RFP No. NIH-NHLBI-HC-99-05

"Iron Overload and Hereditary Hemochromatosis Study--Central Laboratory"

Request for Proposal No.: NIH-NHLBI-HC-99-05
Issue Date: December 15, 1998
Issued By: Lisa T. O'Neill
Contracting Officer
NIH/NHLBI
Contracts Operations Branch
II Rockledge Centre, RM 6122
6701 Rockledge Drive, MSC 7902
Bethesda, Maryland 20892-7902
Purchase Authority: Public Law 95-83, as amended
Small Business Set-Aside: No; SIC Code 8731
Proposal Due Date:
March 15, 1999, 4:00 PM (Eastern Time)


Ladies and Gentlemen:

The National Heart, Lung, and Blood Institute (NHLBI) is soliciting proposals to initiate an epidemiological study of the prevalence, genetic and environmental determinants, and potential clinical, personal and societal impact of iron overload and hereditary hemochromatosis in a multi-center, multiethnic, primary care based sample of 100,000 adults. This RFP NHLBI-HC-99-05, is specifically for the Central Laboratory. This Streamlined Technical Request For Proposal (RFP) consists of this combined solicitation form and cover letter (PART A), and five attachments, as follows:

Attachments:

  1. Background and Work Statement;
  2. Reports/Deliverables;
  3. Evaluation Factors for Award, including Technical Evaluation Criteria and Other Information;
  4. Specific RFP Instructions and Provisions;
  5. Applicable RFP References

Attachments A, B. and C. contain the technical information required for the submission of a proposal for this acquisition. Attachment D., titled "Specific RFP Instructions and Provisions" contains, for example, the proposal intent response form and the address for delivery of your proposal. The section titled "Applicable RFP References" lists those items in the "Streamlined RFP References" directory that apply to this RFP, including forms that can be downloaded and are required for the submission of a proposal. If you are unable to download any of the applicable documents, please contact the Contracting Officer listed above for assistance.

Although sufficient information to submit a proposal is provided, if you intend to submit a proposal in response to this RFP, it is essential that you immediately notify Ms. Lisa O'Neill, Contracting Officer, at the following Internet address:

ONeillL@gwgate.nhlbi.nih.gov

If you fail to notify the Contracting Officer of your organization's interest, you will not receive notice of amendments which may be issued for this RFP, and this could impact your proposal preparation. However, please note that all amendments will be posted on the NIH RFP WEB SITE. Your attention is further directed to the "Proposal Intent Response Sheet" contained in Attachment D. Please complete this form and return it to this office on or before 1/29/99. This will allow us to expedite preparations for the peer review of proposals.

The Business and Technical proposals must be separate from one another in the proposal package. The Business proposal must be signed by an authorized official of your organization and must contain a detailed breakdown of costs by year for each cost category. The basis for costs must be explained and supporting documentation must be submitted with the proposal. (See "STANDARD RFP INSTRUCTIONS and PROVISIONS" in the RFP homepage for more detail on the Business proposal requirements. Your proposal (Business and Technical) must be received no later than March 15, 1999, at 4:00 p.m. local time at the address and quantity specified in Attachment D titled "Packaging and Delivery of Proposals". NOTE: IF YOUR PROPOSAL IS NOT RECEIVED BY THE CONTRACTING OFFICER OR DESIGNEE AT THE PLACE AND TIME SPECIFIED, THEN IT WILL BE CONSIDERED LATE AND HANDLED IN ACCORDANCE WITH THE PHS CLAUSE 352.215-10 TITLED, "LATE PROPOSALS, MODIFICATIONS OF PROPOSALS, AND WITHDRAWALS OF PROPOSALS".

Offers will be valid for 120 days unless a different period is specified by the offeror on the form titled, "Proposal Summary and Data Record, NIH 2043" also located at the site for FORMS, FORMATS, AND ATTACHMENTS. If you have any additional questions regarding this RFP, please contact Mrs. O'Neill through the Internet using the electronic mail address listed above or phone (301) 435-0345, fax (301) 480-3430. COLLECT CALLS WILL NOT BE ACCEPTED. SUBMISSION OF PROPOSALS USING FACSIMILE OR ELECTRONIC MAIL IS NOT AUTHORIZED.

Sincerely Yours,


Lisa T. O'Neill
Contracting Officer

ATTACHMENTS


ATTACHMENT A

BACKGROUND AND WORK STATEMENT

  1. PROJECT DESCRIPTION

    1. A general description of the required objectives and desired results

      The Genetic Epidemiology Scientific Research Group, Epidemiology and Biometry Program, Division of Epidemiology and Clinical Applications, NHLBI, in conjunction with the Blood Diseases Program, Division of Blood Diseases and Resources, NHLBI, and the Ethical, Legal and Social Implications Research Program, Division of Extramural Research, NHGRI, propose to initiate an epidemiologic study of the prevalence, genetic and environmental determinants, and potential clinical, personal, and societal impact of iron overload and hereditary hemochromatosis, in a multi-center, multiethnic, primary care-based sample of 100,000 adults. This information will be used to determine the feasibility and potential individual and public health benefits and risks of primary care-based screening and intervention for iron overload and hereditary hemochromatosis. The specific objectives of the study are to:

      1. Determine the prevalence in a primary care population, by race/ethnicity, of: 1) iron overload, defined as confirmed elevation of transferrin saturation, and hereditary hemochromatosis; 2) demonstrable clinical and pathological abnormalities related to iron overload and hereditary hemochromatosis; and 3) genetic variants related to iron overload and hereditary hemochromatosis including the recently identified HFE C282Y and H63D genotypes and other, as yet unidentified, variants.

      2. Identify risk factors influencing the phenotypic expression of iron overload and hereditary hemochromatosis in regard to demonstrable clinical and pathological abnormalities, and examine interactions between risk factors to determine the relationship between genotype and phenotype. Risk factors would include genetic factors, such as specific hemochromatosis genotype or thalassemia trait, as well as environmental or non-genetic factors such as gender, age, alcohol intake or hepatitis C virus.

      3. Examine ethical, legal and social issues related to the possibility of implementation of primary care-based screening for iron overload and hereditary hemochromatosis, including identification of appropriate health care delivery models and potential personal, societal, or family-related impact of and barriers to primary care- or population-based screening and genetic testing.

      4. Estimate the heritability of iron overload and hemochromatosis, and initiate linkage studies to identify main effect and modifier genetic variants associated with iron overload and hemochromatosis.

      The project duration is planned for five years.

    2. Background information helpful to a clear understanding of the requirements and how they evolved.

      Hereditary iron overload, or hemochromatosis, is a common inherited disorder among Caucasians, with an estimated prevalence of 0.25-0.50%, though it is mistakenly believed by many to be quite rare. The disease is insidious in onset, and many or even most individuals diagnosed with this disorder are not identified until advanced organ damage is present. However, in the absence of anemia, which can be caused by tissue damage from iron in late stages of the disease, it is relatively easy to treat the disorder by removing the excess iron through repeated phlebotomy. Evidence suggests that early diagnosis and treatment can prevent disease manifestations and enable normal life expectancy. The discovery of the HFE C282Y and H63D variants in the HLA gene region on chromosome 6 provides an opportunity for early and rapid genetic identification of individuals at risk for development of hereditary hemochromatosis. Much remains to be learned about the penetrance and expression of these alleles, including their relevance to the full spectrum of clinical disease. To date, the HFE alleles appear predominantly associated with disease mainly in populations of Caucasian descent. While 80-90% of Caucasian hemochromatosis patients have HFE abnormalities, there are hetero- and homozygotes that do not manifest any evidence of disease, or manifest disease at different ages and with different outcomes, implying the existence of other genetic or environmental factors. Similarly, not all hemochromatosis patients have HFE abnormalities. Other genes yet to be discovered are also likely to be involved in pathogenesis of iron overload and familial hemochromatosis in non-Caucasian populations as well. This project is intended to examine the genetic and environmental determinants and correlates of iron overload and hereditary hemochromatosis in diverse populations.

      Increases in body iron may be due to increased absorption (hemochromatosis), increased oral intake of non-therapeutic iron, unneeded iron therapy, or multiple blood transfusions in the absence of bleeding. The excess iron is deposited in body tissues, and can reach toxic levels leading to organ damage. The toxicity can affect most tissues and organs, but particularly the liver, causing cirrhosis; the endocrine system, causing diabetes, hypogonadism, and sometimes hypoparathyroidism; and the heart, causing arrhythmias and cardiomyopathy.

      Iron overload and hereditary hemochromatosis have not been as extensively studied in non-Caucasian racial/ethnic groups as they have in Caucasians. The toxicity of excess iron in non-Caucasians appears to be similar to that in Caucasians, but the prevalence of iron overload is unknown and while a genetic contribution to that overload is suspected it has not been proven in all groups. It has long been assumed that iron storage disease in populations of sub-Saharan Africa is due to increased iron absorption from beer brewed in iron pots, but more recent information suggests there is also a hereditary component to that accumulation of iron. However, iron overload among Africans does not appear to be due to HFE abnormalities, nor to other genes in the HLA region at all. Primary iron overload has been reported in African Americans but it remains to be determined whether or not this is linked to HFE or other genetic factors. Iron overload has been reported in Asian populations, but the frequency and genetic contributions (if any) are not known. In some studies where HFE variants have been found in non-Caucasians, additional genetic testing has suggested that Caucasian admixture may have been involved. Hispanic-Americans appear to have a frequency of iron overload similar to non-Hispanic Caucasians, although further study of the genetic and environmental correlates is warranted. There has been almost no study of iron overload and hereditary hemochromatosis in Native American populations.

      Hemochromatosis may be suitable for detection and intervention through primary care or population-based screening strategies because: 1) it is relatively common; 2) it is asymptomatic in its early stages; 3) screening methods are reliable; 4) standard diagnostic methods are widely available in developed countries and relatively inexpensive; 5) it is easily treatable; and 6) if untreated, the subsequent burden of morbidity and mortality is substantial. The feasibility and benefits of such programs remain to be assessed, however, since the prevalence of the disorder and the factors related to its phenotypic expression (such as the optimal age for reliable detection and effective intervention) are unknown. Other questions needing to be addressed include public acceptability of screening and testing; sensitivity and specificity of the screening methods, particularly in non-Caucasians; optimal timing and setting of screening and testing; as well as the benefits and costs and/or other burdens associated with screening and testing.

      A major objective of the proposed project is to gather information needed to develop recommendations regarding possible primary care- or population-based screening for hemochromatosis. Estimating the burden of preventable illness from unrecognized hemochromatosis is one of the most important of these needs. Comparing the relative value and acceptability of diagnosis and screening by genotype vs phenotype is also important. In particular, differences by racial/ethnic group, age and other characteristics will need to be examined. Some of these issues, such as appropriate thresholds for transferrin saturation screening, may be resolved during the proposed study's planning phase, while others will constitute key research questions to be addressed by the study itself.

  2. INTRODUCTION TO THE STATEMENT OF WORK

    The Iron Overload and Hereditary Hemochromatosis Study is a multi-center study of the prevalence and genetic and environmental determinants of iron overload and hereditary hemochromatosis in a diverse and representative primary care-based sample of men and women aged 25 and older. One hundred thousand patients undergoing routine screening or testing involving a blood draw will be recruited from five to seven Field Centers and screened for transferrin saturation levels. Cost-effective population-based strategies for recruitment will also be considered. A repeat fasting transferrin saturation screen in conjunction with a serum ferritin assay will be used to identify potential case' participants with confirmed elevated transferrin saturation levels and matched random control' participants with confirmed non-elevated transferrin saturation levels.

    In order to obtain data on the prevalence of genetic factors in a routine care population, a random subgroup of approximately 20-40% of the 100,000 screenees will be genotyped for known variants, such as HFE C282Y and H63D, related to iron metabolism and overload. The panel of genotypes to be assayed will reflect the state of knowledge at the time this phase of the study is conducted. In particular, any newly discovered variants related to iron overload and hemochromatosis in non-Caucasian populations, such as for iron overload among Africans, will be included. The results of the genotyping will not directly impact the selection of case and control participants; case/control selection will be based only on the transferrin saturation/serum ferritin screen results. It is likely that many HFE genotype positive persons will have confirmed elevations of transferrin saturation and thus may get selected as confirmed elevated transferrin saturation case participants. Genotype positive persons with non-elevated transferrin saturation levels, who are not randomly selected as controls, will constitute a third group and undergo the same intensive studies as cases and controls.

    A random sample of the individuals being recruited to participate in the genotyping subgroup will be surveyed to determine their knowledge and attitudes about, interest in, and support for such screening programs. Both qualitative and quantitative measures will be employed. Efforts will be made to ascertain reasons for refusal and related information from those who decline participation. An addition 2000 primary care patients will be selected to participate in a substudy comparing phenotype- versus genotype-based screening and testing methods.

    Following these transferrin and random subgroup genotyping screens, a comprehensive clinical examination will be conducted in the confirmed elevated transferrin saturation potential case participants, the genotype-positive participants, and the confirmed non-elevated control participants to assess iron stores, distinguish between primary and secondary causes of iron overload and to examine the associated hepatic, endocrinologic, hematologic and cardiovascular disease correlates and sequelae of hemochromatosis. A detailed family and medical history will be obtained. Examination participants not previously genotyped will undergo genotyping, with a panel of genotypes as described above, for use in association analyses. The genotype-positive participants will receive counseling on their results. The examination will also include an extended ELSI assessment of issues related to genetic screening and testing and diagnosis of disease. Data will be collected on the participants' acceptability of genetic testing, their experience with screening, their understanding and interpretation of their results, and on the impact this information is having on their own lives as well as those of their family members. Specific components of the comprehensive clinical examination will be determined during protocol development. Follow-up ELSI assessments will examine issues such as impact of the screening program on relationships with family members, and any experiences with stigmatization and discrimination.

    A family study, using comprehensive clinical examinees as probands, will seek to identify modifier genetic variants related to the expression of iron overload and hereditary hemochromatosis disorders via genome scanning and assessment of linkage. Identification of new genetic variants, particularly in minorities, is also of great interest, but it is possible this study will not achieve sufficient power to do so. Proposed efforts to improve the power, such as combining data from other studies, will be considered. The family study ELSI assessment will examine family members' experiences with the screening program, the impact of this information on their lives and relationships, and any experiences with stigmatization and discrimination.

    A repository of blood specimens will be established to permit additional studies of genetic and environmental factors relating to iron overload. This will require careful attention to the details of informed consent. For some later studies, the specimens may be anonymized.

    The study will involve five to seven Field Centers, a Coordinating Center (which will subcontract for any necessary Reading Centers such as an ECG Reading Center), and a Central Laboratory (which may subcontract for novel assays and/or the genome-wide scan). Principal Investigators from each of these seven to nine Centers plus the NHLBI Project Officer form the Steering Committee. A Data Safety and Monitoring Board (DSMB) will be appointed by NHLBI to oversee the project and make recommendations on various aspects (e.g., protocol approval, participant safety, project activation, and later milestones). The DSMB is expected to meet initially to review the "final" protocol, to meet routinely (annually) during the study, and to meet on an ad hoc basis when needed for major protocol revisions or for the evaluation of unexpected results.

    Time lines for the study are provided in Table 1 and Figure 1, and a list of probable exam components is shown in Table 2. Protocol planning, informed consent form design, OMB clearance, training and pilot testing will occupy the first twelve months of the study. The initial transferrin saturation screen will then be conducted over a two year period. The repeat fasting transferrin saturation/serum ferritin screen will follow shortly, preferably within one to two months of the initial screen of each participant. Appropriate threshold values for each of the screens should be proposed, with discussion of specificity and sensitivity issues and expected numbers of participants meeting these criteria. It should be recognized that the confirmed elevated transferrin saturation group will be much smaller in number than the initial group of 100,000 screenees. As these confirmed elevated transferrin saturation participants and confirmed non-elevated control participants are identified, scheduling for the comprehensive clinical examination will begin. These examinations will also take place over a two year period, overlapping the transferrin saturation screen period. Similarly, as examinees with hereditary hemochromatosis are identified, recruitment of relatives for the family study will begin. During the last year of the study, follow-up of comprehensive clinical examinees will be performed. Depending on when the examination is performed, the follow-up interval will be between one and three years. Concurrently, final data analysis and study close-out will be completed, although initial data analysis is expected to begin much earlier using data from the initial transferrin saturation screen and random subgroup study.

    The initial 100,000 screenees will include roughly equal numbers of men and women aged 25 and older. Individuals requiring repeated blood transfusions for treatment of other conditions will be excluded. Since iron accumulation increases with age, this broad age span will lead to inclusion of participants with a wide range of iron overload states and related sequelae to be studied. Screening of children and adolescents, however, is not expected to be productive because iron overload is generally not detectable until at least the third or fourth decades of life. In addition, there is evidence that juvenile hemochromatosis is genetically distinct from adult hemochromatosis, and has a different pattern of clinical sequelae. Inclusion of slightly younger adults, that is those 25 and older, will enable analysis of gene and environmental interactions related to the penetrance of HFE and other hemochromatosis-related gene expression during the age span when iron overload is developing but before such interactions may be confounded by hemochromatosis-related organ damage. The initial screenees should represent a range of racial and ethnic groups, with the goal of enrolling approximately 40-50% minority participants. To enable comparisons within as well as across Field Centers, each Center's sample is expected to enroll from two or more racial/ethnic groups, one of which may be non-Hispanic Caucasians. For Field Centers with two racial/ethnic groups in the study, each group is expected to comprise 20% or more of that Center's study population. For Field Centers with three or more racial/ethnic groups, at least two of the groups are expected to each comprise 20% or more of the study population at the Center. Selection of Field Centers will be partly governed by the need to achieve the overall racial/ethnic and gender targets for the study as a whole.

    Clinical sites will be expected to assess the clinical, personal, and societal impact of the screening program. During planning, a common approach to this assessment will be developed and implemented. The development of guidelines for informed consent and the protection of individual rights or prerogatives is an important component of this study. All clinical sites will thus be asked to address issues of consent, protection against discrimination, confidentiality, etc. Public policy implications of screening programs that identify risk or disease states in which much about the natural history of the disease remains unknown, but for which existing medical interventions appear to substantially reduce risk or morbid states, are of interest, but may be beyond the scope of the main study. Offerors are thus encouraged to propose and participate in substudies and ancillary studies, as described in task 3.e. below, to address the broader ethical, economic and health policy issues related to the possible implementation of such screening programs, or other issues related to iron overload and hemochromatosis.

    Ethical considerations mandate that subjects found to have evidence of iron overload or deficiency be treated to prevent or attempt to reverse clinical disease. Accordingly, offerors must be prepared to refer those patients to appropriate sources of standard clinical care for follow-up and/or treatment as indicated, which will not be supported by this research program. Although not a primary goal of the program, differences in the response to treatment by genotypes will be sought through follow-up procedures. Study-wide guidelines for treatment, including assessment of family members as guidelines warrant, will be developed and recommended to care providers of cases detected through the study. The final, detailed protocol will be developed and approved by a Steering Committee-appointed subcommittee, reviewed by the Data and Safety Monitoring Board and approved by the NHLBI/NHGRI staff

    Table 1. Time line for the Iron Overload and Hereditary Hemochromatosis Study
    Activity Time period
    Protocol Development September 30, 1999 - September 30, 2000
    (12 months)
    OMB Clearance April 1, 2000 - September 30, 2000
    (6 months)
    Training, Pilot Testing
    Protocol Modification
    July 15, 2000 - September 30, 2000
    (2.5 months)
    Initial Transferrin Saturation Screen October 1, 2000 - September 30, 2002
    (24 months)
    Random Subgroup Genotyping
    Initial ELSI Assessment
    October 1, 2000 - September 30, 2002
    (24 months)
    Repeat Transferrin Saturation Screen
    Serum Ferritin Assay
    October 1, 2000 - September 30, 2002
    (24 months)
    Comprehensive Clinical Examination
    Genotyping, Extended ELSI Assessment
    January 2, 2000 - September 30, 2003
    (33 months)
    Family Study, ELSI Assessment March 1, 2001 - September 30, 2003
    (31 months)
    Follow-up for ELSI, Morbidity and
    Mortality
    January 2, 2001 - September 30, 2004
    (45 months)
    Final Data Analysis and Close-out October 1, 2003 - September 30, 2004
    (12 months)

    [Note: Some activity periods overlap. Since participant eligibility for screens and examinations following the initial screen is dependent on laboratory or other diagnostic results, some activity periods are on average shorter than the total periods specified.]

    Study years are designated as follows:

    Year 1, September 30, 1999 - September 30, 2000
    Year 2, October 1, 2000 - September 30, 2001
    Year 3, October 1, 2001 - September 30, 2002
    Year 4, October 1, 2002 - September 30, 2003
    Year 5, October 1, 2003 - September 30, 2004

    Figure 1. Time line for the Iron Overload and Hereditary Hemochromatosis Study

    
                       |---Year 1---|---Year 2---|---Year 3---|---Year 4---|---Year 5---|
    
    Protocol
     Development       |------------|
    
    OMB Clearance             |-----|
    
    Screening Exam                  |-------------------------|
    
    Random Sample Genotyping*       |-------------------------|
    
    Case/control Intensive Exam*            |------------------------------|
    
    Family Study*                                 |------------------------|
    
    Case Follow-up*                         |--------------------------------------------|
    
    Analyses                   |---------------------------------------------------------|
    
    Publications                            |--------------------------------------------|
    
                       |---Year 1---|---Year 2---|----Year 3---|---Year 4---|---Year 5---|

    *includes Ethical, Legal, and Social Implications (ELSI) assessment.

    Table 2. Examination Components

    Data to be collected is approximated by the following list of components, which may be modified during protocol development, for the approximate following number of participants (across all Field Centers):

    1. Initial Transferrin Saturation (TS) Screen (N=approximately 100,000):
      1. Serum collection

    2. Random Subgroup:
      1. Whole blood for DNA extraction (N=approximately 20,000-40,000)
      2. Initial Ethical, Legal, and Social Implications (ELSI) (N=approximately 2,000-4,000)

    3. Repeat TS Screen/Serum Ferritin Assay (N=approximately 2,500 initial transferrin saturation elevated participants, and 1,000 non-elevated transferrin saturation participants)
      1. Serum collection

    4. Comprehensive Clinical Examination (N=approximately 750 confirmed elevated transferrin saturation participants and 1,000 confirmed non-elevated transferrin saturation participants)
      1. Extended ELSI assessment
      2. Dietary questionnaire
      3. Demographic, medical history, and medication use questionnaires
      4. Fasting whole blood, serum, plasma, DNA and lymphocyte collection
      5. Anthropometry
      6. Resting blood pressure
      7. Assessment of liver disease
      8. Assessment of blood disorders
      9. Assessment of diabetes
      10. Assessment of arthropathies and arthritis
      11. Assessment of heart failure, and arrhythmias

    5. Family Study (N= approximately 2,000 relatives of comprehensive clinical examinee cases)
      1. Fasting whole blood, serum, plasma, DNA and lymphocyte collection
      2. Components of comprehensive clinical examination as above
      3. ELSI assessment

    6. Follow-up for ELSI, morbidity and mortality:
      1. Follow-up ELSI assessment
      2. Dates of deaths and hospitalizations
      3. Interview data from participants and relatives and other informants
      4. Hospital discharge diagnosis and ICD9 codes

                                                            ------------
                                                            |          |
                                                            | 100,000* |
                                                            |          |
                                                            ------------
    1.  Initial Transferrin Saturation                            |
    Screen (TS1) [Random Subgroup**;              ---------------(1)--------------
    Genotyping Initial ELSI***]                   |                              |
                                            ------------                   -------------
                                            |          |                   |           |
                                            |   2,500  |                   |   97,500  |
    2.  Repeat Transferrin                  |   TS1+   |                   |     TS1-  |
    Saturation Screen (TS2)                 ------------                   -------------
                                                 |                               |
                                          ------(2)------                       (2)
                                          |             |                        |
                                   -------------- --------------          ---------------
                                   |            | |            |          |Random Sample|
                                   |   1,750    | |     750    |          |     1,000   |
                                   | TS1+  TS2- | | TS1+  TS2+ |          |  TS1-  TS2- |
                                   -------------- --------------          ---------------
    3.  Clinical Assessment,                             |                       |
    Extended ELSI***, Geno-                       ------(3)------               (3)
    typing                                        |             |                |
                                            ------------  --------------  ---------------
                                            |    250   |  |    500     |  |     1,000   |
                                            | 2° Iron  |  |1°Iron Over-|  |  TS1-  TS2- |
                                            | Overload |  | load CASES |  |   CONTROLS  |
                                            ------------  --------------  ---------------
    4.  Family Study (4 or more                                 |
    members per case)                                          (4)
                                                                |
                                                          -------------
                                                          |    2000   |
                                                          |   Family  |
                                                          |   Members |
                                                          -------------
    

    * All numbers after the initial 100,000 are estimates and may change during the protocol development or as cases are identified during the course of the study.

    ** During step 1, a random subgroup of 20-40% participants will have additional blood drawn for candidate gene testing concurrent with transferrin saturation assays. Any genotype-positive (for example, HFE C282Y/C282Y or HFE C282Y/H63D) individuals not otherwise selected for steps 2-4 will be invited to participate in these steps (although not shown above).

    ***Ethical, Legal, and Social Implications assessment. An initial ELSI assessment will be conducted in a random subgroup at the beginning of step 1. All step 3, and a subset of step 4 participants will undergo an extended ELSI assessment. A follow-up assessment will be conducted in the hemochromatosis cases (not shown above).

  3. STATEMENT OF WORK

    Independently, and not as an agent of the Government, the contractor shall furnish the necessary services, qualified personnel, equipment, facilities, and materials, not otherwise provided by the Government. [Note: Throughout this statement of work, the terms "Contractor" and "Central Laboratory" are used interchangeably.] Specifically, throughout the period of performance, the Contractor shall provide appropriate senior personnel with expertise in laboratory measurements related to the screening, diagnosis and study of iron overload, hemochromatosis and related clinical hepatic, endocrinologic, hematologic and cardiovascular disease; ethical, legal and social implications (ELSI) of genetic screening; and clinical epidemiology laboratory study management to:

      1. Take responsibility in particular scientific areas for protocol development, including leadership and participation in subcommittees;

      2. Identify, recommend, develop, and conduct laboratory analyses on blood and DNA for measures of potential determinants and correlates of iron overload, hemochromatosis and related hepatic, endocrinologic, hematologic and cardiovascular disease from specimens collected by the Field Centers during transferrin saturation screens, genotyping screens and a comprehensive clinical examination on an adult primary care population;

      3. Participate in meetings and activities of committees, such as the Steering Committee, Publications Committee, Laboratory Committee, and Ethical, Legal and Social (ELSI) Committee, and other subcommittees, and present to the NHLBI-appointed Data Safety and Monitoring Board (DSMB), as appropriate;

      4. Develop and maintain, in collaboration with the Coordinating Center, a quality assurance program for laboratory-based procedures;

      5. Organize, edit, and transmit results of laboratory analyses and quality control assessments at all phases of the study to the Coordinating Center on a regular and timely basis.

      6. Maintain a Specimen Repository;

      7. Maintain confidentiality and security of the specimens, assay results and data files;

      8. Work cooperatively with all study centers, including Field Centers, Coordinating Center and the NHLBI Project Office staff in all relevant aspects of study execution;

      9. Participate actively in data analysis and publication.

    1. SPECIFIC REQUIREMENT AND TASKS:

        [Note: See time line and flowchart in Table 1 and Figures 1 and 2 above, for overview of periods, tasks and study design. A list of examination components is in Table 2 above.]

      1. Provide representation for Steering Committee meetings, DSMB meetings, and for subcommittee meetings as appropriate.

        [Note: For planning purposes, assume the Offeror will be represented on the Steering Committee and three subcommittees and that Steering Committee meetings will take place in Bethesda, Maryland. Assume there will be 4 two-day meetings during the first year, 3 during the second year, and 2 each year thereafter. DSMB and Subcommittee meetings will generally take place in conjunction with Steering Committee meetings, but in the first year assume one additional meeting may need to take place separately.]

      2. Actively participate in development of study protocol, including the assumption of lead roles for development of particular aspects of the protocol;

      3. Identify, recommend and develop the laboratory studies component of the protocol. The protocol will specify: the battery of assays to be performed within the below suggested areas; the laboratory methodology and threshold values for abnormalities of assays; subcontracting of laboratory analyses that are not within the capabilities of the Central Laboratory; quality assurance activities; and coordination of activities of any subcontractor with the Field Centers and the Coordinating Center.

        [Note: For planning purposes, assume that the laboratory analyses for the initial transferrin saturation screen on 100,000 participants will be conducted at the five to seven Field Centers however, the concurrent genotyping on the 20,000-40,000 random subgroup will be conducted at the Central Laboratory. The Central Laboratory will perform assays in conjunction with the repeat transferrin saturation screen (approximately 3,600 participants), the comprehensive clinical examination (approximately 1,800 participants) and the family study (approximately 560 participants and 2240 family members). An additional 2,000 participants will participate in an ELSI-related substudy comparing acceptability of genotype vs phenotype screening methods (with approximately half of the participants in each of the two groups).

        The list of laboratory tests is subject to modification either after the Central Laboratory contract is awarded as a result of protocol development by the Steering Committee, and/or before award, as a result of recommendations, capabilities and proposed costs of potential contractors. In response to the RFP, Offeror must address the list of laboratory tests provided below, but may also recommend, with justification, deletions from or additions to the list. Scientific justification, as well as issues of measurement reproducibility, biological variation, and burden to participants and Field Center staff should be included. For each of the tests listed below, and for any additional tests recommended, the methods to be used for laboratory analysis, as well as expertise and experience with the proposed methods should be described. Budget estimates must be provided for conducting each test separately, for cost efficiencies arising from bundling measurements together, and should include separate estimates for any additional components proposed. Types of equipment and expertise needed at each Field Center in order to collect and process specimens for the proposed tests should be specified. Any additional tests suggested should be ranked by the offeror in terms of scientific importance, ease and reproducibility of measurement, and cost (including cost in time and equipment to the Coordinating Center and the Field Centers).]

        Specific tests to be addressed by the Central Laboratory include:

        1. During repeat transferrin saturation screen, family study and screening method substudy:

        [Note: for planning purposes, assume the initial transferrin saturation assay will be conducted at the Field Centers.]

          1. Iron measures
            1. transferrin saturation
            2. serum ferritin

        [Note: Offerors should address the issue of possible iron contamination from the tubes and materials used for drawing blood and separating serum.]

        1. During comprehensive clinical examination and/or family study as appropriate:

        [Note: For planning purposes, assume a Complete Blood Count (CBC) including MCV and platelet count, and the erythrocyte sedimentation rate assays will be conducted at the Field Centers.]

          1. Liver function tests
            1. alanine aminotransferase (ALT)
            2. aspartate aminotransferase (AST)
            3. carbohydrate-deficient transferrin (CDT)
            4. gamma glutamyl transferase (GGT)
            5. whole blood associated acetaldehyde (WBAA)

          2. Tests for diabetes and glucose intolerance
            1. fasting glucose and insulin
            2. hemoglobin A1C

          3. Antigen/antibody markers of relevant infectious agents such as Hepatitis C, and other blood bank-required infectious disease tests

          4. Markers of immune and inflammatory response
            1. C-reactive protein
            2. Erythrocyte sedimentation rate

        1. During genotyping screen, comprehensive clinical examination, family study and screening method substudy:

          1. Genetic markers of hemochromatosis and iron metabolism
            1. HFE polymorphisms
            2. additional polymorphisms related to iron overload, hemochromatosis and iron metabolism

        [Note: It is anticipated that polymorphisms to be tested will reflect the state of knowledge at the time this phase of the study is conducted. Similarly, advances in technology have led to new genotyping methods with the potential for resource and/or cost savings over conventional methods. Proposed DNA extraction, storage, and genotyping methods, as well as quality control procedures, should be described with justification.]

        1. During family study:

            Genome-wide anonymous marker genotyping

        [Note: For planning purposes assume 10 cM map on approximately 2800 participants in family study. If there are insufficient numbers of families/family members in a particular race/ethnic group to achieve adequate statistical power for linkage analyses, strategies for supplementing families/family members, for instance remote blood collections or including families from other studies, will be considered. Proposed DNA extraction, storage, and genotyping methods, as well as quality control procedures, should be described with justification.]

      4. Develop and maintain a quality assurance program for laboratory based procedures to include but not necessarily be limited to:

        1. Establishing of a Manual of Operations containing written standard operating procedures addressing:

        [Note: The manuals (or sections of manuals) are to be maintained and updated yearly and/or as determined by progression of study events and/or at the direction of the Steering Committee. Current copies of manuals are to be provided to the Coordinating Center for distribution to Field Centers, study investigators, and any interested party upon request, including versions in Web-ready format.

          1. Collecting, processing (including aliquoting protocols as necessary), and shipping of specimens by Field Centers to the Laboratory;

        [Note: This section of the manual should also be provided for inclusion in the Field Center Manual of Operations.]

          1. Processing and analysis of specimens appropriate to the test being conducted;

          2. Quality control procedures;

          3. Security procedures to ensure integrity and privacy of original specimens, data, and computer records;

          4. Tracking of specimens between the Field Centers and the Central Laboratory;

          5. Management of record and specimen archives;

          6. Data analysis appropriate to the activities of the Central Laboratory, and

          7. In cooperation with other Centers, the Central Laboratory's role in developing, maintaining and coordinating communications related to all aspects of laboratory issues.

        1. Assuring the quality of data related to:

          1. Preparation of specimens and laboratory analysis,

          2. Electronic encoding and computer storage,

          3. Storage, retrieval, and transmittal to the Coordinating Center,

          4. Quality control activities of measurement error sources, to include but not necessarily be limited to:
            1. where warranted, measurement of 5% blind duplicate specimens from all assays conducted for the study;

            2. assessment and control of measurement drift (throughout the normative range of a measurement variable) during the course of the study, using external standards for measurements;

            3. maintenance of a log of identified errors;

            4. pursuit of missing data and correctable errors within two weeks of identification of error; and

            5. development, maintenance, and modification of an audit trail for all data entry and data correction activities, including electronically transferred data.

        2. Support quality assurance oversight activities of Coordinating Center staff to include but not necessarily be limited to identification of sources of measurement error, establishing standards of performance, and participating in quality control tests at the behest of the Quality Assurance Committee. Also include orientation training to laboratory methods for professional staff from the Coordinating Center with quality assurance responsibilities.

      5. Participate in planning of pilot testing, and using specimens collected by Field Centers during pilot test, certify that each Field Center's laboratory is capable of conducting the initial transferrin saturation assay following the specified standardized protocol. As warranted, participate in central training of study personnel for specimen collection, processing and shipping procedures.

      6. Redesign and implement changes in protocol and final Laboratory Manuals of Operation, as recommended by the Steering Committee based on pilot testing results.

      7. Conduct laboratory analyses as specified in the Steering Committee approved laboratory protocol, and conduct and participate in quality control assessments at stages of the study including the protocol development/pilot testing phase, the transferrin saturation screens, the genotyping screen, the comprehensive clinical examination, the family study and any substudies and ancillary studies yet to be identified.

      8. Organize, edit, and transmit results of laboratory analyses and quality control assessments to the Coordinating Center according to data management protocols that the Coordinating Center will develop in collaboration with the Central Laboratory. Transmit data monthly or as determined by the Coordinating Center. The Central Laboratory will assist the Coordinating Center in the interpretation of quality control data and participate in the generation of quality assurance reports for the Quality Assurance Committee.

      9. Develop and maintain a Specimen Repository for long-term storage of specimens. The proposal should describe the following features:

        [Note: It is anticipated that specimen types to be stored included whole blood, serum, plasma, DNA and lymphocytes.]

        1. System for cataloguing information about specimens, including type, amount, previous thawing and specific location in repository,

        2. Alarm systems, including persons responsible for responding to alarm, and managing freezers in the event of freezer malfunction, temperature deviations or power failure,

        3. Power systems,

        4. Physical security (padlocks, access to keys) systems,

        5. Responsibilities of personnel for routine periodic checks of freezers,

        6. Certification protocol for personnel responsible for managing freezers, and vii. Safeguards against loss of multiple aliquots from individual participants in the case of freezer failure.

        7. Throughout the period of performance, in conjunction with the Coordinating Center and Field Centers, the Contractor shall analyze collected data and prepare abstracts, presentations, and manuscripts for publication of results.

        [Note: The proposal should include brief descriptions of at least five potential manuscript topics that could be first-authored by the Offeror. It is anticipated that abstracts and manuscripts proposed for presentation or publication will be submitted to the Publications Committee and the NHLBI Project Office in advance for review and approval, as outlined in the section on Deliverables. Due to overlapping interest and expertise, manuscript writing groups will likely include members from several, most or all Centers.]

      10. At the termination of the contract, oversee the transport of all remaining repository specimens from the Specimen Repository to a repository identified by the NHLBI Project Office.

    2. Subordinate Tasks

      1. Participate in site visits to Field Centers, as needed;

      2. Participate in ancillary studies and substudies, as desired, feasible, and recommended by the Steering Committee. Such studies may include, but are not limited to, examinations of ethical, economic and health policy issues related to implementation of screening programs, or other questions related to iron overload and hemochromatosis;

        [Note: Investigators may propose ancillary studies and substudies to be conducted in one or more study Centers. A substudy is an investigation which, although not part of the core exam protocol, is funded by Contract funds, and will yield additional information related to study objectives. An ancillary study is a study not funded by contract funds. Substudies and ancillary studies may include all or a subgroup of the cohort at a given center, and may involve additional interviews or examinations of study participants as well as analysis of blood or tissue specimens, tapes, or images collected previously.

        Ancillary studies and substudies are subject to the same policies, reviews and approvals as the core protocol. Substudies involving additional participant burden will likely require OMB clearance. Investigators proposing substudies will also prepare a request for OMB clearance for the substudy; or, for case-control studies, a request for exemption from OMB review. Examples of such submissions will be provided on request.

        Ancillary study data will be incorporated into the study data set after an appropriate period of time (generally 12 months after completion of data collection). Investigators conducting ancillary studies are to be viewed as collaborating investigators of the primary study, with appropriate access to the full data set. However, use of analytic resources of the study will require additional support from the ancillary study investigators.

        Ancillary studies and substudies will be evaluated by the Steering Committee. Highest priority will be given to studies which: 1) have the highest scientific merit, 2) do not interfere with the main study objectives, 3) produce the least burden on participants, 4) have objectives directly related to the study, and 5) require the unique characteristics of the study participants.

        For all substudies and ancillary studies, the contractor shall define the hypotheses to be investigated and the methodology to be used, and should estimate the cost and burden on participants. Study data collection must not interfere with the conduct of the core examination. All substudies in the proposal should be distinctly identified, with separate descriptions and estimates of costs. Ancillary studies and substudies may be proposed before and/or after contract award as scientific opportunities arise. All studies must be approved by the Steering Committee, reviewed by the Data and Safety Monitoring Board, and approved by the NHLBI Project Office before initiation.]

      3. Cooperate in providing up-to-date lists of publications and presentations coming from the Central Laboratory for a data base to be managed by the Coordinating Center,

      4. Prepare and present to the Steering Committee a Central Laboratory Manual of Operations (or sections to be included in the Field Center Manual of Operations, as appropriate), contents as described above, in draft and final form for NHLBI approval before the end of the protocol development/pilot testing phase of the study.

      5. Provide raw or summary data as required by the Project Office; and

      6. Prepare annual and financial reports, final report and summary of study as outlined under task 4, Reports/Deliverables, for the Project and Contracts Office.


ATTACHMENT B

DELIVERABLES/REPORTING REQUIREMENTS

REPORTING REQUIREMENTS

  1. Annual progress reports (3 copies), indicating general progress in study activities and administrative issues; personnel with FTE level for the reporting period; changes in personnel; specific problems encountered or anticipated and attempts to resolve such problems; and progress in publications activities, including an updated list of ongoing and completed manuscripts (not to exceed 4 pages).

  2. Quarterly financial reports (3 copies). Use form NIH 2706.

  3. A final report, due on or before expiration of the contract on September 30, 2004 (10 copies), documenting and summarizing the results of the entire contract work, including recommendations and conclusions based on both the general experience and the special viewpoint of the center not to exceed ten (10) pages.

  4. With the final report, a summary (not to exceed 200 words) of salient results achieved during the performance of the contract (3 copies).

DELIVERABLES

The following table provides an overview of deliverables:
Item #

Description Quantity Delivery Schedule Delivery Information
1. Draft Manuals of Operations

15-21 July 1, 2000 Coordinating Center
2. Training Materials for Field Centers 15-21 July 1, 2000 Coordinating Center(2 copies)
Field Centers (2 copies each)
Project Office (2 copies)

3. Laboratory certification 5-8 September 15, 2000 Coordinating Center
Field Centers

4. Manuals of Operations

15-21 September 1, 2000 Coordinating Center
5. Quality Control Reports 5-7 Quarterly Project Office, Coordinating Center, All members of Quality Assurance Committee

6. Lab Analysis Results 1 Weekly, within 30 days of specimen receipt

Coordinating Center
7. Raw data 1 As requested Project Office

8. Abstracts 8-10 2 weeks prior to submission Publications Committee (1 copy per member)
Project Office (2 copies)

9. Manuscripts 8-10 4 weeks before submission Publications Committee (1 copy per member)
Project Office (2 copies)

10. Progress Report 3 September 30
Yearly
Project Office (2 copies)
Contracts Office (1 copy)

11. Financial Reports 3 Quarterly Contracts Office
(NIH Form 2706)

12. Lab specimens All End of contract As specified by NHLBI Project Office

13. Final Report and summary 10 September 30, 2002 Project Office (2 copies)
Contracts Office (1 copy)


ATTACHMENT C

EVALUATION FACTORS FOR AWARD WITH TECHNICAL EVALUATION CRITERIA AND OTHER INFORMATION

METHOD OF REVIEW

The technical proposal will receive paramount consideration in the selection of the contractor for this procurement. The evaluation will be based on the demonstrated capabilities of the prospective contractors in relation to the needs of the project as set forth in the RFP. The merits of each proposal will be evaluated carefully, based on the thoroughness and feasibility of the technical approach taken.

Although cost is not a specific evaluation criterion, it will be assessed. In the event that the technical evaluation reveals that two or more offerors are approximately equal in technical ability, then the estimated cost may become significant in determining award(s). In any event, the Government reserves the right to make an award to the best advantage of the Government, cost and other factors considered.

As an agency of the U.S. Public Health Service, the National Heart, Lung, and Blood Institute is responsible for sponsoring research programs and for disseminating information that will serve to improve the health of the population of the United States. Therefore the recruitment into this program of foreign populations that have significantly different social, cultural and economic conditions could substantially alter the study results. As a result, the award of contracts for performance as a Central Laboratory is open to offerors from the United States of America only.

Proposals submitted in response to this solicitation will be reviewed by a peer group of scientists under the auspices of the Review Branch, Division of Extramural Affairs, NHLBI, and subsequently by a review group within NHLBI.

Past performance is not an evaluation criterion but it will be considered when determining contractor responsibility using the information required by the "Qualifications of the Offeror" portion of the "Standard RFP Instructions and Provisions" of the RFP References Directory

TECHNICAL EVALUATION CRITERIA

The evaluation criteria are used by the technical evaluation committee when reviewing the technical proposals. The criteria below are listed in the order of relative importance with weights assigned for evaluation purposes.

  1. Adequacy of plans and documented capacity for fulfilling the Central Laboratory functions outlined in the statement of work. These include soundness of scientific rationale for the proposed clinical, chemical and genetic laboratory measurements for screening, diagnosis, and study of potential determinants and correlates of iron overload, hemochromatosis and related hepatic, endocrinologic, hematologic and cardiovascular disease; development of laboratory protocols; plans for and experience in developing and conducting standardized collection, processing, and laboratory analysis of required number of specimens; ability to develop and maintain the Specimen Repository; active participation in data analysis and publication; and selection and administration of subcontracts as needed. (35 points)

  2. Adequacy of plans and documented ability for developing, maintaining, and modifying quality assurance activities in collaboration with the Coordinating Center, and for the organization, editing, and accurate tracking of specimens from the Field Centers to the Central Laboratory and timely transmittal of laboratory analysis results, including quality control measurements to the Coordinating Center. This includes written standard operating procedures, and procedures to maintain all aspects of data quality including monitoring and reporting of reliable and accurate laboratory measurement performance, and communication among Centers related to these activities. (30 points)

  3. Expertise of key Central Laboratory staff in identifying, developing, and conducting laboratory analyses of the proposed measures; their willingness and ability to provide ongoing and collaborative scientific advice to co-investigators among the Centers and the Project Office; and their willingness and ability to take appropriate leading roles in protocol development, operational collaboration and coordination among centers, quality assurance activities, and scientific data analysis and publication and management of clinical epidemiology laboratory studies. (20 points)

  4. Adequacy of the administrative structure, support staff, and institutional support. This includes the availability of adequate facilities and equipment, including technical hardware, and the ability to develop, maintain, and modify technical software, hardware, and operational procedures, as necessary. (15 points)

    Total ............100 Points


ATTACHMENT D

SPECIFIC RFP INSTRUCTIONS AND PROVISIONS

NOTICE TO OFFERORS: This section contains proposal instructions and information which are specifically related to this acquisition. The information provided below is only a portion of the instructions and notices required for the submission of a proposal. References to additional, more general, information and forms regarding proposal preparation are contained in Attachment E. titled, "Applicable RFP References".

An index of the specific RFP instructions and provisions, which apply, follow:

  1. Proposal Intent Response Sheet (submit prior to proposal submission-by 1/29/99)
  2. Packaging and Delivery of Proposal
  3. Government Notice for Handling Proposals
  4. Privacy Act System of Records
  5. SIC Code and Small Business Size Standard
  6. Number and Type of Award(s)
  7. Estimate of Effort
  8. Service of Protest
  9. Technical Proposal Table of Contents
  10. Safety and Health
  11. Other Provisions


  1. PROPOSAL INTENT RESPONSE SHEET

    RFP No. NHLBI-HC-99-05 (Central Laboratory)

    TITLE OF RFP: "Iron Overload and Hereditary Hemochromatosis Study--Central Laboratory"

    FURNISH THE INFORMATION REQUESTED BELOW AND RETURN THIS PAGE BY 1/29/99. YOUR EXPRESSION OF INTENT IS NOT BINDING BUT WILL ASSIST US IN PLANNING FOR PROPOSAL EVALUATION.

    I INTEND TO SUBMIT A PROPOSAL

    COMPANY/INSTITUTION NAME:

    ADDRESS:

    PROJECT DIRECTOR'S NAME:

    TITLE:

    TELEPHONE NUMBER:

    NAMES OF COLLABORATING INSTITUTIONS AND INVESTIGATORS (include Subcontractors and Consultants):

    ______________________________________________________

    ______________________________________________________


    RETURN TO:

    Review Branch, NIH, NHLBI, 6701 Rockledge Drive, MSC 7924, Bethesda, MD 20892
    ATTN: Dr. James Scheirer
    or FAX TO: Dr. James Scheirer at (301) 480-3541


  2. PACKAGING AND DELIVERY OF THE PROPOSAL

    Your proposal shall be organized as specified in the "Standard RFP Instructions and Provisions." Shipment and marking shall be as follows:

    EXTERNAL PACKAGE MARKING

    In addition to the address cited below, mark each package as follows:

    "RFP NO. NHLBI-HC-99-05

    TO BE OPENED BY AUTHORIZED GOVERNMENT PERSONNEL ONLY"
    The number of copies required of each part of your proposal are:
    TECHNICAL PROPOSAL: ORIGINAL* AND Twenty-five (25) COPIES
    BUSINESS PROPOSAL: ORIGINAL* AND Six (6) COPIES

    DELIVER PROPOSAL TO:

    If hand delivered or delivery service:

    Review Branch, National Heart Lung and Blood Institute, Rockledge Building, Room 7091 6701 Rockledge Drive MSC 7924 Bethesda, MD 20817-7924

    If using U.S. Postal Service:

    Review Branch, Division of Extramural Affairs, National Institutes of Health National Heart, Lung, and Blood Institute, 6701 Rockledge Drive MSC 7924 Bethesda, MD 20892-7924

    *THE ORIGINAL PROPOSAL MUST BE READILY ACCESSIBLE FOR DATE STAMPING.


  3. GOVERNMENT NOTICE FOR HANDLING PROPOSALS

    An offeror shall place this notice on top of each copy of its technical proposal

    "This proposal shall be used and disclosed for evaluation purposes only, and a copy of this Government notice shall be applied to any reproduction or abstract thereof. Any authorized restrictive notices which the submitter places on this proposal shall also be strictly complied with. Disclosure of this proposal outside the Government for evaluation purposes shall be made only to the extent authorized by, and in accordance with, the procedures in HHSAR paragraph 315.608-72."


  4. PRIVACY ACT SYSTEM OF RECORDS

    This procurement action requires the Contractor to do one or more of the following: design, develop, or operate a system of records on individuals to accomplish an agency function in accordance with the Privacy Act of 1974, Public Law 93-579, December 31, 1974 (5 USC 552a) and applicable agency regulations. Violation of the Act may involve the imposition of criminal penalties.

    The Privacy Act System of Records Notice that applies to this RFP was published in the Federal Register dated April 7, 1997, Vol. 62, No. 66. This most recent notice will be incorporated into any contract resulting from this RFP. If you would like a copy, please contact the Contracting Officer identified in the cover letter to this RFP.


  5. SIC CODE AND SMALL BUSINESS SIZE STANDARD

    NOTE: The following information is to be used by the offeror in preparing its Representations and Certifications, specifically in completing the provisions entitled, SMALL BUSINESS PROGRAM REPRESENTATIONS, FAR 52.219-1:

    The standard industrial classification (SIC) code for this acquisition is 8731.

    The small business size standard is 500 employees.

    THIS REQUIREMENT IS NOT SET-ASIDE FOR SMALL BUSINESS. However, the FAR requires in every solicitation (except for foreign acquisitions) the inclusion of the SIC code and corresponding size standard which best describes the nature of the requirement in the solicitation.


  6. NUMBER AND TYPE OF AWARD(S)

    It is anticipated that one award will be made from this solicitation and that award will be made on or about September 30, 1999.

    It is anticipated that the award made from this solicitation will be a multiple-year cost reimbursement, completion type contract with a period of performance of 60 months, and that incremental funding will be used.


  7. ESTIMATE OF EFFORT

    To assist you in the preparation of your proposal, the Government considers the effort to perform this work each year over the five year performance period. This following estimate is furnished for the offeror's information only and is not to be considered restrictive for proposal purposes.

    Labor Category Level of Effort (percentage of effort)

    Year 1

    Year 2 Year 3 Year 4 Year 5
    PI/Proj. Dir. 25% 25% 25% 25% 25%
    Other Investigators 50% 50% 50% 50% 50%

    All staffing levels proposed should be accompanied by specific justifications as to the type and hours of work expected to be performed by all personnel. Technician time to perform the assays is assumed to be in the per assay cost estimates. Offerors will be required to propose levels of commitment whether compensated or donated effort, necessary to complete the work described in their proposals. It is expected that realistic levels of effort will be proposed such that an offeror's understanding of the work will be apparent.


  8. SERVICE OF PROTEST

    In accordance with FAR 52.233-2 SERVICE OF PROTEST (NOV 1988):

    (a) Protests, as defined in Section 33.101 of the Federal Acquisition Regulation, that are filed directly with an agency, and copies of any protests that are filed with the General accounting Office (GAO) shall be served on the Contracting Officer (addressed as follows) by obtaining written and dated acknowledgment of receipt from:

    Mr. Robert R. Carlsen Hand-Carried Address: National Institutes of Health, National Heart, Lung, and Blood Institute, Contracts Operations Branch, II Rockledge Center, Room 6122, 6701 Rockledge Drive, MSC 7902 Bethesda, MD 20817

    U.S. Postal Service: National Institutes of Health, National Heart, Lung, and Blood Institute, Contracts Operations Branch, II Rockledge Center, 6701 Rockledge Drive, MSC 7902 Bethesda, MD 20892-7902

    The copy of any protest shall be received in the office designated above within one day of filing a protest with GAO.


  9. TECHNICAL PROPOSAL TABLE OF CONTENTS

    Please number each page of text. Type density and size must be 10-12 points. If constant spacing is used, there should be no more than 15 cpi, whereas proportional spacing should provide an average of no more than 15 cpi. There must be no more than six lines of text within a vertical inch.

    The technical proposal should be organized as follows:

    1. TECHNICAL PROPOSAL COVER SHEET (Form is located in the Streamlined RFP References under "FORMS, FORMATS, ATTACHMENTS")--Page 1
    2. TECHNICAL PROPOSAL TABLE OF CONTENTS--Page 2
    3. ABSTRACT--Page 3 State the proposal's broad, long-term objectives and specific aims. Briefly and concisely describe the research design and methods for achieving these goals. DO NOT EXCEED one page in providing the abstract. Identify the RFP Number, Institution and Principal Investigator on the abstract.
    4. TECHNICAL PLAN (LIMIT: 25 PAGES) Refer to Technical Proposal Instructions located in the Standard RFP Instructions and Provisions under Streamlined RFP References for more detail.
      1. WORK STATEMENT
        1. Objectives--Page #
        2. Approach--Page #
        3. Methods--Page #
        4. Schedule--Page #
      2. PERSONNEL
        1. List of all Personnel in the project including Subcontractors, Consultants/Collaborators, by name, title, department and organization--Page #
          PROVIDE NARRATIVE FOR:
        2. Principal Investigator/Project Director--Page #
        3. Other Investigators--Page #
        4. Additional Personnel--Page #
          [NOTE: For personnel, include a two-page biosketch under APPENDICES below.]
      3. FACILITIES, EQUIPMENT AND OTHER RESOURCES--Page #
        List/describe all facilities, equipment and other resources available for this project.
      4. OTHER CONSIDERATIONS--Page # (Use specifically titled subparagraphs, as applicable.)
    5. OTHER SUPPORT--Page #
      Complete the Form "Summary of Current and Proposed Activities." All key personnel must be listed on this form. The form is located in the Streamlined RFP References under "FORMS, FORMATS, & ATTACHMENTS."
    6. TECHNICAL PROPOSAL COST INFORMATION--Page #
      (Form located in the Streamlined RFP References under "FORMS, FORMATS, & ATTACHMENTS.")
    7. LITERATURE CITED--Page #
    8. APPENDICES--Page # The total number of appendices SHALL NOT EXCEED 100 PAGES single spaced. List each Appendix and identify the number of pages for each one. Appendices must be clear and legible, and easily located. Include biosketches here.


  10. SAFETY AND HEALTH DEVIATION PHS 352.223-70(AUGUST 1997)

    1. To help ensure the protection of the life and health of all persons, and to help prevent damage to property, the Contractor shall comply with all Federal, State and local laws and regulations applicable to the work being performed under this contract. These laws are implemented and/or enforced by the Environmental Protection Agency, Occupational Safety and Health Administration and other agencies at the Federal, State and local levels (Federal, State and local regulatory/enforcement agencies).

    2. Further, the Contractor shall take or cause to be taken additional safety measures as the Contracting Officer, in conjunction with the project or other appropriate officer, determines to be reasonably necessary. If compliance with these additional safety measures results in an increase or decrease in the cost or time required for performance of any part of work under this contract, an equitable adjustment will be made in accordance with applicable "Changes" Clause set forth in this contract.

    3. The Contractor shall maintain an accurate record of, and promptly report to the Contracting Officer, all accidents or incidents resulting in the exposure of persons to toxic substances, hazardous materials or hazardous operations; the injury or death of any person; and/or damage to property incidental to work performed under the contract al all violations for which the Contractor has been cited by any Federal, State or local regulatory/enforcement agency. The report shall include a copy of the notice of violation and the findings of any inquiry or inspection, and an analysis addressing the impact these violations may have on the work remaining to be performed. The report shall also state the required action(s), if any, to be taken to correct any violation(s) noted by the Federal, State or local regulatory/enforcement agency and the time frame allowed by the agency to accomplish the necessary corrective action.

    4. 4. If the Contractor fails or refuses to comply promptly with the Federal, State or local regulatory/enforcement agency's directive(s) regarding any violation(s) and prescribed corrective action (s), the Contracting Officer may issue an order stopping all or part of the work until satisfactory corrective action (as approved by the Federal, State or local regulatory/enforcement agencies) has been taken and documented to the Contracting Officer. No part of the time lost due to any stop work order shall be subject to a claim for extension of time or costs or damages by the Contractor.

    5. The Contractor shall insert the substance of this clause in each subcontract involving toxic substances, hazardous materials, or operations. Compliance with the provisions of this clause by subcontractors will be the responsibility of the Contractor.


  11. OTHER PROVISIONS

    HUMAN MATERIALS (It is anticipated that this clause will appear in the contract.)

    It is understood that the acquisition and supply of all human specimen material (including fetal material) used under this contract will be obtained by the Contractor in full compliance with applicable State and Local laws and the provisions of the Uniform Anatomical Gift Act in the United States and that no undue inducements, monetary or otherwise, will be offered to any person to influence their donation of human material.

    PUBLICATION AND PUBLICITY (It is anticipated that this article will appear in the contract.)

    The contractor shall acknowledge the support of the National Institutes of Health whenever publicizing the work under this contract in any media by including an acknowledgment substantially as follows: "This project has been funded in whole or in part with Federal funds from the National Heart, Lung and Blood Institute, National Institutes of Health, under Contract No. "TBD"."

    HHSAR 352.270-6 PUBLICATION AND PUBLICITY (JULY 1991) (It is anticipated that this clause will appear in the contract.)

    Unless otherwise specified in this contract, the Contractor is encouraged to publish, and make available through accepted channels, the results of its work under this contract. A copy of each article submitted by the Contractor for publication shall be promptly sent to the Project Officer. The Contractor shall also inform the Project Officer when the article or other publication is published, and furnish a copy of it as finally published.


ATTACHMENT E

APPLICABLE RFP REFERENCES

This section identifies the items located in the Streamlined RFP References that are applicable to this Request For Proposal (RFP).

  1. The entire file entitled "STANDARD RFP INSTRUCTIONS AND PROVISIONS" is applicable to this RFP, except as modified by the inclusion of items from the "OPTIONAL RFP INSTRUCTIONS AND PROVISIONS"
  2. The following items are applicable from the file titled "OPTIONAL RFP INSTRUCTIONS AND PROVISIONS":
  3. The following items are applicable to this specific RFP and are located in the file entitled "FORMS, FORMATS, AND ATTACHMENTS", under Streamlined RFP References:

    SUBMIT WITH TECHNICAL PROPOSAL (with original and every copy of technical proposal)

    1. Technical Proposal Cover Sheet
    2. Summary of Current and Proposed Activities
    3. Technical Proposal Cost Information
    SUBMIT WITH BUSINESS PROPOSAL:
    1. A Contract Pricing Cover Sheet with every copy of business proposal.
    2. Proposal Summary and Data record, NIH-2043, with every copy of business proposal.
    3. Disclosure of Lobbying Activities, OMB SF-LLL, only one completed and signed original.
    4. Representations and Certifications, only one completed and signed original.
    OTHER - TO BE SUBMITTED LATER:
    1. Certificate of Current Cost or Pricing Data, NIH-1397, to be submitted with Final Proposal Revision, if required by the Contracting Officer.
    2. Small Business Subcontracting Plan, to be submitted as directed by the Contracting Officer.
    ANTICIPATED TO BE INCLUDED AS CONTRACT ATTACHMENTS:
    1. Invoice/Financing Requests Instructions for NIH Cost-Reimbursement Type Contracts, NIH(RC)-1
    2. NIH 2706, Financial Report of Individual Project/Contract, the form with instructions
    3. Procurement of Certain Equipment, NIH(RC)-7
    4. Protection of Human Subjects Assurance/Identification/Certification/Declaration, OF 310

    The "SAMPLE CONTRACT FORMAT-GENERAL" under the Streamlined RFP References is applicable to this RFP. Selected clauses applicable to this acquisition will be included in the contract.


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