The best way to find out if a test is good for you is to consult your healthcare provider or a qualified genetics professional. (Note: refer to MMWR PDF page 7, Test Information to Provide to Users of Laboratory Services)
Can the laboratory share my test results with my sister’s physician, who would like to obtain the information to determine what tests my sister needs? I am a carrier of a germline mutation and concerned about how the laboratory that performed the test for me will protect the confidentiality of my test information.
The laboratory should not release your genetic test results to individuals other than your healthcare provider or other authorized persons without your permission. Laboratories may release patient test information only to the authorized person ordering the test, the persons responsible for using the test results (e.g., healthcare providers of the patient designated by the authorized person to receive test results), and the laboratory that initially requested the test. If a healthcare provider who provides care for your family member is authorized to request patient test information, the laboratory should request permission from you to do so before releasing the your genetic test results.
When your consent is required for testing, the consent form should include the laboratory’s confidentiality policies and procedures and describe situations in which test results might be requested by healthcare providers caring for your family members. Laboratory directors should be responsible for determining and approving circumstances in which access to your confidential information is appropriate, as well as when, how, and to whom information is to be released, in compliance with federal, state, and local requirements. (Note: refer to MMWR PDF page 21, left column, Ensuring Confidentiality of Patient Information, Information Regarding Family Members, Requests for Test Results to Assist with Providing Health Care for a Family Member)
This page last reviewed: 5/18/2010