Opportunity Information: Apply for RFA FD 14 021
Apply for RFA FD 14 021
- The Food Drug Administration in the health science and technology and other research and development sector is offering a public funding opportunity titled "Retrospective Analysis on the Impact of Generic Immunosuppressants on Acute Rejection and Long Term Graft Survivals (U01)" and is now available to receive applicants.
- Interested and eligible applicants and submit their applications by referencing the CFDA number(s): 93.103 Food and Drug AdministrationResearch.
- This funding opportunity was created on Apr 18, 2014 and posted on Apr 18, 2014.
- Applicants must submit their applications by Jun 21, 2014. (Agency may still review applications by suitable applicants for the remaining/unused allocated funding in 2026.)
- The funding agency has allocated a total of $2,000,000.00 to eligible and selected applicants.
- Each selected applicant is eligible to receive up to $1,000,000.00 in funding.
- The number of recipients for this funding is limited to 1 candidate(s).
- Eligible applicants include: Nonprofits having a 501(c)(3) status with the IRS, other than institutions of higher education Public housing authorities/Indian housing authorities Public and State controlled institutions of higher education County governments Native American tribal governments (Federally recognized) Small businesses Special district governments State governments City or township governments For profit organizations other than small businesses Independent school districts Private institutions of higher education Others (see text field entitled Additional Information on Eligibility for clarification) Native American tribal organizations (other than Federally recognized tribal governments) Nonprofits that do not have a 501(c)(3) status with the IRS, other than institutions of higher education.
- Foreign Recipients
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Opportunity Summary:
This FDA cooperative agreement (U01) funding opportunity focuses on a practical and long-running debate in solid organ transplantation: whether switching from brand-name immunosuppressant drugs to generics, or switching among different generic manufacturers, can meaningfully change drug exposure in ways that affect real clinical outcomes. Transplant survival has improved greatly in recent decades, largely because modern immunosuppressive regimens prevent immune-mediated damage to the transplanted organ. Standard maintenance therapy commonly combines a calcineurin inhibitor such as tacrolimus or cyclosporine, an antiproliferative agent such as mycophenolate mofetil or mycophenolate sodium (sometimes azathioprine), and corticosteroids, with sirolimus (a proliferation signal inhibitor) sometimes added or substituted depending on the patient and the center. Generics reduce cost, improve access, and can create major savings for patients and insurers, but transplant clinicians worry that even small differences in exposure for narrow-therapeutic-index drugs could tilt the immunosuppressive balance toward rejection or toxicity. While the FDA previously supported pharmacokinetic comparisons of generic tacrolimus to the brand product Prograf in stable adult liver and kidney recipients at moderate to high immunologic risk, the agency notes that longer-term clinical outcomes after widespread generic availability have not been systematically evaluated, leaving a gap in evidence that this program aims to address.
The central objective is to run a multicenter retrospective outcomes study that examines the impact of generic immunosuppressants on short-term acute rejection and long-term patient and graft survival after transplantation, specifically in the era since these generics entered the market. The intent is not simply to compare blood levels or pharmacokinetics, but to evaluate clinically meaningful endpoints: rejection events, graft function, graft loss, and patient survival over extended follow-up. The results are meant to directly inform public and professional concerns about interchangeability, potentially guide FDA review practices for generic immunosuppressants if issues are identified, and provide a stronger evidence base for designing future prospective studies on generic substitution in transplant populations.
The model drugs required for inclusion include at least cyclosporine, tacrolimus, mycophenolate mofetil, and mycophenolate sodium. Applicants are expected to leverage existing clinical data sources such as transplant center databases, electronic medical records, and other relevant datasets to assemble a detailed cohort of kidney, heart, and liver transplant recipients taking one or more of these agents. The retrospective dataset is expected to capture key variables that could influence outcomes or help interpret any differences observed between drug types. These include demographics; the immunosuppressive regimen details (which drug, whether brand or generic, and whether patients stayed on a single generic product or switched among multiple generics); dosing levels and dose adjustments over time; measures of transplant organ function; documentation of acute rejection; biopsy results (renal or liver biopsies where applicable); and other clinically relevant information contained in center records.
A notable component of the project is attention to medication adherence, which is a major confounder in transplant outcomes and particularly relevant when cost or formulary changes drive switching. The opportunity explicitly encourages evaluation of patient adherence to immunosuppressant therapy so that any observed associations between generic use and outcomes can be separated, as much as possible, from the effects of missed doses or inconsistent access. In addition, the analysis is expected to compare outcomes across meaningful exposure groups, such as patients who used only brand products, only generics, or a mix of brand and generic over time. The announcement also suggests analyzing outcomes across multiple time horizons, such as 1-, 3-, 5-, and even 10-year survival, to capture both early rejection-related impacts and later differences in graft durability.
The FDA further recommends subgroup analyses to address populations where risk profiles, pharmacogenomics, or access barriers may differ. Specifically, the announcement calls out analyses in children, adults, and African American recipients, reflecting known differences in immunologic risk, drug metabolism, and historical disparities in transplant outcomes. Beyond the drug exposure categories, the project is expected to account for other determinants of graft and patient survival, including donor-related, transplant-related, and patient-related risk factors. In practice, this implies building statistical models that adjust for variables like donor characteristics, transplant era, comorbidities, baseline organ function, immunologic risk, and center practices, so that comparisons between brand and generic use are as fair and clinically interpretable as possible.
From an administrative standpoint, this was an FDA discretionary grant using the cooperative agreement mechanism (U01), meaning the agency anticipated substantial programmatic involvement compared with a standard research project grant. The funding opportunity number is RFA-FD-14-021 under CFDA 93.103 (FDA Research). The program expected to make one award, with an estimated total funding level of $2,000,000, an award ceiling of $1,000,000, and an award floor of $750,000, with no cost-sharing requirement. It was posted April 18, 2014, with an application closing date of June 21, 2014, and an archive date of July 21, 2014. Eligibility was broad, spanning nonprofits (including and excluding 501(c)(3)), public and private institutions of higher education, various levels of government, tribal entities, and for-profit organizations, and the announcement indicates foreign recipients were eligible. Overall, the opportunity is aimed at generating real-world, multicenter clinical evidence on whether generic immunosuppressants perform comparably to brand products in the outcomes that matter most to transplant patients: avoiding acute rejection and maintaining long-term graft and patient survival.
FAQs: FDA Cooperative Agreement (U01) on Generic Immunosuppressants in Solid Organ Transplantation (RFA-FD-14-021)
What is the main purpose of this funding opportunity?
The purpose is to support a multicenter retrospective outcomes study evaluating whether use of generic immunosuppressant drugs (including switching from brand to generic or switching among different generic manufacturers) is associated with differences in clinically meaningful transplant outcomes. The focus is on endpoints like acute rejection, graft function, graft loss, and patient survival over extended follow-up, rather than only pharmacokinetic or blood-level comparisons.
What type of award mechanism is used?
This opportunity uses an FDA cooperative agreement mechanism (U01). A cooperative agreement implies substantial FDA programmatic involvement compared with a standard research project grant.
Which agency is sponsoring the program?
The program is sponsored by the U.S. Food and Drug Administration (FDA).
What is the funding opportunity number and CFDA listing?
The funding opportunity number is RFA-FD-14-021. The CFDA listing is 93.103 (FDA Research).
What clinical question is this study meant to address?
The study is meant to address a long-running clinical debate in transplantation: whether switching from brand-name immunosuppressants to generics, or switching among generic manufacturers, can change drug exposure in ways that translate into different real-world clinical outcomes (for example, acute rejection, toxicity, graft loss, or patient death) in solid organ transplant recipients.
Why is this issue important in transplant care?
Immunosuppressants are commonly narrow-therapeutic-index drugs, and transplant clinicians have concerns that even small differences in exposure could shift the balance toward rejection or toxicity. At the same time, generics can reduce cost and improve access, creating major savings for patients and insurers. This opportunity aims to generate longer-term, systematic outcomes evidence in the era of widespread generic availability.
Is the study focused on pharmacokinetics or clinical outcomes?
The focus is on clinical outcomes. The intent is not simply to compare blood levels or pharmacokinetics, but to evaluate clinically meaningful endpoints such as acute rejection, graft function, graft loss, and patient survival over extended follow-up.
What study design is expected?
A multicenter retrospective outcomes study is expected, leveraging existing clinical data sources rather than enrolling patients in a new prospective trial.
Which transplanted organs are specifically mentioned for inclusion?
The opportunity specifically calls for assembling a cohort of kidney, heart, and liver transplant recipients.
Which immunosuppressant drugs must be included as model drugs?
The required model drugs include at least cyclosporine, tacrolimus, mycophenolate mofetil, and mycophenolate sodium.
What maintenance immunosuppressive regimens are described as common in transplant practice?
Standard maintenance therapy is described as commonly combining a calcineurin inhibitor (such as tacrolimus or cyclosporine), an antiproliferative agent (such as mycophenolate mofetil or mycophenolate sodium, sometimes azathioprine), and corticosteroids, with sirolimus sometimes added or substituted depending on the patient and the center.
What are the primary outcomes the study should evaluate?
The study is expected to evaluate short-term acute rejection and long-term patient and graft survival, along with related clinical endpoints such as graft function and graft loss.
Does the opportunity suggest specific follow-up time horizons?
Yes. The announcement suggests analyzing outcomes across multiple time horizons, such as 1-, 3-, 5-, and even 10-year survival, to capture both early rejection-related impacts and later differences in graft durability.
How should brand versus generic exposure be categorized for analysis?
The opportunity expects comparisons across meaningful exposure groups, including patients who used only brand products, only generic products, or a mix of brand and generic over time. It also highlights distinguishing patients who stayed on a single generic product from those who switched among multiple generics.
What data sources are applicants expected to use?
Applicants are expected to leverage existing clinical data sources such as transplant center databases, electronic medical records, and other relevant datasets to assemble the retrospective cohort.
What key variables should the retrospective dataset capture?
The dataset is expected to capture demographics; immunosuppressive regimen details (which drug, whether brand or generic, and whether there were switches among generics); dosing levels and dose adjustments over time; measures of transplant organ function; documentation of acute rejection; biopsy results (renal or liver biopsies where applicable); and other clinically relevant information contained in center records.
Why is medication adherence emphasized in this opportunity?
Medication adherence is emphasized because it is a major confounder in transplant outcomes and is particularly relevant when cost or formulary changes drive medication switching. The opportunity encourages evaluating adherence so associations between generic use and outcomes can be separated, as much as possible, from effects of missed doses or inconsistent access.
Are subgroup analyses recommended?
Yes. The FDA recommends subgroup analyses for populations where risk profiles, pharmacogenomics, or access barriers may differ, specifically calling out children, adults, and African American recipients.
What other factors should analyses account for besides drug product type?
The project is expected to account for donor-related, transplant-related, and patient-related risk factors. This implies statistical modeling that adjusts for variables such as donor characteristics, transplant era, comorbidities, baseline organ function, immunologic risk, and center practices to make comparisons between brand and generic use more fair and clinically interpretable.
How is this program intended to be useful to FDA and the transplant community?
The results are intended to inform public and professional concerns about interchangeability, potentially guide FDA review practices for generic immunosuppressants if issues are identified, and strengthen the evidence base for designing future prospective studies on generic substitution in transplant populations.
How many awards were expected under this opportunity?
The program expected to make one award.
What was the estimated total funding level and award size range?
The estimated total funding level was $2,000,000. The award ceiling was $1,000,000 and the award floor was $750,000.
Was cost-sharing required?
No cost-sharing requirement was indicated.
When was the opportunity posted and what were the key dates?
It was posted on April 18, 2014. The application closing date was June 21, 2014. The archive date was July 21, 2014.
Who was eligible to apply?
Eligibility was broad and included nonprofits (including and excluding 501(c)(3)), public and private institutions of higher education, various levels of government, tribal entities, and for-profit organizations. The announcement also indicates foreign recipients were eligible.
What transplant populations are explicitly mentioned for cohort assembly?
The cohort is expected to include kidney, heart, and liver transplant recipients taking one or more of the model immunosuppressant agents.
Does the opportunity build on prior FDA-supported work?
Yes. The opportunity notes FDA previously supported pharmacokinetic comparisons of generic tacrolimus to the brand product Prograf in stable adult liver and kidney recipients at moderate to high immunologic risk, but that longer-term clinical outcomes after widespread generic availability had not been systematically evaluated, creating an evidence gap this program aims to address.
What aspect of generic use is highlighted as a practical concern beyond clinical pharmacology?
The opportunity highlights that cost and formulary changes can drive switching, which makes adherence and consistent access especially relevant when evaluating outcomes related to generic substitution or switching among generic manufacturers.
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