2011-N-13311 - RFP - TBESC.pdf

PAGES

15A. NAME

AND

ADDRESS

OF

OFFEROR

SEC. PAGE(S) SEC. PAGE(S)

(Date) (Hour)

CALENDAR DAYS

14. ACKNOWLEDGMENT OF AMENDMENTS

(The offeror acknowledges receipt of amend-ments to the SOLICITATION for offerors and related documents numbered and dated:

(Type or Print)

SOLICITATION, OFFER AND AWARD 1. THIS CONTRACT IS A RATED ORDER

UNDER DPAS (15 CFR 700)

RATING

PAGE OF

1 77

2. CONTRACT NO.

3. SOLICITATION NO.

2011-N-13311

4. TYPE OF SOLICITATION

SEALED BID (IFB)

X NEGOTIATED (RFP)

5. DATE ISSUED

05/05/2011

6. REQUISITION/PURCHASE

NO.

000HCVJE-2011-93353

7. ISSUED BY CODE 8. ADDRESS OFFER TO (If other than Item 7) Centers for Disease Control and Prevention (PGO)

Acquisition and Assistance Branch 1 2920 Brandywine Road, MS E-15 Atlanta, GA 30341-5539

Approved as to Form and Legality: _____________________________ NOTE: In sealed bid solicitations “offer” and “offeror” mean “bid” and “bidder.”

SOLICITATION

9. Sealed offers in original and 4 copies for furnishing the supplies or services in the Schedule will be received at the place specified in Item 8, or if handcarried, in the depository located in See Section L.9 - General Instructions until 4PM local time 06/13/2011

CAUTION -- LATE Submissions, Modifications, and Withdrawals: See Section L, Provision No. 52.214-7 or 52.215-1. All offers are subject to all terms and conditions contained in this solicitation.

10. FOR INFORMATION

CALL:

A. NAME

Arnette Mayhew

B. TELEPHONE (NO COLLECT CALLS)

AREA CODE NUMBER: EXT:

(770) 488-2883

C. E-MAIL ADDRESS

hrb5@cdc.gov

11. TABLE OF CONTENTS

(x) DESCRIPTION (x) DESCRIPTION

PART I – THE SCHEDULE PART II – CONTRACT CLAUSES

X A SOLICITATION/CONTRACT FORM 1 X I CONTRACT CLAUSES 42

X B SUPPLIES OR SERVICES AND PRICES/COSTS 2 PART III - LIST OF DOCUMENTS, EXHIBITS AND OTHER ATTACH.

X C DESCRIPTION/SPECS./WORK STATEMENT 9 X J LIST OF ATTACHMENTS 53

X D PACKAGING AND MARKING 20 PART IV – REPRESENTATIONS AND INSTRUCTIONS

X E INSPECTION AND ACCEPTANCE 21 REPRESENTATIONS, CERTIFICATIONS, AND

X F DELIVERIES OR PERFORMANCE 22 X K OTHER STATEMENTS OF OFFERORS 54

X G CONTRACT ADMINISTRATION DATA 23 X L INSTRS., CONDS., AND NOTICES TO OFFERORS 58

X H SPECIAL CONTRACT REQUIREMENTS 33 X M EVALUATION FACTORS FOR AWARD 72

OFFER (Must be fully completed by offeror) NOTE: Item 12 does not apply if the solicitation includes the provisions at 52.214-16, Minimum Bid Acceptance Period.

12. In compliance with the above, the undersigned agrees, if this offer is accepted within calendar days (60 calendar days unless a different period is inserted by the offeror) from the date for receipt of offers specified above, to furnish any or all items upon which prices are offered at the price set opposite each item, delivered at the designated point(s), within the time specified in the schedule.

13. DISCOUNT FOR PROMPT PAYMENT

(See Section I, Clause No. 52-232-8)

10 CALENDAR DAYS

20 CALENDAR DAYS

30 CALENDAR DAYS

AMENDMENT NO. DATE AMENDMENT NO. DATE

CODE FACILITY 16. NAME AND ADDRESS OF PERSON AUTHORIZED TO SIGN OFFER

15B. TELEPHONE NO.

AREA CODE NUMBER EXT.

15C. CHECK IF REMITTANCE ADDRESS

IS DIFFERENT FROM ABOVE - ENTER

SUCH ADDRESS IN SCHEDULE.

17. SIGNATURE

18. OFFER DATE

AWARD (To be completed by Government)

19. ACCEPTED AS TO ITEMS NUMBERED 20. AMOUNT

22. AUTHORITY FOR USING OTHER THAN FULL AND OPEN COMPETITION:

21. ACCOUNTING AND APPROPRIATION

10 U.S.C. 2304(c)( ) 41 U.S.C. 253(c)( ) 23. SUBMIT INVOICES TO ADDRESS SHOWN IN (4 copies unless otherwise specified)

ITEM

24. ADMINISTERED BY (If other than Item 7) CODE 25. PAYMENT WILL BE MADE BY CODE 434 Centers for Disease Control and Prevention (PGO) Acquisition and Assistance Branch 1 2920 Brandywine Road, MS E-15 Atlanta GA 30341-5539

Centers for Disease Control and Prevention (FMO) PO Box 15580 404-498-4050 Atlanta, GA 30333-0080

26. NAME OF CONTRACTING OFFICER (Type or print)

27. UNITED STATES OF AMERICA

(Signature of Contracting Officer)

28. AWARD DATE

IMPORTANT -- Award will be made on this form, or on Standard Form 26, or by other authorized official written notice.

AUTHORIZED FOR LOCAL REPRODUCTION STANDARD FORM 33 (REV. 9-97)

PREVIOUS EDITION IS UNUSABLE Prescribed by GSA

FAR (48 CFR) 53.214©

K

Section B - Supplies Or Services and Prices/Costs

Base Contract Period – (6 Months)

ITEM SUPPLIES / SERVICES EST COST FIXED FEE TOTAL EST AMOUNT

0001 Tuberculosis Epidemiologic Studies

Consortium (TBESC) Research entitled, “Improving the Diagnosis and Treatment of Latent TB Infection” and in accordance with Section C, Statement of Work (SOW).

Performance Period:

September 15, 2011 through March 14, TOTAL ESTIMATED CPFF

AMOUNT

Option Period 1 (6 Months):

ITEM SUPPLIES / SERVICES EST COST FIXED FEE TOTAL EST AMOUNT

0002 Tuberculosis Epidemiologic Studies

Consortium (TBESC) Research entitled, “Improving the Diagnosis and Treatment of Latent TB Infection” and in accordance with Section C, Statement of Work (SOW).

Performance Period:

March 15, 2012 through September 14, TOTAL ESTIMATED CPFF

Option Period 2 – Year 2 (12 Months):

0003 Tuberculosis Epidemiologic Studies

Consortium (TBESC) Research entitled, “Improving the Diagnosis and Treatment of Latent TB Infection” and in accordance with Section C, Statement of Work (SOW).

Performance Period:

September 15, 2012 through September 14, 2013

Option Period 3 – Year 3 (12 Months):

0004 Tuberculosis Epidemiologic Studies

Consortium (TBESC) Research entitled, “Improving the Diagnosis and Treatment of Latent TB Infection” and in accordance with Section C, Statement of Work (SOW).

Performance Period:

September 15, 2013 through September 14, 2014

Option Period 4 – Year 4 (12 Months):

0005 Tuberculosis Epidemiologic Studies

Consortium (TBESC) Research entitled, “Improving the Diagnosis and Treatment of Latent TB Infection” and in accordance with Section C, Statement of Work (SOW).

Performance Period:

September 15, 2014 through September 14, 2015

Option Period 5 – Year 5 (12 Months):

0006 Tuberculosis Epidemiologic Studies

Consortium (TBESC) Research entitled, “Improving the Diagnosis and Treatment of Latent TB Infection” and in accordance with Section C, Statement of Work (SOW).

Performance Period:

September 15, 2015 through September 14, 2016

Option Period 6 – Year 6 (12 Months):

0007 Tuberculosis Epidemiologic Studies

Consortium (TBESC) Research entitled, “Improving the Diagnosis and Treatment of Latent TB Infection” and in accordance with Section C, Statement of Work (SOW).

Performance Period:

September 15, 2016 through September 14, 2017

Option Period 7 – Year 7 (12 Months):

0008 Tuberculosis Epidemiologic Studies

Consortium (TBESC) Research entitled, “Improving the Diagnosis and Treatment of Latent TB Infection” and in accordance with Section C, Statement of Work (SOW).

Performance Period:

September 15, 2017 through September 14, 2018

Option Period 8 – Year 8 (12 Months):

0009 Tuberculosis Epidemiologic Studies

Consortium (TBESC) Research entitled, “Improving the Diagnosis and Treatment of Latent TB Infection” and in accordance with Section C, Statement of Work (SOW).

Performance Period:

September 15, 2018 through September 14, 2019

Option Period 9 – Year 9 (12 Months):

0010 Tuberculosis Epidemiologic Studies

Consortium (TBESC) Research entitled, “Improving the Diagnosis and Treatment of Latent TB Infection” and in accordance with Section C, Statement of Work (SOW).

Performance Period:

September 15, 2019 through September 14, 2020

Option Period 10 – Year 10 (12 Months):

0010 Tuberculosis Epidemiologic Studies

Consortium (TBESC) Research entitled, “Improving the Diagnosis and Treatment of Latent TB Infection” and in accordance with Section C, Statement of Work (SOW).

Performance Period:

September 15, 2020 through September 14, 2021

*Amount will be specified in the individual task orders issued under this contract.

B.2 Ordering of Services

The Government contemplates award of an Indefinite Delivery, Indefinite Quantity (IDIQ) contract to provide technical services to the Centers for Disease Control and Prevention (CDC) to obtain research support for the Tuberculosis Epidemiologic Studies Consortium in improving diagnosis and treatment of latent TB Infection (LTBI). Contractors as an independent organization and not as an agent of the Government shall provide CDC with this mechanism in accordance with Section C, Statement of Work and as further defined by individual Task Order Statements of Work.

This solicitation requires the submission of two (2) proposals:

I. A technical proposal for the Basic IDIQ SOW described in this Request for Proposal (RFP);

II. Atechnical and businessproposal in response to the Request for Task Order Proposal (RFTOP) (TBESC) Task Order #0001 as described in Attachement J6 and entitled “Prospective Comparison of the Tuberculin Skin Test (TST) vs. Interferon Gamma Release Assays (IGRAs) in Diagnosing Latent Tuberculosis Infection (LTBI) and in Predicting Progression from LTBI to Active Tuberculosis Disease”

The Contractor shall provide all management, supervision, labor, facilities, and materials necessary to perform the work ordered via task orders issued under this contract.

B.3 Task Order Types

As defined in FAR 16, Type of Contracts, Cost-Plus-Fixed Fee, is permissible for task orders under the Basic contract. The type of order to be awarded will be stated in each Request for Task Order Proposal.

B.4 Consideration –Indefinite Delivery Indefinite Quantity Contract

Each individual task order shall specify the price to perform the services required of that specific task order.

Funds shall be obligated on each individual task order. The Contractor shall not exceed the amount negotiated for each individual task order without prior written approval of the Contracting Officer. The Government is not obligated to reimburse the Contractor for costs incurred in excess of the amount negotiated for each individual task order, or for costs that are specifically identified in this contract as being unallowable.

The Contractor shall not commence work until a task order or other notification for a specific assignment is issued by the Contracting Officer. If mailed, a task order is considered "issued" when the Government deposits the order in the mail. Orders may be issued orally, by facsimile, or electronically.

The Contracting Officer is the only person authorized to request work plans or issue task orders under this contract.

The Government is not obligated to reimburse the Contractor for cost incurred before issuance of a task order or other notification by the Contracting Officer.

B.5 Minimum Guarantee

The Government guarantees that task orders amounting to a minimum of $10,000 will be issued during the base period of the contract term. In the event that during the contract term the Contractor receives obligations of less than this minimum, the Government will reimburse the Contractor for the difference between the actual obligations and the guaranteed minimum.

B.6 Maximum Contract Value

Individual task orders will be awarded as they are identified. The maximum value of the contract, if all options are exercised, is as follows:

Contract Period NTE Base Period 6 Months $30,000 Option Period 1 6 Months $80,000 Option Period 2 12 Months $450,000 Option Period 3 12 Months $450,000 Option Period 4 12 Months $450,000 Option Period 5 12 Months $450,000 Option Period 6 12 Months $450,000 Option Period 7 12 Months $450,000 Option Period 8 12 Months $450,000 Option Period 9 12 Months $300,000 Option Period 10 12 Months $300,000

If the Government's requirements for services set forth in the solicitation do not result in orders in the amounts described as “maximum," the event shall not constitute the basis for an equitable price adjustment under this contract.

B.7 Ordering of Services

Order for services will be placed by individual task orders under this contract in accordance with Section B.8 “Award of Task Orders” and Section I Ordering clauses.

B.8 Award of Task Orders

After contracts are awarded by the Government, services will be ordered by the issuance of individual task orders awarded on a competitive basis. Each awardee will be given a fair opportunity to be considered for award of each individual task order.

The fair opportunity process will operate as follows:

a. Task Orders – General:

(1) A written task order, in accordance with the terms and conditions set forth herein, shall be the only basis for acquisition of services under this contract.

(2) Orders will be placed directly with the Contractor by CDC Contracting Officers as a result of a

Request for Task Proposal (RFTP) competition.

(3) Some orders may be exempt from competition in accordance with FAR 16.505(b)(2) and paragraph B.8 “Fair Opportunity Exceptions,” as shown below.

(4) The Contractor shall be responsible for performance in accordance with the terms and conditions of the contract when a Task Order is placed by a CDC Contracting Officer.

(5) In accordance with FAR 5.202, Task Orders placed under any resultant contract need not be synopsized.

(6) Contractors may not protest the award of the Task Order issued under the resultant contracts, except on the grounds that the order increases scope, period, or maximum value of the contract.

b. Ordering Procedures:

Request for Task Order Proposal (RFTOP) - When the Government identifies a specific requirement for work to be performed under this contract, the contracting officer will issue a written Request for Task Order Proposal (RFTOP) to each awardee under this RFP. The RFTOP will contain information comparable to a competitive solicitation. Such information will include, but is not limited to, (1) Statement of Work that identifies the Government's requirement, (2) instructions to the contractors for responding to the RFTOP, and

(3) evaluation and award factors. RFTOPs will be sent by electronic mail (email) to each awardee and responses will be required via email in Microsoft Word and Microsoft Excel. Therefore, awardees are required to have electronic mail capability.

Task Order Evaluation and Selection Procedures - Awardees that elect to respond to RFTOP must submit their proposals to the CDC Contracting Office within 14 calendar days unless otherwise specified in the RFTOP via electronic mail in Microsoft Word and Microsoft Excel formats. Awardees that elect to respond to a RFTOP shall provide a technical proposal and profile of the personnel assigned or to be assigned to the task. The proposal shall include a Person Loading chart. This chart shall indicate for each proposed labor position, the number of man hours subdivided by the specific components of the task. The purpose of this chart is to associate the roles and the amount of effort to be performed by each individual proposed in the direct labor category for each task component required under the SOW. Responses shall also include a budget detailing the cost of each major subtask identified within the proposal. Each offer received in response to a RFTOP will be evaluated on both technical and cost merits. The Government, may at its discretion, use past performance and cost control on previous projects as an evaluation factor. Evaluation criteria will be specified in the RFTOP.

Evaluation criteria may vary for each RFTOP depending upon the emphasis of the project.

CDC reserves the right to award individual task orders on the basis of initial offers received without discussion, therefore offers should contain the offeror's best terms from a cost/price and technical standpoint.

Offerors are advised that in the evaluation process, the cost/price and technical merit importance will be stated in the RFTOP.

Upon receipt of the Contractors' proposals, the Government will evaluate proposals received and select the Contractor who offers the best value for the Task Order. The Government and the Contractor will negotiate projected levels of effort and cost ceiling for the individual tasks. Negotiated cost ceiling for individual tasks shall not be exceeded during performance without prior written authorization of the Contracting Officer.

Award of Task Order will be made as a result of "best value" source selection. Best value means that the Government will perform a cost/technical trade-off analysis such that business judgment will be exercised in selecting the most advantageous alternative to the Government, considering both the costs and technical merit of proposals. The determination of best value will be made by comparing the differences in the value of performance capability factors with the differences in the costs proposed. The Government will not make an award at a significantly higher overall cost to the Government to achieve only slightly superior performance capability features. The Government will make this assessment through the development of trade-off analyses and other analytic studies that involve the assessment of benefits of superior performance capability features -for example, economic benefits clearly attributable to superior productivity; probability of successful contract performance; and/or unique and innovative approaches or capabilities - versus the added costs. Overall cost to the Government may become the ultimate determining factor for award of the contracts as proposals become more equal based on the other factors. The degree of equality between Offerors' proposals will be measured by the quantity, significance, and applicability of the superior features proposed and not by the total scores achieved.

Cost/price realism and cost risk/probable cost to the Government are of significant importance in the overall task order award decision. Therefore, Offerors are reminded that award will be made to that Offeror whose proposal provides the combination of features that offers the greatest overall value to the Government.

The Cost portion of contractor responses to RFTOP will not be assigned quantitative scores. The information contained in the proposals will be analyzed and evaluated to determine validity, realism and reasonableness of each cost proposed, and to determine the cost risk and most probable cost to the Government. The purpose of this cost realism analysis will be to determine if:

(a) The Offeror's proposed costs are realistic for the work to be performed;

(b) The proposed costs demonstrate that the Offeror understands the Government's requirements; and

(c) The proposed costs are consistent with the various elements contained in the proposal.

Based upon this cost realism analysis, an assessment will be made of the most probable cost to the Government when awarding a Task Order.

Task orders will be issued to the Contractor by the Contracting Officer. Task orders will include written specifications detailing and describing the nature of the work to be performed. Successful Contractor will be authorized to commence work only upon receipt of specific Task Orders issued by the Contracting Officer.

B.9 FAIR OPPORTUNITY EXCEPTIONS FAR 16.505 (b) (1)

Exceptions to the fair opportunity process. The contracting officer shall give every awardee a fair opportunity to be considered for a delivery-order or task-order exceeding $3,000 unless one of the following statutory exceptions applies:

(i) The agency need for the supplies or services is so urgent that providing a fair opportunity would result in unacceptable delays.

(ii) Only one awardee is capable of providing the supplies or services required at the level of quality required because the supplies or services ordered are unique or highly specialized.

(iii) The order must be issued on a sole-source basis in the interest of economy and efficiency because it is a logical follow-on to an order already issued under the contract, provided that all awardees were given a fair opportunity to be considered for the original order.

(iv) It is necessary to place an order to satisfy a minimum guarantee.

Section C – Description/Specification/Work Statement

C. 1 PROJECT BACKGROUND

Tuberculosis (TB) is the world’s second leading cause of death from infectious disease, killing an estimated 1.7 million people each year. Its reservoir is the estimated one-third of the world’s population who are infected with Mycobacterium tuberculosis but have no symptoms. One in ten of these persons with latent TB infection (LTBI) will eventually develop active disease and, on average, spread the infection to an additional 10 to 15 people before dying or recovering.1 In the United States, where an estimated 11 million people have LTBI, identification and treatment of those persons most likely to progress to active TB is a key component of TB prevention and control.

Identification of LTBI

Two methods are available for diagnosis of LTBI: the in vivo Tuberculin Skin Test (TST) and the ex vivo Interferon Gamma Release Assay (IGRA), both of which identify an adaptive immune response to mycobacterial antigens.2

1) Tuberculin Skin Test

The TST, the most widely used screening test, has been in use for over a century.3 It measures cell-mediated immunity in the form of a delayed-type hypersensitivity (DTH) response to the most commonly used purified protein derivative (PPD) of tuberculin. TST reactions in humans are measured by the diameter of induration 48–72 hours after PPD injection.

The TST has well-known problems with sensitivity and specificity. Its sensitivity varies by the chosen cut point for determining a positive result (5, 10, or 15 mm of induration). Tuberculin PPD is a crude mixture of antigens, many of which are shared by a number of nontuberculous mycobacteria that can cause cross-reactions. A negative TST is difficult to interpret in individuals who are immunocompromised from underlying disease, such as HIV, or from drug treatment for cancer and other diseases. However, the biggest problem with TST use in the United States is false positives caused by cross-reactivity with Bacille Calmette-Guerin (BCG) vaccine, widely used abroad to protect newborns against TB meningitis and other severe forms of TB. More than 37 million foreign-born persons live in the United States as permanent residents or visitors. Beginning in 2002, foreign-born persons have accounted for the majority of newly diagnosed TB cases, with the proportion increasing each year. In 2009, 60 percent of newly diagnosed TB cases occurred among foreign-born persons. An estimated 6.9 million foreign-born persons who are permanent residents of the United States have LTBI. Improvements in TB prevention and control in the foreign-born population will require a test for LTBI that is more specific than the TST.

2) Interferon Gamma Release Assays

IGRAs were developed in response to the limitations of TST. IGRA testing is based on the hypothesis that T-cells of individuals sensitized by M. tuberculosis will produce interferon gamma (IFN-γ) when they re-encounter mycobacterial antigens. Specific IFN-γ production in response to mycobacterial antigens, therefore, is presumed to be indicative of M. tuberculosis infection.2, 4

IGRAs measure in vitro IFN-γ production by circulating T-cells after 16–20 hours of stimulation by specific M.

tuberculosis antigens. The antigens used in IGRAs are produced by genes (ESAT-6 and CFP-10) not found in BCG or in most environmental mycobacteria.5,6 Therefore, IGRAs may produce fewer false positives in persons previously vaccinated with BCG or who come from countries where nontuberculous mycobacterial infections are common.5,6 In 2001, the Food and Drug Administration approved the first IGRA, QuantiFERON-TB test (Cellestis Limited, Carnegie, Victoria, Australia) for diagnosing M. tuberculosis infection. The two IGRAs currently marketed in the United States are the QuantiFERON-TB Gold-in-tube test (QFT-GIT) (Cellestis Limited, Carnegie, Victoria, Australia) and the T-SPOT.TB test (T-Spot) (Oxford Immunotec Limited, Abingdon, United Kingdom).

3) TST vs. IGRA

The predictive value of a positive TST (the probability that the patient will develop TB in the near future) is generally poor, while the negative predictive value (the probability that a person with a negative TST will not develop TB in the future) is high. The positive predictive value of an IGRA may be better than the TST because of the higher test specificity and similar, or probably higher, sensitivity.7,8

For testing of immunosuppressed persons, evidence suggests that IGRAs have superior sensitivity compared to

TST. This is because conditions in vitro can be adjusted for immunosuppression by changing incubation time and/or cell numbers. For example, a longer incubation time or a larger number of cells could be used for a person with neutropenia.

A specific advantage of IGRA testing is that stimulation reactions with negative and positive controls (mitogen stimulus) are conducted in parallel to compare test performance to background signals or general T-cell responsiveness. In persons with immune suppression, an impaired mitogen response is an indirect measure of the overall degree of immunosuppression. Thus, unlike the TST, in vitro IGRA tests may be able to better discriminate true negative responses from anergy. In addition, IGRA quantitation may help estimate the degree of individual immunosuppression.

Based on evaluation of studies to date, the CDC in 2005 and 2010 published guidelines supporting the equivalence of TSTs and IGRAs in most situations, with a preference for IGRAs in certain situations, including screening of foreign-born persons.9,10 However, no large-scale population based studies have been done to compare the abilities of the two tests to (1) identify persons with LTBI, overall and in important subpopulations, and (2) determine which persons with LTBI are most likely to progress to TB.

Treatment of LTBI

1) Risk factors for failure to initiate or complete LTBI treatment

Many studies have tried to identify predictors of non-compliance with LTBI treatment, overall and in various high-risk groups:

• A meta-analysis of published studies on adherence to and completion of LBTI treatment found poor adherence and completion rates across high-risk groups, regardless of the regimen.11 In addition, the analysis found inconsistent use of tools for measuring and improving adherence.

• Of 15,035 persons treated for LTBI in New York City Health Department clinics from January 2002 to August 2004, 6,788 (45.2%) completed treatment.12 Those completing treatment were more likely to be <35 years old, contacts of pulmonary TB patients, treated by DOPT, or to have received a shorter rifamycin regimen instead of isoniazid. Of those who failed to complete treatment, 3,748 (47.8%) failed to return for isoniazid and 59 (14.7%) failed to return for rifamycin after the first month of medication dispensing.

• Of 1,723 persons offered LTBI treatment at an urban New Jersey TB clinic in 1998, 1,572 (91.2%) accepted and 607 (38.6%) completed therapy.13 Of those persons who failed to complete treatment, about half dropped out before the end of the first month. Among persons <35 years old, failure to complete therapy was associated with birth in Haiti or the Dominican Republic.

• In an assessment of 217 patients started on LTBI treatment at a pulmonary clinic, 75% of those who failed to complete treatment had one or both of the following risk factors: 1) perception of low risk of progression to active TB without LTBI treatment, and 2) aversion to venipuncture.14 In a Canadian study, male gender and smoking were independent predictors of failure to complete treatment.15

• In a study of 690 LTBI patients offered 9 months of isoniazid at a hospital TB clinic in Rhode Island, 61.7% completed therapy. Failure to complete treatment was associated with younger age, lack of insurance, reporting of side effects, and being post-partum.16

These data suggest that major factors in treatment non-adherence/non-completion vary by study and population.

Some of the more commonly reported risk factors include perceived low risk of progression to TB, complications of LTBI treatment, treatment inconvenience, and aversion to venipuncture. Possible solutions to these problems would be more specific tests that target LTBI patients at highest risk for progression to TB; enhanced education, and shorter-course therapy to decrease treatment complications and inconvenience.

2) The effect of shorter-course LTBI treatment on adherence, hepatotoxicity, and other adverse events

Isoniazid (INH) for nine months (9H) is the standard treatment for LTBI. The length of treatment is considered a major barrier to completion. Other barriers to its use include concerns about hepatotoxicity and the increasing influx of foreign-born persons from countries with a higher prevalence of INH resistance. In 2000, CDC guidelines accepted 4 months of rifampin (4R) as an alternative to 9H.17

A number of studies have compared adherence and completion rates of 9H with shorter regimens.

Comparison of 4R and 9H:

• At a county chest clinic in New Jersey, self-administered 9H was prescribed for patients with LTBI until 2002, when treatment was shifted predominantly to self-administered 4R.18 Among patients treated in 2003 (predominantly 4R), 80.5% completed treatment, compared to 53.2% of patients treated in 2000 (predominantly 9H, p<0.0001). A greater proportion of those lost to follow-up were in the 9H group (34.7% compared to 12.6% in the 4R group, p <0.0001).

• At a public health clinic in the Baltimore area, 71.6% of 1,379 patients prescribed 4R completed therapy, compared to 52.6% of 770 patients prescribed 9H (p<0.001).19 Fewer patients in the 4R group experienced either clinically-recognized hepatotoxicity (0.08% compared to 1.8% in the 9H group, p<0.001) or adverse reactions resulting in permanent discontinuation (1.9% compared to 4.6% in the 9H group, p<0.001).

Comparison of 2 months of pyrazinamide and rifampin (2RZ) and longer INH-based regimens:

Although CDC guidelines had previously accepted 2 months of pyrazinamide and rifampin (2RZ) as an alternative to longer INH regimens, this recommendation was withdrawn after surveys of TB programs identified higher rates of severe liver toxicity, including deaths, associated with this regimen.20 A subsequent meta-analysis of six randomized controlled trials confirmed a higher rate of severe adverse events with 2RZ compared to INH among persons free of HIV infection.21 The following reports include studies conducted before and after the change in CDC guidelines:

• Among 224 patients treated in a community setting from 1991 through 2001, 71% of 110 patients given

2RZ completed therapy compared to 59% of an equal number given 6H.22 Hepatotoxicity (serum aminotransferase [ALT] >160 U/L) was documented in 13% of patients in the 2RZ group and in 4% of patients in the 6H group (p = 0.03). Severe hepatotoxicity (ALT >1,600 U/L) was documented in 2/43 (5%) patients receiving 2RZ before intensive monitoring was instituted, and in none of the remaining 67.

• Among 589 adults treated at three urban TB clinics, 16/207 (7.7%) assigned to 2RZ developed grade 3 or 4 hepatotoxicity compared with 2/204 (1%) assigned to 6H group (OR 8.46, 95% CI, 1.9 to 76.5). The 2RZ regimen was more likely than the 6H regimen to be discontinued because of hepatotoxicity (p = 0.033).23

• In a non-randomized, observational study of 459 patients at a county health department from June 2000 to January 2006,24 treatment was completed by 241/310 (77.7%) receiving either 2RZ or rifampin for 4 to 6 months and by 98/149 (65.8%) receiving 9H (p = 0.009). Moderate to severe hepatotoxicity occurred in 6.1% of patients receiving 2RZ and 2.0% of patients receiving 9H (p=0.09); hepatotoxicity resolved after discontinuation of medication.

• In a trial of three LTBI regimens at 12 Spanish hospitals, 316 HIV-infected patients were randomly assigned to 6H, rifampin and INH for 3 months (3RH), or 2RZ and followed for two years after completion of treatment.25 Seven patients were withdrawn due to hepatotoxicity (5 in 6H, 2 in 3RH, and 0 in 2RZ.

Eleven TB cases occurred during follow-up. When compared to the 2RZ regimen, the relative risk for TB in the 6H and 3RH regimens was 1.76 and 2.34, respectively.

• In Broward County, Florida, 125 HIV-infected patients diagnosed with LTBI from February 1999 through March 2001 received 2RZ by directly observed preventive therapy (DOPT), and were compared to 93 HIV-infected patients diagnosed from 1996 through 1998 who were given 12H by self-administered treatment (SAT).26 Completion rates were 92% for 2RZ and 61% for 12H (p<0.001). Five 2RZ and no 12H patients discontinued treatment because of side effects.

• A randomized trial in the United States, Haiti, Mexico, and Brazil compared 2RZ to 12H in 1,583 HIV-infected patients diagnosed with LTBI from September 1991 to May 1996.27 Completion rates were 80% for 2RZ and 69% for 12H (p<.001). After a mean follow-up of 37 months, 19 (2.4%) of the 2RZ and 26 (3.3%) of the 12H patients developed confirmed TB (rates of 0.8 and 1.1 per 100 person-years, respectively; risk ratio, 0.72 [95%CI, 0.40-1.31]). In multivariate analysis, there were no significant differences in rates for confirmed or probable TB (p=.83), HIV progression and/or death (p=.09), or overall adverse events (p=.27), although drug discontinuation was slightly higher in the 2RZ group (p=.01).

• A study at five county jails and TB outreach clinics for homeless persons in three cities treated 1,211 patients (844 inmates and 367 homeless persons) with 2RZ.28 Treatment was stopped in 66/162 (13.4%) patients with drug-related adverse events. One person died of treatment-related liver failure; of 714 others whose ALT was measured during treatment, 43 measured >5 times the upper limits of normal. In multivariate analyses, increasing age, an abnormal baseline ALT, and unemployment within the previous 24 months predicted hepatotoxicity. Completion rates were similar in jail inmates (47.5%) and homeless persons (43.6%).

Other LTBI treatment regimens:

• Among 116 patients at a Canadian respiratory hospital randomly assigned to 4R or 9H, 86% took >90% of rifampin doses within 20 weeks and 62% took 90% of INH doses within 43 weeks (relative risk 1.4, 95% CI 1.1−1.7). Two patients taking rifampin (3%) and 8 patients taking isoniazid (14%) discontinued therapy because of adverse events; three patients taking isoniazid developed drug-induced hepatitis.29

• A randomized trial comparing once-weekly rifapentine/INH for 12 weeks with daily 2RZ among 399 household contacts of TB cases was halted before completion because of 2RZ-associated hepatotoxicity.30 Twenty (10%) of 193 participants on 2RZ experienced grade 3 or 4 hepatotoxicity, compared with two (1%) of participants on rifapentine/INH (p<0.001). All participants' liver enzyme levels returned to normal during follow-up. Four episodes of active TB developed in two years of follow-up, three in the rifapentine/INH group and one in the 2RZ group (1.46 vs. 0.52%; difference, 0.94%; 95% CI 1.6−3.7%).

In summary, considerable data show that shorter-course LTBI therapy improves adherence and completion and does not compromise effectiveness.

3) Impact of incentives, education, and directly observed preventive therapy (DOPT) on treatment completion

Since directly observed therapy (DOT) demonstrably improves completion of therapy for TB disease, one could expect that DOPT would have a similar effect on completion of LTBI treatment. The following studies have compared DOPT and self-administered therapy (SAT) along with other strategies (education, incentives, convenience) to improve adherence:

• At a San Francisco TB clinic, 70.3% of 460 patients treated with DOPT in 1997-98 completed treatment, compared to 47.9% of 619 historical controls treated with SAT in 1993-4.31 Controlling for gender, age, race/ethnic group and cohort, patients on DOPT were nearly twice as likely to complete LTBI treatment

(OR 1.93, 95% CI 1.25–3.00).

• Twice-weekly DOPT and $10 per visit cash incentives persuaded 24 of 27 injection drug users in San Francisco to complete a 6H regimen.32 In a three-arm randomized study among 163 injection drug and crack cocaine users, INH treatment completion was above 50% if $5 per visit was paid at twice-weekly DOPT administered either at a fixed storefront location (60% completion) or at a location of the participant’s choice (53% completion). Completion was 4% among participants who received no incentive.33

• A study of DOPT among 119 homeless and “marginally housed” adults in San Francisco found no difference in treatment completion (86%) between $5 cash incentives or non-cash equivalents. However, those who received cash required less follow-up for missed doses. Completion was significantly higher among males (OR 5.65, 95%CI 1.36–23.40) and persons living in low-cost residential hotels at study entry

(OR 4.86, 95%CI 1.32–17.94).34

• A randomized trial of 6H treatment completion after release from the San Francisco City and County Jail compared education every two weeks while in jail, a $25 incentive for going to the San Francisco County TB Clinic within 1 month of release, or usual care.35 Of 322 persons followed after release, completion proportions were 23% in the education group and 12% in both the incentive and usual care groups Those in the education group were more than twice as likely to complete therapy (adjusted OR, 2.2; 95% CI, 1.04–4.72; p=.04).

• In a comparison of 2RZ administered by DOPT with self-administered 12H among HIV-infected patients, 92% of 135 2RZ recipients completed treatment compared to 61% of the historical 12H controls.36

These data suggest that DOPT, either alone or in combination with incentives, increases the likelihood that a patient will complete LTBI treatment. Other strategies, including education and incentives alone, may also hold promise in select populations.

C.2 PROJECT NEED

Accurate LTBI diagnosis, safe and effective treatment, and tools to ensure treatment completion are essential for TB elimination. Research is needed to find: 1) diagnostic tests that reliably identify those persons with LTBI at greatest risk of progressing to TB disease; 2) strategies to ensure LTBI treatment acceptance and completion; and 3) LTBI treatment regimens that are short, cost-effective, and that have a lower risk of liver damage than even the small risk currently associated with long-term INH therapy.

Thus, for the next decade, the research focus of the Tuberculosis Epidemiologic Studies Consortium (TBESC) will be LTBI. The results of this project will have a major impact on reducing the prevalence of LTBI in the United States.

C.3 SCOPE OF WORK

Project Identification and Purpose

The purpose of this contract is to support TBESC research to improve the diagnosis and treatment of LTBI.

Research studies to be conducted under this SOW include the evaluation of:

1. TST and IGRAs in diagnosing LTBI and in predicting progression from LTBI to TB disease.

2. Measures to enhance adherence and completion of LTBI treatment, such as:

a. Shorter-course LTBI preventive therapy

b. Self-administered vs. directly observed preventive therapy

c. Education programs, either general or targeted to specific high-risk populations

d. Cash or non-cash incentives

e. Enablers (e.g., community based administration vs. SAT vs. clinic-based administration), and

f. Innovative approaches such as social network contacts of LTBI patients, community networks/organizations, electronic reminders, or outreach to refugee/immigrant communities.

All LTBI patients entered into the studies will be followed and evaluated for signs and symptoms of TB disease at six-month intervals for 24 months. The CDC will conduct periodic matches between registries of persons with LTBI and registries of TB patients to identify study participants who have progressed from LTBI to TB disease.

The CDC will coordinate the design of the research studies. The contractor(s) will provide input into the final protocol. All contractors will agree to follow the CDC protocol in terms of specific LTBI interventions to be implemented, the method(s) of comparison and evaluation, and periodic follow-up data to be collected.

Study Population

Potential study participants are groups at high-risk for LTBI and TB disease including:

• Close contacts of persons known or suspected to have active TB.

• Immigrants and refugees with Class B1 and B2 TB notification status.

• Foreign-born persons from areas that have a high incidence of active TB who have lived in this country for less than 2 years.

• Residents and employees of congregate settings whose clients are at increased risk for active TB (e.g., correctional facilities, long-term care facilities, and homeless shelters).

• Populations defined locally as having an increased incidence of latent M. tuberculosis infection or active

TB, possibly including medically underserved, low-income populations, or persons who abuse drugs or alcohol.

• Persons with human immunodeficiency virus (HIV) infection.

• Persons who are receiving immunosuppressive therapy, such as tumor necrosis factor-alpha (TNF-α) antagonists, systemic corticosteroids equivalent to ≥15 mg of prednisone per day, or immune suppressive drug therapy following organ transplantation.

• Persons with a history of untreated or inadequately treated active TB, including persons with fibrotic changes on chest radiograph consistent with prior active TB.

C.4 Technical Contract Requirements

The contractor(s) shall conduct all phases of the studies, including enrollment, screening, diagnosis, treatment, observation, data collection, and follow-up to determine if the person progresses to active TB disease.

Specific contract requirements are listed below. The contractor shall:

a. Conduct research studies in accordance with each study’s applicable protocol. Each protocol will describe in detail the required procedures, including required laboratory tests (which must be performed in qualified laboratories), TB/LTBI testing, clinical and laboratory follow-up, monitoring of adherence, adverse effects from and completion of LTBI therapy, and follow-up to determine progression to active TB disease within two years of LTBI diagnosis. Each study will provide specific data collection forms for reporting results.

b. Identify, recruit, enroll, screen, consent, treat, and follow patients in groups at high risk for LTBI or active

TB, as defined in each study’s protocol. The patients shall reflect the demographics of the local catchment area. Expected enrollment numbers will be outlined in each study’s protocol.

c. Retain and follow for two years all patients enrolled in studies.

d. Be responsible for the safe and timely shipping of specimens required by individual protocols (such as plasma/serum specimens) to designated laboratories or repositories.

e. Conduct and report on studies according to accepted good clinical practice and in compliance with existing U.S. Federal Regulations (including CDC, U.S. Food and Drug Administration, and the Office of Human Research Protections [OHRP]) and applicable national policies concerning use of investigational agents and protection of human subjects. Because these studies will be funded by the U.S. Government, they must comply with regulatory requirements of the United States.

f. Report adverse events according to specific protocols and in compliance with applicable national and U.S.

regulatory requirements.

g. Enter and submit data into the CDC-developed data entry system using a password-protected entry system.

Report data according to the requirements of the specific protocol using the CDC-provided data management system (DMS).

h. Respond to data queries and requests from the CDC DMS.

i. Perform quarterly study quality assurance (QA) data checks for completeness, use of valid variables and responses, and logical consistency. The contractor shall correct data errors discovered during QA checks.

j. Respond to any QA issues noted by the COTR. The contractor shall investigate all QA issues and respond with written documentation containing a description of: (1) all issues that were identified; (2) issues that were resolved and (3) issues that could not be resolved and why. The errors shall be revised in the data entry system within two weeks after notice of QA issue.

k. Respond to any issues noted by the COTR concerning patient enrollment, management and follow-up. The contractor shall investigate all these issues and respond with written documentation containing a description of: (1) all issues that were identified; (2) issues that were resolved and (3) issues that could not be resolved and why. The contractor will provide an immediate action plan on how the issues will be corrected.

l. Ensure laboratory capacity and performance required by study protocols.

m. Send required administrative reports to CDC by a mutually agreed mechanism and schedule.

n. Provide retrospective historic and prospective data to conduct comparative effectiveness, outcome, and economic analysis. This includes the ability to identify, track, record, and report:

• Actual dollar costs related directly and indirectly to the activity or process of interest from all perspectives. These will include costs to the host agency, other health system components, third party payers, and others.

• Actual or estimated direct or indirect financial cost in lost wages or out of pocket spending to affected or associated individuals, such as patients or persons under surveillance or treatment or affected by these processes.

• Demographic, epidemiologic, and treatment data for individuals or cohorts to be used to model or estimate economic costs such as the burden of morbidity and/or mortality. Examples of these data include patient or comparison subject gender, age, nationality and race; or numbers of LTBI patients diagnosed and treated within a study area’s public and private health systems.

• Medical process, treatment, and outcome data to be used to model or estimate actual or potential effects of treatment or other activities such as TB cases averted or health outcomes related to alternative strategies. Examples of these data include detailed information about diagnostic and treatment program designs and protocols and details of specific courses of treatment such as type and duration.

• Data related to other economic or health impacts of the activity or process of interest that may extend beyond the perspective of the site health system. Examples of these data include TB-related surveillance, control, or treatment carried out by private health systems, employers, and Federal agencies.

o. Participate to the extent needed for co-authorship in development of topics for papers, and drafting and publication of papers.

p. Participate fully as a member of the TBESC throughout the duration of the contract. In particular, as an active member of the consortium, the contractor shall:

• participate in efforts to develop, implement, monitor, and update the TBESC research agenda

• adhere to the policies, procedures, and research protocols that guide all aspects of the TBESC activities and operations

• participate as appropriate in protocol development

• participate actively and as appropriate in TBESC committee activities

• participate fully in TBESC quality assurance activities

• cooperate with the TBESC site monitoring program

• abide by the TBESC policies and procedures for the publication of data

• participate in TBESC conference phone calls and e-mail communications

• attend two TBESC meetings per year.

Each contractor shall, as an independent organization and not as an agent of the Government, furnish all the necessary services, qualified personnel, material, equipment, and facilities to concurrently perform multiple studies to evaluate new approaches to the diagnosis treatment of LTBI using procedures outlined in each study’s applicable protocol. At the study sites, data must be available for external checking by CDC personnel against the original source documentation as required by U.S. Federal regulations. Either DTBE-CDC staff or an external Contract Research Organization (CRO) site monitor will evaluate good clinical practice, data collection and reporting, regulatory compliance, accurate protocol implementation, internal quality management, and test product accountability. DTBE-CDC staff will perform site visits approximately twice a year, or as needed to review implementation of selected protocols, provide training on protocol conduct, review internal quality assurance plans, or document error resolution.

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4. Vincenti D, Carrara S, Butera O, et al. Response to region of difference 1 (RD1) epitopes in human immunodeficiency virus (HIV)-infected individuals enrolled with suspected active tuberculosis: a pilot study. Clin Exp Immunol 2007;150:91–98.

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