"Prevention of Cardiovascular Disease in Diabetes Mellitus--Clinical Center Network"

Amendment No.: One (1)
Amendment Date: March 17, 1999
RFP No.: NIH-NHLBI-HC-99-16
RFP Issue Date: January 7, 1999
Issued By: John C. Taylor
Contracting Officer
NIH/NHLBI
Contracts Operations Branch
II Rockledge Centre, Room 6126
6701 Rockledge Drive, MSC 7902
Bethesda, MD 20892-7902
Names and Addresses of Offerors: To all interested recipients of RFP number NIH-NHLBI-HC-99-16


The purpose of this amendment is to provide clarification to questions asked in response to subject RFP:

Question: It appears to us that the NHLBI has underestimated the personnel requirements for this complex trial. What is the rationale for the "Estimate of Effort" and what is the range of personnel allocation that will be considered reasonable by the NHLBI?

Response: As stated in the RFP for the Clinical Center Networks, the cost of "conventional" or "standard-of-care" medical care provided at the clinical sites will not be reimbursable in part or in whole by the contract. This approach to funding of contract clinical trials is not new to the NHLBI. None of the capitated contract-funded trials, including the ALLHAT study, pay for such care, but only for the additional costs associated with the test treatments and with collecting research data. Although this trial will not be funded on a capitated basis, the recently signed agreement between the NIH and the American Association of Health Plans (AAHP) includes a term that the AAHP will encourage its member plans "to reimburse the routine patient-care costs associated with NIH-sponsored clinical trials provided those costs are not substantially higher than the costs a plan would incur in the course of standard treatment by an in-network plan provider."

In arriving at an estimate of the FTEs needed to provide "conventional" medical care, the NHLBI drew upon the experience of previous cardiovascular and diabetes trials and patterns of conventional clinical practice. We are aware that there is a range of opinions as to what constitutes "conventional" care for Type 2 diabetes, and therefore a range of opinions regarding the personnel requirements for providing such care. There has also been some uncertainty about the FTEs required to perform the Statement of Work as described in the RFP. The major source of such uncertainty is perhaps the estimated frequency and length of clinic visits needed to implement intensive glycemic control. Until the protocol is finalized by the study steering committee, only an estimate of the effort required can be made. Each offeror is encouraged to propose what they consider to be appropriate levels of FTEs for implementing the Statement of Work as described in the RFP, and, if a somewhat different technical approach is proposed (e.g., less intensive HgbA1c targets), the offeror should propose the FTEs considered appropriate for that technical approach. Whatever FTE levels are proposed, adequate justification is necessary. During negotiations with offerors in the competitive range, the NHLBI will hold discussions with each offeror regarding their rationale for the proposed FTEs, which may result in a revision to proposed FTEs.

Question: Will the protocol as presented in the RFP be followed exactly or can modifications occur? For example, can differing targets for HbA1c, differing study designs, or differing eligibility criteria be proposed?

Response: The RFP presents the concept for the study and the technical aspects can be considered a draft protocol. The final protocol will be determined by the Steering Committee after award. With regard to proposing an approach that differs from the Statement of Work outlined in the RFP, the latter states explicitly (Section C): "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 ... 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...."

Question: We are concerned that the HgbA1c target for the intensive glycemic control arms (6.0 to 6.5%) is unrealistic and of uncertain safety in older people, while even the target for the conventional glycemic control arm (between 7.0 and 8.0%) is generally not achieved in clinical practice.

Response: We recognize that there is much controversy over the issue of glycemic targets in persons with Type 2 diabetes. There are some persons who feel that the microvascular disease benefits of relatively tight glycemic control shown in the UKPDS trial mandate such control in all patients, even those older than 65. We considered carefully whether it is ethical to set a HgbA1c target above 7.0%; if not, it would be impossible to achieve sufficient separation in HgbA1c between treatment and control groups to test whether intensive glycemic control prevents CVD. After much deliberation, we decided that it was still ethical to have a HgbA1c target between 7.0 and 8.0%. Raising the HgbA1c target for the intensive control arms to 7.0% or higher would necessitate raising the target for the conventional control arm to 8.5% or higher in order to achieve sufficient separation of HgbA1c levels between the study arms, which we did not feel comfortable doing, though others may consider that reasonable.

We realize that it may prove unrealistic to achieve a HgbA1c level of 6.5% in most patients, and offerors are encouraged to propose alternative strategies, including different HgbA1c targets, that would achieve the study goals without increasing the required sample size. The final decisions will be made by the Steering Committee, on which successful offerors will have representation.

Question: Does the protocol preclude the use of sulfonylureas (SUs) in the study arm entitled "Intensive glycemic control with insulin-resistance-lowering drugs"?

Response: The RFP states that therapy would be initiated with "agents that work by reducing insulin resistance (e.g., biguanides, thiazolidenediones), possibly supplemented by other drugs that are neutral with respect to insulin resistance (e.g., an alpha-glucosidase inhibitor), and adding insulin as necessary." This language does not explicitly preclude the use of SUs in that arm, though it could be interpreted that way. In planning the study design, we were concerned that frequent use of SUs in that arm would impair the study's ability to test one of its major hypotheses, that achieving tight glucose control with insulin-resistance-lowering agents will prevent cardiovascular disease (CVD) better than achieving the same glucose control with agents that don't work primarily by lowering insulin resistance. However, we recognize that in clinical practice the addition of an SU to a regimen of newer oral agents may postpone the need for insulin therapy in some cases. As part of the technical plan, offerors should propose their approach to this issue.

Question: Based on the respective Statements of Work for the Clinical Center Networks (CCNs) and Coordinating Center (CC) RFPs, it appears that there is some overlap of effort between the CCNs and the CC. Please clarify the specific responsibilities of the CCN and CC and how they interface with one another.

Response: While there does appear to be some overlap in responsibilities between the CCN and CC, the intent is that the CC and CCNs collaborate in areas of mutual responsibility, such as maintaining the quality of data collection. In general, the CC's responsibility is to coordinate among and oversee the performance of the CCNs, while each CCN is expected to coordinate among and oversee the performance of its clinical sites. Rather than our spelling out the step-by-step processes involved in performing the work, we encourage offerors to submit their technical approach to accomplishing the work so that we can evaluate the technical merit of each proposal.

Question: What is the appropriate mix of clinical expertise for the CC and a CCN?

Response: Offerors should propose what they consider to be the most appropriate mix of expertise needed to perform the work. Similarly, we have not specified an estimate for the CCNs of the appropriate mix of physicians, physician assistant/nurse practitioners, diabetes-specialist nurses, and other nursing staff.

Question: May the PI of a CCN also be the head of a clinical site?

Response: Yes, that is permissible, though not required.

Question: May the "investigator" level of effort in the CC or CCN be split among more than one investigator?

Response: Yes, that is permissible. Similarly, other personnel categories, such as "clinician," may be apportioned among more than one person as the offeror sees fit.

Question: In the Schedule of Evaluations (Section E.1.), the following items have been designated as components of "standard care," and are thus not directly reimbursable by the contract in whole or in part: HgbA1c, Fasting Plasma Glucose (FPG), and Lipid Profile. However, these items are pivotal measures of the effectiveness of the trial interventions. In Section F.3., it states that the Core Chemistry Laboratory (CCL) will perform "HgbA1c and other blood measurements on all patients." To what extent will the cost of interpreting these tests be borne by the study or by the patient (or his/her third-party payor)?

Response: The assumption was that not all of the repeat tests for these measurements shown in the Schedule of Evaluations would need to be done centrally for the purpose of quality control. Of those done locally that are part of "standard care," the cost would not be reimbursable by the contract in whole or in part. By definition, all tests performed by the CCL are paid for by the contract. Offerors should propose how many tests of each measurement would be done centrally, and how many additional tests, if any, would be done locally. The issue of timely interpretation for the purpose of clinical decision making should be taken into account.

Question: Does the requirement for a Pharmacy Distribution Center (PDC) imply that medications for controlling lipids, blood pressure, and glucose levels, as well as equipment and supplies for glucose monitoring, will be provided free of charge to patients in the study?

Response: It is possible that medications included in the treatment protocols will be provided in whole or nearly so by pharmaceutical companies, therefore, offerors should not include these costs in their budget. The same applies for home glucometers and test strips. In the event that industry support for medications and monitoring supplies is unavailable, it will be assessed whether there is sufficient benefit to the study to warrant funding for these items. If a patient is prescribed a medication not specified in the protocol then it is unlikely that the drug will be supplied by the PDC.

Question: The goals specified for recruitment of Women and Minorities at 50% and 30% respectively, seem unachievable to us given our potential patient population. Will we be automatically excluded if we cannot demonstrate our ability to recruit within the stated goals?

Response: In accordance with the NIH policy on Women and Minorities as referenced on page 24 of the CCN RFP (NHLBI-HC-99-16), women and minority groups and their subpopulations shall be included in this research. The goals stated represent study-wide goals and do not necessarily reflect the required percentages needed at all CCNs, although there are no assurances that other successful offerors have the ability to over-recruit to balance your deficiencies. Every effort should be made by your institution to successfully achieve the stated goals.

Question: We have missed the due date for submitting a Letter of Intent; does this mean we cannot submit a proposal?

Response: You are still eligible to submit a proposal, although we urge you to submit a Letter of Intent even if the deadline is past. In the future, please comply with the requested due date for receipt of this form. * Please note that the requirement for timely submission of your proposal is stated on page 2. of the RFP.

Question: What does the NHLBI consider to be a reasonable budget for the stated effort?

Response: Prior to negotiations, the Government does not engage in discussions regarding costs. The guidance provided in the RFP for "Estimate of Effort" is considered to be a reasonable approach to estimating personnel needs. Each institution's overall cost will vary depending on individual elements of cost such as personnel salaries and financial and administrative burden rates, as well as the technical approach proposed. If your proposal is included in the competitive range, your proposed budget will be discussed with the goal of achieving mutual agreement of what constitutes a reasonable total estimated cost for the effort described.


NAME AND TITLE OF CONTRACTING OFFICER:
/s/
John C. Taylor
Contracting Officer, NHLBI
United States of America
Date Signed: March 17, 1999


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