Opportunity Information: Apply for RFA FD 14 024
Apply for RFA FD 14 024
- The Food Drug Administration in the health science and technology and other research and development sector is offering a public funding opportunity titled "Pharmacokinetic and Pharmacodynamic (PK PD) Studies of Cardiovascular Drugs (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 2, 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 $3,000,000.00 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: Public and State controlled institutions of higher education Small businesses For profit organizations other than small businesses State governments Nonprofits having a 501(c)(3) status with the IRS, other than institutions of higher education City or township governments Native American tribal governments (Federally recognized) Native American tribal organizations (other than Federally recognized tribal governments) County governments Independent school districts Special district governments Nonprofits that do not have a 501(c)(3) status with the IRS, other than institutions of higher education Others (see text field entitled Additional Information on Eligibility for clarification) Public housing authorities/Indian housing authorities Private institutions of higher education.
- Foreign Recipients
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Opportunity Summary:
This FDA grant opportunity (RFA-FD-14-024), offered as a U01 cooperative agreement, is focused on resolving real-world concerns about whether different metoprolol products that meet standard bioequivalence rules in healthy volunteers always perform the same way in patients. Metoprolol is a commonly used selective beta-1 blocker for cardiovascular conditions, especially hypertension, and it comes in multiple salt forms (tartrate, fumarate, succinate) and multiple dosage forms, including extended-release products. The agency notes that different metoprolol formulations can show pH-dependent drug release, and those in vitro and in vivo differences may help explain why some patients and clinicians have reported therapeutic inefficacy or adverse events after switching between brand and generic extended-release metoprolol products. While the FDA monitors postmarketing safety reports through FAERS, the available data have not been sufficient to clearly pin down the cause of these complaints. The central premise of the funding opportunity is that studies performed directly in the target patient population, with pharmacokinetic (PK) measurements linked to pharmacodynamic (PD) effects over time, are needed to better understand therapeutic equivalence in practice.
The scientific goal is to run a prospective PK/PD study in hypertensive patients that connects metoprolol concentration-time profiles to the time course of drug effect, with the intention of identifying which product characteristics and patient-specific factors most strongly influence clinical performance. The opportunity lays out four specific objectives: first, to characterize and quantify the PK/PD relationship for metoprolol in hypertensive patients; second, to evaluate how switching products (before and after a switch at the same dose level) changes that PK/PD relationship; third, to examine the role of pH variation across the patient population and the formulation-dependent rate of drug delivery in shaping both PK and PD; and fourth, to determine how CYP2D6 phenotype affects metoprolol PK profiles and downstream PD activity. CYP2D6 is emphasized because metoprolol is primarily metabolized by this enzyme, and CYP2D6 genetic polymorphisms can create meaningful differences between extensive metabolizers and poor metabolizers, potentially altering exposure and response in ways that may matter when products are switched.
Methodologically, the FDA suggests a prospective, randomized crossover design, where patients are stabilized on one metoprolol product and then switched to a different product at the same dose. The trial is expected to include a set of products chosen specifically because they produce different shapes of PK profiles, which is important for testing whether profile shape and release behavior (not just total exposure) relates to differences in PD response. The announcement recommends collecting PK and PD samples simultaneously at steady state, both before and after the switch, to support a direct linkage between concentration-time patterns and measured pharmacologic effects. It also stresses that the PD endpoint or endpoints must be carefully selected and well justified, since the credibility of PK/PD conclusions depends heavily on whether the PD measures truly capture metoprolol activity in a clinically meaningful way (for example, endpoints reflecting beta-blockade intensity over time). Another explicit expectation is that the study enroll both CYP2D6 extensive metabolizers and poor metabolizers, so the analysis can directly test phenotype-driven differences in exposure and response, including whether certain metabolizer groups are more sensitive to product-to-product differences. Separately, the study is expected to evaluate how patient-specific pH variability influences extended-release tablet dissolution and release in vivo, and how that pH effect interacts with the rate of delivery to change PK and PD.
The funding is structured as a single expected award under a cooperative agreement mechanism, meaning the FDA anticipates substantial scientific involvement during the project rather than a fully investigator-directed grant. The estimated total program funding is $3,000,000, with an anticipated project budget range per award of $750,000 to $1,000,000. No cost sharing or matching is required. The activity category is health science and technology and other research and development, and the awarding agency is the Food and Drug Administration under CFDA 93.103. Eligible applicants are broad and include public and private institutions of higher education, nonprofits (including but not limited to 501(c)(3) organizations), small businesses and other for-profit organizations, and multiple levels of government entities; the announcement also indicates foreign recipients are eligible. Operationally, the first year is expected to be heavily focused on foundational setup: developing a protocol suitable for FDA Research in Human Subject Committee (RIHSC) and the investigator institution IRB approvals, arranging product blinding, conducting quality testing of products, validating bioanalytical methods, and initiating patient enrollment.
In practical terms, the opportunity is aimed at producing evidence that can explain and potentially predict when two metoprolol products that pass standard bioequivalence testing (based on 90 percent confidence intervals for Cmax and AUC falling within 80.00 to 125.00 after a single dose in healthy subjects) might still differ in ways that matter for patients taking chronic therapy, particularly extended-release formulations. By tying formulation behavior (including pH-dependent release), patient biology (including CYP2D6 phenotype), and real PD responses together in a controlled switching design, the project is intended to help the FDA and the broader clinical community better understand therapeutic equivalence and reduce uncertainty around switching experiences reported in routine care.
FAQs: FDA Grant RFA-FD-14-024 (U01) - Metoprolol PK/PD Switching Study
1) What is this grant opportunity about?
This FDA funding opportunity (RFA-FD-14-024) supports research to address real-world concerns that different metoprolol products can meet standard bioequivalence criteria in healthy volunteers yet still perform differently in patients, especially after switching between products. The project is intended to generate evidence in the target patient population that links metoprolol pharmacokinetics (PK) to pharmacodynamics (PD) over time.
2) Which drug and patient population are the focus of the study?
The focus is metoprolol, a selective beta-1 blocker commonly used for cardiovascular conditions, particularly hypertension. The study is expected to be conducted in hypertensive patients, not only in healthy volunteers.
3) Why is metoprolol a concern for switching between products?
The FDA notes that different metoprolol formulations can have pH-dependent drug release and may show in vitro and in vivo differences. These differences may help explain reports from patients and clinicians of therapeutic inefficacy or adverse events after switching between brand and generic extended-release metoprolol products.
4) What is the central premise behind the research being funded?
The central premise is that studies performed directly in the target patient population, with PK measurements linked to PD effects over time, are needed to better understand therapeutic equivalence as it plays out in real clinical use, particularly for chronic therapy and extended-release products.
5) What are the specific scientific objectives described in the announcement?
The opportunity describes four objectives:
- Characterize and quantify the PK/PD relationship for metoprolol in hypertensive patients.
- Evaluate how switching products (before and after a switch at the same dose level) changes that PK/PD relationship.
- Examine the role of pH variation across patients and formulation-dependent delivery rate in shaping PK and PD.
- Determine how CYP2D6 phenotype affects metoprolol PK profiles and downstream PD activity.
6) What study design does the FDA recommend?
The FDA suggests a prospective, randomized crossover design in which patients are stabilized on one metoprolol product and then switched to a different product at the same dose. PK and PD sampling is expected at steady state both before and after the switch.
7) What types of metoprolol products are involved?
The announcement highlights that metoprolol comes in multiple salt forms (tartrate, fumarate, succinate) and multiple dosage forms, including extended-release products. The trial is expected to include a set of products selected specifically because they produce different shapes of PK profiles.
8) Why does the announcement emphasize extended-release metoprolol?
Extended-release metoprolol is emphasized because pH-dependent release and formulation-dependent delivery rates can affect the shape of the concentration-time curve. The funding opportunity is focused on whether differences in profile shape and release behavior (not just total exposure) translate into meaningful differences in PD response in patients.
9) How does this relate to standard FDA bioequivalence testing?
The opportunity is motivated by the possibility that products can pass standard bioequivalence testing (typically based on 90% confidence intervals for Cmax and AUC within 80.00 to 125.00 after a single dose in healthy subjects) yet still differ in patients during chronic use, particularly for extended-release formulations.
10) What kinds of endpoints does the FDA expect for pharmacodynamics (PD)?
The FDA stresses that PD endpoint(s) must be carefully selected and well justified, because the credibility of PK/PD conclusions depends on whether the PD measures truly capture metoprolol activity in a clinically meaningful way. The announcement gives an example category: endpoints reflecting beta-blockade intensity over time.
11) What is meant by linking PK and PD "over time"?
It means measuring metoprolol concentration-time profiles (PK) and the time course of drug effect (PD) in a coordinated way, with PK and PD samples collected simultaneously at steady state. This supports analyzing how changes in concentration patterns correspond to changes in pharmacologic effect across the dosing interval.
12) Why is CYP2D6 a major focus in this grant?
CYP2D6 is emphasized because metoprolol is primarily metabolized by this enzyme. Genetic polymorphisms in CYP2D6 can create meaningful differences between extensive metabolizers and poor metabolizers, which can change drug exposure and response and may matter when patients switch between products.
13) Does the study need to include specific CYP2D6 metabolizer groups?
Yes. The announcement explicitly expects enrollment of both CYP2D6 extensive metabolizers and poor metabolizers so analyses can test phenotype-driven differences in exposure and response, including whether certain metabolizer groups are more sensitive to product-to-product differences.
14) What role does pH play in the proposed research?
The study is expected to evaluate how patient-specific pH variability influences extended-release tablet dissolution and release in vivo, and how that pH effect interacts with formulation-dependent rate of delivery to change PK and PD outcomes.
15) Why are products chosen for different PK profile shapes?
Because the grant is aimed at testing whether the shape of the PK profile and release behavior (not just total exposure metrics like AUC and Cmax) is related to differences in PD response. Selecting products with distinct PK shapes helps evaluate that hypothesis.
16) What does "switching at the same dose level" mean in this context?
It refers to keeping the dose constant while changing the metoprolol product, so that any differences observed in PK/PD can be more directly associated with product characteristics and patient-specific factors rather than a dose change.
17) What is the mechanism and why does it matter?
The award mechanism is a U01 cooperative agreement. This matters because the FDA anticipates substantial scientific involvement during the project rather than it being fully investigator-directed.
18) How many awards are expected and what is the funding level?
The opportunity is structured as a single expected award. Estimated total program funding is $3,000,000, with an anticipated project budget range per award of $750,000 to $1,000,000.
19) Is cost sharing or matching required?
No. The announcement states that no cost sharing or matching is required.
20) Who is the awarding agency and what is the CFDA number?
The awarding agency is the Food and Drug Administration (FDA). The CFDA number listed is 93.103.
21) What types of organizations are eligible to apply?
Eligibility is broad and includes public and private institutions of higher education, nonprofits (including but not limited to 501(c)(3) organizations), small businesses and other for-profit organizations, and government entities at multiple levels. The announcement also indicates that foreign recipients are eligible.
22) What activity category does this funding fall under?
The activity category is health science and technology and other research and development.
23) What kinds of startup activities are expected in the first year?
The first year is expected to focus heavily on foundational setup, including developing a protocol suitable for FDA Research in Human Subject Committee (RIHSC) and the investigator institution IRB approvals, arranging product blinding, conducting quality testing of products, validating bioanalytical methods, and initiating patient enrollment.
24) Why does the announcement mention FAERS if the study is prospective?
The FDA notes it monitors postmarketing safety reports through FAERS, but available data have not been sufficient to clearly identify the cause of complaints related to switching. This opportunity is designed to generate more definitive evidence through controlled, prospective PK/PD research in hypertensive patients.
25) What is the intended impact of the research?
The project is intended to help explain and potentially predict when two metoprolol products that pass standard bioequivalence testing might still differ in ways that matter for patients on chronic therapy, especially with extended-release formulations. By linking formulation behavior (including pH-dependent release), patient biology (including CYP2D6 phenotype), and PD responses in a controlled switching design, the work aims to reduce uncertainty around switching experiences reported in routine care and improve understanding of therapeutic equivalence.
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