Sincerely,
/s/ John C. Taylor
Contracting Officer

2. WORK STATEMENT
   1. Project Description

      The Prevention of Cardiovascular Disease in Diabetes Mellitus trial (PCDD) is a contract program initiated by the National Heart, Lung, and Blood Institute (NHLBI). Two Requests For Proposals (RFPs) are being issued for the selection of approximately 8--10 Clinical Center Networks (CCN) and one Coordinating Center (CC) to conduct a multicenter randomized clinical trial, enrolling and following a total of 10,000 patients for a minimum of 4 years. The entire study is scheduled for a nine year period of performance. The specific objectives of the study are to determine if the rate of major cardiovascular events in diabetes mellitus (DM) Type 2 patients can be reduced by:

      1. Intensive glycemic control using a non-insulin-resistance-lowering drug regimen, compared with conventional glycemic control using a non-insulin-resistance-lowering drug regimen;

      2. Intensive glycemic control using an insulin-resistance-lowering drug regimen compared with conventional glycemic control using a non-insulin-resistance-lowering drug regimen;

      3. Intensive glycemic control using an insulin-resistance-lowering drug regimen, compared with intensive glycemic control using a non-insulin-resistance-lowering drug regimen;

      4. Intensive compared with conventional levels of lipid and blood pressure control.

      These objectives will be addressed in patients with Type 2 DM not currently requiring insulin for glycemic control, with a composite annual event rate of 4 to 5% some marker(s) for subclinical macrovascular disease or other risk factor(s) will be used as selection criteria in younger patients. Quality of life data and health care costs related to the above strategies will also be assessed.

      Final drug strategies and analyses which will be incorporated into the Protocol will be defined collaboratively during the Protocol Development and Pilot Testing phase by the Steering Committee.

   2. Background and History

      Diabetes mellitus is a common disorder which is frequently misunderstood and often not treated optimally. Although usually thought of in terms of the acute symptoms and long term consequences associated with elevated glucose levels, diabetes is a complex metabolic disorder with abnormalities in carbohydrate, lipid, and protein metabolism. Declines in CVD mortality in this country in the past 30 years have been smaller among diabetics than among non-diabetics. Most diabetic patients die of cardiovascular disease (CVD), with CVD rates in diabetics two to four times those of the non-diabetic population. This increased CVD risk, along with the increasing prevalence of obesity and increasing numbers of elderly and minorities in the U.S. population, means that diabetes-associated CVD will become an even greater public health problem in the future.

      Diabetes can increase the risk of CVD in several ways, including the effects of elevated blood sugar (e.g., acute alterations in blood lipids and coagulation factors, protein glycosylation causing damage to the kidneys and secondary hypertension, direct toxic effects on the vasculature potentiating the development of atherosclerosis), the combination of hyperglycemia with other CVD risk factors to exacerbate the risk for a given profile of non-glucose CVD risk factors, and the worsening of multiple other CVD risk factors levels (insulin resistance syndrome). Due to these complex co-morbid conditions, control of hyperglycemia, although important, may not be sufficient to substantially reduce morbidity and mortality.

      Diabetes is not a single disease and although common forms of diabetes are associated with an increased risk of CVD, the type of diabetes may have implications for the approach to preventing its cardiovascular complications. Current recommendations for CVD prevention generally apply to both Type 1 and Type 2 diabetes. In the U.S., approximately 10 percent of diabetic patients have Type 1 diabetes (previously called insulin dependent diabetes or IDDM) while approximately 90 percent have Type 2 diabetes (previously called non-insulin dependent diabetes or NIDDM). The optimal treatment for the young, Type 1 diabetic patient with severe, labile hyperglycemia may not be the best treatment for the older, Type 2 diabetic with mild, stable glucose elevations. Type 1 diabetes is an immunologic disease characterized by severe insulin deficiency, and restoration of normal glucose levels by intensive insulin therapy may be more successful in reducing risk of all chronic complications of this disorder. Type 2 diabetes, a complex disease with generally elevated levels of insulin resistance and variable levels of circulating insulin, is often accompanied by multiple other CVD risk factor abnormalities. While glucose control also appears important for Type 2 patients, it is critical not to overlook treatment of other associated CVD risk factor abnormalities. For prevention of cardiovascular complications, control of these other risk factors may have a greater effect than glucose control. Nevertheless, several recent studies indicate that in clinical practice, neither hyperglycemia nor other CVD risk factors are adequately controlled in patients with diabetes {Savage 1998}.

      2. Hyperglycemia

         For decades, the value of "tight control" of glucose levels was debated. The Diabetes Control and Complications Trial provided unequivocal evidence of major reductions in the chronic microvascular complications (nephropathy, retinopathy, and neuropathy) among a group of Type 1 diabetic patients where intensive therapy maintained glucose at near normal levels over a six-year period--mean attained glycosylated hemoglobin (HbA_1c) slightly over 7%, compared with about 9% in controls {DCCT Research Group, 1993}. The recently published results of the United Kingdom Prospective Diabetes Study (UKPDS) show a significant reduction in the risk of microvascular events. The benefit reported is attributable primarily to a reduction in retinal photocoagulation and cataract extraction {UKPDS Group 1998}. These results are consistent with observational evidence that these microvascular benefits of normalizing glucose will apply to all diabetics {Klein, 1995}.

         It is less certain, however, that these benefits can be extrapolated to predict reduction in the chronic macrovascular complications of diabetes. The results of the University Group Diabetes Program (UGDP) in the 1960s suggested that treatment of Type 2 diabetes with tolbutamide (a sulfonylurea) may increase the rate of clinical CVD events compared with placebo {UGDP, 1970}. That study and its results remain controversial, but do cast doubt on the macrovascular benefits of standard drug therapy for diabetes. The recent Veterans Affairs Diabetes Feasibility Trial showed a trend towards greater risk of a cardiovascular event in the intensive glycemic treatment arm (mean HgbA_1c = 7.1%) than in the standard treatment arm (mean HgbA_1c = 9.2%), and lower attained HgbA_1c level was an independent predictor of cardiovascular events {Abraira, 1997}. On the other hand, the UKPDS results suggest a trend towards reduction in the rate of myocardial infarction in the aggressive glycemic control group. The study did not show unequivocally, however, that an intensive glucose control strategy reduces the occurrence of major CVD events in Type 2 diabetes patients {UKPDS Group 1998}. It is not clear whether the separation in HgbA_1c levels between control and intervention groups achieved in that study was adequate to definitively test the hypothesis that intensive glucose control can reduce the incidence of macrovascular disease. Also, that study did not examine the benefit of lowering glucose using drugs that lower with regard to insulin resistance.

         While the microvascular complications are essentially unique to diabetes, the macrovascular complications are largely associated with accelerated atherosclerosis, another complex disorder with multiple causes. For macrovascular disease, hyperglycemia or some associated metabolic abnormality may have different effects depending upon the patient's underlying predisposition to CVD. This variable susceptibility may explain why rates of macrovascular complications are more variable than those of microvascular complications among diabetic populations around the world.

         A recent review summarizes the metabolic abnormalities of Type 2 diabetes and discusses currently available treatment strategies. Appropriate diet and exercise are the foundation of all therapy for diabetes. New drugs such as metformin and troglitazone may permit a higher percentage of diabetics to attain good glucose control without undue risk of hypoglycemic episodes. {Dagogo-Jack and Santiago 1997}

      3. Hyperinsulinemia and Insulin Resistance

         Elevations in circulating insulin level have been associated with an increased risk of CVD in some but not all studies. A direct causal role of insulin has been questioned due to the inconsistency of evidence from population studies. In recent years it has become more common to ascribe the primary defect to an increase in resistance to insulin action. A recent study has shown an association of insulin resistance with carotid atherosclerosis {Bonora 1997}. Dyslipidemia, blood pressure elevations, and abnormalities in hemostasis have been associated with this state and a common cause has been postulated (Syndrome X, multiple CVD risk factor syndrome, insulin resistance syndrome). Clarification of the importance of hyperinsulinemia and insulin resistance is important for several reasons including: 1) if hyperinsulinemia stimulates progression of atherosclerosis, the intensive therapy needed to achieve glucose control in many patients could increase the risk of CVD; and 2) if elevated insulin resistance is a primary cause of multiple CVD risk factor abnormalities, treatment of this defect might be a simpler way to reduce CVD risk.

         Recently, a new class of drugs that reduce insulin resistance, the thiazolidinediones, has opened new approaches to the treatment of diabetes {Johnson 1998}. Troglitazone, the only drug of this class approved for use in the U.S., could be a potent new tool for improving diabetes management. In addition to reducing insulin resistance and its accompanying hyperinsulinemia, it has variable effects on other CVD risk factors associated with Syndrome X. However, isolated reports have appeared of severe liver toxicity associated with its use, and the drug has been removed from the market in Europe. It remains to be determined whether this problem will prove sufficient to limit the usefulness of this agent. Newer drugs in the same class are expected to be approved within the next two years, and they may have less of a problem with liver toxicity.

      4. Hypertension

         A subgroup analysis of diabetics in the Systolic Hypertension in the Elderly Program (SHEP) showed a similar relative benefit for CVD events of treatment in diabetics and non-diabetics {Curb 1996}. The revised guidelines for the treatment of hypertension by the Joint National Committee (JNC-6) recommend that blood pressure in diabetic patients be treated to a goal of 130/85 mm Hg, a level lower than previously advocated. Although this level is not based on clinical trial data, new data from the results of the UKPDS trial provide substantial support for the an intensive blood pressure control strategy. The UKPDS results show that more intensive blood pressure control (attained mean 144/82 mm Hg) was associated with a 32% reduction in diabetes- related deaths and a 44% reduction in stroke {UKPDS Group 1998}. Diabetics (N÷1500) included in the Hypertension Optimal Treatment (HOT) trial showed a 51% reduction in major cardiovascular events in the DBP target group <80 mm Hg compared with the DBP target group <90 mm Hg, but this was a post hoc analysis and the number of events was relatively small {Hansson, 1998}. Some clarification of this issue may be provided by the Appropriate Blood Pressure Control in Diabetes (ABCD) trial, which is designed to compare the effects of intensive with moderate blood pressure control on the prevention and progression of diabetic nephropathy, retinopathy, cardiovascular disease and neuropathy in Type 2 diabetes {Schrier 1996}. The ALLHAT study includes approximately 15,000 diabetics, and although it is primarily designed to compare different types of anti-hypertensive drugs, it may provide data on the benefit of different levels of blood pressure control in diabetics. None of these trials or others in progress, however, will provide data on the marginal effect on CVD morbidity and mortality of blood pressure-lowering on top of intensive glycemic control or vice versa, in diabetics.

      5. Dyslipidemia

         Elevated triglycerides and reduced high density lipoprotein cholesterol (HDL-C) levels are the characteristic lipid abnormalities of diabetes. While levels of these lipids are generally correlated with the level of fasting hyperglycemia, control of hyperglycemia does not generally lead to their complete normalization. Current recommendations for treatment of lipid levels in diabetic patients concentrate on reduction of LDL-C to levels recommended for those with additional CVD risk factors (< 130 mg/dl). Some experts favor lowering LDL-C to levels recommended for those with existing CHD (< 100 mg/dl); the rationale is that diabetic patients are a high risk population most likely to benefit from aggressive cholesterol lowering.

         A recent subgroup analysis of data from diabetic patients in the Simvastatin Survival Study (4S) found a reduction in coronary heart disease (CHD) events and suggested that the absolute clinical benefits achieved by cholesterol-lowering in this group may be greater in diabetic than in nondiabetic persons with CHD {Pyorala 1997}. Although there is increasing evidence that cholesterol-lowering is beneficial for diabetic patients, the benefits of more aggressive lowering of cholesterol levels and the optimal target levels remain to be quantified in clinical trials. Large trials are currently underway investigating the effect of statins, fibric-acid derivatives (fibrates, another class of lipid-modifying agents), or a combination of the two on CHD risk in diabetic populations. One of these is the ALLHAT lipid component, which is comparing pravastatin with usual care in persons with an LDL between 130 and 185 mg/dl (between 100 and 129 if CHD is present), and includes about 3,500 diabetics. None of these trials, however, is designed to answer the question of optimal target levels nor the marginal benefit of lipid-lowering on top of intensive glycemic control or vice versa.

      6. Conclusions of Recent Expert Panels

         The report of the Macrovascular Disease Subcommittee of the NIH-sponsored diabetes conference in September 1997 notes that "about 50 percent of excess heart disease in diabetics can be attributed to associated abnormalities in other known CVD risk factors" and that "the same risk factors that predict large vessel disease (i.e. stroke, heart attack and peripheral arterial disease) in the general population also affect the diabetic." This panel "enthusiastically recommended a large scale clinical trial to determine whether the level of glucose control and altering levels of insulin and insulin resistance will decrease the incidence of CHD in a diabetic population." A trial comparing the cost effectiveness of different therapeutic approaches (such as contrasting optimal glucose control with aggressive lipid lowering) was advocated by some members of the panel. The panel also emphasized the importance of selecting diabetics at particularly high risk for developing CVD for inclusion in clinical trials, using such markers as microalbuminuria or carotid artery wall thickness by ultrasound.

         Similar conclusions were reached by the NHLBI Special Emphasis Panel on Prevention and Treatment of Cardiovascular Disease in Diabetes Mellitus in September 1997. Notably, however, a number of panel members recommended testing not only the relative benefit of different diabetic regimens, but also different target levels or intensities of treatment for lipids or blood pressure, using a factorial design. The rational for such a design is that although a number of studies in progress are collectively addressing treatment of lipids, blood pressure or glycemic control in diabetics, none of them will shed light on the comparative benefit of treating hyperglycemia and aggressively treating blood pressure and lipids.

         Additional support for a large clinical trial testing the benefit of tight glycemic, lipid, and blood pressure control as well as insulin resistance lowering therapy was given by an ad hoc advisory group convened by NHLBI in May 1998.

         The PCDD trial has grown out of the findings of these advisory panels, and is designed to test the CVD risk-reducing benefit of intensive glycemic control, intensive lipid and blood pressure control, and insulin resistance-lowering therapy.

   3. Statement of Work

      (This section is common to both RFPs)

      1. OBJECTIVES OF THE SOLICITATION AND BACKGROUND INFORMATION

         The purpose of this program is to conduct a multicenter randomized trial assessing the effect on macrovascular morbidity and mortality in persons with Type 2 diabetes mellitus (DM) of the following pharmacologic strategies:

         1. Intensive glycemic control using a non-insulin-resistance-lowering drug regimen, compared with conventional glycemic control using a non-insulin-resistance-lowering drug regimen

         2. Intensive glycemic control using an insulin-resistance-lowering drug regimen compared with conventional glycemic control using a non-insulin-resistance-lowering drug regimen

         3. Intensive glycemic control using an insulin-resistance-lowering drug regimen, compared with intensive glycemic control using a non-insulin-resistance-lowering drug regimen

         4. Intensive compared with conventional levels of lipid and blood pressure control

         These objectives will be addressed in patients with Type 2 DM who do not yet require insulin therapy, but who are considered at especially high risk for clinical cardiovascular disease (CVD) events on the basis of age, evidence of subclinical atherosclerosis, or clinical CVD. Quality of life and health care costs related to the above strategies will also be assessed. The information will provide a rational basis for control of blood glucose, blood lipids, and blood pressure in Type 2 diabetics.

      2. THE STUDY DESIGN

         The following research design features constitute the initial draft protocol and serve as a guide to offerors. Offerors are expected to discuss their understanding of the study in their proposals and to present their technical approach to accomplish the study objectives as set forth in this draft protocol. They should also propose any modifications to the Protocol that the Steering Committee should consider. Offerors must be willing to abide by design decisions of the Steering Committee. Final drug treatment strategies will be defined collaboratively during the Protocol Development phase. The final protocol will be submitted to a Protocol Review Committee (PRC) appointed by National Heart, Lung and Blood Institute (NHLBI). The first year of recruitment and follow up will constitute an internal pilot study or vanguard phase, the results of which would determine whether the study will proceed as planned. If a decision is made to proceed with the remainder of the study, the patients already recruited and any endpoint events already accrued will be included in the main study. Criteria for deciding whether to proceed would include the success of patient recruitment and the ability to meet treatment targets and obtain separation of the arms.

         B.1. Objectives:

         The primary trial objectives are to determine 1) which if any of the three glycemic control strategies--conventional glycemic control using a non-insulin-resistance-lowering drug regimen, intensive glycemic control using a non-insulin-resistance-lowering drug regimen, and intensive glycemic control using an insulin-resistance-lowering drug regimen--results in the lowest rate of CVD events; and 2) whether more aggressive lipid and blood pressure control results in a lower rate of CVD events compared with conventional control. Each strategy will be accompanied by current anti-platelet therapy and current lifestyle counseling for DM (including diet, exercise, and smoking cessation). Thus, the primary aims of this program are to determine if the rate of major cardiovascular events in Type 2 DM patients can be reduced by:

         1. Intensive glycemic control using a non-insulin-resistance-lowering drug regimen, compared with conventional glycemic control using a non-insulin-resistance-lowering drug regimen

         2. Intensive glycemic control using an insulin-resistance-lowering drug regimen compared with conventional glycemic control using a non-insulin-resistance-lowering drug regimen

         3. Intensive glycemic control using an insulin-resistance-lowering drug regimen, compared with intensive glycemic control using a non-insulin-resistance-lowering drug regimen

         4. Intensive compared with conventional levels of lipid and blood pressure control

         Other objectives include:

         5. To determine the relative impact of the various treatment strategies on other macrovascular endpoints, such as total mortality, MI, stroke, hospitalization for CHF, and limb amputation

         6. To determine the relative impact of the various treatment strategies on microvascular endpoints, such as retinopathy, vision, albuminuria, renal function, and peripheral neuropathy

         7. To determine the relative impact of the various treatment strategies on quality of life

         8. To compare the relative cost effectiveness of the various treatment strategies.

         B.2. General study design and primary outcome

   Diabetes treatment arms-->	Conventional glycemic control starting with non-insulin resistance-lowering drugs (CNRL)	Intensive glycemic control starting with non-insulin resistance-lowering drugs (INRL)	Intensive glucose control starting with insulin resistance-lowering drugs (IIRL)
   Lipids/Blood Pressure Treatment Arms
   Conventional lipid/BP control (current recommended levels) (CLBP)	Cell #1	Cell #2	Cell #3
   Intensive lipid/BP control (lower target levels) (ILBP)	Cell #4	Cell #5	Cell #6

   The study population is persons with Type 2 DM, not currently requiring insulin, aged 50 or 55 to 75. The study design is a 3-by-2 factorial randomized clinical trial, with three glycemic control strategies (C_NRL, I_NRL, and I_IRL) on one axis and two lipid and blood pressure control strategies (C_LBP and I_LBP) on the other axis. A total sample size of 10,000 is estimated to enable adequate power to test the primary hypotheses, given an average follow-up time of 5 years. Some marker(s) for subclinical macrovascular disease or other risk factor(s) will be used as selection criteria in younger patients in order to recruit a study population with a composite annual event rate of 4 to 5% candidates include ankle-brachial index (ABI), microalbuminuria, and carotid intimal-medial wall thickness. The sample size calculation was based on selection by ABI.

   The three glycemic control strategies are: Conventional Glycemic Control with Non-insulin Resistance-Lowering Drugs (C_NRL--e.g., sulfonylureas); Intensive Glycemic Control with Non-insulin-Resistance-Lowering Drugs (I_NRL); and Intensive Glycemic Control with Insulin-Resistance-Lowering Drugs (I_IRL--e.g., thiazolidinediones, biguanides). A difference in attained HgbA_1c of 1.0 to 1.5 percentage points between conventional and intensive glucose control arms is presumed to be needed to test the hypothesis that intensive control reduces CVD risk. The target hemoglobin A1C (HgbA_1c) level for the C_NRL arm is anticipated to be between 7.0 and 8.0%. and the target HgbA_1c for I_NRL and I_IRL is anticipated to be between 6.0 and 6.5%.

   The two lipid and blood pressure (BP) control strategies are: Conventional Lipid/BP Control (C_LBP) and Intensive Lipid/BP Control (I_LBP). The target levels for C_LBP are Low Density Lipoprotein Cholesterol (LDL-C) < 130 mg/dl if no clinical CHD and < 100 mg/dl if CHD and systolic BP (SBP) < 130; the target levels for I_LBP are LDL-C < 100 mg/dl if no clinical CHD and < 75 mg/dl if CHD and SBP < 120 mmHg.

   Standard advice regarding diet and physical activity appropriate for diabetics will be provided to all patients.

   The primary outcome measure is a combination of CVD mortality and major morbidity, including myocardial infarction (MI--clinical and "silent"), stroke, and CVD death.

   B.3. Sample size

   It is estimated that a total sample size of 10,000 patients meeting the eligibility criteria (Section B.4. below), followed for an average of five years, will be needed (1,667 per cell, i.e., 3,333 for each of the three glycemic control arms and 5,000 for each of the lipid/BP arms in a factorial design) to assure 90% power for any two-group comparison of glycemic control strategies with two-sided alpha = 0.017 (0.05 divided by three to adjust for three comparisons), to detect a difference of 20% in the primary outcome, i.e., CVD death, MI (hospitalized or by ECG), or stroke. The 5-year event rate assumed for Cell #1 in the above schemata (conventional glycemic and lipid/blood pressure control) was assumed to be .209. This rate was based on five-year event rates in the ARIC and CHS population-based observational studies (persons aged 55 to 75) in diabetics not on insulin in the lowest quintile of ankle-brachial index; that rate was reduced by 20% to allow for a "healthy volunteer effect" and tighter risk factor control in the conventional glycemic control arm. Glycemic control was assumed to reduce this rate by 20% and blood pressure and lipid control was assumed to reduce this rate by 30%. This latter assumption is is conservative for the glycemic control comparisons, since the greater the effect of lipid and BP control, the lower the event rate in the conventional glycemic control arm (C_NRL). The calculation also assumed a small interaction of the two intervention types (glycemic control and lipid/BP control) where a 17% reduction (rather than 20%) was assumed for the additional effect of glycemic control on top of intensive blood pressure and lipid lowering.

   With this sample size, power to detect a 20% difference in the primary outcome between the lipid/BP arms is greater than 99% at a 2-sided alpha level of 0.05.

   B.4. Eligibility Criteria

   This section describes the anticipated inclusion and exclusion criteria. Offerors must describe how they will implement these criteria. The details of the specific eligibility criteria and measurements will be finalized by the investigators during protocol development, so alternative criteria, justified by scientific or pragmatic rationale, may be proposed.

   The definition of Type 2 diabetes mellitus for purposes of determining eligibility for this study is anticipated to follow the new American Diabetes Association guidelines (a fasting plasma glucose (FPG) level >126 mg/dl (7.0 mmol/l) or a 2-hour postload value in the oral glucose tolerance test (OGTT) >200 mg/dl, with confirmation by retesting). It is expected that mainly previously diagnosed diabetics will be included. Persons already requiring insulin will be excluded because the use of insulin will hamper the study's ability to test the benefit of reducing insulin resistance in the I_IRL arm. In making sample size estimates for this initiative, it was assumed that such persons would be excluded. Persons with chronic conditions that would seriously hamper their full participation in the trial for the full follow-up period would be excluded.

   The age range is assumed to be 50 or 55 to 75 years. The inclusion of younger patients would lower the expected event rates and raise the required sample size, while the oldest patients (over 75 or 80 years) may have more problems with lactic acidosis from biguanides and hypoglycemic complications resulting from intensive glucose lowering. The sample size calculations are based on persons aged 55-75 years. Evidence of subclinical atherosclerosis, and/or other relatively prevalent risk indicators in the presence of which CVD risk is at least doubled, will be used to determine eligibility in order to increase the expected event rates and reduce the required sample size. Given the above definition of diabetes and exclusion of persons on or requiring insulin, it is expected that few otherwise eligible patients would be excluded because of a HgbA_1c that is too low (e.g., < 6% without medication) or too high (e.g., > 12%). Patients will need to have LDL-cholesterol or SBP above specified levels, at least above the target levels for the intensive lipid and BP treatment arm. Persons with very high LDL-cholesterol or BP (cutpoints to be determined) will also be excluded.

   B.5. Endpoints

   1. The primary trial endpoint will be a major CVD event, defined as an MI (hospitalized or by ECG), stroke, or death attributed to CVD.

   2. Other endpoints will include: total mortality, MI, stroke, hospitalization for CHF, limb amputation, retinopathy, vision, albuminuria, renal function, peripheral neuropathy, quality of life, and cost effectiveness.

   B.6. Duration of the trial

   The trial is planned to last a total of 9 years, consisting of:

   Protocol Development (8 months)
   Pilot Testing and Training (4 months)
   Vanguard Recruitment and Follow-up (12 months)
   Main Recruitment and Follow-up (24 months)
   Follow-up (48 months)
   Close Out and Analysis (12 months)

   3. TREATMENT STRATEGIES

      (See also Section B.2.) Each treatment strategy will be accompanied by standard advice regarding lifestyle, including diet, physical activity, and smoking cessation, appropriate for diabetics.

      The specific combinations of drugs and escalation schedules for the strategies described below will be determined by the participating investigators during protocol development. However, offerors should be comfortable with the strategies and the therapeutic options, and they are expected to refine these plans. Offerors should not hesitate to propose alternative treatment strategies that would achieve the study goal without increasing the required sample size, but they should demonstrate that they could follow the plans described below.

      C.1. Glycemic Control Strategies

      1. Conventional Glycemic Control using Non-insulin-Resistance-Lowering Drugs(C_NRL)

         In this arm "conventional" glycemic control will be the therapeutic goal, starting with agents that do not work by reducing insulin resistance (e.g., sulfonylureas, meglitinides), and adding insulin as necessary. It is expected that the target level of HgbA_1c for this arm will be between 7.0 and 8.0%. Problems with hypoglycemia and other drug side-effects may require acceptance of less strict glycemic control in individual patients.

      2. Intensive Glycemic Control using Non-insulin-Resistance-Lowering Drugs (I_NRL)

         In this arm intensive glycemic control will be the therapeutic goal, starting with agents that work by stimulating insulin secretion (e.g., sulfonylureas, meglitinides), and adding insulin as necessary. It is expected that the target level of HgbA_1c for this arm will be between 6.0 and 6.5%, in order to achieve adequate separation in HgbA_1c between this study arm and the conventional glycemic control arm. Problems with hypoglycemia and other drug side-effects may require acceptance of less strict glycemic control in individual patients.

      3. Intensive Glycemic Control with Insulin-Resistance-Lowering Drugs (I_IRL)

         In this arm intensive glycemic control will be the therapeutic goal, starting with agents that work by reducing insulin resistance (e.g., biguanides, thiazolidinediones), possibly supplemented by other drugs that are neutral with respect to insulin resistance (e.g., an alpha-glucosidase inhibitor), and adding insulin as necessary. The HgbA_1c goal will be the same as in I_NRL, i.e. between 6.0 and 6.5%. Problems with hypoglycemia and other drug side-effects may require acceptance of less strict glycemic control in individual patients.

      C.2. Lipid/Blood Pressure Control Strategies

      1. Conventional Lipid/Blood Pressure Control (C_LBP)

         In this arm "conventional" control of lipids and blood pressure (BP) is the therapeutic goal.

         For lipids, the goal and level for institution or adjustment of drug therapy, following ADA and NCEP ATP2 guidelines, is anticipated to be LDL-cholesterol <130 mg/dl in persons without clinical CVD and <100 mg/dl in persons with clinical CVD (including CHD, cerebrovascular disease, and PVD). Problems with drug side-effects in an individual patient may require acceptance of less strict lipid control. Primary emphasis will be on LDL lowering, but treatment to lower triglyceride levels and raise HDL cholesterol levels may also be considered during protocol development. Initial drug therapy will be with an HMG-CoA reductase inhibitor, with possible supplementation, as needed, with another type of lipid-lowering agent.

         For BP, the goal is SBP <130 mmHg. Initial drug therapy will be with an appropriate anti-hypertensive agent and will be based on JNC-6 or other evidence-based guideline for BP treatment in DM. It is expected that in persons with BP >130/85 mmHg and microalbuminuria or clinical albuminuria and in persons with BP <130/85 and progression of albuminuria, an angiotensin converting enzyme inhibitor (ACE-I) or possibly an angiotensin-II inhibitor (AII-I) will be recommended if tolerated.

      2. Intensive Lipid/Blood Pressure Control (I_LBP)

         In this arm intensive control of lipids and blood pressure (BP) is the therapeutic goal.

         For lipids, the goal and level for institution or adjustment of drug therapy is anticipated to be LDL-cholesterol <100 mg/dl in persons without clinical CVD and <75 mg/dl in persons with clinical CVD (including CHD, cerebrovascular disease, and PVD). Problems with drug side-effects in an individual patient may require acceptance of less strict lipid control. Primary emphasis will be on LDL lowering, but treatment to lower triglyceride levels and raise HDL cholesterol levels will be considered during protocol development. Initial drug therapy will be with an HMG-CoA reductase inhibitor, with possible supplementation, as needed, with another type of lipid-lowering agent.

         For BP, the goal is SBP <120 mmHg. Initial drug therapy will be with an appropriate anti-hypertensive agent. In persons with BP >130/85 mmHg and microalbuminuria or clinical albuminuria, or with BP <130/85 and progression of albuminuria, an angiotensin converting enzyme inhibitor (ACE-I) or possibly an angiotensin-II inhibitor (AII-I) is recommended if tolerated. In persons with BP <130/85 mmHg and stable albuminuria, the issue of recommending use of an ACE-I or AII-I will be considered.

   4. GENERAL MEDICAL THERAPY FOR ALL PATIENTS

      All patients should receive other currently recommended medical therapy, unless contraindicated. Offerors should propose an appropriate regimen; the anticipated regimen is shown below: General medical therapy included in the Protocol, since it will be part of standard care, will not be reimbursable by the contract.

      1. Anti-thrombotic therapy with aspirin (enteric-coated) 80-325 mg/day, or other appropriate antiplatelet agent;
      2. Smoking Cessation: all smokers will receive advice and referral
      3. Physical Activity: All patients will be provided with advice and recommendations for a physical activity program, utilizing regular aerobic exercise and maximizing daily activities around the house and at work, unless contraindicated. It is anticipated that the recommendation will be for moderate intensity activities (e.g., walking) carried out for greater than or equal to 30 minutes at least 4 times per week.
      4. Obesity Management: Recommendations for control of body weight will be based on the 1998 NHLBI Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. Patients with a Body Mass Index greater than or equal to 25 will receive advice and referral for dietary counseling and advice and recommendations for a physical activity program.
      5. New Risk Reduction Therapies: It is anticipated that new therapies with proven safety and efficacy will be incorporated into the medical management plan for all arms of the trial as they become available.

   5. FOLLOW-UP PROCEDURES

      The follow up activities consist of both standard care medical management activities and protocol-derived activities. Standard care medical management (see table below) activities will not be reimbursable by the contract in whole or in part.

      E.1. Regular Follow-Up

      All patients will have the same minimum follow-up schedule. The anticipated schedule is outlined and shown in the table below. Offerors must describe how they would implement this schedule, and may propose alternative schedules.

      1. clinic visits at baseline (including screening history and physical examination), monthly for 6 months, and every 2 months thereafter, to assess symptoms, control of glycemia, lipids, and blood pressure (BP), and to measure weight and compliance with therapy and risk factor modification;
      2. monthly follow up by phone for months in which patient not seen in clinic, to assess symptoms, control of glycemia (by home glucose monitoring), and compliance with therapy and risk factor modification;
      3. 1. HgbA_1c and fasting plasma glucose (FPG, if able to fast), at baseline and every 2 months
         2. chemistry profile including electrolytes, blood urea nitrogen (BUN), and creatinine, and liver function tests (LFTs) monthly for 6 months, every 2 months for 6 months, and every 6 months thereafter; if more economical, may do the electrolytes, BUN, and creatinine separately from the LFTs, once every six months throughout; LFTs may be done less often in patients not receiving drugs that require such frequent monitoring
      4. fasting lipid profile at baseline and every 2 months;
      5. urinalysis--complete at baseline and yearly, including albumin:creatinine ratio;
      6. white blood cells (WBCs) for frozen storage (for future DNA studies);
      7. sitting BP at every clinic visit, using uniform equipment study-wide;
      8. resting electrocardiogram (ECG) at baseline and annually thereafter;
      9. mydriatic (dilated) eye exam by ophthalmologist and visual acuity (by EGDRS chart) at 4 meters, at baseline and annually;
      10. assessment for CVD events, procedures (including cardiac, cerebrovascular, peripheral vascular, renal, and ophthalmic), and hospitalizations, at baseline and every 6 months at clinic visits or by phone if no clinic visit; annual surveillance for hospitalizations in all patients and for deaths in persons lost to follow up;
      11. quality of life assessments at baseline and annually thereafter (detailed assessments may be done in subset of study population);
      12. cost and health resource utilization assessments annually (detailed assessments may be done in subset of study population).

      The table below shows a schematic representation of the scheduled protocol evaluations. Certain evaluations, such as detailed quality of life and costs may be done only in representative subset(s) of the patient population.

   Evaluations	Schedule of Evaluations (in months)
   	Baseline	1	2	3	4	5	6	7	8	9	10	11	12	q M	q 2M	q 6M	q 12M	60§
   Full History & Exam	X
   Clinic Visit	X	X	X	X	X	X	X		X		X		X		X			X
   #Phone follow-up								X		X		X			X			X
   +HgbA1c, FPG	X		X		X		X		X		X		X		X			X
   +§Chemistry Profile	X	X	X	X	X	X	X		X		X		X			X
   +Lipid Profile	X		X		X		X		X		X		X		X			X
   +Urinalysis	X												X				X	X
   WBCs for storage	X
   +Body weight	X	X	X	X	X	X	X		X		X		X		X			X
   +Sitting BP	X	X	X	X	X	X	X		X		X		X		X			X
   +ECG	X												X				X	X
   +Eye exam	X												X				X	X
   Interim events assessment	X						X						X			X		X
   Hospital/death surveillance													X				X	X
   *Quality of Life	X												X				X	X
   *Costs	X												X				X	X

   # phone follow up monthly when patients not seen in clinic
   + some evaluations are largely components of standard care; they are not directly reimbursable by the contract in whole or in part
   * these evaluations may be done in a subset(s) of study patients
   ¶ chemistry profile includes liver function tests (LFTs), electrolytes, blood urea nitrogen (BUN), creatinine; if more economical, may do the electrolytes, BUN, and creatinine separately from the LFTs, once every six months throughout; LFTs may be done less often in patients not receiving drugs that require such frequent monitoring
   

   HgbA1c=glycosylated hemoglobin BP=blood pressure

   FPG=fasting plasma glucose ECG=electrocardiogram

   WBCs=white blood cells

   E.2. Monitoring Compliance

   Compliance with study medication will be assessed by querying patients about their pill taking regimen and consumption. The Pharmacy Distribution Center, Clinical Center Networks, and the Coordinating Center will collaborate in assessing and assuring the highest level of compliance with the drug regimen according to the protocol assignment. Success at smoking cessation, weight control, exercise, and dietary modifications will be assessed using appropriate measures.

   6. ORGANIZATIONAL STRUCTURE

      The anticipated organizational structure and responsibilities of the Prevention of Cardiovascular Disease in Diabetes Mellitus (PCDD) trial follow those of similar NHLBI trials. Clinical Center Networks (CCN) will be established that will recruit the participating clinical sites and investigators, and will work with them during the trial on recruitment, compliance with protocol, and quality control. While these clinical site/investigators will interact principally through their CCNs, for some matters such as data collection, the sites recruiting patients will transmit their data directly to the Coordinating Center (CC) and other central units as described below.

      F.1. Steering Committee and Other Committees

      Scientific leadership will be provided by the Steering Committee. The Steering Committee will be composed of the study chair, the NHLBI, and representatives of the Coordinating Center (CC), the Clinical Center Networks (CCNs), the Core Chemistry Lab (CCL), and the Pharmacy Distribution Center (PDC). The Steering Committee will meet semiannually following the first year of the study and more frequently during the first year.

      Day-to-day trial operations will be run by the Executive Committee (EC) as an extension of the Steering Committee, with representatives from the CC, the Study Chair, NHLBI, and other participants as required to ensure efficient, high quality performance. Weekly conference calls during the recruitment phases of the study, and biweekly thereafter, will be conducted to ensure that important issues are appropriately addressed and problems solved. Protocol changes will be discussed by the EC and will be ratified by the Steering Committee.

      The subcommittees will be composed of experts appointed by the Study Chair and the Steering Committee. Subcommittees will address study policy as well as major operational issues of the trial and will make recommendations to the Steering Committee. All substudy and/or ancillary study proposals will be reviewed by an appointed subcommittee for feasibility and compatibility with the main protocol, as well as acceptable scientific merit, and approved or disapproved by the Steering Committee.

      The PCDD trial will have a Study Chair appointed by the NHLBI Director. The Study Chair will have leadership responsibility for the scientific direction of the trial. The Study Chair will: advise the NHLBI on data monitoring and other issues of importance to the overall trial; maintain, with advice from other investigators, an internal organizational structure that meets the needs of the trial and the NHLBI; be informed about all aspects of study operations; lead in the formulation of the study protocol; take actions as necessary to ensure smooth and efficient operation of the trial; and appoint study investigators and staff to appropriate subcommittees as needed, with concurrence of the Executive Committee.

      F.2. Clinical Center Networks (CCN)

      It is anticipated that there will be approximately 8 to 10 CCNs. Each CCN will consist of a network of collaborating clinical units, which may consist of medical facilities and/or individual practices that will be involved in the evaluation, enrollment and treatment of patients in the trial. Each CCN will be responsible for timely recruitment and clinical care quality assurances according to the protocol, and for providing the network's scientific leadership and operational management.

      Each CCN will be responsible for recruitment of a minimum of 1000 patients, including meeting study-wide goals for recruitment of women and specific minorities (African Americans, Hispanic, Native American, Asian). The CCN will have the primary responsibility for timely evaluation and correction of recruitment problems, including development and implementation of alternative strategies to achieve the stipulated goal, and funding the related activities. It is anticipated that the leading center of the CCN will conduct at least yearly site visits within the network to supervise recruitment activities and assure high quality performance. The CCN activities will be coordinated with the CC, and may include site visits conducted by the CC along with other organizational components of the study leading to certification of new sites, cessation of recruitment at existing sites, and appropriate follow-up of patients enrolled from sites whose recruitment is stopped. Each CCN will closely collaborate with and assist the CC in implementation and standardization of the protocol within their network. Each CCN will have a communication network, including Internet capability. The data will be transferred directly, in timely fashion, from the individual recruitment sites to the CC and other relevant central units, unless arranged otherwise.

      F.3. Coordinating Center (CC)

      The CC will be responsible for protocol drafting and finalization; development and distribution of a manual of operations; training of CCNs and Core Laboratories and other central units in standardized protocol implementation and data collection; rapid feedback to the CCN and Core Laboratories on the quality of data submitted and proposed corrections; and analysis of all data. The CC will conduct yearly visits to each CCN, to monitor and assure high performance throughout the trial.

      The CC will establish the two Core Laboratories, the Core ECG Laboratory (CEL) and the Core Chemistry Laboratory (CCL), to provide central interpretation of resting ECG, HgbA1c and other blood measurements on all patients. The CC will also provide for the central interpretation of quality of life and costs data collected on subsamples of participants. Each Core Laboratory will be responsible for development and distribution of specific measurement procedures, timely data gathering, and analysis under the leadership from the CC.

      The central units will provide their data to the CC for central analyses. The CC will coordinate study activities between the CCNs and Core Laboratories, and facilitate communications among all organizational study components, including meetings of study committees, appropriate subcommittees, and the Protocol Review Committee/Data and Safety Monitoring Board (PRC/DSMB). The CC will prepare OMB clearance materials, if the trial is not granted a clinical exemption, in a timely manner. The CC will prepare and distribute to the Steering Committee regular reports and minutes, prepare and distribute regular progress reports and minutes for the DSMB, assure the quality and accuracy of data collection, and monitor endpoint results.

      F.4. Pharmacy Distribution Center

      The Pharmacy Distribution Center (PDC) will be responsible for the development and implementation of plans for drug acquisition, packaging, labeling, and dispensing according to the study protocol, and monitoring compliance. It will provide data to the CC for further analyses.

      F.5. Morbidity and Mortality Classification Committee

      The Morbidity and Mortality Committee (MMCC) will establish guidelines for coding causes of death, diagnosis of MI and stroke, and evaluation of other cardiac events. These guidelines will be provided to the Steering Committee. The MMCC will be selected by the Executive Committee, and is expected to consist of qualified study investigators. The MMCC will regularly review and adjudicate suspected trial endpoints, both fatal and selected nonfatal events, while masked for patient randomization assignment, and provide the data to the CC for further analyses.

      F.6. Data and Safety Monitoring Board

      It is required that an independent Data and Safety Monitoring Board (DSMB) be established to monitor data and oversee patient safety in clinical trials. The DSMB, which will be appointed by the Director of NHLBI, is an operational component of NHLBI trials. Members will be senior experts in the areas of cardiovascular medicine, diabetes, biostatistics, and bioethics, with the possibility of experts in neurology and ophthalmology. The Study Chair, the Director and senior staff of the CC, and representatives from the NHLBI will participate as non-voting members.

      The DSMB's predecessor, the Protocol Review Committee (PRC), will review the protocol prior to implementation. The protocol will define the study background, design, measurement, intervention, outcomes, quality control procedures, safety monitoring, analysis approach, and rules regarding access to data, type of data entry system, and publications. Progression from protocol development to participant enrollment is dependent upon the favorable recommendation of the PRC and approval of the NHLBI.

      Interim and final results will be submitted to the DSMB. The DSMB will meet approximately twice a year to monitor safety and to advise the Institute about study progress. In addition, the CC will provide data to the DSMB Chair at his or her request at regular intervals to ensure early identification of any major adverse outcomes of therapy. Its charge is to monitor baseline, adverse effects, and response variable data, and to evaluate contractor performance. It has the responsibility to recommend whether the study should continue, whether the protocol should be modified, or whether there should be early termination. Its ethical responsibilities to the participants, as well as to the integrity of the study, are of paramount importance to the NHLBI. The DSMB will provide reports to the Institute through an Executive Secretary, which will be the NHLBI Project Officer. Recommendations by the DSMB must be approved by the NHLBI prior to implementation.

      F.7. NHLBI Program and Contract Office

      NHLBI Program and Contract Offices will be responsible for the administration and monitoring of the trial. The Program and Contract Offices will participate in the scientific, general organizational, and fiscal management of the trial. Statistical consulting will be provided by NHLBI statisticians.

      End of Statement of Work portion common to both the Clinical Center Networks and Coordinating Center RFPs.

      Specifically, the Clinical Center Network Contractor shall:

      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, as needed to perform the work below. All proposed Protocol activities are subject to change during finalization of the Protocol. The Prevention of Cardiovascular Disease in Diabetes Mellitus (PCDD) trial shall be conducted in six phases: I) Protocol Development; II) Pilot Testing and Training; III) Vanguard Recruitment and Follow-up; IV) Main Recruitment and Follow-up; V) Follow-up; and VI) Close-out and Analysis. The proposed timetable is shown below. All study documents, including forms and reports, should be produced in a format suitable for internet transmission. The following is a list of key activities required of the contractor for the Clinical Center Network (CCN) for the PCDD. The CCN contractor for PCDD shall:

      1. Present a proposal to the Steering Committee for any suggested modifications to the draft Protocol. Present a proposal to the Steering Committee for the step treatment drug regimens for the glycemic, lipid, and blood pressure strategies and for background therapy (pharmacologic and non-pharmacologic). Collaborate with other CCNs, the Coordinating Center (CC) and other central units, and the Project Office in finalizing the Protocol and Manual of Procedures (MOP). The MOP should include detailed descriptions of intervention and measurement as well as procedures for staff training.

      2. Have or develop a communication system within the CCN, including availability of access to Internet transmission. This plan should include means of assisting the CC in facilitating data gathering links between the CCN and central units (CC, Core Labs, Pharmacy Distribution Center (PDC)).

      3. Have or obtain IRB clearance/assurances for all participating units within the network. Provide an approved informed consent document.

      4. Assist the CC in training and monitoring staff within the CCN in uniform protocol implementation, and in following the MOP for standardization of protocol-directed procedures and data collection. Collaborate with the CC in correcting problems with missed, delayed, and erroneous data at the respective clinical sites within the CCN. (It is anticipated that the CC will conduct one site visit per year to each CCN to assure protocol compliance and quality control measures.) Send appropriate measurements (e.g., blood samples, ECGs) to the central units in a timely fashion, as specified in the Protocol and MOP. It is anticipated that the data will be transmitted from individual clinical sites within the CCN directly to the central units.

      5. Recruit, randomize, manage, and follow up a minimum of 1000 patients according to the study Protocol and MOP. Address recruitment shortfalls in a timely fashion. Participate with the CC and other CCNs in classifying clinical events in study patients.

      6. Accumulate and maintain appropriate data files and maintain appropriate confidentiality and security of these files at the respective clinical sites.

      7. Provide timely data on recruitment and measurements to the CC. Recruitment data should include numbers of participants screened and numbers randomized, and should be categorized by gender and race. Measurement data should include number and type of measurement taken (e.g., blood samples, ECGs) and sent to the central units, as well as data for measurements performed locally (e.g., some electrolytes and liver function tests).

      8. Coordinate, arrange, participate in, and provide any information necessary for regular clinical investigator meetings within the CCN, including preparation and distribution of minutes of each meeting and any other correspondence necessary to the meeting participants, the CC and the Project Office, in a timely manner. Have a plan for selection of experts from within the CCN to represent the CCN at the Steering Committee meetings (once per month for at least the first six months, then approximately twice a year) and to attend other appropriate study activities.

      9. Assist the CC in capturing major adverse drug effects in timely fashion to maximize patient safety, and promptly report adverse drug events from the appropriate clinical unit, through the CCN leadership, to the Project Office and the CC, according to the Manual of Procedures and the protocol.

      10. Ascertain and respond to clinical alerts in data measured or interpreted within the CCN, and respond to clinical alerts reported by the CC or Core Laboratories.

      11. Participate in preparing publications in collaboration with other study investigators, the CC, and the NHLBI Project Office.

      12. Provide a concise final report which will serve as a technical reference document, describing all of the phase activities (2 copies).

      The trial shall be conducted in the following six phases:

      Phase I	Protocol Development (8 months): Functions performed and/or plans implemented in Tasks #1-3, 8.
      Phase II	Pilot Testing and Training (4 months): Functions performed and/or plans implemented in Tasks #3, 4, 8.
      Phase III	Vanguard Recruitment and Follow-up (12 months): Functions performed and/or plans implemented in Tasks #4-10.
      Phase IV	Main Recruitment and Follow-up (24 months): Functions performed and/or plans implemented in Tasks #4-11.
      Phase V	Follow-up (48 months): Functions performed and/or plans implemented in Tasks #4-11.
      Phase VI	Close Out and Analysis (12 months): Functions performed and/or plans implemented in Tasks #6, 8-12.

3. Phasing--Phases are anticipated as follows:

   Phase	Period
   Protocol development	09/30/1999-05/21/2000
   Pilot Testing and Staff Training	06/01/2000-09/30/2000
   Vanguard Recruitment and Follow-up	10/01/2000-09/30/2001
   Main Recruitment and Follow-up	10/01/2001-09/30/2003
   Follow-up	10/01/2003-09/30/2007
   Analysis & Publication	10/01/2007-09/30/2008

4. Period of Performance--September 30, 1999 through September 30, 2008.

5. Reference Materials--See Statement of Work above and background information for the study design and requirements.

3. DELIVERABLES/REPORTING REQUIREMENTS
   1. Reports:
      1. Data on a minimum of 1000 patients shall be delivered to the CC.

      2. Quarterly Financial Status Reports (NIH 2706).

      3. A brief annual Technical Progress report, which will focus on major changes and issues not previously reported, and will also include reports related to quality monitoring of the units within the CCN. Reports should not repeat written material distributed to the Steering Committee. Instead, the Contractor shall report on administrative matters, staffing changes, current staff (name, position and level of effort), and any problems, occurring or anticipated, related to its contract responsibilities, on solutions to the problems, and on general progress in each major activity. Reports shall be due on or before the thirty-first calendar day following each year of performance, except that the annual report will not be required for the final year of the contract when the final technical progress report is due.

      4. A final technical report, to include a summation of the work performed for the entire contract period of performance. This report shall be brief, describing the phase activities achieved. The Final Report shall be submitted on or before the last day of the contract performance period in accordance with ARTICLE F.1, DELIVERIES, of this contract.

      5. Abstracts and manuscripts, upon publication.

   2. Deliverables:

      The following table provides an overview of deliverables:

      Item	Description	Delivered to	Delivery Schedule
      a.	Data on about 1000 Patients	IAW the Protocol and Manual of Operations	As recruited and followed
      b.	Annual Progress Report	Project Officer(s) and Contracting Officer	Annually
      c.	Financial Status Report	Contracting Officer	Quarterly
      d.	Draft Final Report	Project Officer(s)	30 days prior to Contract expiration date
      e.	Final Report, hard and electronic copies	Project Officer(s) and Contracting Officer	September 30, 2008
      f.	Abstracts and Manuscripts	Project Officer(s)	Upon publication

      Copies of reports shall be sent to the following addresses:

      Addressee	Item	Quantity
      Project Officer Clinical Trials and Prevention Program, DECA, NHLBI 6701 Rockledge Drive MSC 7936 Bethesda MD 20892-7936	b. d. e. f.	1 1 2 As directed
      Contracting Officer Contracts Operations Branch, DEA, NHLBI 6701 Rockledge Drive MSC 7902 Bethesda MD 20892-7902	b. c. e.	1 2 1
      Coordinating Center To be Determined	a.	As directed

4. EVALUATION FACTORS FOR AWARD WITH TECHNICAL EVALUATION CRITERIA

   Proposals submitted in response to this RFP will be reviewed by (1) a primary technical review group using peer review procedures under the auspices of Review Branch, Division of Extramural Affairs, National Heart, Lung, and Blood Institute, and (2) a secondary review group composed primarily of members of NHLBI professional staff from the Division of Epidemiology and Clinical Applications (DECA).

   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 Clinical Center Networks under this program shall be made only to offerors who are located in the United States of America and Canada. Proposals received from offerors located outside of the United States of America and Canada will not be considered for contract award.

   The technical proposal will receive paramount consideration in the selection of the Contractor for this acquisition. The evaluation will be based on the demonstrated capabilities of the prospective contractor 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 proposed. Although cost is not a specific evaluation criteria, it will be assessed. In the event that the technical evaluation reveals that two or more offers 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.

   The factors to be evaluated are as follows:

   No.	Criterion	Points
   1	Technical Approach of the Clinical Center Network (CCN): Adequacy of documentation of the proposed plans for the network to recruit and follow a minimum of 1000 patients for an average of 5 years and minimum of 4 years, including screening, consent, and randomization to the stipulated treatment strategies. Adequacy of planned collaboration with participating clinical units/clinical investigators within the proposed network. Adequacy of the proposed methods to implement the proposed intervention strategies, including study treatments and background therapy (pharmacologic and non-pharmacologic). Adequacy of the proposed follow-up of study patients, including ascertainment of clinical events. Adequacy of the proposed methods to monitor and manage adverse drug effects including hypoglycemia, and to detect and respond to clinical alerts. Suitability of the proposed treatment protocol, notably the timing and nature of adjustments in drug therapy (step-care) for the various proposed intervention strategies in relation to measured levels of glycemia, blood lipids, and blood pressure. Suitability of specific drug choices to be used in the various intervention strategies.	50
   2.	Knowledge and understanding of scientific issues: Adequacy of knowledge and understanding of scientific issues related to the rationale and design of the trial and of the proposed treatment strategies. These issues include the importance of the research question and knowledge of Type 2 diabetes mellitus and cardiovascular disease, particularly management of hyperglycemia, hyperlipidemia, and hypertension in Type 2 diabetics.	20
   3.	Personnel Qualifications: Suitability and availability of the proposed personnel, including specific competence and prior experience of professional, technical, and administrative staff pertinent to the operation of a CCN in large, multi center randomized clinical trials in cardiovascular disease. Medical and scientific expertise in cardiovascular medicine and therapy, Type 2 diabetes mellitus and therapy, and clinical interpretation of medical data for purpose of ensuring and monitoring patient safety. Ability to perform the protocol related work. Evidence of administrative and scientific leadership necessary for soliciting cooperation from participating clinical investigators and exercising appropriate leadership in matters of patient recruitment and patient management. Ability to take scientific leadership in data publication.	20
   4.	Institutional Support, Corporate Facilities and Resources: Adequacy of the CCN institution's support to provide data on health care costs data related to the conduct of the PCDD trial. Adequacy of institutional commitment to the program, and of the proposed facilities, equipment, and space for accomplishing the statement of work.	10
   	Total:	100

   Inclusion of Women and minorities in research involving human subjects

   It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of subjects or the purpose of the research. This new policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43) and supersedes and strengthens the previous policies which have been in effect since 1990. The new policy contains some new provisions that are substantially different from the 1990 policies. The recruitment goal for women and minorities reflects the prevalence of Type II Diabetes Mellitus in the U.S. population. Specifically, our goal is to recruit 50% women and 30% minorities.

   All investigators proposing research involving human subjects should read the NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical Research, which has been published in the Federal Register of March 2, 1994 (FR 59 14508-14513), and reprinted in the NIH GUIDE FOR GRANTS AND CONTRACTS of March 18, 1994, volume 23, number II. Offerors may obtain copies from these sources or from the contact personnel listed in the RFP.

   Unless otherwise specified in this solicitation, the Government has determined that the work set forth herein does not involve a gender specific study or a single or limited number of minority population groups. Therefore, the NHLBI believes that the inclusion of women and minority populations is appropriate for this project. The goals of women and minorities to be recruited will be in accordance with the prevalence of the disease in the study population.

   Inclusion of Children as Participants in Research Involving Human Subjects

   As the atherosclerotic coronary artery disease is exceedingly rare in children the PCDD program application and implications relate to adults. Unless otherwise specified in this solicitation, the Government has determined that the work set forth herein does involve an adult specific study. Therefore, the NHLBI believes that the exclusion of children is appropriate for this project.

THE REMAINDER OF THIS RFP CONSISTS OF THE FOLLOWING SECTIONS:

2. Specific RFP Instructions and Provisions, and

3. Applicable RFP References

2. 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 under Section III. Applicable RFP References.

   The following specific RFP instructions and provisions apply to this Request For Proposal:

   1. Proposal Intent Response Sheet (Please submit on or before February 8, 1999)
   2. Packaging and Delivery of Proposal
   3. SIC Code and Small Business Size Standard
   4. Number and Type of Award(s)
   5. Government Notice for handling of proposals
   6. Privacy Act System of Records
   7. Estimate of Effort
   8. Travel requirements for proposal preparation purposes
   9. Service of Protest
   10. Technical Proposal Table of Contents
   11. Other Provisions

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   1. PROPOSAL INTENT RESPONSE SHEET

      RFP No. NHLBI-HC-99-16
      TITLE OF RFP:Prevention of Cardiovascular Disease in Diabetes Mellitus -- Clinical Center Network.

      FURNISH THE INFORMATION REQUESTED BELOW AND RETURN THIS PAGE BY February 8, 1999. YOUR EXPRESSION OF INTENT IS NOT BINDING BUT WILL ASSIST US IN PLANNING FOR PROPOSAL EVALUATION. *Please include in your response a listing of all intended collaborators (Investigators) to your proposal by name and institution or organization.

      ---

      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 20892-7924 Attention: 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-99-16; 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
      Division of Extramural Affairs
      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. 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 8099, Health and Allied Services, N.E.C..

      The small business size standard is $5,000,000 average annual receipts over the three preceding fiscal years.

      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.

   4. NUMBER AND TYPE OF AWARD(S)

      It is anticipated that eight to ten (8-10) awards will be made from this solicitation and that award will be made on or before September 30, 1999.

      It is anticipated that the award from this solicitation will be a multiple-year cost reimbursement, completion type contract with a period of performance of nine years (one-hundred and eight months), and that incremental funding will be used.

   5. GOVERNMENT NOTICE FOR HANDLING OF 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."

   6. 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.

   7. ESTIMATE OF EFFORT

      It is estimated that percent effort to be provided per Phase is as indicated below.

      It is expected that a completion, cost-reimbursement type contract will be awarded as a result of this RFP. To assist you in the preparation of your proposal, the Government considers the effort below to be approximate. This information is furnished for the offeror's information only and is not to be considered restrictive for proposal purposes. The levels of effort shown below are based on recruitment and follow-up of 1,250 patients, and includes levels of effort anticipated from all clinical sites within each network.

      Labor Category	Phase 1	Phase 2	Phase 3	Phase 4	Phase 5	Phase 6
      Investigator	70.0%	70.0%	35.0%	35.0%	35.0%	70.0%
      Clinician*	22.5%	175.0%	510.0%	1000.0%	630.0%	90.0%
      Pharmacist	5.0%	25.0%	120.0%	150.0%	55.0%	30.0%
      Project Coordinator	60.0%	60.0%	100.0%	100.0%	100.0%	20.0%
      Support Staff	25.0%	80.0%	500.0%	375.0%	225.0%	60.0%
      Total:	182.5%	410.0%	1265.0%	1660.0%	1045.0%	270.0%

      *Includes Physician, Physician Assistant/Nurse Practitioner, Nurse (R.N. or L.P.N.)

      All staffing levels should be accompanied by specific justifications as to the type and percent effort of Full Time Equivalency (FTE) 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.

   8. TRAVEL REQUIREMENTS FOR PROPOSAL PREPARATION PURPOSES

      Investigators should plan to travel to Bethesda, Maryland for all Steering Committee and Protocol Review Committee and Data Safety Monitoring Board meetings (but see below for specifics pertaining to each RFP). Assume that each trip will be two (2) days long except for the annual Protocol Review Committee and Data Safety Monitoring Board meetings and site visits which will be one (1) day long. Planning and Steering Committee Meetings are scheduled for four meetings during the first year, and two meetings per year during years two through eight. Planning Review Committee and Data Safety Monitoring Board meetings are estimated to take place annually, at a rate of one meeting per year in each of years one through eight.

      Approval for travel to general scientific meetings may be approved if there can be shown a direct benefit to the study and funds are available, but each trip must be pre-approved by the Contracting Officer. Specific to Clinical Center Networks:

      Clinical Center Network offerors should plan for attendance of one investigator at each Steering Committee meeting. Up to a total of six investigators from the multiple clinical sites (i.e. one investigator from each clinical site assuming six clinical sites within each clinical network) may attend two Planning and Steering Committee meetings per year (years one through eight.)

      A central Project Coordinator meeting will be held during Year 1 (assume Bethesda, Maryland for budgeting purposes). Clinical Center Networks should plan to send their Project Coordinator to a two (2) day meeting for this purpose.

   9. 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.

   10. TECHNICAL PROPOSAL TABLE OF CONTENTS

       IMPORTANT: Technical proposals submitted in response to this RFP MUST NOT EXCEED 30 PAGES; however, this limitation does not include the cover sheet, table of contents, abstract or copies of biosketch or appendices. 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 (NOT TO EXCEED 30 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 from your institution, 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 #
          List each Appendix and identify the number of pages for each one. Appendices must be clear and legible, and easily located. Include biosketches here.

       ---

   11. OTHER PROVISIONS
       1. GOVERNMENT FURNISHED FACILITIES AND EQUIPMENT

          No Government furnished material, facilities, or equipment are envisioned for this acquisition.

       2. COST/PRICING INFORMATION

          The offeror's business proposal shall include the basic cost/pricing information specified in the Standard RFP Instructions and Provisions, under the Streamlined RFP References Directory referenced in this RFP. In addition, the Government may require offerors included in the competitive range to submit additional information substantiating their proposed costs or prices. This additional cost/pricing information will be requested after establishment of the competitive range, and potentially includes payroll documentation, vendor quotes, invoice prices, and/or any other information deemed necessary by the Contracting Officer to evaluate the reasonableness of the price or to determine cost realism. The information may also include submission and certification of cost or pricing data.

          Note that the cost proposal you will prepare in response to this RFP will cover the period September 30, 1999 through September 30, 2008. Costs should be proposed for each year of the contract as follows: September 30, 1999 through September 30, 2000; October 1, 2000 through September 30, 2001; October 1, 2001 through September 30, 2002, and so on through September 30, 2008.

          If possible, please submit a computer disc with the cost proposal in Excel format. For your convenience, a standard cost proposal spreadsheet in Excel format is available under the Standard RFP References directory in the FORMS, FORMATS, AND ATTACHMENTS file: "http://www4.od.nih.gov/ocm/contracts/rfps/buscost.htm".

       3. NHLBI PUBLIC USE DATA CLAUSE--Clinical Center (This clause will be made a part of the contract.)

          Public use data will be released under this clinical trial. After publication of the primary clinical trial results, the coordinating center shall prepare the data 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 three years after the primary publication. The coordinating center shall provide the data to the NHLBI within two years of the primary publication 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.

          The public use data set will include the baseline visit, interim visit(s), and outcome data, including laboratory measurements. 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 study investigators will 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.

       4. FAR 52.215-16, FACILITIES CAPITAL COST OF MONEY (October 1997)
          (This is applicable if you are a commercial organization.)
          1. Facilities capital cost of money (see FAR 15.408(h) will be an allowable cost under the contemplated contract, if the criteria for allowability in subparagraph 31.205-10(a)(2) of the Federal Acquisition Regulation are met. One of the allowability criteria requires the prospective Contractor to propose facilities capital cost of money in its offer.

          2. If the prospective Contractor does not propose this cost, the resulting contract will include the clause "Waiver of Facilities Capital Cost of Money."

       5. 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.

       6. PUBLICATION AND PUBLICITY (It is anticipated that this clause 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. N01-HC-XXXXX."

       7. 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.

3. APPLICABLE RFP REFERENCES

   This section identifies the items located in the Streamlined RFP References at URL "http://www4.od.nih.gov/ocm/contracts/rfps/mainpage.htm" that are applicable to this Request For Proposal (RFP).

   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" below and except for the new RFP provision, FAR 52.215-1 which is included in full text at the end of this section. This provision is important to review because it describes new rules for conducting negotiated competitive acquisitions. The following items are applicable from the file entitled "OPTIONAL RFP INSTRUCTIONS AND PROVISIONS". The full text of the provisions is available in the file.

   List of provisions which apply to this specific RFP:

   3. Notice: This requirement is Not Set-Aside for Small Business
   5. Late Proposals, Modifications of Proposal, and Withdrawal of Proposals, PHS 352.215-10
   8. Small, Small Disadvantaged and Women-Owned Small Business Subcontracting Plan
   15. "Just in Time"

   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. No Form Available--but you must submit a detailed contract pricing proposal, signed by an official authorized to legally bind your organization, with every copy of the business proposal. (Note that the Contract Pricing Proposal Cover Sheet, SF1411 is no longer a required form for use in cost proposals submitted to the Government. However, it would be acceptable if you wish to use it in your response to this RFP.) Include a computer disc (one with the original) in Excel format containing all the detailed computations used for the cost proposal. Note that an NIH standard spreadsheet in Excel format is available for your use on the NIH Web site: "http://www4.od.nih.gov/ocm/contracts/rfps/buscost.htm".

   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
   5. Research Patient Care Costs, NIH(RC)-11

   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.

INSTRUCTIONS TO OFFERORS--COMPETITIVE ACQUISITION [FAR Clause 52.215-1 (October 1997)

1. Definitions. As used in this provision--

   Discussions are negotiations that occur after establishment of the competitive range that may, at the Contracting Officer's discretion, result in the offeror being allowed to revise its proposal.

   In writing or written means any worded or numbered expression which can be read, reproduced, and later communicated, and includes electronically transmitted and stored information.

   Proposal modification is a change made to a proposal before the solicitation's closing date and time, or made in response to an amendment, or made to correct a mistake at any time before award.

   Proposal revision is a change to a proposal made after the solicitation closing date, at the request of or as allowed by a Contracting Officer as the result of negotiations.

   Time, if stated as a number of days, is calculated using calendar days, unless otherwise specified, and will include Saturdays, Sundays, and legal holidays. However, if the last day falls on a Saturday, Sunday, or legal holiday, then the period shall include the next working day.

2. Amendments to solicitations. If this solicitation is amended, all terms and conditions that are not amended remain unchanged. Offerors shall acknowledge receipt of any amendment to this solicitation by the date and time specified in the amendment(s).

3. Submission, modification, revision, and withdrawal of proposals.
   1. Unless other methods (e.g., electronic commerce or facsimile) are permitted in the solicitation, proposals and modifications to proposals shall be submitted in paper media in sealed envelopes or packages (i) addressed to the office specified in the solicitation, and (ii) showing the time and date specified for receipt, the solicitation number, and the name and address of the offeror. Offerors using commercial carriers should ensure that the proposal is marked on the outermost wrapper with the information in paragraphs (c)(1)(I) and (c)(1)(ii) of this provision.

   2. The first page of the proposal must show--
      1. The solicitation number;
      2. The name, address, and telephone and facsimile numbers of the offeror (and electronic address if available);
      3. A statement specifying the extent of agreement with all terms, conditions, and provisions included in the solicitation and agreement to furnish any or all items upon which prices are offered at the price set opposite each item;
      4. Names, titles, and telephone and facsimile numbers (and electronic addresses if available) of persons authorized to negotiate on the offeror's behalf with the Government in connection with this solicitation; and
      5. Name, title, and signature of person authorized to sign the proposal. Proposals signed by an agent shall be accompanied by evidence of that agent's authority, unless that evidence has been previously furnished to the issuing office.

   3. Unless otherwise specified in the solicitation, the offeror may propose to provide any item or combination of items.

   4. Proposals submitted in response to this solicitation shall be in English and in U.S. dollars, unless otherwise permitted by the solicitation.

   5. Offerors may submit modifications to their proposals at any time before the solicitation closing date and time, and may submit modifications in response to an amendment, or to correct a mistake at any time before award.

   6. Offerors may submit revised proposals only if requested or allowed by the Contracting Officer.

   7. Proposals may be withdrawn at any time before award. Withdrawals are effective upon receipt of notice by the Contracting Officer.

4. Offer expiration date. Proposals in response to this solicitation will be valid for the number of days specified on the solicitation cover sheet (unless a different period is proposed by the offeror).

5. Restriction on disclosure and use of data. Offerors that include in their proposals data that they do not want disclosed to the public for any purpose, or used by the Government except for evaluation purposes, shall--
   1. Mark the title page with the following legend: This proposal includes data that shall not be disclosed outside the Government and shall not be duplicated, used, or disclosed--in whole or in part--for any purpose other than to evaluate this proposal. If, however, a contract is awarded to this offeror as a result of--or in connection with-- the submission of this data, the Government shall have the right to duplicate, use, or disclose the data to the extent provided in the resulting contract. This restriction does not limit the Government's right to use information contained in this data if it is obtained from another source without restriction. The data subject to this restriction are contained in sheets [insert numbers or other identification of sheets]; and

   2. Mark each sheet of data it wishes to restrict with the following legend: Use or disclosure of data contained on this sheet is subject to the restriction on the title page of this proposal.

6. Contract award.
   1. The Government intends to award a contract or contracts resulting from this solicitation to the responsible offeror(s) whose proposal(s) represents the best value after evaluation in accordance with the factors and subfactors in the solicitation.

   2. The Government may reject any or all proposals if such action is in the Government's interest.

   3. The Government may waive informalities and minor irregularities in proposals received.

   4. The Government intends to evaluate proposals and award a contract without discussions with offerors (except clarifications as described in FAR 15.306(a)). Therefore, the offeror's initial proposal should contain the offeror's best terms from a cost or price and technical standpoint. The Government reserves the right to conduct discussions if the Contracting Officer later determines them to be necessary. If the Contracting Officer determines that the number of proposals that would otherwise be in the competitive range exceeds the number at which an efficient competition can be conducted, the Contracting Officer may limit the number of proposals in the competitive range to the greatest number that will permit an efficient competition among the most highly rated proposals.

   5. The Government reserves the right to make an award on any item for a quantity less than the quantity offered, at the unit cost or prices offered, unless the offeror specifies otherwise in the proposal.

   6. The Government reserves the right to make multiple awards if, after considering the additional administrative costs, it is in the Government's best interest to do so.

   7. Exchanges with offerors after receipt of a proposal do not constitute a rejection or counteroffer by the Government.

   8. The Government may determine that a proposal is unacceptable if the prices proposed are materially unbalanced between line items or subline items. Unbalanced pricing exists when, despite an acceptable total evaluated price, the price of one or more contract line items is significantly overstated or understated as indicated by the application of cost or price analysis techniques. A proposal may be rejected if the Contracting Officer determines that the lack of balance poses an unacceptable risk to the Government.

   9. If a cost realism analysis is performed, cost realism may be considered by the source selection authority in evaluating performance or schedule risk.

   10. A written award or acceptance of proposal mailed or otherwise furnished to the successful offeror within the time specified in the proposal shall result in a binding contract without further action by either party.

   11. The Government may disclose the following information in postaward debriefings to other offerors:
       1. The overall evaluated cost or price and technical rating of the successful offeror;

       2. The overall ranking of all offerors, when any ranking was developed by the agency during source selection;

       3. A summary of the rationale for award; and

       4. For acquisitions of commercial items, the make and model of the item to be delivered by the successful offeror.

          (End of provision)

Alternate I (October 1997). As prescribed in 15.209(a)(1), substitute the following paragraph (f)(4) for paragraph (f)(4) of the basic provision:

(f)(4) The Government intends to evaluate proposals and award a contract after conducting discussions with offerors whose proposals have been determined to be within the competitive range. If the Contracting Officer determines that the number of proposals that would otherwise be in the competitive range exceeds the number at which an efficient competition can be conducted, the Contracting Officer may limit the number of proposals in the competitive range to the greatest number that will permit an efficient competition among the most highly rated proposals. Therefore, the offeror's initial proposal should contain the offeror's best terms from a price and technical standpoint.