"Iron Overload and Hereditary Hemochromatosis Study--Coordinating Center"
| Request for Proposal No.: | NIH-NHLBI-HC-99-19 |
| Issue Date: | July 12, 1999 |
| 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 Intent Due Date: | August 13, 1999 |
| Proposal Due Date: |
September 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-99-19, is specifically for all responsible offerors interested in performing as a Coordinating Center for this study. This Streamlined Technical Request For Proposal (RFP) consists of this combined solicitation form and cover letter (PART A), and five attachments, as follows:
Attachments:
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:
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 8/13/99. 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 September 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
BACKGROUND AND WORK STATEMENT
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:
The project duration is planned for five years.
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.
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. In addition, 2,000 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 | December 31, 1999-December 31, 2000 (12 months) |
| OMB Clearance | July 1, 2000-December 31, 2000 (6 months) |
| Training, Pilot Testing Protocol Modification |
October 15, 2000-December 31, 2000 (2.5 months) |
| Initial Transferrin Saturation Screen | January 2, 2000-December 31, 2002 (24 months) |
| Random Subgroup Genotyping Initial ELSI Assessment |
January 2, 2000-December 31, 2002 (24 months) |
| Repeat Transferrin Saturation Screen Serum Ferritin Assay |
January 2, 2000-December 31, 2002 (24 months) |
| Comprehensive Clinical Examination Genotyping, Extended ELSI Assessment |
April 1, 2000-December 31, 2003 (33 months) |
| Family Study, ELSI Assessment | June 1, 2001-December 31, 2003 (31 months) |
| Follow-up for ELSI, Morbidity and Mortality |
April 1, 2001-December 31, 2004 (45 months) |
| Final Data Analysis and Close-out | January 1, 2003-December 31, 2004 (12 months) |
Study years are designated as follows:
Year 1, December 31, 1999-December 31, 2000
Year 2, January 1, 2001-December 31, 2001
Year 3, January 1, 2002-December 31, 2002
Year 4, January 1, 2003-December 31, 2003
Year 5, January 1, 2004-December 31, 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.
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):
------------
| |
| 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).
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 "Coordinating Center" are used interchangeably.] Specifically, throughout the period of performance, the Contractor shall provide appropriate senior personnel with expertise in the epidemiology of iron overload and hereditary hemochromatosis; clinical hepatic, endocrinologic, hematologic and/or cardiovascular disease; genetic epidemiology; genetic counseling; the ethical, legal and social implications (ELSI) of genetic screening and testing; quality control; and multi-center clinical epidemiological study coordination and management to:
[Note: Offerors should provide evidence of timeliness in protocol development, data analysis and data set preparation; flexibility; helpfulness; and ability to collaborate with other Centers in all relevant aspects of Coordinating Center functions.]
[Note: See time line and flowchart in Table 1 and Figures 1 and 2, for overview of periods, tasks and study design. A list of examination components is in Table 2.]
[Note: For planning purposes, assume the Offeror will be represented on the Steering Committee and three subcommittees. Also assume that Steering Committee meetings will take place in Bethesda, Maryland, and that 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.]
[Note: It is anticipated that a total of 100,000 participants will be recruited among five to seven Field Centers for an initial transferrin saturation screen. For purposes of the proposal, assume that 20,000 participants will be recruited by each of five Field Centers. Concurrent with this screen, a genotyping screen is expected to be performed on a 20-40% random subgroup, and an initial ELSI assessment on a 2-4% random subgroup. Following the initial screen, approximately 3,600 participants are expected to participate in a repeat transferrin saturation screen and serum ferritin assay, with approximately 1,800 participants continuing on to a comprehensive clinical examination, and approximately 560 participants and 2240 of their family members are expected to participate in a family study. A morbidity, mortality and ELSI follow up of the comprehensive clinical examinees, for up to two years, is also planned. 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).]
[Note: The Offeror should plan pilot testing to include components of the initial and repeat transferrin saturation screens, the comprehensive clinical examination, and initial and extended ELSI assessments. The protocol for the initial transferrin saturation screen and ELSI assessment will likely require clearance from the Office of Management and Budget (OMB). After draft protocols have been developed and approved by the Steering Committee, staff are to be centrally trained for each screen or examination component. Pilot testing will be conducted after training is complete and OMB clearance has been obtained, and will consist of performing the study components, according to the draft Manual of Operations, in approximately 10-20 non-study participant volunteers per Field Center. Repeat measurements should be planned for any examination component for which reproducibility is in question. The pilot tests also are to include shipping blood specimens as specified by the protocol. As the initial transferrin saturation assays are planned to be conducted on-site, rather than at the Central Laboratory, each Field Center's laboratory will need to obtain study certification documenting the ability to conduct standardized assays as specified in the protocol. The Coordinating Center will coordinate and monitor completion of all pilot testing, central training, certification and laboratory tasks are completed.]
[Note: These data sets will contain all the non-individual identifier data deriving from a data collection activity, but may exclude raw data that are used solely for the purpose of creating summary or derived variables. Data will not be released if believed to be unreliable or invalid by the Steering Committee or the NHLBI Project Office. Data may be delayed for release if they are actively being used by study investigators with documented time lines for completion of analyses and publication of results, and upon review of justification by the NHLBI Project Office. Adequate protection for participants, particularly for family and genetic study data, must be provided.
Reimbursement for costs of the public use data set and documentation from public requests is recommended to be limited to $50 per tape, diskette, or CD ROM, and $0.10 per page of photocopying. The Coordinating Center and designated investigators of the study are expected to respond to questions about data set characteristics, format, and content during the study, and it is expected that such questions will be minimized by high quality of documentation.]
[Note: These analyses will seek to identify modifier genetic variants related to the expression of iron overload and hereditary hemochromatosis disorders. 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. 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.]
[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.]
[Note: For planning purposes, assume that the Steering Committee meetings will take place in Bethesda, Maryland and that 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. Conference calls will be held at least monthly; assume these calls will require connections to 10 telephones (one per Center).]
[Note: Assume the Monitoring Board will meet approximately every year and will consist of 6 members.]
Throughout the period of performance the Contractor shall participate in other activities related to the successful completion of the project, as specified by the Steering Committee and/or NHLBI Project Office. This includes, but is not necessarily limited to the following:
[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.]
ATTACHMENT B
DELIVERABLES/REPORTING REQUIREMENTS
The following table provides an overview of deliverables:
| Item # | Description | Quantity | Schedule | Delivery Information |
|---|---|---|---|---|
| 1. | Web site for investigators |
1 | April 1, 2000 | Notify Project Office and Steering Committee of operationalization |
| 2. | Draft consent forms |
1 | May 15, 2000 | Project Office |
| 3. | Final consent forms |
2 | June 15, 2000 | Project Office |
| 4. | Package for OMB clearance |
1 | June 30, 2000 | Project Office |
| 5. | Draft forms | 8-10 | September 15, 2000 | Field Centers Project Office |
| 6. | Draft Field Center Manual of Operations |
15-21 | October 15, 2000 | Field Centers (2 copies each) Project Office (1 copy) Coordinating Center (2 copies) |
| 7. | Training Materials Final Forms |
15-21 | October 10, 2000 | All Centers (2 copies each) Project Office (1 copy) |
| 8. | Data-entry systems | 8-10 | October 15, 2000 | All Centers |
| 9. | Final Manuals of Operations (hard copy and electronic) |
15-21 | December 15, 2000 | Field Centers (2 copies each) Project Office (1 copy) Coordinating Center (2 copies) |
| 10. | Web site for public |
1 | April 1, 2000 | Notify Project Office and Steering Committee of operationalization |
| 11. | Site visit reports | 2 | 2 weeks after visit | Project Office |
| 12. | Steering Committee Reports |
1 per attendee |
2 weeks prior to meeting |
All Centers Project Office Contracts Office |
| 13. | Steering Committee meeting minutes |
1 per attendee |
10 days after meeting |
All Centers Project Office Contracts Office |
| 14. | Data Analysis Manual (hard copy and Web-ready) |
8-10 | December 31, 2001 | All Centers Project Office (2 copies) |
| 15. | Data Analysis Manual updates (hard copy and Web-ready) |
8-10 | Yearly after December 31, 2001 |
All Centers Project Office (2 copies) |
| 16. | Progress Reports | 3 | December 31 Yearly |
Project Office (2 copies) Contracts Office (1 copy) |
| 17. | Quality Control reports |
5-7 | Quarterly | Project Office All members of Quality Assurance Committee |
| 18. | Monitoring Board reports |
1 per attendee |
2 weeks before meeting |
All Centers Project Office Contracts Office Board Members |
| 19. | Monitoring Board meeting minutes |
1 per Center |
1 week after receipt from Project Office |
All Centers |
| 20. | Reprints of published articles |
5 | 2 weeks after publication |
Project Office All Centers |
| 21. | Raw data | 1 | as requested | Project Office |
| 22. | Abstracts | 8-10 | 2 weeks prior to submission |
Publications Committee |
| 23. | Manuscripts | 8-10 | 4 weeks before submission |
Publications Committee Project Office |
| 24. | Financial Reports | 3 | Quarterly | Contracts Office (Form NIH 2706) |
| 25. | Master Data Base | 1 | 4 months after completion of each phase of data collection or as requested |
Project Office Field Centers |
| 26. | Public-use data sets with documentation |
See below | Project Office Other requestors |
|
| Transferrin screens Genotyping subgroup |
1 | December 31, 2007 | ||
| Comprehensive clinical examination |
1 | December 31, 2008 | ||
| Follow-up data | 1 | December 31, 2009 | ||
| 27. | Final Report and Summary |
10 | December 31, 2004 | Project Office (2 copy) Contracts Office (1 copy) |
ATTACHMENT C
EVALUATION FACTORS FOR AWARD WITH TECHNICAL EVALUATION CRITERIA AND OTHER INFORMATION
The technical proposal will receive paramount consideration in the selection of the Contractor(s) for this acquisition. All technical evaluation factors, when combined, are significantly more important than cost/price or small disadvantaged business (SDB) participation. In the event that two or more offerors are determined to be essentially equal following the evaluation of all technical evaluation factors, cost/price or SDB participation may become critical factors in source selection Cost/Price is significantly more important than SDB participation. 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 the Coordinating Center under this program shall be made only to offerors who are located in the United States of America.
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.
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:
RFP No. NHLBI-HC-99-19 (Coordinating Center)
TITLE OF RFP: "Iron Overload and Hereditary Hemochromatosis Study--Coordinating Center"
FURNISH THE INFORMATION REQUESTED BELOW AND RETURN THIS PAGE BY 8/13/99. YOUR EXPRESSION OF INTENT IS NOT BINDING BUT WILL ASSIST US IN PLANNING FOR PROPOSAL EVALUATION.
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
or FAX TO: Dr. James Scheirer at (301) 480-3541
ATTN: Dr. James Scheirer
Your proposal shall be organized as specified in the "Standard RFP Instructions and Provisions." Shipment and marking shall be as follows:
EXTERNAL PACKAGE MARKINGIn addition to the address cited below, mark each package as follows:
"RFP NO. NHLBI-HC-99-19TO 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.
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."
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.
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.
It is anticipated that one award will be made from this solicitation and that award will be made on or about December 31, 1999.
It is anticipated that the awards 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.
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 (full-time equivalents) | ||||
|---|---|---|---|---|---|
| Year 1 | Year 2 | Year 3 | Year 4 | Year 5 | |
| PI/Project Director | .25 | .25 | .25 | .25 | .25 |
| Other Investigators | 1.25 | 1.50 | 1.50 | 1.75 | 1.50 |
| Other | 4.00 | 7.00 | 7.00 | 7.00 | 6.00 |
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. 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.
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.
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:
PROVIDE NARRATIVE FOR:
[NOTE: For personnel, include a two-page biosketch under APPENDICES below.]
List/describe all facilities, equipment and other resources available for this project.
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."
(Form located in the Streamlined RFP References under "FORMS, FORMATS, &ATTACHMENTS.")
Compliance with the provisions of this clause by subcontractors will be the responsibility of the Contractor.
In accordance with FAR Clause 52.219-23, Notice of Price Evaluation Adjustment for Small Disadvantaged Business Concerns, incorporated in Section I.3., offerors will be evaluated by adding a factor of 10 percent to the price of all offers, except offers from small disadvantaged business (SDB) concerns that have not waived the price evaluation adjustment. In addition, offerors that satisfy the exception requirements under subparagraph (b) of FAR Clause 52.219-23 will not have the price evaluation adjustment factor added to their offers.
A SDB concern may elect to waive the price evaluation adjustment, in which case the factor will be added to its offer for evaluation purposes. (The agreements in paragraph (d) of FAR Clause 52.219-23 do not apply to offerors that waive the price evaluation adjustment.) If the SDB concern elects to waive the price evaluation adjustment, it will be evaluated under the Small Disadvantaged Business Participation Factor cited in Section M, and participation in performance of the resultant contract shall include the work expected to be performed by SDB concerns at the prime contract level. Small businesses, other than SDB concerns, will also be evaluated under the Small Disadvantaged Business Participation Factor cited in Section M. Any targets will be incorporated into and become part of the resulting contract.
CREDIT UNDER THE SMALL DISADVANTAGED BUSINESS PARTICIPATION FACTOR IS NOT AVAILABLE TO SMALL DISADVANTAGED BUSINESS CONCERNS THAT RECEIVE A PRICE EVALUATION ADJUSTMENT.
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.
NHLBI PUBLIC USE DATA CLAUSE--EPIDEMIOLOGY COORDINATING CENTER
Public use data will be released under this observational epidemiology study. After completion of the closing date of each examination cycle, the coordinating center shall prepare the data from the examination component and deliver it to the NHLBI. The data shall be prepared in a format suitable for use by the public. Such release is expected to occur no later than five years after the closing date of an examination cycle. The contractor shall provide the data to the NHLBI within four years of the last data of each examination cycle so that the NHLBI can check the data before release. This will provide time for NHLBI review, discussion of the data and opportunity for any changes needed in content or presentation prior to release. If the contract expiration data does not allow the contractor to comply with the above time frame, the data shall be prepared and delivered at least thirty days prior to the contract expiration date.
The public use data set will include all of the examination data obtained in the examination cycle, and/or all of the follow-up information available up to the cutoff time. Inclusion of raw data that has been processed into summary information shall be discussed with the Project Officer prior to submission. Data prepared for release shall not contain personal identifiers. The contractor shall coordinate preparation of the data with the NHLBI to assure patient confidentiality. The data shall be submitted on CD ROM, or other mutually agreed upon data medium that include complete electronic documentation and data.
The contractor shall produce clear documentation for the public use data. The documentation must allow for use by investigators not familiar with the data set. The documentation must be written in WordPerfect or ASCII format, and must be included as a data set in the storage medium.
The study investigators wil be expected to answer basic questions regarding data set characteristics, format and content, during the study. Documentation is expected to be of the highest quality so that such questions will be minimized.
Data will not be prepared for public use if the investigators and NHLBI believe that they are unreliable or invalid. These exceptions must be justified in writing to the NHLBI and will be reviewed and, if the NHLBI concurs, approved in writing by the Director of the Division that sponsored the study.
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).
SUBMIT WITH TECHNICAL PROPOSAL (with original and every copy of technical proposal)
SUBMIT WITH BUSINESS PROPOSAL:
OTHER - TO BE SUBMITTED LATER:
ANTICIPATED TO BE INCLUDED AS CONTRACT ATTACHMENTS:
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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