Call for Data Contribution #2

Background

FDA has awarded a grant (1U01FD007906) to Simulations Plus to:

  1. Develop and verify/validate physiologically based pharmacokinetic (PBPK)[1] models for their intended purpose, which is to detect formulation differences between the reference standard drug product and a prospective generic drug product.
  2. Develop a workflow for designing and performing a reliable virtual bioequivalence (BE) study by leveraging modeling approaches such as PBPK modeling and by utilizing the models developed under (1).
  3. Explore considerations and reasonable assumptions related to performing a virtual BE assessment using mechanistic modeling and simulation tools of increased complexity, such as PBPK models. The models developed under (1) will be utilized as case studies.

To meet the objectives outlined above, and to maximize the outcomes and impact of this collaborative agreement for supporting generic drug product development and regulatory assessment, Simulations Plus is inviting interested “contributors” to share relevant data to support this research, which will develop in silico tools to facilitate the development and assessment of generic products.

Opportunity for Data Contribution

The predictive capabilities of the in silico models developed and verified/validated under this grant (1U01FD007906) will depend upon the type and amount of data that are leveraged when constructing the models. Moreover, the credibility of these models will depend upon comparing their predictions with observed in vivo data in humans. When the model predictions align with empirical in vitro or in vivo data, and the model is sufficiently verified/validated, these models can be used to support decisions related to the development and assessment of the drug products they are describing, which can support the availability of safe, reliable, and high quality generic drug products, including complex generics.

Thus, contributors are invited to support the eventual utility of these models for generic drug development and assessment by providing in vitro and/or in vivo clinical study data for specific drug products (listed below) that are within the scope of this research project.

Key Dates

  • Proposal submission deadline: May 20, 2024
  • Proposal acceptance notification: June 30, 2024
  • Data sharing deadline: September 15, 2024

Requested Data

Below is a non-exhaustive list of data that prospective contributors are invited to provide for one or more oral drug products with the following active pharmaceutical ingredients (APIs): Bupropion hydrochloride, Metoprolol, Nifedipine, Omeprazole, Lamotrigine, Carbamazepine, Cimetidine, Acyclovir, Metformin, Digoxin, Ciprofloxacin, Dexamethasone, Budesonide, Mesalamine, Sulfasalazine:

Data

  1. In vitro measurement of the API’s physicochemical properties necessary to develop and validate a PBPK model (e.g., drug solubility, octanol/water partition coefficient, and ionization constants among others) for the drug products with the APIs listed above.
  2. In vitro dissolution data (at multiple dissolution media under the consideration of gastrointestinal physiology, the BCS classification of the API and the drug product complexity) of test and reference drug products used in the submitted clinical trials under bullets 4 and 5.
  3. In vitro measurements of formulation critical quality attributes of test and reference drug products used in the submitted clinical trials under bullets 4 and 5 besides dissolution (e.g., particle size distribution) necessary to develop and validate a PBPK model (the list may vary based on API’s BCS class and the complexity of the drug product) for the drug products with the APIs listed above.
  4. De-identified individual subject PK concentration-time course data obtained during a clinical trial used to demonstrate the bioequivalence or non-bioequivalence of test and reference drug products for the APIs listed above.
  5. De-identified individual subject PK concentration-time course data obtained during a clinical trial used to demonstrate the bioequivalence or non-bioequivalence of test and reference drug products providing information on intra-subject variability on the APIs listed above.
  6. Available de-identified individual PK concentration time course providing information on intra-subject variability for other APIs than the fifteen (15) listed above may be shared to support this research project. Please include a detailed description of available data in the proposals.

Proposal and Process Details

Proposals are due by 11:59 pm ET on Monday, May 20, 2024. Proposals 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.

Before May 20, 2024, prospective contributors are invited to submit a brief proposal (3 pages maximum using the proposal template provided below) summarizing their interest in supporting this research project.

  • The proposal should describe the state of the experimental data (mean data vs. individual replicate data) and the availability of the data (i.e., whether all the data are already available, or when the data will become available).
  • For human clinical data (pharmacokinetic, demographic, and other), contributor(s) should be able to share existing data immediately with the selection of their proposal (the referenced clinical PK study should be completed by the time of proposal submission).
  • Summary and individual-level human clinical data may be shared with Simulations Plus provided that the shared datasets are de-identified.
  • The contributed data should be reproducible, robust, and collected using qualified/validated methodologies.
  • The contributors should be able to attest to and demonstrate the quality of the data they are contributing.

The proposal must specify drug name and nature of drug product, list of datasets that a prospective contributor is willing to contribute (i.e., partial vs full contribution to the requested data), very brief descriptions of study designs, and targeted/approximate date of availability for the dataset(s) to be contributed. Contributors are required to use the proposal template available at the link below.

Download the proposal template

Proposals submitted to the CRCG do not need to include the actual in vitro or in vivo data that would be contributed to Simulations Plus. Contributor(s) would be expected to transfer the contributed data directly to Simulations Plus as soon as possible during the next few months, and no later than September 15, 2024. Simulations Plus will work with selected contributors directly to preserve data confidentiality and on other related issues based on independent agreements established between the contributor and Simulations Plus, as discussed below. The expectation is that the contributor’s data confidentiality and the proprietary nature of the data will be ensured. The CRCG and FDA will have no direct access to individual level human clinical data, the human clinical data will remain deidentified and the CRCG and FDA won’t have access to the deidentification process (no access to codes).

Simulations Plus scientists will review the received brief proposals by June 30, 2024. The selection of contributors will be based on the completeness of the proposal, the quality and value of the data to the model development, the verification/validation process, and the timely availability of the data. The intention is that all eligible contributors would be afforded an equal opportunity to contribute to this research. Contributor(s) will be notified of decisions by June 30, 2024.

The participation of contributor(s) is not intended to change the objective of this project as defined in RFA-FD-23-016, or in the awarded research project under 1U01FD007906. The terms of the engagement between Simulations Plus and each contributor will be established in an independent agreement between the selected contributor and Simulations Plus. Establishment of those independent agreements will be the responsibility of each contributor and Simulations Plus exclusively. The project will be managed entirely by Simulations Plus. CRCG will be involved only during proposal solicitation and selection process. Contributor(s) will work with Simulations Plus directly during the entire term of this project. Once an independent agreement between Simulations Plus and each contributor is established, Simulations Plus will utilize the contributor’s data to build/inform the mechanistic PBPK models for relevant drug products (which have been pre-selected within the scope of the awarded research project under 1U01FD007906).

Project outcomes (e.g., details of PBPK model development and the verification/validation process for each selected drug product) will be shared, separately, with each contributor in essentially the same manner, based upon the terms of the individual agreements. Contributor(s) will receive updates on the project progress at regular intervals (e.g., in the form of mid-year or annual report). Consistent with the provisions for public access to the data and results generated within the scope of this grant from FDA, the outcomes of the research performed under award 1U01FD007906 will eventually be made publicly available in the form of manuscripts, oral presentations and the GDUFA Research Report published annually.

Project Period: 09/05/2023- 08/31/2025

Funding: There is no funding associated with this opportunity.

Eligibility

All institutions, domestic and international, including academic, industrial, governmental, or collaborative groups/consortia are eligible to apply.

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, are allowed.

Application Submission Contact: info@complexgenerics.org

[1] Physiologically based pharmacokinetic (PBPK) models are in silico (computational modeling and simulation) tools that can mechanistically describe, in a quantitative manner, the disposition (i.e., absorption, distribution, metabolism and elimination) of an active ingredient in the human body after administered through a variety of routes, e.g., intravenous, parenteral, oral, inhalation, etc. These in silico models are integrated into a mathematical framework consisting of information about the physicochemical properties and pharmacokinetic characteristics of the active ingredient; the formulation composition of the drug product, its manufacturing process, and its product quality characteristics; and features of a device component that could potentially impact the product’s in vivo performance.