RFI No. NIH-NHLBI-98-RFI-01

Study of Coronary Revascularization And Therapeutics Evaluations (SOCRATES)

The National Heart, Lung and Blood Institute (NHLBI) is soliciting information to determine whether capitation rates (i.e. total cost per subject or task as a fixed rate) can be utilized for a Clinical Coordinating Center. Respondents are asked to study the Statement of Work, decide whether capitation rates are an appropriate mechanism for reimbursement and provide information on projected rates should the answer be affirmative.

Below is a general description of the study.

The Study of Coronary Revascularization And Therapeutics Evaluations (SOCRATES) trial will assess the benefits and risks from a strategy of early revascularization and medical anti-ischemic strategies with respect to long term morbidity and mortality, and the information will provide a rational basis for safe and effective therapy for these types of patients with stable CHD. The SOCRATES trial will also provide scientific insight into the role of ischemia in the long-term clinical outcome of CHD patients. Furthermore, the results will be evaluated for significant health care cost implications.

The trial will address two key questions of therapeutic strategy in the management of coronary heart disease (CHD): first, in medical management, does anti-ischemic therapy escalated to a maximum tolerated regimen, targeted to alleviate all of the ischemia, confer long-term morbidity and mortality benefits beyond anti-ischemic therapy targeted just for relief of angina; and second, have advances in medical management of CHD, i.e., particularly aggressive lipid management, anti-thrombotic therapy, and life style risk factor modification, changed the threshold at which mechanical revascularization is warranted? These questions will be addressed in patients with stable CHD and objective evidence of ischemia who are eligible for catheter-based revascularization (such as PTCA) or surgical revascularization with coronary artery bypass surgery (CABG). Functional status and health care costs related to the above strategies will also be assessed.

The study will enroll a total of 6,000 patients with stable coronary disease (CHD) and other eligibility and exclusion criteria detailed below, and in whom there is equipoise between medical therapy and revascularization (catheter-based or surgical). The choice between the potential revascularization approach that might be used, PTCA or CABG, will be made by physician and patient before randomization. The draft protocol, including study design, entry criteria, randomization procedures, and treatment strategies are provided in the attachment. Drug regimens for medical strategies and analyses which will be incorporated into the final protocol will be defined collaboratively during the implementation phase developed by a planning committee that will include representation from the successful offeror. The planning committee is already in existence and will have many remaining details established before the contract is awarded.

The respondent should provide an estimate of reimbursement costs that they consider appropriate for the tasks involved as well as information on how the reimbursement was calculated. The proposed reimbursement schedule is as follows:

Randomization (Entry):
3 month Follow up (includes visits 1 and 2):
6 month Follow up:
Annual Follow up:
Semiannual Follow up:

The respondent should address any potential problems or concerns with reimbursement of costs using capitation rates.

This Request For Information (RFI) is for information and planning purposes only and shall not be construed as a solicitation or as an obligation on the part of the Government to issue a Request for Proposal or award a contract. The Government does not intend to award a contract on the basis of responses nor otherwise pay for the preparation of any information submitted or the Government's use of such information. Acknowledgment of receipt of responses will not be made, nor will respondents be notified of the Government's evaluation of the information received. However, should such a requirement materialize, no basis for claims against the Government shall arise as a result of a response to this Request For Information or the Government's use of such information as either part of our evaluation process or in developing specifications for any subsequent requirement. Responses should be identified with NHLBI No. 98-RFI-01, and are due by July 31, 1998. Please submit three copies of your response to: William M. Stevens, Contracts Operations Branch, National Heart, Lung and Blood Institute, II Rockledge Centre, 6701 Rockledge Drive MSC 7902, Sixth Floor, Room 6118, Bethesda, MD. 20892-7902. Phone (301) 435-0345, Email: StevensW@gwgate.nhlbi.nih.gov.

STATEMENT OF WORK
Clinical Data Coordinating Center
REQUEST FOR INFORMATION

1. Objectives:

The trial primary objectives are to determine which of the three strategies outlined, accompanied by advances in medical management of CHD, namely, aggressive lipid management, anti-thrombotic therapy, and life style risk factor modification confers the best benefit:

1. anti-ischemic therapy escalated to a maximum tolerated dose confers long-term morbidity and mortality benefits beyond anti-ischemic therapy targeted just for relief of angina

2. mechanical revascularization (PTCA or CABG) confers long-term morbidity and mortality benefits beyond anti-ischemic therapy targeted just for relief of angina accompanied by advances in medical management of CHD, namely, aggressive lipid management, anti-thrombotic therapy, and life style risk factor modification, and

3. anti-ischemic therapy escalated to a maximum tolerated dose confers long-term morbidity and mortality benefits compared to mechanical revascularization (PTCA or CABG)

Other objectives include:

1. to determine the relationship between the extent of ischemia reduction and the incidence of cardiac events,
2. to determine the "dose-response" relationship between heart rate reduction and ischemia and the incidence of cardiac events,
3. to determine the impact of different drugs (with different physiological profiles) on objective evidence of ischemia,
4. to determine prognostic significance of residual ischemia,
5. to determine the relationship(s) between ECG ischemia and major risk factors over a period of time,
6. and economic implications.

Other issues studied will include functional status, quality of life, cost, and utilization of health resources.

Sample size:

It is estimated that a total sample size of 6,000 patients will be needed (2,000 for each of the three treatment strategies) to assure at least 80% power for any two-group comparison with alpha = 0.05, to detect a difference of 20% or greater in the primary outcome. The yearly event rate in the angina-directed arm of ACIP was 6.245%, a rate comparable to those of other studies. This was reduced by 20%, to approximately 5% per year, to reflect more aggressive risk factor modification in SOCRATES. The five year event rate in SOCRATES is therefore, assumed to be 22.6%.

Power is based on a two-stage procedure in which the three arms are first compared using an overall test at alpha = 0.05, and then pairwise comparisons are made at level alpha = 0.05, provided that the overall test is significant.

4. FOLLOW-UP PROCEDURES
   1. Regular Follow-Up

The follow up activities consist of both usual practiced-based medical management activities and protocol-derived activities. All patients will have the same follow-up schedule, as outlined below and shown in the table 2:

1. clinic visits at 2, 3, 6, and 12 months, and at 6 month intervals thereafter, to assess symptoms, control of ischemia, and compliance with therapy and risk factor modification;

2. rest ECG at 3 months, 6 months, 12 months, and annually thereafter;

3. ambulatory ECG at 3 months, 6 months, 12 months, and annually thereafter;

4. stress test (preferably exercise, or stress test done initially at baseline) at 6 months, 1 year and 3 years;

5. quality of life assessments at 6 months, 1 year and 3 years; and

6. cost and health resource utilization assessments annually

Monitoring Compliance

Compliance with study medication will be assessed by querying patients about their pill taking regimen and consumption. Clinical Network Centers, the Clinical Data Coordinating Center, and the Drug Distribution Center will collaborate and assure the highest level of compliance. Success at smoking cessation, weight control, exercise, and dietary and lipid levels modifications will be assessed using appropriate measures.

Table 1 below shows a schematic representation of the scheduled protocol evaluations. Certain evaluations, such as AECG, detailed quality of life, and costs may be done only in representative subset(s) of the patient population.

Table 1 Evaluations	Schedule of Evaluations - months after randomization
	Prior	Entry	1	2	3	6	12	18	24	30	36	42	48	54	60
Angiogram	X	or X
History & Exam		X	X	X	X	X	X	X	X	X	X	X	X	X	X
Stress Test	X					X	X				X
Events Check			X	X	X	X	X	X	X	X	X	X	X	X	X
ECG		X			X	X	X		X		X		X		X
Ambulatory ECG		X			X	X	X		X		X		X		X
Risk Factor Check		X	X	X	X	X	X	X	X	X	X	X	X	X	X
Lipid Profile Check		X			X	X	X	X	X	X	X		X		X
Drug Effects Check		X	X	X	X	X	X	X	X	X	X	X	X	X	X
Quality of Life		X			X	X	X	X	X	X	X		X		X
Costs		X					X		X		X		X		X

ORGANIZATIONAL STRUCTURE

The anticipated organizational structure and responsibilities of the SOCRATES trial follow those of similar NHLBI trials. However, Clinical Network Centers (CNC) 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 CNCs, for some matters such as data collection they will relate directly to the Clinical Data Coordinating Center (CDCC) as described below.

1. Steering Committee and Other Committees

Scientific leadership will be provided by the Steering Committee. The members of the Steering Committee will be representatives from major medical sites within the Clinical Network Centers, the Core ECG Laboratory, Ambulatory ECG Laboratory, Core Angiographic Laboratory, the Quality of Life and Economics Center, the Clinical Data Coordinating Center, the Pharmacy Drug Distribution Center, study chair, and the NHLBI. The Steering Committee will meet semiannually.

Day-to-day trial operations will be run by the Operations Committee as an extension of the Steering Committee, with representatives from the Clinical Data Coordinating Center, Core Laboratories, Pharmacy Drug Distribution Center, Study Chair, NHLBI, and other participants as required to ensure efficient, high quality performance. Weekly conference calls during the recruitment phase 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 Operation Committee and will be ratified by the Executive and Steering Committees.

The Executive Committee will be composed of appointed members of the Steering Committee. The Executive Committee will address policy as well as major operational issues of the trial and will make recommendations to the Steering Committee. All substudy and/or ancillary study requests will be reviewed by an appointed subcommittee for scientific merit and approved or disapproved by the Steering Committee.

Study Chairperson

The SOCRATES trial will have Study Chairperson 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 study participants, 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 study policy; take actions as necessary to ensure smooth and efficient operation of the trial; and appoint study participants to appropriate positions and committees as needed.

Clinical Network Centers (CNC)

It is anticipated that there will be approximately ten CNCs. Each CNC will consist of a network of collaborating clinical units, which may consist of medical sites and/or clinician that will be involved in the evaluation, enrollment and treatment of patients in the trial. Each CNC will be responsible for recruitment of patients, protocol implementation within their network, and clinical care quality assurance according to the trial protocol. Each CNC will be responsible for enrolling 600 patients, and, in the case of recruitment problems, will develop and implement alternative strategies to achieve the stipulated goal. It will implement standardization of the protocol and assure timely data transfer to the Clinical Data Coordinating Center.

Clinical Data Coordinating Center (CDCC)

The CDCC will be responsible for protocol finalization; development and distribution of a manual of operations; training in standardized protocol implementation and data collection in each CNC, including individual clinical sites, and Core Laboratories; rapid feedback to the CNC and Core Laboratories on the quality of data submitted and proposed corrections; and analysis of all data. Core Laboratories will analyze and provide their data to the CDCC for further analyses. The CDCC will coordinate study activities among the CNCs and Core Laboratories, and facilitate communications among all organizational study components, including meetings of study committees and appropriate subcommittees. The CDCC will prepare and distribute regular progress 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.

Pharmacy Drug Distribution Center

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

Other Centers and Core Laboratories

Trial data will be interpreted and analyzed by the following four core laboratories: 1) the Core ECG Laboratory, 2) the Ambulatory ECG Laboratory, 3) the Core Angiographic Laboratory, and 4) the Quality of Life and Economics Center. Each Core Laboratory or Center will be responsible for development and distribution of a specific protocol, timely data gathering and analysis, and will provide data to the CDCC for further analysis.

Morbidity and Mortality Committee

An independent Morbidity and Mortality Committee (MMCC) will establish guidelines for coding causes of death, diagnosis of MI, and evaluation of other cardiac events. These guidelines will be provided to the Steering Committee. The MMCC will meet regularly to review and adjudicate suspected trial endpoints, both fatal and nonfatal cardiac events, while blinded for group assignment.

Data and Safety Monitoring Board

An independent Data and Safety Monitoring Board (DSMB) will be appointed by the NHLBI. Members will be senior experts in the area of cardiovascular medicine, biostatistics, and bioethics. The Study Chair, the Director of the CDCC, and representatives from the NHLBI will also participate as non-voting members. 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 CDCC will provide data to the DSMB Chair at regular intervals to ensure early identification of any major adverse outcomes of therapy. The DSMB will review any changes in the protocol/trial conduct recommended by the Steering Committee. The DSMB will formulate recommendations for continuation or termination of the trial based on evidence of beneficial or adverse effects of therapy or on the enrollment of a sufficient number of patients. Recommendations by the DSMB must be approved by the NHLBI prior to implementation.

NHLBI Program and Contract Office

An 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 guidance of the trial. Statistical consulting will be provided by NHLBI statisticians.

SUMMARY OF TASKS

The offeror for the Clinical Data Coordinating Center for SOCRATES specifically shall:

1. Provide a near final draft and participate in the finalization of the study protocol and Manual of Operations, and have the documents also Web ready.

2. Develop, implement, and ensure quality data gathering forms for assessment of study endpoints, and have the documents also Web ready.

3. Establish procedures for data entry at each site participating in the recruitment of patients.

4. Provide randomization scheme to all Clinical Network Centers (CNC) on 24 hours basis. Make the necessary arrangements for carrying out random assignments at the individual CNC.

5. Develop, implement, and maintain Web site for all units of the study.

6. Monitor patient recruitment and provide weekly reports to the CNCs, the Program Office, core laboratories and the Pharmacy Distribution Center during recruitment period, and have the documents also Web ready. This report shall specifically include data on recruitment of women and specific minorities (African Americans, Hispanic, Native American, Asian).

7. Train staff at CNCs in protocol implementation, standardization of protocol-directed procedures and data collection.

8. Maintain appropriate data files and maintain appropriate confidentiality and security of these files.

9. Develop appropriate methods of analysis and presentation of data collected during the course of the study. Begin analysis activities from the start of data collection through the study.

10. Develop quality control measures and monitor status of performance of the CNCs, and report these and related matters annually to the Program Office, and have the documents also Web ready. Assume responsibility to review, on a regular basis, the quality of all data transmitted by the clinical units.

11. Develop quality control measures and monitor status of performance of the core laboratories, and report these and related matters annually to the Program Office, and have the documents also Web ready. Assume responsibility to review, on a regular basis, the quality of all data transmitted by the core laboratories.

12. Coordinate, arrange, participate in, and provide any information and funds necessary for regular Steering Committee meetings (approximately twice a year), and prepare and distribute minutes of each meeting and any other correspondence necessary, within 4 weeks of the meeting. Coordinate, arrange, participate in, and provide any information for any other meetings with the CNCs and clinical investigators, as needed.

13. Closely monitor adverse effects to maximize patient safety. In cases of major adverse events (death, cardiopulmonary arrest, emergent cardiopulmonary interventional procedures) notify the Program Office, and prepare a report to the Program Office and the DSMB no later than 48 hours after knowledge of the event.

14. Develop, finalize and provide a manual of operations for a morbidity and mortality classification committee (MMCC), and have the documents also Web ready, and provide data in a timely fashion to the MMCC, when requested.

15. Participate in preparing reports of the study for publication in collaboration with other study investigators and the NHLBI Program Office.

The SOCRATES trial shall be conducted in four phases: Recruitment, Implementation, Follow-up, and Analysis. The proposed time-table is as follows:

Phase I - Implementation Phase (3 months) Now may 6 months

1. Develop a detailed study protocol and manual of operations for the conduct of this multi center clinical trial. In conjunction with NHLBI staff, experts in cardiovascular medicine, biostatistics, clinical pharmacology may be selected to participate in the Steering Committee.

2. Distribute manual of operations to all participating clinicians/sites.

3. Develop, pretest, reproduce, and distribute appropriate data collection forms.

4. Develop communication and data gathering links among CNC networks and Core Labs.

5. Conduct training sessions regarding standardized protocol and directed procedures.

6. Conduct training sessions regarding standardized data collection from the clinical units and test forms for recording data.

Phase II - Recruitment (24 months)

1. Provide randomization system to CNCs on 24 hours basis with real time access.

2. Participate in the assessment of recruitment targets, including evaluation and correction of problems; such as coordination of site visits to a site with recruitment problems, certification of new clinical units, termination of recruitment at existing sites, and assuring appropriate follow up of patients enrolled from the terminated site within the CNC.

3. Coordinate patient follow-up.

4. Collect and transmit clinical information and tests data required by the protocol and transmit to the CDCC in a timely fashion.

5. Accumulate and maintain appropriate data files on all patients in a timely manner, including data entry and editing.

6. Maintaining confidentiality and security of data files.

7. Review on a regular basis the quality of all data transmitted from the participating units within the CNC, and provide monthly reports to the CNCs, the Program Office and appropriate core laboratories.

8. Assume the primary responsibility for reporting major and life threatening events to the Program Office and CDCC within 48 hours of knowledge of the event.

9. Assume the responsibility for missed, delayed, and erroneous data, and for appropriate corrective action among CNC and core laboratories.

10. Obtain all tasks and reports required by the protocol.

11. Prepare monthly reports on data quality and clinical performance ( enrollment, protocol compliance from completion.

12. Regularly prepare a report of patient screening, recruitment, status of data collection and quality control or any other matters needed to be discussed at clinical investigator meetings.

13. Organize, and participate in meetings between representatives from CNCs, core laboratories and the Program Office and fund representatives from the CNC.

14. Provide a comprehensive annual report which will serve as a technical reference document, describing all of the activities and presenting the result of the year's efforts; this is typically phased for availability prior to any annual incremental funding negotiations (_____ copies).

Phase III - Follow-up (48 months)