SOURCES SOUGHT
R -- Professional Services
- Notice Date
- 8/7/2008
- Notice Type
- Sources Sought
- NAICS
- 622310
— Specialty (except Psychiatric and Substance Abuse) Hospitals
- Contracting Office
- Department of Health and Human Services, Food and Drug Administration, Office of Acquisitions and Grants Services, 5630 Fishers Lane, Room 2129, Rockville, Maryland, 20857-0001
- ZIP Code
- 20857-0001
- Solicitation Number
- FDA-08-1045939
- Point of Contact
- Karen R. Petty,, Phone: 301-827-8774
- E-Mail Address
-
karen.petty@fda.hhs.gov
- Small Business Set-Aside
- Total Small Business
- Description
- Solicitation: FDA-08-1045939 Agency/Office: Food and Drug Administration Location: Office of Acquisitions and Grants Services Title: Professional Services Description(s): THIS IS A SOURCES SOUGHT NOTICE to determine the availability and capability of small businesses (including certified 8(a), Small Disadvantaged, and HUBZone firms; veteran and service-disabled veteran-owned small businesses, and women-owned small businesses. This notice is for planning purposes only, and does not constitute an Invitation for Bids, a Request for Proposals, Solicitation, Request for Quotes, or an indication the Government will contract for the items contained herein. This notice is not to be construed as a commitment on the part of the Government to award a contract, nor does the Government intend to pay for any information submitted as a result of this notice. The Government does not reimburse respondents for any cost associated with submission of the information being requested or reimburse expenses incurred to interested parties for responses to this sources sought. Any responses received will not be used as a proposal. The U.S. Food and Drug Administration (FDA) is seeking to identify any sources with capabilities or prior experience that can provide Professional Services for a Fellowship program in accordance with the following statement of work: STATMENT OF WORK: I. Background Warfarin is an oral anticoagulant that is indicated for the prevention of thromboembolic events in children with heart disease or whom have undergone surgery for repair of congenital heart defects. As in adults, it is also used in pediatrics to treat patients with atrial fibrillation and thromboembolic disease. Warfarin consists of a racemic mixture of R- and S-enantiomers which are metabolized by differing pathways. S-warfarin, the more potent enantiomer, is mainly metabolized to 7 -hydroxywarfarin by cytochrome P450 2C9 (CYP2C9). CYP2C9 is polymorphically expressed and variant alleles (CYP2C9*2 and *3) have been shown to result in reduced clearance of free warfarin in both adults and children. This reduction leads to an increase in the anticoagulant effect of and a consequent decrease in the mean daily dose required to maintain the international normalized ratio (INR) or the prothrombin time (PT) within the target therapeutic range. Initiation of warfarin treatment is often problematic in both children and adults because of multiple factors that lead to wide variations in drug response. Physiologic and pharmacologic factors, such as interacting drugs and illnesses, can affect both the pharmacokinetics and pharmacodynamics of warfarin. Factors that affect the intestinal availability of vitamin K (e.g., dietary intake, concomitant antimicrobial administration) and/or the synthetic or metabolic fate of the vitamin K-dependent coagulation factors (e.g., hepatocellular disease) can also affect warfarin pharmacodynamics. This is concerning since hemorrhage is the major risk of warfarin therapy. Bleeding events in adult patients receiving warfarin therapy have been reported to be 7.6 to 16.5 per hundred patient –years with major or life-threatening bleeds occurring every 1.3 to 2.7 per hundred patient-years. Although major bleeding can occur even at warfarin doses that are considered to be therapeutic, the risk of serious hemorrhage rises proportionately with increasing intensity of anticoagulation. Several investigations conducted in adult patients have suggested that genetic polymorphisms influence the safety and efficacy of warfarin. Previous studies have shown that patients with one or more variant CYP2C9 alleles have decreased warfarin dose requirements. Patients with CYP2C9*2 or *3 variant alleles require lower mean daily doses and have more frequent INR values above the upper limit of the therapeutic range during the induction phase of warfarin therapy than patients carrying only wild-type alleles. These patients also required a longer time to achieve stable dosing, and had a significantly increased risk of serious or life threatening bleeding events when compared to patients with the CYP2C9*1/*1 (homozygous wild-type) genotype. Adult studies have also shown that the maintenance dose of warfarin is significantly related to genotype. Therefore, knowing the CYP2C9 genotypes of patients and adjusting the dose of warfarin based on this information before initiating warfarin therapy may improve the clinical safety and efficacy of the drug. It has now been shown that polymorphic expression of CYP2C9 alone does not account for the variability in the dose-response relationship for warfarin. Warfarin exerts its pharmacodynamic effect by inhibiting the vitamin K epoxide reductase enzyme complex (VKORC) which is responsible for recycling vitamin K 2,3-epoxide to vitamin K hydroquinone. Recently, the gene that encodes vitamin K epoxide reductase complex subunit 1 (VKORC1) has been identified. Point mutations in the gene encoding VKORC1 have been shown to lead to warfarin resistance and increased dose requirements. Collectively, the CYP2C9 and VKORC1 genotypes have been shown to account for approximately 45% of the variability in warfarin dose requirements. The cumulative data obtained and available computer based clinical pharmacogenetic programs for warfarin dosing ignore implications for pediatric patients. Because of the intrinsic developmental differences in the coagulation systems, adult guidelines for antithrombotic therapy cannot be extrapolated to pediatrics. While several warfarin studies have been performed in children, there is a paucity of data regarding how developmental expression affects warfarin pharmacokinetics and pharmacodynamics. This is especially true for VKORC1 where the patterns of developmental expression are not known. Studies have also shown that body weight normalized unbound oral clearance for S-warfarin is significantly greater than that for adults and that developmental alterations occur for other proteins that influence the anticoagulation effect of warfarin (e.g., Protein C). II. Purpose & Objective Warfarin remains the mainstay of pediatric chronic anticoagulation therapy. As in adults, the management of warfarin therapy is difficult and adverse effects are common. Two distinct pediatric patient populations receive warfarin frequently; one population is the young children with complex congenital heart disease who have surgery and abnormal blood flow, and the other are the adolescent patients who have valve replacement. Only three pharmacologic studies of warfarin in children have been conducted, and they suggest that developmental and genetic factors contribute to pediatric patient variability in response. The purpose and objectives of the study is to examine the relationship between warfarin dosing, CYP2C9 and VKORC1 polymorphisms, and patient demographic factors in order to develop a warfarin dosing algorithm that can be validated for pediatric patients. Hypothesis: DNA polymorphisms in CYP2C9 and VKORC1 are predictive of warfarin dose requirements in children once a stable INR has been achieved. III. Purpose & Objective Pediatric centers with anticoagulation clinics will be recruited for participation, and one PPRU will coordinate the clinical centers. The study will take place in two phases; a data collection phase which will generate sufficient data for the construction of a dosing nomogram, and a prospective phase in which patients will be randomized to routine management versus nomogram-guided dosing. All studies will be IRB-approved at their site in order for them to participate. Independently, and not as an agent of the U.S. Federal Government, the Contractor shall furnish the necessary personnel, materials, services, and otherwise do all things necessary for: A. Study Design Patients less than 18 years of age who are currently followed by the participating institutions and who have received warfarin treatment for greater than 7 days within the past one year will be eligible for the study. Patients and/or parents/guardians will be fully informed about the study during clinic visits and informed consent will be obtained from patient’s parent/guardian during these regularly scheduled visits or during scheduled laboratory visits that are performed as part of standard care. When appropriate (i.e., age > 6 years), patient assent will be obtained. Once consent/assent is obtained, each subject will be given a study identification number. A sample of 1 mL of whole blood (for genomic DNA) and 5mL of plasma (for warfarin R/S ratios and future studies) will be obtained with the routine blood draw. The blood sample will only be identified by the ID number. In some cases, a venipuncture will be required for patients who are not previously scheduled to have a blood test for clinical care. This will be fully explained during the consent process. Blood and plasma samples will be batched at the investigative sites and will be maintained at -70°C until they are shipped to the Children’s Mercy Hospital Pediatric Clinical Pharmacology laboratory where the leukocyte DNA will be extracted (from whole blood) and genotype analysis will be performed. The plasma warfarin R/S concentration ratio will be determined by quantitation of each enantiomer from plasma using a validated HPLC/MS/MS technique. Retrospective longitudinal review of data will then be performed and will include age, weight, height, gender, warfarin dose, other medical illness or medications, adverse effects, PT(prothrombin time), and INR(international normalized ratio). These will be obtained from the existing patient records and documented under the study ID number. The data will be analyzed along with the testing for genetic polymorphisms for CYP2C9 and VKORC1, and warfarin R/S ratios. B. Subject Selection Criteria: 1.Recruitment of Subjects: Patients will be recruited from 2 hospials and 1 to 2 additional sites from the NICHD supported Pediatric Pharmacology Research Unit Network that are known to have a substantial number of pediatric patients who receive warfarin. 2.Expected Sample Size: Total study: 100 3.Number expected per study site: 34 4.Inclusion Criteria: Patients who are less than 18 years of age who have received warfarin treatment for more than 7 days. 5.Exclusion Criteria: Patient’s who have been on warfarin for less than 7 days or whom have been deemed to be non-compliant with treatment by the treating team will be excluded. C. Data collection phase: Centers will recruit current and past patients on which they can collect DNA and data on the patient’s clinical course and laboratory monitoring. When it can be coordinated with a blood draw, plasma will be obtained for an s-warfarin concentration. The number of patients will be guided by the previous experience of the Pharmacometrics Division of OCP with adult warfarin patients. D. Prospective evaluation phase: Pediatric patients requiring warfarin therapy will be randomized to receive the standard of care or will be genotyped and have their warfarin dosing determined by a pediatric dosing nomogram. The primary outcome measure will be time to stable INR. E. Methods/Observations/Measurements: Information on previous warfarin dosing, INR, illnesses, adverse effects and other medication use will be collected and analyzed on each patient from the time of initiation of the drug until the time of enrollment into the study. A database that contains information for each subject will be created and maintained by the coordinating site (Children’s Mercy Hospitals and Clinics). Information will be analyzed in the Pharmacometrics Division, Office of Clinical Pharmacology, US Food and Drug Administration by NONMEM. The number of patients available (n=100) should be sufficient to develop a model of warfarin dosing that can account for greater than 50% of the variability in warfarin dosing, based upon adult studies. It is anticipated that as in adults, a multiple regression model will be used to explore the relationships between measured covariates and warfarin dose to produce a desired INR (the response surrogate endpoint). Two working assumptions in developing a multivariable predictive model are that: (1) the CYP2C9 and VKORC1 genotypes will be included in all models developed, and (2) the magnitude of the genetic effects is a strong reason to assume that effects of other predictors will not be strictly additive, and interaction terms must be considered in the models. F. Confidentiality of Subjects and Data After enrollment in the study, each participant will be assigned a study ID number. This number will be used to identify the blood sample. The research nurse coordinator will enter all the data from the patient into the database using only the study ID number. The blood samples will be analyzed without any personal identifiers and results given to the PI. The investigators involved in direct care to the patient will be unaware of the genetic test results produced as part of this research investigation and will provide routine care using clinical information (which may include CYP2C9 and VKORC1 genotype) performed by each study site. 1.What subject identifiers are used in: a.study documents to funding agency Subjects will be identified only by a unique study number b.study documents retained at CMH Subjects will be identified only by a unique study number 2.Where will data be stored and how will confidentiality be maintained? Data will be stored in a locked drawer and locked computer file in the PI's office. Access to the key will be limited to the PI and a study nurse coordinator. The data that will be entered into the database the computer will be coded, and the link between the coded data and the subjects will be kept in the research files in the locked cabinet in the PI’s office. 3. Will tissue/blood samples be stored beyond the end of the study? Data will be kept after completion of this study for 10 years. Identifiers will be destroyed after the completion of the study. This will be clearly stated on the consent form. G. Metric for Evaluating impact: The impact of these studies are to establish a new standard of care for pediatric patients who require warfarin therapy. If we can establish a warfarin dosing nomogram that functions more efficiently than traditional fixed arbitrary dosing at rapidly achieving a stable INR in warfarin-treated children, then the outcome will be a major advance in drug therapy for pediatric patients. The nomogram will be available to all clinicians via the Internet, and it will establish a new standard of care for warfarin dosing in pediatric patients. Companies are encouraged to respond if they have the capability and capacity to provide the identified services with little or no disruption of services to the current users at the FDA. Interested small business potential offerors are encouraged to respond to this notice. However, be advised that generic capability statements are not sufficient for effective evaluation of respondents' capacity and capability to perform the specific work as required. Responses must directly demonstrate the company's capability, experience, and/or ability to marshal resources to effectively and efficiently perform each of the tasks described above at a sufficient level of detail to allow definitive numerical evaluation; and evidence that the contractor can satisfy the minimum requirements listed above wile in compliance with FAR 52.219-14 ("Limitations on Subcontracting"). Failure to definitively address each of these factors will result in a finding that respondent lacks capability to perform the work. Responses to this notice shall be limited to 15 pages, and must include: 1. Company name, mailing address, e-mail address, telephone and fax numbers, website address (if available), and the name, telephone number, and e-mail address of a point of contact having the authority and knowledge to clarify responses with Government representatives. 2. Name, title, telephone number, and e-mail addresses of individuals who can verify the demonstrated capabilities identified in the responses. 3. Business size for NAICS 622310 with size limitation standards of $6.5M and status, if qualified as an 8(a) firm (must be certified by the Small Business Administration (SBA), Small Disadvantaged Business (must be certified by SBA), Woman-Owned Small Business, HUBZone firm (must be certified by SBA), and/or Service-Disabled Veteran Owned Small Business (must be listed in the VetBiz Vendor Information Pages). 4. DUNS number, CAGE Code, Tax Identification Number (TIN), and company structure (Corporation, LLC, partnership, joint venture, etc). Companies also must be registered in the Central Contractor Registration (CCR) at www.ccr.gov to be considered as potential sources. 5. Identification of the firm's GSA Schedule contract(s) by Schedule number and contract number and SINs that are applicable to this potential requirement are also requested. 6. If the company has a Government approved accounting system, please identify the agency that approved the system. Please submit copies of any documentation, such as letters or certificates to indicate the firm's status (see item #3 above). To the maximum extent possible, please submit non-proprietary information. Any proprietary information submitted should be identified as such and will be properly protected from disclosure. Interested offerors should submit their capability statement not exceeding fifteen (15) pages in length, excluding standard brochures. SUBMISSIONS ARE DUE no later than 12:00pm, Eastern Time, August 14, 2008. The capabilities response shall be e-mailed to: Karen.petty@fda.hhs.gov. All information received in response to this notice that is marked Proprietary will be handled accordingly. Responses to the notice will not be returned, nor will there be any ensuing discussions or debriefings of any responses. Information provided in response to this notice will be used to assess alternatives available for determining how to proceed in the acquisition process. This notice is part of Government Market Research, a continuous process for obtaining the latest information on the commercial status of the industry with respect to their current and near-term abilities. The information provided herein is subject to change and in no way binds the Government to solicit for or award a competitive contract. The FDA will use the information submitted in response to this notice at its discretion and will not provide comments to any submission; however, the content of any responses to this notice may be reflected in subsequent solicitation. FDA reserves the right to contact any respondent to this notice for the sole purpose of enhancing FDA's understanding of the notice submission. This announcement is Government market research, and may result in revisions in both its requirements and its acquisition strategy based on industry responses. It is emphasized that this is a notice for planning and information purposes only and is not be construed as a commitment by the government to enter into a contractual agreement, nor will the government pay for information solicited.
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