CISAAttachment J.4 5_24_2012.docx

ATTACHMENT J.4

PERFORMANCE WORK STATEMENT

CISA SAMPLE TASK ORDER # 4

Subject to FAR 52.232-18 Availability of Funds

Title of Project: Fever after Live Attenuated Influenza Vaccine in Young Children

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 4 is from $349,000 to $524,000.

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

Base contract year: 9/20/2012-9/19/2013 Option year 1: 09/20/2013-9/19/2014

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

5. Background and Need Transient fever is a relatively common event after childhood vaccination and onset patterns of fever and rates differ by vaccine type.[endnoteRef:1] Studying clinically important outcomes associated with post-immunization fever is a specified research need on the Centers for Disease Control and Prevention’s (CDC) Immunization Safety Office Scientific Agenda.[endnoteRef:2] Surveillance and research for rare events is best covered through the passive and active surveillance systems and large-linked databases. The Clinical Immunization Assessment (CISA) Project is well-suited to conduct clinical research for adverse events, such as fever, that are relatively common and likely to occur outside the medical setting. Additionally CISA may address questions about biological mechanisms and host risk factors. [1: ] [2: ]

Since 2008 CDC’s Advisory Committee on Immunization Practices (ACIP) has recommended routine annual influenza vaccination in the United States for all children aged ≥6 months to prevent influenza.[endnoteRef:3] Healthy children age ≥2 years and non-pregnant adolescents may receive either trivalent inactivated influenza vaccine (TIV), administered as an injection or trivalent live, attenuated influenza vaccine (LAIV), administered via the intranasal route. ACIP has not stated a preference for TIV or LAIV in the indicated populations. Recently, the ACIP has adopted procedures for conducting evidence-based reviews to shape vaccination policies.[endnoteRef:4] The ACIP Influenza Working Group is currently conducting an evidence-based review to guide policies for influenza vaccination. One step of this process will be synthesis of evidence for preventing of influenza in young children through the use of influenza vaccines.[endnoteRef:5] A randomized controlled clinical trial conducted among children aged 6--59 months during the 2004--05 influenza season demonstrated that LAIV had higher efficacy than TIV for preventing influenza in this age group.[endnoteRef:6] To fully assess the risk-benefit profile of LAIV vaccine use in young children, it is important to carefully assess potential risks of LAIV use in this population. [3: ] [4: ] [5: ] [6: ]

Studies have supported an overall favorable safety profile for trivalent LAIV in healthy children aged 2-17 years. 6,[endnoteRef:7] A pre-licensure study assessed rates of adverse events in children aged 2-4 years after LAIV compared with TIV, using the 2004-05 formulation.6 Rates of two events in this age group were higher during the 10 days after LAIV than TIV: fever >100○ F on day 2 after dose 1 (5.4% after LAIV versus 2.0% after TIV) and runny nose/nasal congestion. A study conducted in the Vaccine Safety Datalink (VSD) after licensure, did not find evidence for increased risk for pre-specified adverse events, including seizure and wheezing, after LAIV (trivalent 2009-10 formulation) or monovalent H1N1 live attenuated vaccine used in the 2009-10 pandemic; medically attended fever was not assessed.[endnoteRef:8] Limited data are available on the safety of trivalent LAIV, administered concomitantly with other childhood vaccines.[endnoteRef:9] [7: ] [8: ] [9: ]

To provide broader protection for influenza B disease, particularly in children, quadrivalent influenza vaccines that include two B strains are in development and clinical trials are underway.[endnoteRef:10],,[endnoteRef:11] In March 2012 FDA approved quadrivalent LAIV (Q-LAIV) (FluMist Quadrivalent, MedImmune) to prevent seasonal influenza in people aged 2 years through 49 years.[endnoteRef:12] Preliminary data from a clinical trial of Q-LAIV were presented during the 2011 Infectious Diseases of Society (IDSA) Meeting.11,[endnoteRef:13] Findings showed adverse event rates were similar in children receiving quadrivalent LAIV and trivalent LAIV. However, the frequency of fever ≥38°C was higher in quadrivalent LAIV versus trivalent LAIV recipients (rate difference 1.8%); it was not noted if the finding was statistically significant. Age-specific fever rates were not described.13 Taken together, data from clinical trials suggest that children who receive annual trivalent or quadrivalent LAIV vaccines, may have higher fever rates than those observed in children who receive inactivated influenza vaccines. The clinical importance of an increase in fever rates is not clear. Fever after vaccination may lead to more medical visits and, in the 2-4 year age group, febrile seizures may occur in susceptible children when fever occurs.[endnoteRef:14] Two particularly relevant gaps for LAIV vaccine safety are: 1) fever rates in formulations containing the 2009-H1N1 influenza A strain and 2) fever rates after LAIV when it is administered with other childhood vaccines. [10: ] [11: ] [12: ] [13: ] [14: ]

Characterizing rates of fever and clinical characteristics and health outcomes of febrile reactions after LAIV vaccines may help inform national policies for pediatric influenza policies. In addition, implementing a clinical study of LAIV vaccine safety may provide a platform for conducting influenza vaccine safety research studies of biomarkers and genomics more broadly. It may also expand national capacity for evaluating quadrivalent vaccines as they are introduced and enhance pandemic influenza preparedness.

6. Project Objective The purpose of the project is to complete a study in young children to better understand the risk for and clinical importance of fever after LAIV vaccines. The primary objective is to assess rates of fever in healthy children aged 2-4 after LAIV, compared with rates after inactivated influenza vaccines and to describe the characteristics of the febrile events (e.g., height of the fever, onset interval, and associated health outcomes). A secondary objective is to assess whether fever rates after vaccination are higher in children who concomitantly receive LAIV with other childhood vaccines at the same visit, compared with children who receive LAIV without other vaccines. Another secondary objective is to assess the feasibility of conducting a study of biomarkers associated with febrile reactions in children who receive influenza vaccines. This study will involve the influenza vaccine products that are licensed, recommended by the ACIP, and available for use in healthy children aged 2-4 years during the study period. The vaccines studied would also be covered by the Vaccine for Children’s Program.15 It is possible that trivalent and/or quadrivalent influenza vaccines would meet these criteria.

7. Scope of Work This Task Order is for the Contractor to develop a scientifically sound research protocol to conduct a clinical study of fever after LAIV during a single influenza season. Results should be provided before the following influenza season to help inform vaccination policies. This study should collect data on measured fever prospectively in children alter receipt of LAIV and inactivated influenza vaccines. The Contractor will collect data and conduct analysis as described in the protocol.

8. Technical Requirements Working with technical guidance from CDC, the Contractor shall accomplish the following:

1. Research Protocol Functions

a) Serve as the lead site on this study and oversee the scientific and administrative aspects of the study.

b) Develop a protocol and associated study instruments.

c) Seek Institutional Review Board approval for protocol and ensure protection of human subjects

d) Develop a sound analytical plan, with consideration of statistical power to address the objectives.

e) Implement and oversee the study, in collaboration with CDC. These activities include:

· Identify the study population and ensure adequate numbers of LAIV and inactivated influenza vaccine recipients can be recruited during the influenza season.

· Recruit and enroll subjects; ensure information about vaccines received at the influenza vaccination visit will be accurately collected

· Assess measured fever rates for at least 10 days. Collect information about fever rates in an accurate manner that will be simple and acceptable to parents, preferably using modern technologies (e.g., text messaging or via the web).

· Assess clinical characteristics and health outcomes of the children who experience fever to help understand clinical importance

· Manage the data and run appropriate analyses; allow CDC access to coded data (data without personal identifiers).

· Collect information through appropriate methods to assess the feasibility of conducting a future study of biomarkers associated with febrile responses to influenza vaccines.

f) Coordinate routine calls for study investigators and staff from the Contractor, CDC and any other relevant participants.

g) Make presentations for CDC staff and potentially other groups, such as the ACIP

h) Prepare a draft and final report to CDC documenting the study methods and findings, as well as any lessons learned that might inform public health or clinical practice or research. A manuscript for a peer review journal shall also be prepared; CDC human subjects protection and clearance policies shall apply (see section C10.2 and C.9.3 of the basic Performance Work Statement).

2. Administrative Activities

a) The Contractor shall organize working group conference calls with CDC and participating investigators for ongoing discussion of 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 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 disposition instructions for all technical documents (including, all databases, software documentation, questionnaires, case summaries, electronic files, etc.).

10. Travel With concurrence from CDC, the Contractor may travel to an academic meeting in 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 CDC IT Security

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 1 Marcy MS, Kohl KS, Dagan R et al Fever as an adverse event following immunization: case definition and guidelines of data collection, analysis, and presentation. Vaccine. 2004;22: 551–556, available at http://www.lareb.nl/LarebCorporateWebsite/media/publicaties/vaccine2004_1567.pdf, accessed on March 4, 2012 .

2 Centers for Disease Control and Prevention’s Immunization Safety Office Scientific Agenda, available at http://www.cdc.gov/vaccinesafety/Activities/agenda.html, accessed on January 15, 2012.

3 Fiore A, Shay D, Broder K et al. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2008. MMWR 2008;57(RR-7):1-60, available at http://www.cdc.gov/mmwr/preview/mmwrhtml/rr57e717a1.htm, accessed on February 29, 2012 4 CDC, Advisory Committee on Immunization Practices , GRADE Evidence Tables -- Recommendations in MMWR, available at http://www.cdc.gov/vaccines/recs/acip/GRADE/table-refs.htm, accessed on January 27, 2012.

5 CDC, ACIP presentation slides October, 2011, Influenza presentation, available at http://www.cdc.gov/vaccines/recs/acip/slides-oct11.htm, accessed on January 27, 2012.

6 Beshe RB, Edwards KM, Vesikari T et a. Live attenuated versus inactivated influenza vaccine Infants and young children. The New England Journal of Medicine. 2007;356(7):685-96, available at . http://www.nejm.org/doi/full/10.1056/NEJMoa065368#t=articleTop, accessed on February 29, 2012 7 Ambrose C, Yi T, Falloon J. An integrated, multistudy analysis of the safety of Ann Arbor strain live attenuated influenza vaccine in children aged 2–17 years. Influenza and Other Respiratory Viruses. 2011;5, 389–397, available at. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3256242/, accessed on February 29, 2012 8 Lee GM, Greene SK, Weintraub ES et al. H1N1 and seasonal influenza vaccine safety in the vaccine safety datalink project. Am J Prev Med. 2011 Aug;41(2):121-8, available at www.cfah.org/hbns/archives/viewSupportDoc.cfm?...1027, accessed on February 29, 2012 9 FDA. Flumist package insert, available at http://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM123743.pdf, accessed on January 21, 2012.

10 Christopher S. Ambrose CS, Levin J. The rationale for quadrivalent influenza vaccines. Human Vaccines & Immunotherapeutics. 2012; 8(1):1–8; available at http://www.landesbioscience.com/journals/13/article/17623/, accessed on February 29, 2012 11 Clinical Trials.gov, search results available at http://clinicaltrials.gov/ct2/results?term=quadrivalent+influenza+vaccine, accessed on January 21, 2012.

12 FDA FluMist Quadrivalent MedImmune, available at http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm293952.htm, accessed on March 4, 2012.

13 Block S, MD1, Yi T, Falloon J. Noninferior Immunologic Response of Quadrivalent, Live Attenuated Influenza Vaccine (Q/LAIV) Compared With Trivalent LAIV (T/LAIV) in Children. Poster abstract for the Infectious Diseases Society of America, Boston, MA, October 21, 2011, available at http://idsa.confex.com/idsa/2011/webprogram/Paper30253.html, accessed on January 21, 2012.

14 American Academy of Pediatrics Steering Committee on Quality Improvement and Management, Subcommittee on Febrile Seizures. Febrile Seizures: Clinical Practice Guideline for the Long-term Management of the Child With Simple Febrile Seizures. Pediatrics. 2008; 121 (6): 1281-1286, available at pediatrics.aappublications.org/content/121/6/1281.full.pdf, accessed on February 29, 2012 15 CDC. Vaccines for Children Program, available at http://www.cdc.gov/vaccines/programs/vfc/default.htm, accessed on January 21, 2012.

15. Deliverables

Within 1 month of contract award

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 proposal for the LAIV 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 study, including the following:

a. Description of IRB processes, including ability to meet the timeline requested above.

b. Description of the study design and statistical approach planned to address the study objectives.

c. Description of the proposed study population. The Offeror should describe how they can ensure adequate numbers of subjects can be enrolled (under the assumption that both LAIV and inactivated vaccines are licensed, recommended, available and covered by ACIP).

d. Description of how accurate vaccine exposures will be assessed

e. Description of the methods they plan to use to assess fever (e.g., type of thermometer to be used).

f. Description of the methods used to record and track the temperatures after vaccination. If modern informational technologies are used, additional technical information may be provided in an appendix.

g. Description of procedures used to assess health outcomes potentially related to fever (e.g., health visits associated with fever).

h. Description of potential biases and limitations that might occur in the study and how the adverse impact of these biases will be minimized.

i. Description of approach to assessing feasibility of a future biomarker study for influenza vaccines and febrile responses.