Questions Responses.doc.rtf

Response to Question RFP –NIMH-08-DS-0009 June 26, 2008

1. For Phase I, SOW pp 3-4 state that intervention refinement should involve stakeholders and investigators "not involved in contractor's initial offer." SOW p 12 indicates these external stakeholders and investigators be proposed by the contractor after the initial offer during the funded phase 1, with approval by the NIMH GPO. May the offeror propose a list of external stakeholders and investigators at the time of initial application or must it wait until Phase 1? May the external stakeholders and investigators subsequently participate as internal investigators in Phases 2 and 3, and be listed as such in the contractor’s initial offer?

The offeror is expected to demonstrate relationships with stakeholders at the time of the proposal. Additional stakeholders should be brought in During Phase 1 to help vet the proposed intervention and its implementation. At the time of the initial application the offeror may propose a list of external stakeholders and investigators for this exercise. However, external stakeholders and investigators should neither be involved in developing the initial offer, nor committed a priori to participating in Phases 2 and 3. The intent in Phase 1 is to conduct an independent review of the proposed intervention in order to achieve broad-based consensus regarding the public health importance of the intervention and the scientific merit of the study design. External stakeholders and investigators may subsequently participate in the project, but this should be worked out after the Phase 1 review is completed.

2. SOW p 5 indicates the contractor must identify an operations team for protocol management and oversight of data acquisition, among other tasks. SOW p 10 says the operations unit will be required for Phases 2 and 3 and says the operations unit should have prior procedures and outcomes acceptable to NIMH. Is it recommended that contractors propose to hire a Contract Research Organization? Should such proposal be made at the time of initial offer or after funding of Phase 1?

NIMH does not mandate a CRO. However, the NIMH does expect the offeror to identify the proposed operations team at the time of the initial application; the qualifications of this team will be part of the overall evaluation.

NIMH does not mandate when the operations team should be in place. The offeror should consider the financial implications of when the full operations team needs is brought on board. In part, this may be determined by the length of time the offeror proposes for Phase 1.

3. SOW p 6 indicates that costs should be identified for Phase 1 and cost estimates for Phases 2 and 3. Do the Solicitation Business Proposal Instructions on pp 70-82 and the Business Proposal Breakdown of Proposed Estimated Costs (Attachment 13) and Technical Proposal Cost Summary (Attachment 6) for the initial offer apply only to Phase 1? Are there guidelines/forms for level of detail for the cost estimates for Phases 2 and 3?

No, the attachments apply to all phases. Attachment 13 gives detailed instruction and example of how you should complete you cost estimate.

4. If Phase 1 is expected to require longer than 1 year, should the initial budget cover the entire Phase 1 or only the first year (see Solicitation, Incremental Funding p 80)?

Given that the length of the phases may vary according to the offerors plan, the offeror should budget for the full life of all phases, however long each phase may be.

5. Should Dec 24, 2008 be used as the expected initial date of award for budgeting purposes?

December 24, 2008 should be used as an expected initial date of award for budget purposes.

6. When does NIMH plan to decide about Phase 1 awards?

NIMH plans to decide about Phase 1 awards in Fall 2008.

7. After completion of Phase 1 deliverables, when would NIMH decide about Phase 2 funding and when would funding begin?

Although not stated, NIMH anticipates that a decision to move forward to Phase 2 would be made approximately six weeks after NIMH receives the final Phase 1 deliverables. We expect that Phase 2 award(s) will be made as soon after the decision as possible, so as not to create a gap in funding.

8. The suggested maximum number of subjects for Phase 2 N=40? See SOW p 7. Does this mean 40 subjects randomized to the experimental intervention? And in addition an appropriate number of subjects randomized to the control condition? Or 40 subjects as the total of both conditions (SOW pp 13-14)? Page 14 of SOW states that an important consideration for moving forward to the Phase 3 practical clinical trial is whether adequate baseline, treatment delivery, outcome, and cost data can be collected for both experimental and comparison conditions. Would it be possible to specify standards of adequacy in more detail?

The SOW expects that there will be a total of 40 patients, not 40 patients to each condition.

The ‘standards of adequacy’ for the Phase 2 feasibility study are stated in the text on page 14: “The randomization plan is reasonable and patients will accept randomization; the multi-element treatment intervention can be delivered in real-world settings; patients and clinicians accept the intervention; baseline, treatment delivery, outcome, and cost data can be collected for experimental and comparison subjects.” These are important and critical considerations, but not the sole considerations, for continuing to a Phase 3 RCT. As is always the case, costs and availability of funds are additional important considerations.

The RFP refers to the preparation of manuals in several places. For example, in section V, Services to be Performed and Deliverables, Initial Offer, bullet number 5 states the following:

Deliver a manual that presents the integrated and comprehensive package of interventions, the actual model for delivering the intervention effectively, a credible comparison condition, and proposed strategies for evaluating treatment feasibility in Phase 2 and clinical effectiveness in Phase 3.

Could you please clarify several points for proposers:

A. We assume that by a manual you mean a set of detailed tools for training clinicians to provide specific services. Is that correct?

Yes. Manuals will be used to train clinicians, to guide the delivery of the intervention protocol, and to promote fidelity over time. The manuals might include medication algorithms, structured instructions to guide the delivery of psychoeducational/psychotherapeutic interventions, and decision-aids to guide the selection/sequencing of treatment components.

B. Do you expect the project to develop training manuals for any comparison conditions as well?

If the offeror proposes to use an alternative structured intervention as a comparator condition, we expect to see a manual that is relatively similar (in general format, not content) to that of the manual for the experimental condition. If the offeror proposes “usual care” (UC) as a comparator, then we do not expect a manual per se, but rather a document that describes the content, quality, and quantity of the UC, how care will be delivered, and degree of overlap with the experimental condition.

C. Do you expect the offeror to include a version of all proposed manuals to be developed in the initial offer (i.e. the proposal response)? Or do you expect the initial offer to present a plan for developing one or more manuals during phase 1 and phase 2? Or do you expect a preliminary manual in the initial offer, to be refined and prepared in phase 1 and further revised in phase 2 for use in phase 3?

NIIMH expects draft manuals to be included in the initial offer. These manuals may be refined in Phase 1, will be tested and possibly further refined in Phase 2, and will be used in Phase 3. We expect the draft manuals to provide a well-developed conceptual framework for the intervention and to clearly describe treatment targets, procedures, and desired outcomes.

10. We are not entirely clear about the nature of the sites to be used in developing and testing the effectiveness of the designed experimental and comparison interventions in the RAISE project. There are references to “real world”, “community based” and “ecologically valid” clinical sites but at the same time reference to “well-staffed mental health clinics” which are often in academic settings. Please clarify.

As stated in Section I, Specific Aims, RAISE intends to “develop and refine a comprehensive and integrated treatment intervention that can be delivered in real world practice settings.” During the intervention refinement phase of RAISE, the offeror may choose to test and modify the intervention package in the more controlled environment of a First Episode Psychosis research clinic. For subsequent phases, however, the majority of sites should be reflective of typical community-based care, rather than conditions found in specialized academic research-based clinics. Many community-based mental health clinics possess sufficient clinical staff to support the feasibility testing and practical clinical trial phases of RAISE.

11. Neither the solicitation nor the SOW offers information about an expected level of effort for any phase of the study or scope of the budget. Can the agency provide some guidance in this area, especially for phases 1 and 2?

See Section L, (Pg 46) to assist you in preparation of your proposal the Government considers the effort to be approximately 2080 labor hours per year for each FTE. Note: this information is furnished for the offerors informational purpose only and is not to be considered restrictive for proposal purposes

12. Are there any page limits or document format requirements for the technical proposal?

None were stated.

13. Is the offeror to form a RAISE specific DSMB or should we plan to utilize the NIMH DSMB.

Since this will be a contract-supported study, the NIMH DSMB will be utilized.

14. How is NIMH defining "non-academic" when referring to participating sites? What if a site has any of the following characteristics: residents rotate through the site; medical students rotate through the site; academic consultants visit the site; the site has an affiliation with an academic institution; professionals at the site have academic appointments?

As stated in Section I, Specific Aims, RAISE intends to “develop and refine a comprehensive and integrated treatment intervention that can be delivered in real world practice settings.” During the intervention refinement phase of RAISE, the offeror may choose to test and modify the intervention package in the more controlled environment of a First Episode Psychosis research clinic. For subsequent phases, however, the majority of sites should be reflective of typical community-based care, rather than conditions found in specialized academic research-based clinics. Many community-based mental health clinics possess sufficient clinical staff to support the feasibility testing and practical clinical trial phases of RAISE.

15. NIMH is not proposing a definition of non-academic sites. The goal is to test the RAISE intervention in everyday settings where patients with schizophrenia are commonly seen, and is therefore not restricted to academic mental health research facilities.

Can NIMH clarify how a usual care control group can receive manualized care and still be considered to be receiving usual care? It is our belief that usual care in the US does not currently involve any degree of manualization.

If the offeror proposes to use an alternative structured intervention as a comparator condition, we expect to see a manual that is relatively similar (in general format, not content) to that of the manual for the experimental condition. If the offeror proposes “usual care” (UC) as a comparator, then we do not expect a manual per se, but rather a document that describes the content, quality, and quantity of the UC, how care will be delivered, and degree of overlap with the experimental condition.

Although usual care in not usually a manualized treatment, in an intervention study there is need to understand the parameters around the delivery of care in order to distinguish treatment as usual from the experimental intervention.

16. It is explicitly stated that "the service system delivery partner will make significant contributions to facility and personnel costs during the intervention testing phases." Can such contributions be expected of "real world' clinical settings and would this ultimately limit the generalizability of the findings regarding feasibility and cost-effectiveness?

Please see SOW Section III, Objectives, where the rationale for real-word partners is discussed. NIMH is interested in developing a treatment package that can be implemented in everyday treatment settings where patients with schizophrenia are seen. Thus, the treatment components and staffing included in the intervention package are expected to be able to be integrated into and carried out in real-world settings utilizing real-world billing codes and funding mechanisms. The goal is to have uptake by service delivery partners and providers such that the intervention, if successful, can actually become standard practice.