![](media/image1.png){width="0.75in" height="0.75in"}**DEPARTMENT OF
VETERANS AFFAIRS**

**Veterans Health Administration**

**Washington, DC 20420**

**Date: IL**

**In Reply Refer to: 121**

**Office of Research and Development Information Letter**

**Clinical Science Research and Development Service**

**Request for Applications**

**CLINICAL TRIAL DEVELOPMENT AWARDS FOR EVALUATING EFFECTIVENESS OF
TREATMENT-DIAGNOSTIC COMBINATIONS**

**Introduction.** Clinical Science Research and Development Service
requests Merit Review applications to investigate novel clinical trial
design and biostatistical strategies assessing the effectiveness a
diagnostic device (test) in combination with a clinical treatment (drug)
on a disease of particular relevance to veterans. Proposals will include
a methodology development stage and a small clinical trial stage to
evaluate the effectiveness of a drug-diagnostic device combination in
therapeutic decision making. Successful proposals are expected to result
in novel clinical trial designs which can be adapted to a variety of
specific combination products and which may be widely adopted throughout
the biomedical community.

**Background.** The development of "personalized medicine" is based upon
the proposition that through the use of appropriate clinical laboratory
testing one may identify the most appropriate treatment for an
individual patient. This concept is becoming well-established in cancer
treatment, in which the decision to use a therapeutic drug (such as
Herceptin® for breast cancer) is based upon identification of proteomic
or genomic evidence of a genetic abnormality (such as amplification of
the ERBB2 gene). It has been suggested that similar use of
pharmacogenomic data may be useful in therapeutic decision making for a
variety of drugs used to treat chronic conditions, including mental
disorders, hypertension, and diabetes.

Evaluation of these drug-diagnostic device combinations has proven
difficult for both clinicians and regulatory agencies. In many cases,
clinical trials are being performed under the supposition that the
diagnostic laboratory device (test) is both specific and sensitive for
determining therapeutic response, in the absence of supporting evidence.
Evaluation of the laboratory device may be limited to analytical
characteristics, without a full understanding of the test performance
until adopted by the medical community. To some extent, this state
appears to reflect absence of widely accepted clinical trial
methodologies designed to effectively test both the laboratory
diagnostic, and the therapeutic intervention, of these "drug-device
combinations."

**Scope.** There are two cases of particular interest:

1.  The use of a single laboratory test to select patients for therapy.
    Both the effectiveness of the laboratory test for selecting therapy,
    and the effectiveness of the therapy itself, must be evaluated. An
    example of such a combination is the use of an immunohistochemical
    or gene amplification test to select patients for cancer therapy
    (for example, Gleevec or Herceptin).

2.  The use of a group of related laboratory tests to determine the
    appropriate dosage of a therapeutic drug. An example would be the
    use of a pharmacogenomic profile consisting of several independent
    genomic markers to select a dose of an antipsychotic drug, with the
    objective of achieving effective therapy while minimizing potential
    adverse drug reactions.

Applications prepared in response to this RFA should propose two stages:

Stage 1. Methodology development stage to develop the methodology to
advance the clinical trial design capable of assessing the sensitivity
and specificity of the laboratory test(s) for selecting therapy and
assessing the effectiveness of the therapy.

Stage 2. Test stage to apply the methodology developed in a small
clinical trial study designed to evaluate the effectiveness of the
proposed laboratory test(s) and therapeutic intervention in a veteran
population. Successful results should be further developed into a full
clinical trial in a separate Merit Review proposal.

Information generated may be integrated into the electronic medical
record for both treatment and research purposes.

An interim review will assess whether the first methodology development
stage has met administrative and scientific milestones to progress to
the second stage to conduct a clinical trial pilot. Funding for the
second test stage is contingent upon a satisfactory progress with
methodology development.

**Eligibility.** It is anticipated that a team of investigators
(non-clinician methodologists and clinicians) would be involved in the
proposed work, including, but not limited to:

1.  Biostatistician/epidemiologist -- an expert with knowledge of
    advanced scientific principles in clinical trial design and
    statistical analyses.

2.  Clinical investigator/trialist -- a clinician or investigator with
    clinical research experience who has a thorough understanding of key
    clinical trial methodological principles.

While not required, it is recommended that the team collaborate with a
Cooperative Studies Program Coordinating Center (see
[www.vacsp.gov](http://www.vacsp.gov/)).

The Principal Investigator may be a biostatistician, epidemiologist,
and/or clinical investigator meeting current eligibility requirements
(described in VHA Handbook 1200.15, Eligibility for VA Research Support,
<http://www.va.gov/vhapublications/ViewPublication.asp?pub_ID=440>.
Individual exceptions to the rule limiting a principal investigator to a
single project funded by CSRD will be considered on a case-by-case
basis, dependent on the alignment of proposed research to VA research
priorities.

**Intent to Submit Information.** [An E-mail attachment from the VA
research office]{.underline} (ACOS for Research or Administrative
Officer), with the Subject line "Intent to Submit Methodology
Development Merit", should be sent to: <vhacocenter@va.gov>, with the
following information:

 

\(a\) Principal Investigator's Name, Degree, and VA appointment (in
eighths),

\(b\) VA Medical Center

\(c\) Title of proposal

\(d\) Keywords (up to six keywords covering major topic area and any
special methodology)

\(e\) List of collaborating investigators. Include names, VA and/or
university affiliation, laboratory locations of personnel to contribute
more than 5% effort

\(f\) Abstract (limit one page, single-spaced) information about the
hypotheses to be tested, specific objectives, relevance, subject
population, procedures to be used, and the significance of potential new
findings. It must include enough information so that the proposal can be
referred to the appropriate Merit Review Subcommittee and reviewers.

\(e\) Requests for exception, if required, to the CSRD single-project
rule.

Due Date: The email notification of intent to submit must be received by
BLRD/CSRD [sixty days]{.underline} prior to the submission cycle for the
Merit Review round (January 15 for March 15 Merit Review deadline, July
15 for September 15 Merit Review deadline). Intent information received
after the deadline will be referred to the next round.

 

A confirmation e-mail acknowledging receipt of intent to submit
information will be sent to the local VA research office. This
confirmation [must be included as the last page of the full proposal
when submitted.]{.underline} Intent to submit notification from anyone
other than the local facility research office personnel (e.g. the
Principal Investigator, etc.) [will not be accepted or
acknowledged.]{.underline}

 

Intent to submit information will be reviewed for responsiveness to the
scope of this solicitation, for eligibility, and to plan for expertise
needed in the review process.

**Proposal Preparation and Submission.** In general applications should
follow the guidance provided for the Merit Review program, specifically
for the Clinical Research Program (described in Appendix C of the Merit
Review Handbook,
<http://www1.va.gov/resdev/resources/policies/docs/1202_Merit_Review_Handbook_JIT.doc>).
The narrative however should include two sections to describe Stage 1
and Stage 2.

Stage1. As a specific addition to the Merit Review narrative, the
proposal must contain a section describing the plan for the methodology
development stage. Describe the proposed plan for developing the
clinical trial design and analytic/methodological strategies to evaluate
the specificity and sensitivity of the diagnostic-treatment combination.

Included in this section must be one to three proposed milestones for
assessing acceptable completion of this stage of the program. Milestones
are concrete, quantitative measures of success of the feasibility stage
(the methodology development stage) of the proposal. They are not the
steps to proceed through the specific aims but rather should be the set
of criteria to assess the success of Stage1 and to make the decision as
to whether or not Stage 2 funding is approved. Thus, these milestones
should be sufficiently precise and comprehensive to guarantee that any
clinical trial conducted during Stage 2 is scientifically sound. One
method by which this objective can be achieved is to propose a milestone
that includes submission of a scientifically sound and novel protocol
for the Stage 2 clinical trial to ORD for internal and external
evaluation.

If approved for funding, VA staff and the PI may work together to refine
the assessment measures. A clear timeline must be included that shows
the total duration for the entire program, including the steps and
duration of time planned for Stage 1and Stage 2. If funded, VA staff
will determine the interim assessment schedule for evaluating Stage 1
progress.

Stage 2. This section of the narrative should provide a broad outline
for conducting a small clinical trial. Because the final clinical trial
design will depend upon the outcome of Stage 1, we would expect this
section of the proposal to be relatively abbreviated and based upon
currently accepted methodology. We would further expect that the
proposal will provide substantial rationale for the clinical problem
selected for investigation, as well as detailed evaluation of patient
selection criteria and clinical trials recruitment issues. This section
should follow the guidelines for a Clinical Merit Review trial. Approval
for this stage will be contingent upon satisfactory progress on Stage 1.

The overall goal will be to obtain sufficient information to submit a
Merit Review proposal for full support of an interventional trial or a
Letter of Intent to the Cooperative Studies Program for a multi-site
trial.

**Review.** Proposals will be reviewed in a Merit Review subcommittee.
Proposals that do not address the programmatic objectives outlined in
this announcement or follow stated guidelines will not be accepted for
review.

**Funding.** Proposals are limited to \$750,000 over a maximum of five
years. Stage 1 (methodological development) will be limited to \$200,000
over two years. Satisfactory administrative and scientific review of
Stage 1 milestones and progress is required prior to initiation of Stage
2; Stage 2 is limited to three years, but may utilize funds not expended
during Stage 1. The proposed research program should be appropriate and
efficient, with all budget categories well justified. In planning
budgets, applicants are reminded to adhere to ORD guidelines regarding
allowable use of research funds for specific items. Appropriateness of
the proposed budget will be evaluated by the Merit Review subcommittee;
the budget may be adjusted if not adequately justified or supported by
the proposed research.

**Term.** This Information Letter is valid until the last working day of
March 2007 unless otherwise rescinded.

**Inquiries.** Please direct all questions regarding this RFP to Terri
Gleason, Ph.D., at <Theresa.gleason@va.gov>.

Joel Kupersmith, MD

Chief Research and Development Officer

Attachment

DISTRIBUTION: CO: Emailed

FLD: VISN, MA, DO, OC, OCRO, and 200: Emailed