and Human Services (HHS)
EXPIRED
Participating Organization(s) |
U.S. Food and Drug Administration (FDA) The FDA does not follow the NIH Page Limitation Guidelines or the Enhanced Peer Review Scoring Criteria. Applicants are encouraged to consult with FDA Agency Contacts for additional information regarding page limits and the FDA Peer Review Process. |
Center of Drug Evaluation and Research/Office of Pharmaceutical Science/Office of Generic Drugs (CDER) |
|
Funding Opportunity Title |
Pharmacokinetics Studies of Tacrolimus in Transplant Patients (U01) |
Activity Code |
U01 Research Project Cooperative Agreements |
Announcement Type |
New |
Related Notices |
|
Funding Opportunity Announcement (FOA) Number |
RFA-FD-12-021 |
Companion Funding Opportunity |
None |
Catalog of Federal Domestic Assistance (CFDA) Number(s) |
93.103 |
Funding Opportunity Purpose |
The goal of this proposal is to compare the pharmacokinetics of two sources of generic tacrolimus capsules to Prograf in stable transplant patients. Patients will be switched between both brand and generic and generic and brand. The outcome of this study can help address the public concerns regarding the quality of generic tacrolimus and improve review practices of generic tacrolimus if necessary. |
Posted Date |
April 27, 2012 |
Open Date (Earliest Submission Date) |
May 1, 2012 |
Letter of Intent Due Date |
Not Applicable |
Application Due Date(s) |
(New Date June 8, 2012 per NOT-FD-12-010), Original Date May 31, 2012, by 5:00 PM local time of applicant organization. |
AIDS Application Due Date(s) |
Not Applicable |
Scientific Merit Review |
June, 2012 |
Advisory Council Review |
August, 2012 |
Earliest Start Date(s) |
September, 2012 |
Expiration Date |
(Extended to June 9, 2012 per NOT-FD-12-010), Original Date June 1, 2012 |
Due Dates for E.O. 12372 |
Not Applicable |
Required Application Instructions
It is critical that applicants follow the instructions in the SF 424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.
Part 1. Overview Information
Part 2. Full Text of the Announcement
Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission
Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information
1. Background
Tacrolimus is the primary immunosuppressive drug used to prevent
rejection of transplanted organs. It was first approved as capsule and
injectable dosage forms with tradename Prograf by the U.S. FDA in 1994. The
first generic version of tacrolimus capsules was approved in Aug 2009.
Currently there are four additional approved generic tacrolimus capsules, and
more Abbreviated New Drug Applications (ANDAs) referencing Prograf capsules are
pending for FDA review.
In the US, the average annual patient cost for standard tacrolimus regimen is substantial. On one hand, the transplantation community supports the availability of generic immunosuppressants as they may potentially reduce medication costs and improve patient compliance. On the other hand, they have questioned the interchangeability of the generic tacrolimus with the brand product as well as other approved generics. They have stressed that bioequivalence (BE) of generic immunosuppressants should be demonstrated in transplant patients and subjected to tighter BE standards.
However, there are no definitive reports of clinical failures with generic tacrolimus approved by current FDA standards. Some recent publications indicate that generic tacrolimus is safe for transplant patients but tacrolimus blood levels must be monitored following generic substitution. A generic drug is considered interchangeable with the brand product and other approved generics under all approved indications and conditions of use, and no additional testing of patients should be necessary when a generic substitution occurs. Considering the multiple sources generic tacrolimus available, if therapeutic drug monitoring has to be conducted for every switch of drug supplier, the testing costs may offset some savings from generic substitution.
The Agency believes that single-dose, two-way crossover BE studies in healthy subjects are generally more sensitive at detecting formulation difference than BE studies in patients that are usually carried out to steady state. However, regarding generic tacrolimus, a well controlled, prospective pharmacokinetic study that makes a direct comparison between brand and generic tacrolimus in transplant patients could address public concerns. This type of study would be to verify that the current FDA standards for generic approvals are sufficient to ensure the interchangeability of generic tacrolimus with the brand product and other approved generics. .
2. Objectives
The objectives of this proposal are to compare the pharmacokinetics of
two sources of generic tacrolimus capsules to Prograf in stable transplant
patients. Patients will be switched between both brand and generic and generic
and brand. The outcome of this study can help respond to public concerns
regarding the quality of generic tacrolimus and improve review practices of
generic tacrolimus if necessary.
3. Detailed Description
The study design is preferred to be a prospective, randomized, full replicated, 6-period crossover (steady-state) bioequivalence study in stable liver and kidney transplant patients who have been treated with tacrolimus. Drug products will be fully characterized in terms of potency, impurity, in-vitro dissolution, and other quality attributes. A blinding process may be needed to ensure that patients familiar with one particular product cannot detect that they are being switched. In addition, appropriate monitoring of patient adherence should be included.
Statistical analyses will be conducted to determine whether there are any significant pharmacokinetic differences before and after the product switch in patients. Tacrolimus trough concentrations are often monitored in clinical practices to manage the risks of concentration-related rejection and toxicities. Thus, besides Cmax and AUC, the impact of product switch on predose tacrolimus trough concentrations can also be compared. The full replicated design will allow evaluation of the variability of both the brand and generic products. Any side effects or adverse reactions, as well as liver and kidney function will be monitored in patients during the study period.
Due to the sequential nature of in vivo pharmacokinetic studies, this project is non-severable.
4. References
Klintmalm, GB. Immunosuppression. Generic Drugs and the FDA. Amer J of Transplant. (2011) 11: 1765 1766
McDevitt-Potter, LM et al. A multicenter experience with generic tacrolimus conversion. Transplant. (2011) 92: 653-657
Momper, JD et al. The impact of conversion from prograf to generic tacrolimus in liver and kidney transplant recipients with stable graft function. Amer J of Transplant. (2011) 11: 1861 1867
Funding Instrument |
Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, FDA scientific or program staff will assist, guide, coordinate, or participate in project activities. |
Application Types Allowed |
New The OER Glossary and the SF 424 (R&R) Application Guide provide details on these application types. |
Funds Available and Anticipated Number of Awards |
The number of awards is contingent upon FDA appropriations and the submission of a sufficient number of meritorious applications received. FDA/CDER intends to commit up to $300,000 Total Costs (direct plus indirect) in Fiscal Year 2012.. |
Award Budget |
The amount of financial assistance requested from FDA may not exceed the following: Year 01: $300,000 |
Award Project Period |
The total project period will be 3 years. An additional 2 years of support will be available depending upon fiscal year appropriations and successful performance. The total project period for an application requesting support may not exceed 3 years. |
FDA grants policies as described in the HHS Grants Policy Statement will apply to the applications submitted and awards made in response to this FOA.
Higher Education Institutions
The following types of Higher Education Institutions are always encouraged to apply for FDA support as Public or Private Institutions of Higher Education:
Nonprofits Other Than Institutions of Higher Education
For-Profit Organizations
Governments
Other
Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.
Foreign components, as defined in the FDA Grants Policy Statement, are allowed.
Applicant organizations must complete the following registrations
as described in the SF 424 (R&R) Application Guide to be eligible to apply
for or receive an award. Applicants must have a valid Dun and Bradstreet
Universal Numbering System (DUNS) number in order to begin each of the following
registrations.
All Program Directors/Principal Investigators (PD(s)/PI(s))
must also work with their institutional officials to register with the eRA
Commons or ensure their existing eRA Commons account is affiliated with the eRA
Commons account of the applicant organization.
All registrations must be completed by the application due date. Applicant
organizations are strongly encouraged to start the registration process at
least 4-6 weeks prior to the application due date.
Any individual(s) with the skills, knowledge, and resources
necessary to carry out the proposed research as the Program Director/Principal
Investigator (PD/PI) is invited to work with his/her organization to develop an
application for support. Individuals from underrepresented racial and ethnic
groups as well as individuals with disabilities are always encouraged to apply
for FDA support.
For institutions/organizations proposing multiple PDs/PIs, visit the Multiple
Program Director/Principal Investigator Policy and submission details in the Senior/Key
Person Profile (Expanded) Component of the SF 424 (R&R) Application Guide.
The PD/PI should at a minimum have a graduate degree in the area related to clinical pharmacokinetics and pharmaceutical science, or equivalent training and experience in this area. Key personnel should have clinical experiences with transplant patients, demonstrated ability to manage complex and diverse clinical pharmacokinetic studies, and characterize tacrolimus drug products.
This FOA does not require cost sharing as defined in the HHS Grants Policy Statement.
Applicant organizations may submit more than one application, provided that each application is scientifically distinct.
FDA will not accept any application in response to this FOA that is essentially the same as one currently pending initial peer review unless the applicant withdraws the pending application. FDA will not accept any application that is essentially the same as one already reviewed.
Applicants must download the SF424 (R&R) application package associated with this funding opportunity using the Apply for Grant Electronically button in this FOA or following the directions provided at Grants.gov.
It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.
For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.
The forms package associated with this FOA includes all applicable components, mandatory and optional. Please note that some components marked optional in the application package are required for submission of applications for this FOA. Follow all instructions in the SF424 (R&R) Application Guide to ensure you complete all appropriate optional components.
All page limitations described in the SF424 Application Guide and must be followed, with the following exceptions or additional requirements:
All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:
Resource Sharing Plan
Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) as provided in the SF424 (R&R) Application Guide, with the following modification:
Appendix
Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.
Foreign (non-US) institutions must follow policies described in the HHS Grants Policy Statement, and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide.
Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit in advance of the deadline to ensure they have time to make any application corrections that might be necessary for successful submission.
Organizations must submit applications via Grants.gov, the online portal to find and apply for grants across all Federal agencies. Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, FDA’s electronic system for grants administration.
Applicants are responsible for viewing their application in the eRA Commons to ensure accurate and successful submission.
Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.
This initiative is not subject to intergovernmental review.
All FDA awards are subject to the terms and conditions, cost principles, and other considerations described in the HHS Grants Policy Statement.
Pre-award costs are allowable only as described in the HHS Grants Policy Statement.
Applications must be submitted electronically following the instructions described in the SF 424 (R&R) Application Guide. Paper applications will not be accepted.
Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.
For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically.
Important
reminders:
All PD(s)/PI(s) must include their eRA Commons ID in the
Credential field of the Senior/Key Person Profile Component of the SF
424(R&R) Application Package. Failure to register in the Commons and
to include a valid PD/PI Commons ID in the credential field will prevent the
successful submission of an electronic application to FDA.
The applicant organization must ensure that the DUNS number it provides on the
application is the same number used in the organization’s profile in the eRA
Commons and for the Central Contractor Registration (CCR). Additional
information may be found in the SF424 (R&R) Application Guide.
See more
tips for avoiding common errors.
Upon receipt, applications will be evaluated for completeness by the FDA Grants Office and responsiveness by components of participating organizations, FDA. Applications that are incomplete and/or nonresponsive will not be reviewed.
Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-10-115.
Only the review criteria described below will be considered in the review process. As part of the FDA mission, all applications submitted to the FDA in support of biomedical and behavioral research are evaluated for scientific and technical merit through the FDA objective review system.
Reviewers will provide an overall impact/priority score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).
Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.
Significance
Does the project address an important problem or a critical barrier to progress in the field? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?
Investigator(s)
Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?
Innovation
Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?
Approach
Are the overall strategy, methodology, and analyses
well-reasoned and appropriate to accomplish the specific aims of the project?
Are potential problems, alternative strategies, and benchmarks for success
presented? If the project is in the early stages of development, will the
strategy establish feasibility and will particularly risky aspects be managed?
If the project involves clinical research, are the plans for 1) protection of
human subjects from research risks, and 2) inclusion of minorities and members
of both sexes/genders, as well as the inclusion of children, justified in terms
of the scientific goals and research strategy proposed?
Environment
Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?
As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact/priority score, but will not give separate scores for these items.
Protections for Human Subjects
For research that involves human subjects but does
not involve one of the six categories of research that are exempt under 45 CFR
Part 46, the committee will evaluate the justification for involvement of human
subjects and the proposed protections from research risk relating to their
participation according to the following five review criteria: 1) risk to
subjects, 2) adequacy of protection against risks, 3) potential benefits to the
subjects and others, 4) importance of the knowledge to be gained, and 5) data
and safety monitoring for clinical trials.
For research that involves human subjects and meets the criteria for one or
more of the six categories of research that are exempt under 45 CFR Part 46,
the committee will evaluate: 1) the justification for the exemption, 2) human
subjects involvement and characteristics, and 3) sources of materials. For
additional information on review of the Human Subjects section, please refer to
the Human
Subjects Protection and Inclusion Guidelines.
Inclusion of Women, Minorities, and Children
When the proposed project involves clinical research, the committee will evaluate the proposed plans for inclusion of minorities and members of both genders, as well as the inclusion of children. For additional information on review of the Inclusion section, please refer to the Human Subjects Protection and Inclusion Guidelines.
Vertebrate Animals
The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.
Biohazards
Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.
Resubmissions
Not Applicable
Renewals
Not Applicable
Revisions
Not Applicable
As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact/priority score.
Applications from Foreign Organizations
Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.
Select Agent Research
Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).
Resource Sharing Plans
Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: 1) Data Sharing Plan; 2) Sharing Model Organisms; and 3) Genome Wide Association Studies (GWAS).
Budget and Period of Support
Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.
Applications will be evaluated for scientific and technical merit by (an) appropriate Objective Review Group(s) in accordance with FDA's Objective Review Policy and Procedures using the stated review criteria.
As part of the objective review process, all applications:
Appeals of initial peer review will not be accepted for applications submitted in response to this FOA.
Applications will be assigned to the appropriate FDA Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the National Cancer Advisory Board. The following will be considered in making funding decisions:
Information regarding the disposition of applications is available in the HHS Grants Policy Statement.
If the application is under consideration for funding, FDA
will request "just-in-time" information from the applicant as
described in the HHS Grants
Policy Statement.
A formal notification in the form of a Notice of Award (NoA) will be provided
to the applicant organization for successful applications. The NoA signed by
the grants management officer is the authorizing document and will be sent via
email to the grantee’s business official.
Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection
of an application for award is not an authorization to begin performance. Any
costs incurred before receipt of the NoA are at the recipient's risk. These
costs may be reimbursed only to the extent considered allowable pre-award costs..
Any application awarded in response to this FOA will be subject to the DUNS,
CCR Registration, and Transparency Act requirements as noted in the HHS Grants
Policy Statement.
All FDA grant and cooperative agreement awards include the HHS Grants Policy Statement as part of the NoA. For these terms of award, see the HHS Grants Policy Statement.
Cooperative Agreement Terms and Conditions of Award
The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), and other HHS, PHS, and FDA grant administration policies. The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial FDA programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the FDA purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the FDA as defined below.
The PD(s)/PI(s) will have the primary responsibility for:
Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and FDA policies.
FDA staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:
Participate in developing a study protocol;
Participate in data analysis;
Review method validation;
Review and conduct quality assurance of results;
Participate in writing manuscripts for publication;
Additionally, an agency program official or IC program director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.
Areas of Joint Responsibility include:
None; all responsibilities are divided between awardees and FDA staff as described above.
When multiple years are involved, awardees will be required to submit the Non-Competing Continuation Grant Progress Report (PHS 2590) annually and financial statements as required in the HHS Grants Policy Statement.
A final progress report, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the HHS Grants Policy Statement.
The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable FDA grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the HHS Grants Policy Statement for additional information on this reporting requirement.
We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.
Grants.gov
Customer Support (Questions regarding Grants.gov registration and
submission, downloading or navigating forms)
Contact Center Phone: 800-518-4726
Email: support@grants.gov
GrantsInfo (Questions regarding application instructions and
process, finding FDA grant resources)
Telephone 301-710-0267
TTY 301-451-5936
Email: GrantsInfo@nih.gov
eRA Commons Help Desk (Questions regarding eRA Commons
registration, tracking application status, post submission issues)
Phone: 301-402-7469 or 866-504-9552 (Toll Free)
TTY: 301-451-5939
Email: commons@od.nih.gov
Wenlei Jiang
Food and Drug Administration /Center of Drug Evaluation and Research/Office of Pharmaceutical
Science/Office of Generic Drugs
Telephone: 240-276-8607
Email: wenlei.jiang@fda.hhs.gov
Lisa Ko
Food and Drug Administration/Office of the
Commissioner/Office of Acquisitions and Grants Services
Telephone: 301-827-5095
Email: Lisa.Ko@fda.hhs.gov
Wenlei Jiang
Food and Drug Administration /Center of Drug Evaluation and Research/Office of Pharmaceutical
Science/Office of Generic Drugs
Telephone: 240-276-8607
Email: wenlei.jiang@fda.hhs.gov
Lisa Ko
Food and Drug Administration/Office of the
Commissioner/Office of Acquisitions and Grants Services
Telephone: 301-827-5095
Email: Lisa.Ko@fda.hhs.gov
Recently issued trans-FDA policy notices may affect your application submission. All awards are subject to the terms and conditions, cost principles, and other considerations described in the HHS Grants Policy Statement.
Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92.
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