Call for Proposals
Funding Opportunity Purpose
The purpose of this funding opportunity is to develop in vitro test methods for evaluating and comparing the adhesive qualities and adhesion performance of transdermal and topical delivery systems (collectively, TDS) in a manner that can identify the potential for, and mitigate the risk of, differences in TDS adhesion performance in vivo. Differences in product design, formulation (including post-approval changes), or quality attributes between a test (e.g., generic) TDS and its reference TDS may result in differences in product quality and/or performance. The in vitro test methods developed are expected to provide meaningful insights that can assist the development or reformulation of generic TDS, and to support the comparative assessment of whether any differences between a test and reference TDS has the potential to alter the in vivo adhesion performance of a test vs. reference TDS.
Background
For TDS, the amount of drug delivered into and through the patient’s skin is dependent, in part, on the surface area dosed. Under ideal conditions, the entire contact surface area of a TDS should remain consistently and uniformly adhered to the patient’s skin throughout the duration of wear. When a TDS loses its adherence during wear, the amount of drug delivered to the patient may be reduced. Also, as progressively larger areas of the adhesive surface of a TDS detach, the risk of those areas interfacing with other surfaces such as clothing or bedding increases, leading to a greater risk of further or complete detachment, which may create a drug exposure hazard for other individuals, including children. Thus, the adhesion performance of a prospective generic TDS and its reference TDS is routinely evaluated in vivo.
In addition, the adhesiveness of TDS products is routinely evaluated in vitro with tests that assess peel adhesion, release liner peel, and tack, as outlined within the United States Pharmacopeia General Chapter <3> on Topical and Transdermal Drug Products – Product Quality Tests. Each of these tests measures the force required to separate the TDS from another surface. Additionally, cold flow and shear tests measure the cohesive properties of the TDS based on the resistance to flow of the adhesive matrix. The compendial in vitro tests are not designed to be biorelevant, and the results of these in vitro tests have limitations that make it challenging to correlate them with the in vivo adhesion performance of TDS.
Objective
The objective of this work is to support research to develop in vitro test methods for TDS that can be predictive of TDS adhesion performance in vivo. The expected outcome of this research is that novel or refined in vitro test methods will be developed. These tests would subject the TDS to biorelevant conditions that make it possible to use in vitro test methods to distinguish clinically meaningful differences in the TDS adhesion performance providing an efficient way for the industry to evaluate potential failure modes related to TDS adhesion during the development of generic TDS (and over the life cycle of the drug product), and facilitate FDA’s assessment of potential differences in the adhesion quality and performance of generic TDS relative to their reference TDS.
Detailed Description
The intent of the funding opportunity is that the award recipient will work collaboratively with a CRCG Expert Committee (EC) on TDS Adhesion (“the EC”) to refine the research strategy, develop study designs and protocols, orchestrate study conduct, analyze data and publish the results. The final research strategy would be developed based upon the innovation and expertise of the award recipient, in collaboration with feedback from the EC to ensure that the study designs are aligned with the objectives of the award.
Specific areas of scientific interest would include research to:
1) Develop a theoretical framework for all the factors, intrinsic and extrinsic to the TDS product, that influence its adhesion performance in vivo.
2) Develop study designs to characterize the in vitro adhesion performance of the custom-manufactured TDS formulations using skin-mimetic surface substrates, and substrate support systems. It will be critical to evaluate the appropriateness of a potential skin mimetic substrate(s) for the intended purpose. For example, it will be important to identify study conditions that emulate the extrinsic factors that can impact TDS adhesion, anatomically relevant temperature, curvature, torsion/flexion, elasticity, texture including porosity and micro-topographical features, moisture, water exposure, surface energy, and interfacial properties (flaking/micro-delamination) of the substrate(s). The temporal dimension of adhesion performance following application of a TDS in vivo should be carefully considered during the development of the system. For example, it may be critical to consider how the interaction of the TDS with the skin/substrate changes over time as the product delivers drug through the skin, experiences solvent loss, absorbs moisture from the skin, or otherwise changes in composition.
3) Once a substrate(s) has been identified it will be important to evaluate the in vitro adhesion performance of marketed TDS products (reference listed drug and generic TDS) for which the FDA has access to comparative in vivo adhesion study results. The methodology used for scoring adhesion should support a precise assessment of the percent surface area that remains adhered (e.g., using a 100-point scale). This will enable a direct comparison of the in vitro and in vivo adhesion performance as a function of the percent surface area that remains adhered at progressive time points throughout the duration of wear.
4) Identify strategies to systematically modulate the intrinsic factors in custom-manufactured non-drug containing TDS formulations ranging from excellent to poor, including factors such as size, shape, adhesive type/system/formulation and design (single vs. multi-layer systems, backing membrane flexibility/stretchability/occlusivity, etc.) that are expected to influence adhesion performance. The influence of drug and excipients concentration in a TDS, on TDS adhesion, may also be important to explore.
5) Evaluate the adhesion performance of the custom-manufactured TDS formulations in vitro using skin mimetic substrate(s) and study designs, to identify test conditions that appear to be reproducible and discriminating.
6) Conduct adhesion studies with TDS products in vitro and in vivo under controlled, harmonized study conditions to evaluate whether in vitro results are predictive of in vivo performance in situations where the same intrinsic and extrinsic factors are present.
7) Establish in vitro test methods that are reflective of TDS adhesion performance in vivo.
Expected Deliverables
At the completion of the research project period, the deliverables for this project are expected to include a body of evidence that demonstrate that the developed in vitro adhesion test methods are reflective of TDS adhesion performance in vivo. The awardee would be expected to provide the CRCG with a comprehensive annual report detailing the research and results, which may be made publicly available.
The expectation for data sharing is that the data and results generated as an outcome of this research award, including but not necessarily limited to any individual replicate/subject-level data (not just summary results), any model constructs and data sets, and/or any computer code that represents an outcome of the award, should be shared by the awardee contemporaneously in monthly research update meetings with the Center for Research on Complex Generics (CRCG) and the CRCG’s relevant Expert Committee, including the U.S. Food and Drug Administration (FDA) Office of Generic Drugs. The awardee will provide annual research reports to the CRCG and prepare technical reports encompassing completed phases of research. The CRCG and the FDA would make such data and results publicly available after a reasonable amount of time following the completion of the award period (e.g., 1 year after the end of the award period) to allow sufficient time for the research team and key collaborators to publish the work in scientific journals. The applicant should budget sufficient funds to pay for open access fees for scientific journals from the award funds. The applicant’s data sharing plan will specifically be considered when scoring the ‘Significance’ of the application.
Project Period and Budget
The scope of the proposed project should determine the project period. The maximum project period is five (5) years. Budget should reflect the actual needs of the proposed project and should not exceed the following in total costs (direct and indirect):
Year 1: $250,000
Year 2: $250,000
Year 3: $250,000
Year 4: $250,000
Year 5: $250,000
Indirect cost rate cannot exceed 20%.
Eligibility
All institutions, domestic and international, including academic, industrial, governmental, or collaborative groups/consortia are eligible to apply.
Application Details
Applications are due by 11:59 pm ET on Friday, September 15, 2023. Applications should be emailed as a single PDF file (maximum 8 Megabytes) to info@complexgenerics.org. Movie and sound file attachments, URL Links, or other additional files will not be accepted.
Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows the CRCG staff to estimate the potential review workload and plan the review. By Thursday, July 27, 2023, at 5 pm ET, prospective applicants are asked to submit a letter of intent that includes the following information: Descriptive title of proposed activity; Name(s), email address(es), and telephone number(s) of the Program Director(s)/Principal Investigator(s); Names of other key personnel; Participating institution(s); and Title of this funding opportunity. The letter of intent should be sent to: info@complexgenerics.org
A technical session will be held for prospective applicants on Wednesday, August 2, 2023, 10 am – 11am ET. The conference call information will be provided to prospective applicants that submit a letter of intent. The technical session will provide an overview of the submission requirements and allow prospective applicants an opportunity to ask questions regarding the application process. Participation in the technical session is optional, but strongly encouraged.
Applications should include a cover page, quad chart, white paper proposal, and a budget. Combine all files and forms into a single PDF file before submitting. A cover page (one page) should include information about the applicant, including elements relevant to applicant eligibility (see the section below on ‘Eligible Organizations’). A quad chart (one page) and white paper (12 pages maximum) should address this call for proposals.
Quad chart should include: Title Of Project, Principle Investigator(s), Company Name; Bullet list of the major goals/milestones by Project Year; total requested annual funding for each year (up to five years); Contact Information (name, email, phone)
White paper shall provide a brief technical discussion of the objective, approach, level of effort, and the nature and extent of the anticipated results. Specifically, the White Paper shall include, at a minimum, the following core elements: a) a high-level freestanding Gantt chart showing an overview of the proposed activities and timelines; b) a brief description of intellectual property ownership of the proposed project; c) an overview of capabilities and experience (past and current) as they relate to the proposed program; and d) overviews (two pages maximum) of the key personnel who will perform the research, highlighting some of their qualifications and experience.
A budget page (one page) should include a budget (including a brief cost estimate revealing the component parts of the proposal and a breakdown of the total cost per year) and budget justification.
All applications should include a data sharing plan that describes the applicants’ intentions related to public disclosure and publication of data and information developed in conjunction with the award. All applications should state that they will collaboratively work with the Center for Research on Complex Generics, including providing periodic updates to, and receiving advice from, the CRCG Expert Committee on TDS Adhesion.
Reviewers will consider each of the review criteria below in the determination of scientific merit.
Significance (10 Points)
Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? Considering the usefulness of the research outcomes and the provisions for public access to the data and results described in the data sharing plan, 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) (20 Points)
Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early-Stage Investigators or those 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 (20 Points)
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 (30 Points)
Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? 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? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?
If the project involves human subjects and/or clinical research, are the plans to address – 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?
Environment (20 Points)
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?
Applicants will be notified of award decisions by October 31, 2023. Applicants may or may not receive review feedback.
Awards are generally subject to the terms and conditions, cost principles, and other considerations described in the HHS Grants Policy Statement (https://www.hhs.gov/sites/default/files/grants/grants/policies-regulations/hhsgps107.pdf). Additional funding restrictions and requirements may be part of any award.
Eligible Organizations
Higher Education Institutions
- Public/State Controlled Institutions of Higher Education
- Private Institutions of Higher Education
The following types of Higher Education Institutions are always encouraged to apply for FDA support as Public or Private Institutions of Higher Education:
- Hispanic-serving Institutions
- Historically Black Colleges and Universities (HBCUs)
- Tribally Controlled Colleges and Universities (TCCUs)
- Alaska Native and Native Hawaiian Serving Institutions
- Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)
Nonprofits Other Than Institutions of Higher Education
- Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
- Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)
For-Profit Organizations
- Small Businesses
- For-Profit Organizations (Other than Small Businesses)
Governments
- State Governments
- County Governments
- City or Township Governments
- Special District Governments
- Indian/Native American Tribal Governments (Federally Recognized)
- Indian/Native American Tribal Governments (Other than Federally Recognized)
- U.S. Territory or Possession
Other
- Independent School Districts
- Public Housing Authorities/Indian Housing Authorities
- Native American Tribal Organizations (other than Federally recognized tribal governments)
- Faith-based or Community-based Organizations
- Regional Organizations
- Non-domestic (non-U.S.) Entities (Foreign Institutions)
Foreign Institutions
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 HHS Grants Policy Statement (https://www.hhs.gov/sites/default/files/grants/grants/policies-regulations/hhsgps107.pdf), are allowed.