Report of Expert Consultations on Rapid Molecular Testing to Detect Drug-Resistant Tuberculosis in the United States

Appendix 2: Roles and Responsibilities in a Regional Laboratory System for Providing for Molecular Drug-Resistance Testing for TB

CDC should establish regional laboratories to provide molecular DR testing for rifampin resistance and isoniazid resistance for TB control programs in the United States and affiliated jurisdictions. The goal is to provide sufficient testing capacity to enable molecular drug-resistance testing for (1) one AFB smear-positive or NAA-positive respiratory specimen or one Mycobacterium tuberculosis culture from each TB patient or TB suspect (‘universal testing’) and (2) specimens or isolates from persons that the TB Program designates as high priority for molecular DR testing (‘judicious use testing’). For universal testing, it should be noted that there were ~5000 pulmonary AFB-smear-positive TB cases reported to CDC in 2007; an approximately equal number of AFB-smear-positive specimens due to non-tuberculosis mycobacteria; and ~7,400 pulmonary and ~3000 extrapulmonary culture-confirmed TB cases reported to CDC in 2007. Thus, universal testing would entail testing 10,000 to 20,000 samples per year.

A phased approach to developing and implementing a molecular DR testing service will be needed. As a first step, it would be essential to provide molecular DR testing services for testing TB patients or suspects at high-risk of having MDR TB and those deemed high priority by the program. This could be accomplished by providing sufficient new funding to existing, proficient molecular DR testing laboratories to allow them to expand their capacities to meet this need. If done as supplements to existing cooperative agreements, this could be done quickly. These programs could also serve as pilot projects by offering universal testing for selected programs. Such an interim service would allow time to

1. compare the performances and costs of currently available validated molecular DR tests and select one or more for use in the molecular DR testing service;
2. assess and overcome potential obstacles and barriers to a regional approach to diagnostic testing such as local regulations regarding out-of-state testing, reporting requirement, and need for memoranda of agreement;
3. develop a strategy to coordinate or integrate services provided by the molecular DR testing laboratories and the TB genotyping laboratories to avoid unnecessary duplication of efforts and shipment of isolates;
4. develop a roll-out strategy for the molecular DR testing service to include informing potential service users of the availability of the service, how to access the service, and the appropriate use and interpretation of molecular DR tests for TB;
5. define the scope of the molecular DR testing service more precisely by providing reliable estimates of the anticipated numbers of non-processed specimens, processed specimens, and cultures to be tested;
6. design a molecular DR testing service to meet the needs of local and state TB control programs; and
7. develop, compete, and award a request for contract to provide the services.

In addition to molecular DR testing, the resources of the molecular DR testing laboratory might be leveraged to provide other services for state and local TB programs and laboratories, such as NAA testing for detection, culturing, second-line drug susceptibility testing, or genotyping. The scope of any additional service must be clearly defined and adequately funded.

Cost estimate for 2500 samples per year (10 per day)
One laboratory needed for judicious use; a second laboratory may be needed as a backup. Four laboratories are likely to be needed for universal testing.
Estimates do not include the cost of processing specimens at the molecular DR testing laboratory.

CDC Responsibilities

1. Develop a request for contract (RFC) that specifies the duties and responsibilities of the regional molecular DR testing laboratories and the proposal evaluation criteria. Advertise and compete the RFC. Review applications and select successful offerors. Provide funds.
2. Develop and fund a process (e.g., ‘bill-to-recipient’ FedEx account) for shipping M. tuberculosis cultures to the regional molecular DR testing laboratories.
3. Develop and fund a process for shipping specimens to the regional molecular DR testing laboratories for public health laboratories or programs that can not afford the cost of shipping specimens.
4. Provide guidance, templates, or models to assist TB Programs to develop criteria for selecting TB suspects or patients for molecular DR testing and develop and implement protocols for accessing the regional molecular DR testing services.
5. Work with molecular DR testing laboratories to develop standardized reporting.
6. Work with molecular DR testing laboratories to develop an external quality assurance, proficiency testing, or rechecking program for the molecular DR testing laboratories.
7. Develop a robust process for monitoring and evaluating the performance of the molecular DR testing laboratories. This should include post-market surveillance of the molecular DR testing to determine the performance, cost, and benefit of the molecular DR testing in a high-throughput setting.
8. Work with regional laboratories and programs to develop protocols to analyze discrepancies in the results of molecular and conventional DS tests. Serve as a referee laboratory to analyze discrepant results. Collect data on and investigate all discrepancies to better understand the performance of molecular and conventional DS testing.
9. Provide additional molecular and conventional DS testing for samples determined to be rifampin resistant.
10. Provide technical assistance and consultation.

Regional Molecular DR Testing Laboratory Responsibilities

1. Design and implement a molecular DR testing service to detect rifampin resistance and isoniazid resistance. The service should include
   1. protocols and standard forms for submitting specimens for testing,
      1. for universal testing, acceptable specimens should include non-processed respiratory specimens from TB suspects or patients who produced an AFB smear-positive or NAA positive specimen, processed AFB smear-positive respiratory specimens (sediments) from TB suspects or patients, and AFB-positive cultures from TB suspects or patients;
      2. specimens (respiratory or non-respiratory) or cultures identified by the TB program as high priority for molecular DR testing are acceptable.
   2. protocols for accessioning samples and entering data in a laboratory information management system;
   3. an algorithm and protocols for molecular DR testing of specimens and cultures;
      1. include appropriate positive and negative controls
      2. ensure that testing includes the assessment of PCR inhibitors
      3. if inhibitors detected or suspected, appropriate follow-up testing
      4. if results are indeterminate, appropriate follow-up testing
      5. if an open NAA system is used, protocols to prevent end-product contamination
   4. procedures for result review and reporting – system must maintain patient confidentiality;
   5. a quality management system and an external quality assurance program; and
   6. procedures for archiving samples.
2. Preferably provide six-day-a-week testing.
3. Select, establish and validate rapid molecular test(s) to detect rifampin resistance and isoniazid resistance in accord with pertinent CLIA and FDA rules and regulations.
4. Conduct testing and report results of molecular DR testing within 2 business days of specimen receipt for at least 90% of samples received.
5. Work with programs to develop and implement protocols for reporting molecular DR test results. At the discretion of the program, this may include reporting to the TB Program, TB public health laboratory, local public health officials, sample submitter, etc. Results should be reported electronically to individuals designated by TB programs. The detection of resistance should be reported by telephone to individuals designated by the TB program.
6. Work with each TB program to develop and implement a reflex testing protocol to expedite testing of susceptibilities to first-line and second-line drugs for all rifampin-resistant samples.
   1. The testing may be done in the same facility as the molecular DR testing, in another laboratory proficient in drug-susceptibility testing, or the original referring laboratory.
   2. In addition, all isolates found to be rifampin resistant should be referred to CDC for additional molecular and conventional DS testing.
7. Work with CDC and TB Programs to develop and implement a protocol for analyzing discrepant results.
8. Participate in an external quality assessment or proficiency testing program.

Tuberculosis Control Program Responsibilities

1. Develop and implement a protocol that enables health care providers to access the molecular DR testing services in their jurisdiction. Include criteria for selecting TB suspects or patients for testing. For universal testing, criteria should allow testing of one AFB smear-positive or NAA-positive respiratory specimen orM. tuberculosis culture from each TB patient or TB suspect. Criteria for high priority or judicious testing might include:
   1. Persons at risk of having MDR-TB such as persons exposed to an MDR-TB case, from a population with a high rate of MDR TB, failing or failed therapy with first-line anti-TB drugs, persons who have been previously treated for TB and relapse cases.
   2. Specimens or isolates for which the result would alter case management or TB Control decisions, outbreak or contact investigations, preventive therapy, infection control, etc.
   3. High profile situations needing test results in a short time frame (e.g. outbreaks in schools or congregate settings; placing persons on a ‘Do Not Board’ list).
   4. Specimens or isolates that can not be tested easily with conventional methods such as non-viable specimens and mixed or contaminated cultures.
2. Ensure that health care providers are aware of the molecular DR testing service and protocol for accessing the service.
3. Coordinate programmatic and laboratory activities:
   1. optimize communication between program, laboratory, and clinicians,
   2. ensure that the public health laboratory is engaged early in the testing process for samples being submitted by other laboratories to facilitate referral and tracking of samples and expediting submission of samples to the public health laboratory, and
   3. ensure that the public health laboratory is informed of all positive mol DS test results regardless of submitter to facilitate and expedite follow-up drug-susceptibility testing.
4. Develop protocols for approving requests for molecular DR testing.
5. Develop protocols for shipping specimens to the molecular DR testing laboratory. Work with CDC or specimen submitters to arrange for payment of costs, or pay for shipping costs if necessary.
6. Develop a protocol for shipping cultures to the molecular DR testing laboratory. Develop protocols for shipping specimens to the mol-DS testing laboratory. Work with CDC or specimen submitters to arrange for payment of costs, or pay for shipping costs if necessary
7. Designate individuals to be notified of test results or subsets of test results (e.g., negative test results, detection of M. tuberculosis DNA, detection of drug resistance, etc.). As appropriate, develop protocols to act upon test results.
8. Work with the molecular DR testing laboratory and CDC to develop and implement a reflex testing protocol that ensures prompt culture-based testing of susceptibilities to first-line and second-line drugs for all rifampin-resistant samples. Work with CDC and testing laboratories to arrange payment of the costs of the reflex testing. Cost to be paid by the TB program. For example, all rifampin-resistant isolates could be tested for susceptibility to first-line and second-line drugs at 1) the molecular DR testing facility, 2) the program’s public health laboratory, or 3) at another laboratory proficient in drug-susceptibility testing.
9. Develop and implement a protocol for detecting and analyzing discrepancies in the results of molecular and conventional DS tests. Work with CDC and the molecular DR testing laboratory to evaluate discrepancies.
10. Provide technical assistance and consultation on the appropriate use and interpretation of molecular DR tests to health care providers in their jurisdiction.

Local and State Public Health Laboratories

1. Work with local and state TB Control Programs to ensure that clinical laboratories in their jurisdictions are aware of the molecular DR testing service and protocol for accessing it.
2. Coordination of programmatic and laboratory activities.
3. Develop protocols with TB Control Programs for shipping specimens or isolates to the molecular DR testing laboratory.
4. Develop protocol with TB Control Programs to detecting and analyzing discrepancies in the results of molecular and conventional tests.
5. Work with TB Control Programs and the molecular DR testing laboratory to develop and implement a reflex testing protocol that ensures prompt culture-based testing of susceptibilities to first-line and second-line drugs.
6. Work with programs to develop and implement protocols for reporting molecular DR test results.
7. Provide technical assistance and consultation on the interpretation of molecular DR tests to laboratorians and health care providers in their jurisdiction.

Regional Training and Medical Consultation Center Responsibilities

1. Provide technical assistance and consultation on clinical and programmatic aspects of the appropriate use and interpretation of molecular tests for drug resistance.
2. Provide medical consultation as appropriate.
3. Develop and disseminate education material on molecular drug-resistance testing.