Att 03 SOW.pdf

NIH-NICHD-CDBPM-10-15-RFP – Attachment 3 Page 1 of 4

BACKGROUND & STATEMENT OF WORK

May 4, 2010

Background

The intent of newborn screening is to detect potentially fatal or disabling conditions in newborns, thereby providing a window of opportunity for early treatment, often while the child is still asymptomatic. Such early detection and treatment can have a profound impact on the clinical severity of the condition in the affected child. If left undiagnosed and untreated, the consequences of the targeted disorders can be dire, many causing irreversible neurological damage, intellectual, developmental and physical disabilities, and even death. In 2006 the American College of Medical Genetics (ACMG) developed newborn screening guidelines that recommend that all newborn infants be screened for 29 "core conditions" and that 25 secondary conditions identified during the core evaluations be reported. These recommendations have been accepted by the HHS Secretary's Advisory Committee on Heritable Disorders in Newborns and

Children (ACHDNC) (authorized by the Children's Health Act of 2000), and have been recommended to the Secretary of HHS. Most states now use this or very similar panels for newborn screening. Currently there are thousands of rare disorders that have been identified and hundreds that could potentially benefit from newborn screening. A report, "Newborn Screening: Toward a Uniform Screening Panel and

System" (httm://mchb.hrsa.gov/screening), which the Maternal and Child Health Bureau, Health

Resources and Services Administration sponsored and the American College of Medical Genetics developed, identifies some of these "high priority" conditions.

Current Novel Technologies in Newborn Screening Contracts

2006 – Present – Contract with the University of Washington (Contract No. HHSN267200603429C) –

Evaluating tandem mass spectrometry as an instrument for the enzymatic detection of Fabry, Pompe & mucopolysaccharidosis-I in newborn screening.

2006 – Present - Contract with HRI, New York State (Contract No. HHSN267200603430C) –Use

Luminex universal DNA array assays to detect mutations associated with galactosemia, biotinidase deficiency and MCADD. Use multiplex immunoassay techniques to test for congenital hypothyroidism, congenital adrenal hyperplasia, cystic fibrosis, Krabbe Disease and Severe Combined Immunodeficiency.

TECHNICAL REQUIREMENTS

I. GENERAL DESCRIPTION OF THE SCOPE AND OBJECTIVES

The purpose of this contract is to develop multiplexed assays that can be automated and utilized in a high throughput environment for newborn screening. The end result may be an integrated platform of screening technologies or a single analytic technique that State Newborn Screening Programs or large commercial laboratories involved in newborn screening can adopt.

Objectives

Develop multiplexed assays that the can be automated and utilized in a high throughput environment for newborn screening Provide evidence for the feasibility of the technologies in the environment of newborn screening.

Develop a prototype of the technologies for validation clinically.

Compare different platforms or technologies for determination of the most practical approach for large-scale newborn screening.

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II. TECHNICAL SPECIFICATIONS

Independently, and not as an agent of the Government, the Contractor shall furnish all the necessary services, qualified personnel, material, equipment and facilities, not otherwise provided by the

Government, as needed to perform the Statement of Work set forth below.

1. Develop multiplexed assays that can be automated and utilized in a high throughput environment for newborn screening. The end result should be an integrated platform of screening technologies or a single component that tests for several conditions and that State Newborn Screening

Programs or large commercial laboratories can easily incorporate into large systems. The conditions to be screened might include but are not limited to the following: inborn errors of metabolism (such as lysosomal storage diseases), hematological and immunodeficiency disorders, congenital endocrinopathies, muscular dystrophies (such as Duchenne muscular dystrophy or spinal muscular atrophy), chromosomal disorders (e.g., trisomies, monosomies), Fragile X syndrome, or those disorders characterized through control mechanisms of gene expression (e.g., epigenetics). In addition, the screening technology platform may be based on a range of technologies that include, but are not limited to the following: microchip technologies, microbead technologies, nanotechnologies, microfluidic assays, biophysical assays, and/or technologies based on DNA, RNA or protein analysis.

2. Develop a bioinformatics component using current language and standard terminology for data collection and analysis, which will be a fundamental feature of the proposed technology platform.

3. Develop appropriate protocols to use in conjunction with the technology. The finalized protocols shall include a technical research plan, a measurement plan, performance metrics and a quality assurance plan. The Contractor shall develop the final protocols with the input of the Project

Officer. The final protocols must be approved in writing by both the Project Officer and the

Contracting Officer.

4. Ensure that all technology developed under the contract is compatible for use with dried bloodspots on a standard filter paper matrix used in state newborn screening laboratories.

5. Develop a technology that includes analytic performance of the test under conditions that permit its adoption into a high throughput environment. As part of the development of the technology, the Contractor must validate the performance of the test in appropriate samples, using population-based newborn samples.

6. Perform comparative effectiveness testing on screening for “high priority" conditions with current or promising effective therapeutic interventions. For the purpose of this contract, a "high priority" condition is a condition for which the development of a screening test would make the condition amenable to newborn screening. The testing should compare the new technology to an existing platform(s) (if such a platform exists) in large scale applications.

7. Analyze and report results of comparative effectiveness testing for newborn screening.

8. Provide data management and quality assurance methodologies that are consistent with the

Centers for Disease Control and Prevention’s Newborn Screening Quality Assurance Program

(NSQAP) quality control assurance protocols.

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9. Provide definitive answers concerning the utility of the new technology for newborn screening in a state newborn screening environment. In particular, the Contractor must determine the technology's:

a. utility to screen newborns for high priority conditions within the United States (including its predictive value, sensitivity, and specificity);

b. utility to screen conditions for which investigators could, potentially, develop therapeutic interventions in the near future;

c. efficacy in screening newborns for conditions currently screened, comparing this new technology with traditional and alternative techniques;

d. ability to exhibit sufficient and inherent flexibility to facilitate expansion of its multiplexing capabilities to include new conditions in the future;

e. ability to streamline and fully automate, so that it is suitable for population-based screening;

f. bioinformatics capabilities for data collection and analysis for use in follow-up care and public health research;

g. appropriateness, based on the framework of established screening procedures;

potential risks and benefits (e.g., its ability to detect genetic variants, clinical heterogeneity, carrier status); and

h. Detailed quality control and quality assurance standards.

10. Characterize the following elements of the proposed technology or compound technologies relating to analytical validity, quality control, and assay limitations by the end of the Period of

Performance:

a. Sensitivity/Specificity: Determine the sensitivity, specificity, positive and negative predictive values for each condition.

b. High Throughput: Calculate the run-time per specimen.

c. Reproducibility: The Clinical and Laboratory Standards Institute (CLSI), (formerly the

National Committee for Clinical Laboratory Standards (NCCLS)), EP-5A and EP-12A publications provide guidelines to determine the reproducibility of the technology. When appropriate, characterize the within-run and total imprecision for the proposed technology. Use sample bloodspots with three relevant concentrations of analyte being diluted, including concentrations near medical decision points and at concentrations near the limits of the reportable range.

d. Interference: Characterize the effects of potential interfering substances (endogenous and exogenous) on the performance of the assay. The CLIS/NCCLS document, "Interference

Testing in Clinical Chemistry; Approved Guideline" EP-7A (2002) provides guidelines to select interfering substances for testing and examples of experimental designs.

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e. Effect of excess sample and limiting sample: Calculate the functional sensitivity of the test system, defined as the lowest analyte concentration that the proposed technology can detect reliably. Determine sample concentrations and conditions that reproducibly yield acceptable results.

f. Linearity: Characterize the linear range of the assay by evaluating samples whose concentration levels are known, relative to one another. The CLIS/NCCLS document, "Evaluation of the Linearity of Quantitative Measurement Procedures: A Statistical

Approach; Approved Guidelines" EP-GA (2003) provides protocols to determine linearity.

g. Calibration and Control Materials: Describe all controls (negative and positive, characterize as internal or external) and calibrators.

h. Carryover and Drift: Evaluate each analyte for any effects of carryover or drift, using reference materials.

i. Cut-Offs/Reference Interval(s): Validate cut-off values and reference range(s) (when appropriate) for each analyte. To determine reference ranges, Food and Drug

Administration (FDA) recommends following CLIS/NCCLS C28 "How to Define and

Determine Reference Intervals in the Clinical Laboratory."

j. Software Validation: Document computational methods for data processing and software validation for all programs associated with the technology. Two FDA guidance documents to reference include: "Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices: Final" and "Guidance for Off-the-shelf

Software Use in Medical Devices: Final."

k. Cost Determination: Estimated cost to run each specimen in a high throughput environment and the cost of any additional specialized processing, handling, or detection equipment that will be needed by labs.

11. Ensure that the technology developed satisfies any applicable requirements of FDA statutes and regulations and/or the Clinical and Laboratory Standards Institute's (CLSI) voluntary standard controls and guidelines.

12. Establish a collaborative partnership with at least one State Newborn Screening Program. Utilize the partnership throughout the development and conduct of the contract to ensure consideration of the range of capabilities and limitations that exist in state-based newborn screening laboratories.

13. Provide formal documentation that supports collaboration with state newborn screening laboratory(ies) in the form of a letter. The letter should include:

a. Detailed description of the laboratory’s commitment to the project

b. Available resources within and limitations of the collaboration (specimens, equipment, manpower, other).

c. Description of Institutional Review Board Procedures (IRB) and timeline for approval process.