CISAAttachment J.3 5_24_2012.docx

ATTACHMENT J.3

PERFORMANCE WORK STATEMENT

CISA SAMPLE TASK ORDER # 3

Subject to FAR 52.232-18 Availability of Funds

Title of Project: Adverse Events Following Immunization in Persons with Autoimmune Diseases

1. Applicability This effort is within the scope of the basic contract discussed in Requirement 2 section C.4.2 of the basic Performance Work Statement (PWS).

2. Order Type The Task Order shall be Cost-Plus-Fixed-Fee. Offerors are to submit the year one base period cost estimates for this Task Order. The year 1 base period estimate cost range for Task Order 3 is from $231,000 to $346,500.

3. Period of Performance The period of performance for this Task Order is from the date of the contract award for twelve months.

Base contract year: 9/20/2012-9/19/2013

4. Place of Performance Services will be performed at Contractor specified site in the United States.

5. Background and Need

One goal of vaccine safety research is to study adverse events following immunization (AEFI) in sub-groups of the population who may be at increased risk for the vaccine-preventable disease or AEFI.[endnoteRef:1],[endnoteRef:2] CDC’s Immunization Safety Office has specified a research need to study vaccine safety in persons with autoimmune diseases.2 [1: ] [2: ]

Autoimmune disease occurs when a person produces an abnormal immune response to self-antigens that results in tissue injury.[endnoteRef:3] A wide spectrum of diseases are considered to be autoimmune diseases; however, it is often difficult to distinguish true autoimmune diseases from diseases where antibodies or T-cells reacting to self-antigens may be present but not causing pathologic effects. Autoimmune diseases may be organ specific (e.g., Guillain-Barré, Syndrome (GBS), multiple sclerosis, type 1 diabetes mellitus) or systemic (e.g., Systemic lupus erythematosus (SLE), rheumatoid arthritis (RA)).3 Many of these systemic diseases are also considered rheumatic diseases. The incidence rates of autoimmune diseases vary by disease type, gender and age-group. For example, a review showed that the burden of SLE varied by ethnicity, gender, and age-group.[endnoteRef:4] Risk of infection in patients with chronic rheumatologic diseases is also twice as high as in unaffected individuals.[endnoteRef:5] [3: ] [4: ] [5: ]

Few studies have assessed the safety of vaccines in persons who already have an autoimmune disease at the time of vaccination. A recent Institute of Medicine (IOM) review assessed the evidence for causality between specific US vaccines and adverse events.[endnoteRef:6] In this review IOM assessed the evidence for a vaccine causing an exacerbation or relapse of an underlying autoimmune disease in 16 instances and in each concluded that the evidence was “inadequate to accept or reject a causal relationship” between the vaccine and AEFI (Table 1). The Pediatric Rheumatology Department of the Pediatrics Society of Sao Paulo conducted an evidence review about vaccination in children with rheumatologic disease.5 Of 16 antigens/vaccines assessed, the strength of evidence for safety was relatively limited for 11 (graded based on no studies, expert opinion or case reports only).5 At the time of this review’s completion in 2009, no studies had been identified to evaluate the safety of human papillomavirus vaccine (HPV), varicella vaccine, MMR, or rotavirus vaccine in this population. [6: ]

Having an autoimmune disease at the time of vaccination presents three potential safety concerns. The first concern is that exposure to a vaccine might exacerbate the underlying autoimmune disease, as may be observed with infections.6 Because persons with autoimmune diseases are expected to have flare-ups of their disease, it is challenging to distinguish whether exacerbations of the disease after vaccination are causally linked to the vaccine or due to chance. Moreover, without careful collection of clinical and laboratory data in these individuals it is difficult to understand whether transient elevations after vaccination of certain laboratory values (e.g., antinuclear antibodies (ANA) levels in persons with SLE) are clinically meaningful. Gaining a better understanding of risk for exacerbation and clinical and laboratory manifestations in persons with autoimmune diseases after vaccination could assist in developing vaccination and clinical guidance for the management of these patients. The research might also provide some insight into potential biological mechanisms for AEFI.

A second concern is that persons with an autoimmune disease may produce an abnormal immune response to a vaccine, which might lead to increased risk for AEFI, other than exacerbation of the underlying autoimmune disease. A third concern is that people with autoimmune diseases have an associated immunodeficiency, either from the disease itself or from treatment with immunosuppressive therapy. This concern is particularly relevant for live, attenuated vaccines. CDC’s Advisory Committee on Immunization Practices (ACIP) has stated that the safety of attenuated vaccines administered concurrently with recombinant human immune mediators and immune modulators are unknown.7 ACIP recommends avoiding use of live, attenuated vaccines during immunosuppressive therapy “unless the benefit of vaccination outweighs the hypothetical increased risk for an adverse reaction after vaccination.”7 Because the risk for the vaccine-preventable disease is increased in these individuals, it is not known how many persons with autoimmune diseases receive live vaccines. It is also not known how frequently clinically important AEFI occur in this group after vaccination.

6. Project Objective The purpose of this project is to study AEFI in persons with autoimmune diseases to identify risk factors and to advance the knowledge of vaccine safety and inform clinical and public health practices.

7. Scope of Work The Contractor will develop a scientifically sound research protocol to conduct a study that will evaluate AEFI in persons with autoimmune diseases to advance knowledge of vaccine safety. The Contractor will conduct a first phase, pilot study. In the pilot study clinical and laboratory data will be collected for a prospective cohort of consented participants who are followed.

8. Technical Requirements With technical guidance from CDC, the Contractor shall accomplish the following two activities: 1) Develop a draft protocol for a prospective clinical study of vaccine safety in persons with autoimmune diseases and 2) complete an IRB approved pilot study within 12 months of the Contract award. The Contractor shall be the primary site and lead the pilot study, under technical guidance from CDC. The Contractor could conduct the study as a single or multi-site study. All Contractors or sub-Contractors involved in the study must adhere to federal and institutional policies for human subjects protection. In addition, CDC policies for scientific review and clearance of protocols, abstracts, and manuscripts would apply (see the Special Considerations Section C.9.2 and C.9.3 of the Basic PWS). Additional specifications are described below.

1. Draft Protocol Development for a Full Scale Autoimmune Study

a. Background and rationale: The background and rationale for the specific study must be described, including the specific autoimmune conditions and vaccine exposures that will be evaluated. Appropriate literature should be cited. It should be noted how this study might 1) advance scientific knowledge and 2) improve clinical or public health practice.

b. Objective: The primary objective is to assess whether vaccines(s) increase risk for exacerbation or relapse for autoimmune diseases in a population with one or more autoimmune diseases. The Contractor is encouraged to consider the evidence gaps identified in the 2011 IOM review (Table 1)6 in defining objectives, although other relevant well-documented evidence gaps may be proposed. Secondary objectives may address other aspects of vaccine safety in persons with autoimmune diseases (e.g., vaccine safety in persons using immunosuppressive drugs).

c. Study population: The study population should be specified. The study may target pediatric and/or adult subjects with ≥1 autoimmune disease(s). The study population should include adolescents (within the age group 11-21 years) who are recommended to receive several vaccines, including recently licensed or recommended vaccines.8 The Contractor is also encouraged to enroll subjects of different race and ethnicity backgrounds, when feasible. The study must describe the criteria that will be used to enroll subjects, including how the specified autoimmune diagnoses will be determined. If more than one autoimmune condition is grouped together for a study (e.g., different forms of arthritis), the Contractor will describe rationale for the groupings. The Contractor must describe procedures to recruit and retain an adequate number of subjects (see analytic plan below). The study must also describe how selection of a healthy control group would occur if applicable or if a self-control design would be suitable. If a specialty referral center or network will be used to recruit patients, this should be described. The study should be designed to enroll enough patients to be able to achieve its primary objectives and should specify how many years would be needed to complete a full-scale study, assuming a successful pilot in the first year.

d. Vaccination: The study must assess outcomes after receipt of US-licensed vaccines recommended by the ACIP. Because live vaccines, may not be widely used in persons with autoimmune diseases, the primary objective should either focus on inactivated vaccines or document that the study population recruited would have sufficient numbers of subjects receiving live, attenuated vaccines. The Contractor must also document how accurate immunization information will be obtained for subjects.

e. Clinical and laboratory data collection: This prospective clinical cohort study should obtain accurate and thorough baseline health information and assess clinical and laboratory data at specified points in time after vaccination. In addition to short-term assessment points (e.g., 0-42 days after vaccination), information about the patient’s health outcomes 4-6 months after enrollment should be considered in at least a sub-set of patients. The Contractor must specify how clinical data and laboratory information will be collected and how data will be stored. At least one component of the study must assess laboratory values, in addition to clinical information, after vaccination. The Contractor must describe the rationale or reference literature to support why selected clinical or laboratory features (beyond those routinely collected in vaccine safety studies) would be collected (e.g. specific biomarkers that are associated with flare-ups of the autoimmune diseases).

f. Analysis Plan: The protocol should clearly describe the analytic plan that would be used to assess the study objectives, including power calculations and the statistical tests that will be used.

g. Data management: The protocol should describe how data would be managed and stored. Data sharing with CDC, or across multiple sites if applicable, should also be addressed.

h. Patient Registry: The Contractor may establish a registry of consented study subjects with the autoimmune diseases following the study to conduct future vaccine safety studies.

2. Pilot Autoimmune Study

The protocol must include plans for a pilot study during the 12-month period of performance of this Task Order that would inform the design and procedures for a potential full-scale study. This pilot shall be IRB approved and be implemented during the first 12 months of the Task Order award. The proposed timeline for the pilot is approximately as follows: draft protocol and instruments (months 1-3), conduct pilot (months 4-9), evaluate pilot (months 10-11); a faster path would be acceptable if feasible.

The Contractor shall provide a report and presentation of interim findings from the pilot to CDC during the second half of the Task Order period of performance. The specifications above should be considered for the pilot, along with the following points.

· Objective: The objective of the pilot should be to assess the feasibility and refine the methods for a potential full-scale study. Clear benchmarks should be provided to show how the pilot would establish feasibility of the full-scale study, including identification and enrollment of patients, participation rates, and rates of disease recurrence or “flares” (regardless of vaccination).

· Design and Analysis: The pilot study should establish procedures for recruitment and enrollment of subjects, clinical and lab data collection and analysis, and database management. Drafts for study instruments (e.g., patient intake forms or diary cards) should be developed. The pilot should enroll and prospectively follow patients (N of at least 25) in the short-term (30 to 42 days) to collect clinical and laboratory data, in a manner that would be similar to the full-scale study. Lab samples should be sent to appropriate facilities for testing.

· Dissemination of Findings: Preliminary findings may be shared with advisory committees (e.g. ACIP) or professional societies to inform policies; the Contractor may be required to participate in working groups to discuss these data. The Contractor shall submit a report to CDC. With the concurrence of CDC, the Contractor may submit a manuscript to a peer reviewed journal based on this work under the technical guidance with CDC. Standard CDC Human Subjects Protection and Clearance policies shall apply, (see section C.9.2 and C.9.3 of the Basic PWS)

3. Administrative Activities

a. The Contractor shall organize working group conference calls with CDC and participating investigators for ongoing discussion on the study. The Contractor will provide the meeting minutes for these calls.

b. The Contractor shall provide the appropriate facilities, data management, and other equipment for conducting the Task Order. This includes the appropriate office facilities, record keeping, disaster recovery plans, computer hardware and software, communication, and conferencing equipment.

9 Reporting Schedule

Monthly Status Report The Contractor shall provide a Monthly Status Report, in accordance with this Task Order. The report shall include a summary of the study progress, program management, and financial activities. The Contractor shall electronically submit a copy of the monthly report to the Contracting Officer’s Representative (COR) and the Contracting Officer. The report shall be due the 15th day of each month following the month reported. In addition, the report shall describe and include:

1. The project’s schedule, milestones, and progress

2. Work accomplished in prior month; and work scheduled on tasks for the next month

3. Current and anticipated problems that will impact the Contractor’s performance.

4. Proposed solutions or lessons learned in response to current and anticipated problems

5. The person-hours, percentage of effort, personnel costs, costs for experts, and other costs – for the present reporting period and year to date.

Annual Report The Contractor shall provide a written report to the Government documenting significant work activities for the preceding 12-month period. The report should detail major accomplishments, ongoing activities, lessons learned and milestones not accomplished for the reporting period. As an appendix to the annual report, the Contractor shall deliver to the Government, standard operating procedures, and any user manuals. The Contractor shall submit a draft annual report two months before the end of the contract period for CDC review and guidance. The final annual report shall be delivered no later than twenty (20) calendar days immediately following the specified reporting period.

Form Format Specific form, format and additional content requirements of the delivery schedule items shall be coordinated between the Contractor and the Government. The COR will provide the Contractor with instructions for all relevant documents.

10 Travel With concurrence from CDC, the Contractor may travel to one academic meeting within the United States to present an abstract related to this study. The Contractor may also travel to a CDC meeting, such as a CISA annual meeting or an ACIP conference.

11 Training The Contractor may receive training identified by the CDC IT security staff.

12 Special Considerations

12.1. Human Research Protection

The Special Consideration’s Human Research Protection section C.9.2 of the Basic PWS applies to this Task Order.

12.2. CDC Scientific Review and Clearance

The Special Consideration’s CDC Scientific Review and Clearance section C.9.3 of the Basic PWS applies to this Task Order.

12.3 Assurance of Confidentiality 308(d)

The Special Consideration’s Assurance of Confidentiality 308(d) C.9.4 of the Basic PWS applies to this Task Order.

12.4. Rehabilitation Act

The Special Consideration’s Rehabilitation section Act C.9.5 of the Basic PWS applies to this Task Order.

12.5. Information Security and Confidentiality

The HHS Acquisition Regulation (HHSAR) clauses 352.239-70, 352.239-71, 352.239-72, in section H, and the addendums to 352.239-72 in the Information Security and Confidentiality section C.9.6 of the Basic Performance Work Statement apply to this Task Order.

13 Government Furnished Property / Information Not Applicable

14. References

1US Department of Health and Human Services. 2010 National Vaccine Plan, available at http://www.hhs.gov/nvpo/vacc_plan/2010%20Plan/ nationalvaccineplan.pdf, accessed on October 16, 2011.

2CDC’s Immunization Safety Office Scientific Agenda, available at http://www.cdc.gov/vaccinesafety/Activities/agenda.html, accessed on October 20, 2011.

3National Institutes of Health. National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) Understanding Autoimmune Diseases, available at http://www.niams.nih.gov/Health_Info/Autoimmune/default.asp, accessed on March 8th, 2012 4Guillermo J. Pons-Estel, Graciela S. et al. Understanding the Epidemiology and Progression of Systemic Lupus Erythematosus. Seminars in Arthritis and Rheumatism. 2010 February; 39(4): 257, available at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2813992/, accessed on March 8th, 2012 5Silva CA, Terreri MT, Hilario MO. Immunization consensus for children and adolescents with rheumatic diseases. Bras. Rheumatol 2009;49(5):562-589, available at www.scielo.br/pdf/rbr/v49n5/en_v49n5a07.pdf, accessed on February 29, 2012 6Institute of Medicine, Adverse Effects of Vaccines: Evidence and Causality August 2011, available at http://www.iom.edu/Reports/2011/Adverse-Effects-of-Vaccines-Evidence-and-Causality.aspx, accessed on October 23, 2011.

7CDC, General Recommendations on Immunization: Recommendations of the ACIP. MMWR; Recommendations and Reports. January 28, 2011 / 60(RR02);1-60, available at www.cdc.gov/mmwr/pdf/rr/rr6002.pdf, accessed on February 29, 2012 8CDC. Recommended Immunization Schedules for Persons Aged 0 Through 18 Years --- United States, 2012. Morbidity and Mortality Weekly Report (MMWR); February 10, 2012 / 61(05);1-4, available at http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6105a5.htm, accessed on March 8, 2012

15. Deliverables The following deliverables shall be provided to the COR and relevant CDC staff not later than the dates specified in the summary table below:

Research task

Within 6 weeks of award

a. the Draft Protocol for the Full scale Autoimmune Study

b. the Pilot Autoimmune Study

a. the Draft Protocol for the Full scale Autoimmune Study

b. the Pilot Autoimmune Study

E: Electronic COR: Contracting Officer’s Representative CO: Contracting Officer

16. SPECIFIC TASK ORDER INSTRUCTIONS (to be included as part of technical proposal response in Volume 2)

In preparing the technical response portion of the Task Order proposal, the Offeror shall provide narrative and other information that is considered relevant to the work required to provide the services identified in the Task Order. The Offeror should respond to the areas listed below:

The Offeror should describe a concept summary for the autoimmune pilot study. This narrative should demonstrate that the Offeror could meet the technical specifications for the study objectives in the timeframe. The Offeror shall describe how they will conduct the autoimmune pilot study, including the following:

a. The Offeror shall describe their rationale for studying a selected AEFI in a certain population with an autoimmune disease

b. The Offeror shall describe a hypothesis that should be tested along with a brief description of their methods and analysis plan

c. The Offeror shall explain their strategy for recruiting study participants

d. The Offeror shall describe how they will design and benchmark the pilot study so as to inform the development of a potential larger full study

e. The Offeror shall describe their IRB processes, including ability to meet the timeline requested above.

Table 1. 2011 IOM Conclusions about Exacerbation or Relapse of Autoimmune Diseases after Vaccination

Insufficient (onset)

Insufficient (onset) Weak (exacerbation)

Lacking (onset) Inadequate

Insufficient (exacerbation)

Insufficient (onset)

Insufficient (diphtheria toxoid, acellular pertussis)

Insufficient (acellular pertussis)