Request for Applications: PHL Reference Center for Mycobacterium tuberculosis complex Drug Susceptibility Testing

Transcription

1 Request for Applications: PHL Reference Center for Mycobacterium tuberculosis complex Drug Susceptibility Testing Application Due Date: October 13, 2014 Submit to: Kelly Wroblewski, Director of Infectious Disease Programs Summary: The Association of Public Health Laboratories (APHL), in cooperation with the U.S. Centers for Disease Control and Prevention (CDC) Division of Tuberculosis Elimination, is seeking to identify one (1) state or local public health laboratory that will serve as a drug susceptibility reference center for other public health laboratories from jurisdictions with low to moderate incidence of TB. The Reference Center will serve as an extension of the CDC DTBE Laboratory Branch and will provide services that are complementary to those at CDC based on methods and protocols that will be provided by APHL and CDC. Services provided by the reference center for PHLs with low volumes of drug susceptibility testing (DST) (<50 isolates per year will include: 1) quality-assured first-line DST; 2) standardized second-line DST; and 3) molecular detection of drug resistance. Services will be provided at no cost to the submitter. Funding will be awarded via a contract with APHL. Background: Performing DST is technically demanding and maintaining proficiency in performing testing and interpreting results is critical to ensuring accuracy. It is clear from the data outlined below, that while PHLs are a vital provider of TB DST services; many PHLs perform little DST for TB, raising concerns about the cost effectiveness and ability to maintain a high level of proficiency in every laboratory. The recently completed National TB Laboratory Services Survey 1 revealed that 60/96 (63%) of responding laboratories performing first-line DST were PHLs. However, 42% of these laboratories performed testing for five or fewer Mycobacterium tuberculosis complex (MTBC) isolates per month. Similarly, in 2013, 71% of laboratories participating in CDC s Model Performance Evaluation Program for DST of MTBC were PHLs. Thirtyseven (41%) of these laboratories reported performing fewer than or equal to 50 DST per year 2. The current recommendation is referral if performing DST for fewer than 50 isolates per year 3. These data indicate that PHLs are an essential provider of first-line DST for MTBC in the United States. Nevertheless, many of these laboratories have low testing volumes. Of 58 PHL supported in part through the CDC TB Elimination and Laboratory Cooperative Agreement, 22 reported performing first-line DST for fewer than 50 patients per year (mean for the time period ). Second-line DST is critical when isolates are resistant to rifampin (RMP) or any two first-line drugs as well as situations where additional information to design an effective regimen is needed (e.g., drug intolerance). Methods for second-line DST are not standardized and currently, there are no FDA-cleared assays for this purpose. Therefore, laboratories may choose to follow established consensus guidelines (e.g., CLSI or WHO) or evaluate their own test concentrations and interpretive criteria. As a result, discordance among laboratories and methods is common for some second-line drugs. In the National TB Laboratory Services Survey, 23 of the 29 (79%) of respondents performing second-line DST were PHL. Each of the 22 PHL performing fewer than 50 first-line DST per year currently refer for second-line DST 1. 1

2 Molecular detection of mutations associated with drug resistance can provide rapid results within hours or days versus the weeks required for growth-based DST. CDC offers the molecular detection of drug resistance (MDDR) service for concurrent molecular and phenotypic testing of isolates and nucleic acid amplification test (NAAT) positive sediments meeting submission criteria. With the recent FDA market authorization of the Cepheid Xpert MTB/RIF assay, rapid confirmation of drug resistance by molecular methods takes on increasing importance as more clinical laboratories adopt this technology. Performing molecular testing (primarily DNA sequencing) requires technical expertise and extensive experience in interpreting test results. Laboratories performing molecular testing must be competent in providing consultative services and must continually adapt to advancements in the field. These requirements limit the number of laboratories that should be providing molecular testing for drug resistance. Eligibility: Eligible laboratories include all APHL member state and local PHLs with the following capabilities and facilities in place. Specific expectations regarding the methodologies to be used by the reference center are outlined in Appendix A. All applicants are required to agree to the minimum requirements outline in Appendix B. Infrastructure for unidirectional workflow for molecular methods Availability of adequate laboratory space Availability of necessary equipment (e.g. MGIT) and sufficient space for expansion or purchase of additional equipment if necessary anticipating no more than 600 additional first-line DSTs Sufficient workforce capacity for expanded testing volume or the ability to hire additional qualified staff Established culture capacity for MTBC Established capacity to perform first AND second-line DST methods to detect drug resistance in MTBC Willingness to alter or amend existing testing protocols Willingness to amend specimen submission form to include additional variables Willingness to alter existing reporting language to a standard message Award Mechanism: Funding will be distributed via contract with APHL. Award Amount: Up to $200,000 for the December 1, 2014 June 30, 2015 award period. The awardee will be eligible to receive up to $400,000 per year in subsequent award period per the availability of funds and successful performance. Term of Project: November 1, 2014 June 30, 2015 with potential for renewal. Test validation and equipment purchase will begin November 2014 with anticipated roll out of first-line DST beginning March Use of Funds: Funds should be used for necessary equipment upgrades or expansion; validation of new testing services; testing of referred specimens beginning March 2015; and personnel time required to conduct these activities. Request for Applications: To apply to become the PHL Reference Center for Mycobacterium tuberculosis complex DST, please respond to the following questions. Responses should be limited to no more than ten (10) single spaced pages. 1. Please describe the current methodology used in your laboratory for growth-based first-line DST for MTBC. Include information on how long the methodology has been in use, how often it is performed, 2

3 your annual volume, the amount of experience your laboratory staff has in using that methodology, and any training your staff has received. 2. Please describe the current methodology used in your laboratory for growth-based second-line DST for MTBC. Include information on how long the methodology has been in use, how often it is performed, your annual volume, the amount of experience your laboratory staff has in using that methodology and any training your staff has received. 3. Please describe the current methodology used in your laboratory, if any, for molecular detection of drug resistance for MTBC. Include information on specimen types tested, how often it is performed, how long the methodology has been used, your annual volume, the amount of experience your laboratory staff has in using that methodology and any training your staff has received. Also include information on which platforms are currently available for molecular-based testing (include real-time PCR, pyrosequencing, and next generation sequencing platforms; where those platforms are located (e.g. TB laboratory, a core molecular facility, etc.) and if they are available for the purposes of this RFP (i.e., molecular detection of resistance for MTBC)? 4. What is the current turnaround time (TAT) for the growth-based DST results (first and second line) for isolates from diagnostic specimens and for reference isolates received by your laboratory? What is the current TAT for the molecular detection of drug resistance for MTBC, if performed, from receipt of a primary specimen or isolate? 5. Describe your laboratory s ability to absorb increased workload in performing growth-based and molecular testing for drug resistance at current staffing levels by defining the additional monthly volume your laboratory would be able to undertake for growth-based DST (first and second line) as well as molecular based testing. Does the facility have laboratory space available for additional instrumentation or staff that may be needed to accommodate increased workload? Does the laboratory have the ability to hire additional staff to accommodate the workload if necessary? 6. Does your laboratory have staff with the subject matter expertise to provide guidance and interpretation of growth-based and molecular test results including discordant results? Please describe the qualifications and experience staff have in providing consultative services. 7. If selected, would your laboratory be willing to evaluate and incorporate additional new technologies as they become available? Please briefly describe your experience in participating in method or platform evaluation(s). 8. Briefly describe your laboratory s experience, if any, in providing reference testing for other public health laboratories in a shared service model including but not limited to coverage for a limited period of time to assure continuity of operations. 9. Briefly describe your procedures for validating laboratory developed tests? 10. Please describe the types of reporting mechanisms you currently have in place (e.g. web portal, secure fax, etc.). If you have an electronic reporting system, is it possible to provide access to PHLs who may be using a TB DST Reference Center? 11. Provide a 6 month budget outlining at least the following line items: equipment purchase or upgrade based on the methods requirements outlined in Appendix A; staff time; charge per specimen/isolate tested by each method; and anticipated overhead charges if any. 12. Include a signed copy of Appendix B as an attachment. 3

4 Evaluation Criteria The proposals will be reviewed by a team of TB subject matter experts (SMEs) from DTBE and a panel of APHL members selected from non-applicant public health laboratories. Proposals will be evaluated based on responses to the questions above. Laboratories will be given preference based on more extensive experience with the test methods, ability to handle increased volume, existing in-house subject matter expertise, experience serving as reference center and ability to comply with expectations laid out in Appendix A and be able to meet the minimum expectations outlined in Appendix B. Please see the scorecard template that will be used to evaluate applications in Appendix C. Conditions of Award Acceptance: The eligible laboratories must be able to contract directly with APHL or have an existing relationship with a third-party organization that can contract directly with APHL on behalf of the laboratory. Laboratories must agree to comply with expectations outlined in Appendix A. Prior to making the official award, a group of individuals from CDC and APHL will tour the facilities to assess compliance with requirements for testing. Post award, monitoring site visits will include an assessment of continued compliance. Additional Information and Deadlines for Application Submission: All questions should be directed to Kelly Wroblewski at kelly.wroblewski@aphl.org. Applications should be submitted to Kelly Wroblewski at APHL (kelly.wroblewski@aphl.org; 8515 Georgia Ave Suite 700, Silver Spring, MD, 20910; telephone: ; fax: T0). Applications must be received at APHL, attention Kelly Wroblewski by close of business October 13, Either electronic or physical submission is acceptable. APHL will send an acknowledging the receipt of your application. An optional informational teleconference will be held Friday, September 5, 2014 at 2:00 pm ET. The purpose of this call will be to provide a brief overview of the project and to allow potential applicants to ask CDC and APHL questions. Please come with questions prepared. Bridge: Passcode: # References: 1. Association of Public Health Laboratories. (2012). National TB Laboratory Services Survey Report. Silver Spring, MD. Available at: 2. Centers for Disease Control and Prevention. (2013). Mycobacterium tuberculosis Complex Drug Susceptibility Testing Program Report of Results. Atlanta, GA. Available at: 3. Association of Public Health Laboratories. (2007). TB Drug Susceptibility Testing Expert Panel Meeting Summary Report. Silver Spring, MD. Available at: 4

5 Report.pdf 5

6 Appendix A: Expectations for PHL Reference Center for Mycobacterium tuberculosis complex Drug Susceptibility Testing Molecular Testing Pyrosequencing is the selected method for performing molecular testing due to this platform being widely available, the availability of SOPs, limited concerns regarding throughput for molecular testing, cost, and DTBE/LB experience with the method. The minimal panel for testing will include RRDR of rpob, codon 176 in rpob, the promoter region of inha, and regions of katg, maba, and ahpc to define resistance to RMP and INH (i.e., multidrug resistant TB). SOPs, primers, analytics/bioinformatics, and reference strain(s) used will be identical to those used by the DTBE/LB Reference Laboratory. Laboratory must independently verify heat inactivation protocol and provide documentation of verification. The DST Reference Center will use the same pre-submission notification form as DTBE/LB Reference Laboratory with defined criteria indicating reasons for suspicion of drug resistance. Communication regarding approval will be provided by the reference center. Submission criteria will be systematically catalogued. Universal molecular testing will not be performed. The reference center will accept NAAT positive sediments for testing with one exception. Sediments submitted for confirmation of an Xpert MTB/RIF result RMP resistance detected, should be referred directly to CDC s MDDR from the submitting laboratory for confirmation and the expanded molecular panel available at CDC. o Cultures will be set up from sediments for growth-based first-line DST. o When RMP resistance is detected by pyrosequencing, an aliquot of the residual sediment (if available) or isolate will be referred to CDC s MDDR as soon as possible for additional molecular testing and concurrent second-line DST. Second-line DST will also be performed at the reference center. The reference center will accept referred isolates of MTBC for molecular testing upon request. Universal molecular testing of all isolates will not be performed o Pyrosequencing and set up for growth-based first-line DST will be performed. o If RMP resistance is detected by molecular testing, an aliquot will be referred to CDC for MDDR and concurrent second-line DST. Second-line DST will also be performed at the reference center. First-line DST First-line DST will be performed by the MGIT method with a panel of rifampin (RMP), isoniazid (0.1 and 0.4 µg/ml) (INH), pyrazinamide (PZA), and ethambutol (EMB). Pre-submission notification for first-line DST will not be required. Submitting laboratories will be asked to refer an aliquot of positive growth (optimally from broth) as soon as the culture becomes positive and identification of MTBC is confirmed. A purity plate will be set up as well by the reference laboratory. 6

7 If growth-based testing reveals resistance to any first-line drug, reflex testing for second-line drugs and to confirm resistance will be performed. If growth-based testing reveals resistance to RMP, isolate will be referred to CDC s MDDR as soon as possible for additional molecular testing and concurrent second-line DST. Second-line DST will also be performed at the reference center. If culture for first-line DST is contaminated, pyrosequencing will be used to screen for MDR. If no mutation is detected or amplification fails, results will be reported. No further action will be taken pending receipt of pure culture from submitting laboratory. If mutation in rpob is detected, results will be reported and aliquot of contaminated culture will be sent to CDC for MDDR. Referral of pure culture from submitting laboratory will be requested. DST Reference Center will not be tasked with isolating pure cultures of M. tuberculosis complex. Second-line DST Second-line DST will be performed on reflex when RMP-resistance is detected through molecular analysis or first-line DST, when resistance is detected to any first-line drug through growth-based DST (with the exception of mono-pza), and when requested due to clinical need (e.g., drug intolerance). Method used for second-line DST will be determined at a later date in consultation with the selected Reference Center. Reference laboratory will optimally receive aliquots of liquid broth and subculture to broth and purity plate. Expectations for phased-approach to testing at reference laboratory will take into account time required for validation of new methods or drugs. DTBE/LB Reference Laboratory will provide access to isolates needed for validation. DTBE/LB can assist with training if needed. Performance Monitoring and Evaluation APHL in collaboration with CDC/ DTBE Laboratory Branch will implement procedures for routine monitoring of workload, reasons for submission to reference center, data quality, transport times, turnaround times, data anomalies and outliers, discordant results, level of drug resistance, types of mutations detected, appropriate use of reporting language, appropriate use of reflex testing algorithms, effective consultative services, customer satisfaction, referrals to CDC, and service costs on a quarterly basis. Data Review On a quarterly basis, a complete report to include the following will be provided to APHL and CDC. o Individually line-listed genotypic (e.g., locus, nucleotide sequence, amino acid substitution [when applicable] and interpretive comments) and associated phenotypic data (to include contaminated and no growth when applicable) for each sample tested o Sample type, date of specimen collection, date of receipt in the submitting laboratory (if available), report date of MTBC ID in submitting laboratory, date shipped to DST Reference Center, date of receipt in the DST Reference Center, report dates, date of referral to CDC (if applicable), and date of referral of isolate to genotyping laboratory 7

8 o Reasons for referral to CDC, if applicable o Reference laboratory is expected to develop its own QA monitors, in conjunction with CDC, for their own performance and that of submitting laboratories Reference laboratories will share documentation of QA procedures upon request. Development of a quarterly QA report to include a listing of nonconforming events, complaints, and QC failures. Pending phenotypic data will be matched with genotypic data during the subsequent collection period. Data will be exported to Excel and personal identifying information (PII) removed prior to submitting to APHL and CDC. If matching of patient results between CDC and the DST Reference Center is needed, a representative from the DTBE Reference Laboratory Team will coordinate communication to protect personal identifying information. Data will be analyzed by a team at APHL and CDC with feedback provided to the DST Reference Center within 4 6 weeks of receipt. An annual report will developed by APHL and CDC detailing yearly statistics. Genotypic and correlated phenotypic data may be added to the DTBE Reference Laboratory database. Site visits and teleconferences During the first year of service, APHL is collaboration with CDC will perform a minimum of 2 site visits. Contingent on satisfactory performance, future project years will include a single site visit. Additional monitoring visits may be needed based on data review and any ongoing challenges mutually identified. Site visits could include data review, review of laboratory workflow, procedural observation, QC information, worksheets for DST, and review of pyrograms (i.e., raw sequencing data). APHL in collaboration with CDC will host a teleconference upon receipt of quarterly reports to assess successes, challenges, and potential solutions. Customer satisfaction APHL will perform an annual customer satisfaction survey that may include key informant interviews with select submitters to assess satisfaction with service, turnaround time, reporting format, expert consultation, and continued use of reference laboratory. Performance Assessment The DST Reference Center is required to participate in the CDC-sponsored Model Performance Evaluation Program (MPEP) and test the panel against all funded methods. In addition, to MPEP, APHL will collaborate with CDC to provide 2 additional challenges of isolates each year to specifically assess genotypic and phenotypic testing. Quality of consultations will be assessed. Reporting Language Reporting language and disclaimers harmonized with the DTBE Reference Laboratory must be used by the DST Reference Center. Genotypic results must be provided in an interim report with phenotypic results to follow. 8

9 A catalog of interpretative comments for wild-type, novel mutations, and common rpob, inha, katg and maba mutations will be provided. A list of sensitivity and specificity for specific mutations in these loci will be provided and updated. The final report will include a categorical result of R or S for each drug. Perceived discordance between genotypic and phenotypic testing should be clearly indicated and additional interpretative comments provided. CDC can assist with language around discordant results. Consultation Subject matter expertise within the DST reference center available for consultation by phone or dedicated address CDC DTBE Reference Laboratory may be consulted when discordant results are seen. Dedicated website and user s guide available to submitters Submission of isolates to genotyping laboratory Within 7 days of a positive culture from sediment or subculture of a referred isolate, the reference laboratory will package and ship isolates to the Michigan Department of Community Health (MDCH) for genotyping. o The submitting laboratory will be notified that the isolate was submitted for genotyping. Prior to shipping the isolates, isolate information will be entered into the Tuberculosis Genotyping Information Management System (TB GIMS) by the reference laboratory. If submitting laboratory sends directly to CDC MDDR service based on sediment submitted for confirmation of an Xpert MTB/RIF result RMP resistance detected, CDC will be responsible for isolate submission to the genotyping laboratory. Archiving isolates Isolates will be stored frozen by the DST Reference Center for a period of 2 years. Isolates will be archived at the genotyping laboratory and eventually shipped to CDC for long-term storage. Evaluation of new platforms The service laboratory could serve as an evaluation site for new diagnostic platforms. Opportunities for evaluation will be explored with the reference center to determine sufficient facilities, personnel, and time resources. Evaluation of new diagnostic platforms should in no way negatively impact service provision under the statement of work (SOW). APHL and CDC will work with the DST Reference Center to assess opportunities under the SOW and complete any IRB-related documentation. 9

10 Appendix B: TB DST Reference Center Minimum Requirements Please review and respond to each of the minimum requirements below. By signing this agreement you are affirming that your laboratory can meet each of the minimum requirements described. If your laboratory cannot respond yes to one or more of the minimum requirements, your laboratory does not meet the minimum qualifications required to apply for this award. Yes No Would your laboratory Quality Assurance officer allow you to perform and report LDT or RUO assays? Does your laboratory have the infrastructure to ensure unidirectional workflow for molecular testing? Does your laboratory have sufficient space for expansion/ purchase of additional equipment if necessary? Does your laboratory have established capacity for MTBC culture as well as first AND second-line DST methods to detect drug resistance in MTBC? Would your laboratory be willing to increase the frequency with which certain methods are performed in your laboratory if required by APHL and CDC to meet expected turnaround times? Does your laboratory have sufficient workforce capacity for expanded testing volume or the ability to hire additional qualified staff? Would your laboratory be willing to alter or amend existing testing protocols at the request of APHL and CDC? Would your laboratory be willing to accept at least annual site visits from APHL and/or CDC? Would you be willing to amend specimen submission form to include additional variables? Would your laboratory be willing to provide copies of QA or biosafety documentation to APHL and CDC upon request? Would you be willing to alter your laboratory reports to use standardized reporting language suggested by APHL and CDC with input from the selected laboratory? On behalf of the applicant laboratory, I agree that the applicant laboratory is able to meet the minimum requirements necessary to apply for this award as outlined above. X authorized signer 10

11 Appendix C: PHL Reference Center for Mycobacterium tuberculosis complex Drug Susceptibility Testing RFA Score Card PHL Reference Center for Mycobacterium tuberculosis complex Drug Susceptibility Testing RFA Score Card Reviewer Name: Laboratory Reviewed: Overall Comments and Recommendation: Date: Final Score: Category 1. Does the applicant have sufficient capacity and experience performing first line DST for TB to comply with the requirements described in Appendix A of the RFP? Consider experience with described method(s), experience of existing staff? (Excellent = 13-15; High= 9-12; Moderate =5-8; Low =1-4; No experience = 0) 2. Does the applicant have sufficient capacity and experience performing second line DST for TB to comply with the requirements described in Appendix A of the RFP? Consider experience with described method(s), experience of existing staff? (Excellent = 13-15; High= 9-12; Moderate =5-8; Low =1-4; No experience = 0) 3. Does the applicant have sufficient capacity and experience performing testing molecular detection of drug resistance for TB to comply with the requirements described in Appendix A of the RFP? Consider experience with described method(s), experience of existing staff? (Excellent = 13-15; High= 9-12; Moderate =5-8; Low =1-4; No experience = 0) 4.Does the applicant demonstrate the ability to increase testing capacity for all required methods? Consider the available of existing staff, equipment and space and the ability of the laboratory to purchase additional equipment or hire additional staff. (Excellent = 13-15; High= 9-12; Moderate =5-8; Low =1-4; No experience = 0) Maximum Value Score Comments 11

12 5. Does the applicant demonstrate the ability to regularly meet target turnaround times as recommended in the CDC Tuberculosis Elimination and Laboratory Cooperative Agreement.? (High = 7-10; Moderate =3-6; Low = 0-2) 5. Does the applicant describe in-house subject matter expertise that is sufficient to provide consultation to submitting jurisdictions on discordant results or other issues? (High = 7-10; Moderate =3-6; Low = 0-2) 6. Rate the applicant s level of experience in performing evaluation of new diagnostic methods and/or platforms (High = 7-10; Moderate =3-6; Low = 0-2) 7. Rate the applicant s level of experience in providing reference testing services for other public health laboratories in a shared service model. (Very experienced = 7-10 points; Some experience = 3-6 points; No experience = 0-2 points.)