The Food and Drug Administration (FDA) is seeking Full and Open Competition for vendors to write an analytical report on Pharmacogenetic Testing on Drug Efficacy.

Background: The notion that drugs do not have the same effects in every patient is well spread among healthcare professionals. For decades physicians have used characteristics such us age, weight and sex to select the right treatment for their patients. This approach, though very useful in the clinical practice, seems to have reached its limit. There are still a large number of patients that do not respond to standard treatments or suffer from adverse effects. In recent years, advances in genomic research offered new possibilities toward the individualization of drug therapies. One good example is the application of genomics to the use of warfarin. The important variability in the response to warfarin is explained in part by genetic variants in the warfarin target, an enzyme called VKORC1, as well as the enzyme that clears warfarin from the body (CYP2C9). Patients with certain VKORC1 genetic variants are warfarin sensitive and require low warfarin doses. Likewise, patients with certain CYP2C9 genetic variants eliminate warfarin slowly and are more likely to have serious bleeding events when administered standard doses of warfarin. Pharmacogenetic testing, along with other characteristics of the patient, can provide an estimate of the therapeutic warfarin dose, improving the effectiveness and safety of anticoagulant therapy. Diagnostic tests to identify these and many other genetic variants relevant to the prescription of drugs are commercially available. However, the integration of genetic information to guide drug prescription is still limited. One of the reasons for such limitation is the scarcity of data supporting the clinical utility and the practical application of pharmacogenetic testing. The collection of that kind of data for each pharmacogenetic test and each drug by performing traditional clinical studies can be very costly and as such unlikely to occur. Therefore, it is important to identify other resources that can assist us in obtaining the necessary information to facilitate the use of genomics in the clinical practice. Pharmacy benefit providers collect and organize clinical and prescription data from their users. Many of these providers have also encouraged physicians to use certain pharmacogenetic tests as a guide to their prescription decisions and have developed the infrastructure to allow the prescription of the tests and the delivery of the results in a timely manner within their system, assuring the test results can be used effectively. The significant amount of data these providers collect and their experience in implementing pharmacogenetic testing make them a valuable resource to evaluate the utility of using genomics to aid drug prescribing.

A. Key Objectives

1) Identify drugs whose effectiveness and/or safety profiles can be improved by utilizing genetic information to guide prescription: Many drugs pose challenges in selecting the right dose or the patients that may benefit from them. However, pharmacogenetic tests are not available for all of these drugs. FDA aims at identifying the drug-test pairs that could be effectively applied to guide prescription.

2) Identify available pharmacogenetic tests that can be effectively performed and utilized using a prescription-driven program: Some technical characteristics of the test can limit the application of pharmacogenetic testing to the patient care (e.g. by requiring sophisticated methods to obtain the sample or taking several days to deliver results).

3) Quantify the prescription of these drugs among users of the selected pharmacy benefits provider: For most drugs, the utility of pharmacogenetic testing in the clinical practice is related to the number of patients that are prescribed the drug and, therefore, would benefit from the new approach.

4) Identify prescription patterns among users of the selected pharmacy benefits provider: In addition to the number of patients that could potentially benefit from genetic-guided drug prescriptions, the characteristics of the patients that receive the drug (e.g. age, weight, race, etc.), the disease being treated, other drugs these patients receive, etc. are important factors affecting the utility of pharmacogenetic testing.

5) Evaluate the utility of pharmacogenetic testing in the clinical setting: Pharmacogenetic testing has the potential to increase the number of correct prescriptions for the selected drugs (the right drug at the right dose).

6) Evaluate the effect of pharmacogenetic testing on the effectiveness and safety of the selected drugs in the clinical setting: By guiding prescribers in selecting the right drug at the right dose, pharmacogenetic testing can improve clinical outcome by increasing the rate of treatment response and decreasing the rate of treatment failure and the number and severity of adverse events.

7) Evaluate the ability of a prescription-driven feedback program to facilitate the utilization of pharmacogenetic tests in the clinical practice: It is necessary to identify effective ways to inform prescribers and patients about the test and its results, to make and implement the decisions based on the test results.

C. Scope of Work

This project shall be a collaborative effort of the FDA with a Pharmacy Benefit Provider (PBP). PBP shall have access to a large patient database, which will allow us to measure the impact of pharmacogenetic testing. Upon selecting the drug-test pairs to be included in the study, FDA shall investigate the collaborator s database to identify two cohorts of patients: those receiving the standard therapy and those receiving the pharmacogenetic-aided treatment. Effectiveness and/or safety of the selected drugs will be compared between the two cohorts. The metrics for evaluating impact on effectiveness/safety will be specific to each drug/pharmacogenetic test included in the study. Examples of these metrics are: Dose adjustment Treatment discontinuation or treatment substitution Number/ length of hospitalization Emergency room visits Adverse events: bleeding events, sedation, vomiting, headache, insomnia, tremor, weight loss

Phase 1: A pilot study with warfarin shall be conducted to measure the impact of genetic testing for CYP2C9 and VKORC1. This will provide a solid case study and will serve to establish the process (standard operating procedures or SOP). Duration: 6 months. Phase 2: Project expansion following the SOP developed in phase 1, a list of other drug-test pairs, e.g. CYP2D6 and atomoxetine or selected opioids (codeine, oxycodone, hydrocodone, tramadol) shall be explored. Duration: 18 months.

This project will be completed in two years. All results will be published in peer-reviewed literature.

D. Key Tasks

1)Access to database containing rich and quality data from users on: Drugs prescription, dose, dose adjustments and discontinuation of treatment Moderate and severe adverse events to treatment, number of doctor s office visits and number of hospitalizations with the corresponding length of stay and cause in the period of drug prescription Time data to allow analysis of temporal relationship of all the above mentioned parameters

2) Access, experience and infrastructure to facilitate pharmacogenetic testing and appropriately organize and store the test results

3) Access to database containing rich and quality data from at least 1000 patients on: Warfarin prescription, dose, dose adjustments and number of INR tests for at least 6 months CYP2C9 and VKORC1 test results or capability to facilitate testing and appropriately organize and store test results Bleeding events, number of doctor s office visits and number of hospitalizations with the corresponding length of stay and cause in the period of warfarin prescription Time data to allow analysis of temporal relationship of all the above mentioned parameters

4) Delivery of: Weekly oral reports and monthly meetings on the progress of the project Quarterly written progress reports (electronic version) Draft of final report for FDA review due 60 days before the completion of the project. Electronic versions of all presentations, reports, methodologies, and models in formats compatible with IBM PC Systems, preferably Microsoft Office The weekly and monthly meetings will be used to monitor the progress of the project and to make adjustments to the plan as needed. The quarterly written reports will be evaluated, edited and kept for our records. The final report shall be a joint effort between the contractor and the FDA.

5) Optional: A minimum of one of the PBP staff member who is knowledgeable about the use of the software and the organization of the data within the database to work directly in the project. This staff member shall dedicate significant amount of his/her time to the project and shall be readily available to address our questions, comments and needs on the project. 6) Optional: Publishing the results in peer-reviewed literature

E. Deliverables

Please note that the deliverables listed below are sequential and may overlap as the study progresses. These are also one-time deliverables.

1) List of drugs whose effectiveness and/or safety profiles can be improved by utilizing genetic information to guide prescription. Timeline: 3 months.

2) List of available pharmacogenetic tests that can be effectively performed and utilized using a prescription-driven program. Timeline: 3 months.

3) Written report on selected drugs utilization among users of the selected pharmacy benefits provider. Timeline: 6 months.

4) Written report on prescription patterns among users of the selected pharmacy benefits provider. Timeline: 6 months.

5) Written report on the effect of pharmacogenetic testing on the effectiveness and safety of warfarin in the clinical setting. Timeline: 8 months.

6) Written report on the effect of pharmacogenetic testing on the effectiveness and safety of the selected drugs in the clinical setting. Timeline: 24 months.

7) Written report on the utility of a prescription-driven feedback program to facilitate the utilization of pharmacogenetic tests in the clinical practice. Timeline: 24 months.

F. Capability Statement

1) Detailed quote of the PBP will have a maximum length of 15 pages and will be delivered as original with two copies.

2) PBP shall invoice on a monthly basis (or as appropriate) detailing accomplishments.

The performance period will be two years from the time of award.

This is a REQUEST FOR QUOTATION (RFQ). This announcement constitutes the only solicitation and a written solicitation will not be issued. QUESTIONS DEADLINE: all questions must be received by email (david.kordel@fda.hhs.gov) before 5:00 pm (1600) EST on June 2, 2008. All responsible sources must be registered in the Central Contractor Registry System (CCR) at www.ccr.gov to be considered. FDA intends to make an award soon after the response date of this notice and all bids must be submitted via email and be received by 10:00 AM (1000) EST on 11 June 2008 to the attention of David Kordel, david.kordel@fda.hhs.gov. Evaluation/Award will be based on the technically acceptable quote that offers the best value to the Government. The award will be made in accordance with FAR Part 13, Simplified Acquisition Procedures.