FDA’s New Alternative Methods Program is intending to spur the adoption of alternative methods for regulatory use that can replace, reduce, and refine animal testing (the 3Rs), help prevent products with increased toxicological risk from reaching the market, and improve predictivity of nonclinical testing to streamline the development of FDA-regulated products. FDA recognizes alternative methods also may provide opportunities to assess potential toxicities, risks, safety, and effectiveness and give insight into disease processes.
The Fiscal Year 2023 budget provided $5 million in new funding to support this program through FDA core operations. FDA’s Office of the Chief Scientist is supporting the New Alternative Methods Program through central coordination and management, with FDA centers responsible for specific programmatic objectives.
Through this initiative, FDA will:
- Expand processes to qualify alternative methods for regulatory use
- Provide clear guidelines to external stakeholders developing alternative methods
- Fill information gaps with applied research to advance new policy and guidance development
Collaborations across a wide variety of external stakeholders—including federal partners, public-private partnerships, and international regulators—are vital to these efforts. Further details are available in a June 2022 presentation to the FDA Science Board Advancing Alternative Methods for Regulatory Use (PDF).
Qualification is a process that allows for an alternative method to be evaluated by FDA in advance for a specific context of use. The qualified context of use defines the boundaries within which the available data adequately justify use of the tool. The concept is similar to a drug or medical device’s indications for use.
What is a “specific context of use” for an alternative method?
The manner and purpose of use for an alternative method; the specific role and scope of an alternative method to address the question of interest. When FDA qualifies an alternative method, it is qualified for a specific context of use.
Product developers can then use the alternative method for the qualified context of use with confidence that it is an acceptable method. Current qualification programs at FDA include:
- Center for Drug Evaluation and Research (CDER) / Center for Biologics Evaluation and Research (CBER) Drug Development Tool (DDT) Qualification Programs
- Animal model qualification program
- Biomarker Qualification
- Clinical Outcome Assessment Qualification
- Innovative Science and Technology Approaches for New Drugs (ISTAND) Pilot Program
- Designed to expand drug development tool types, examples include, microphysiological systems to assess safety or efficacy questions, development of novel nonclinical pharmacology/toxicology assays
- Medical Device Development Tools (MDDT)
- Clinical Outcome Assessment
- Biomarker Test
- Nonclinical Assessment Model
- A nonclinical test model or method that measures or predicts device function or in vivo device performance. Examples include tools that can reduce or replace animal testing or reduce test duration or sample size.
As a recent example of a qualified alternative method, Center for Devices and Radiological Health (CDRH) qualified the CHemical RISk Calculator (CHRIS) - Color Additives tool in November 2022. You can find more information on the CHRIS non-clinical assessment model for toxicology, biocompatibility product areas here: https://www.fda.gov/media/163472/download
CDER and CBER accepted the first submission to the ISTAND Pilot Program in September 2022 for a tool that proposes to evaluate off-target protein binding for a variety of biotherapeutic modalities, potentially reducing or eliminating the need to conduct some of the more standard nonclinical toxicology tests. Read more here: CDER and CBER accept first submission to ISTAND Pilot Program
FDA guidance documents that reference alternative methods approaches are listed below, with the most recent first. For more information about FDA guidance documents, including a full listing, see Search for FDA Guidance Documents:
- Assessing the Credibility of Computational Modeling and Simulation in Medical Device Submissions, draft guidance, 2021 – Describes risk-based framework, including context of use examples, that can be used in the credibility assessment of computational modeling and simulation (CM&S) used in medical device regulatory submissions.
- S5(R3) Detection of Reproductive and Developmental Toxicity for Human Pharmaceuticals Guidance for Industry, 2021 – Description of testing strategies utilizing alternative assays for the assessment of malformations and embryofetal lethality, and the qualification process for these alternative assays.
- Oncology Pharmaceuticals: Reproductive Toxicity Testing and Labeling Recommendations Guidance for Industry, 2019 – Potential use of alternative assays, such as fit-for-purpose in vitro or ex vivo, or nonmammalian in vivo assays for assessment of reproductive toxicity.
- S3A Guidance: Note for Guidance on Toxicokinetics: The Assessment of Systemic Exposure in Toxicity Studies: Focus on Microsampling Questions and Answers Guidance for Industry, 2018 – Use of microsampling in toxicity studies.
- M7(R1) Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk Guidance for Industry, 2018 – Use of computational approaches for the assessment of mutagenic potential of drug impurities.
- S10 Photosafety Evaluation of Pharmaceuticals Guidance for Industry, 2015 – Use of in chemico and in vitro approaches to assess phototoxicity potential.
- Guidance for Industry: Pyrogen and Endotoxins Testing: Questions and Answers, 2012 – Discusses alternative assays to tests in the United States Pharmacopeia (USP) for a compendial article.
FDA also accepts alternative methods from Organisation for Economic Cooperation and Development (OECD) guidelines for some product types, examples include:
- OECD Test Guideline No. 437: Reconstructed human cornea-like epithelium model replaced rabbit tests for eye irritation for pharmaceuticals
- OECD Test Guideline No. 439: A 3D reconstructed human epidermis model is accepted for human pharmaceuticals, when warranted, to assess primary dermal irritation
FDA has launched multiple working groups to support specific components of our goal to advance alternative methods and reduce animal testing, including:
Alternative Methods Working Group
The FDA Alternative Methods Working Group was established in 2019 to further the goals of the FDA Predictive Toxicology Roadmap (more on this below) and is composed of senior reviewers and researchers from all centers and the Office of Regulatory Affairs (ORA). This group focuses on opportunities for evolving innovative technologies to advance useful tools, and new areas of science to support alternative methods to traditional toxicity and effectiveness evaluation that extend across FDA’s product areas. It also:
- Discusses FDA-wide new in vitro, in vivo, and in silico methods, including research, training, and communication
- Acts as a catalyst to foster the development and potential application of alternative systems, such as microphysiological systems, to support decision-making in regulatory toxicology
- Facilitates interactions with global regulatory bodies interested in implementing alternative methods in toxicology
- Examines opportunities and viable ways by which emerging methods and new technologies can support regulatory review of risk, safety, and efficacy of FDA-regulated products
- Identifies the performance criteria of microphysiological systems by engaging with FDA experts and FDA stakeholders through public-private partnerships.
The activities of FDA's Alternative Methods Working Group are informational and do not serve as official regulatory guidance.
Modeling and Simulation Working Group
Computational (computer) modeling and simulation are powerful tools that complement traditional methods for gathering evidence about FDA-regulated products or developing FDA policy. FDA scientists routinely review modeling and simulation results submitted by product sponsors and use modeling and simulation for scientific research and regulatory decision-making.
In 2016, to help disseminate information across different FDA product centers and collaborate on projects, FDA launched the Modeling and Simulation Working Group, bringing together the expertise of nearly 200 FDA scientists from across FDA. Key objectives of this working group include:
- Raising awareness about modeling and simulation to advance regulatory science for public health
- Fostering enhanced communication about modeling and simulation efforts among stakeholders
- Serving as a scientific resource on modeling and simulation and emerging technologies for FDA
- Collaborating with national and international organizations pursuing similar activities
- Promoting consistent review and decision-making with modeling and simulation across FDA
The activities of FDA's Modeling and Simulation Working Group are informational and do not serve as official regulatory guidance.
Toxicology Working Group
As part of efforts to advance alternative methods at FDA, the FDA Toxicology Working Group, published the FDA Predictive Toxicology Roadmap in 2017, describing FDA’s thoughts on viable ways to foster the development and evaluation of emerging toxicological methods and new technologies and incorporate them into FDA regulatory review.
This six-part framework outlines Agency priorities and engagement in predictive toxicology, emphasizes the importance of the context of use, and identifies toxicology issues related to FDA-regulated products. FDA’s Predictive Toxicology Roadmap also identifies the toxicology areas that could benefit from improved predictivity as well as promising new technologies that could potentially meet these needs and support the 3Rs.
The activities of FDA's Toxicology Working Group are informational and do not serve as official regulatory guidance.
Examples of FDA work to advance alternative methods include:
- Human organ chips for radiation countermeasure development - In an FDA-funded project, scientists are developing models of radiation damage in lung, gut, and bone marrow organs-on-chips and using these models to test medical countermeasures to treat such damage. This study was expanded to add development and evaluation of new organs-on-chips to aid development of countermeasures for COVID-19.
- CFSAN’s Work on Organ-Chip Technology - Beginning with a liver-chip, scientists in FDA’s Center for Food Safety and Applied Nutrition (CFSAN) will be evaluating the effectiveness of this technology to better understand the effects of chemicals in food on the human body.
- Strengthening coronavirus models with systems biology and machine learning - The scientific community currently uses several methods to evaluate nonclinical models in support of COVID-19 medical countermeasure development, including virus replication, histopathology, immunology data read-outs, and observation of clinical signs. The research performed during this project will help refine the methods to assess existing nonclinical models for SARS-CoV-2 and develop new models using novel approaches and technologies, which can ultimately support development and evaluation of medical countermeasures against COVID-19 as well pathogens that may emerge with pandemic potential.
- Three-Dimensional (3D) Cell Culture (Microphysiological) Platforms as Drug Development Tools - CDER researchers are investigating new alternative methods, including microphysiological (MPS) platforms, that can provide additional and sometimes more focused safety information, to expand upon the in vivo data submitted by drug sponsors in regulatory applications. Some of these platforms recreate 3D physiological settings in vitro that may enhance the understanding of both drug pharmacology and toxicology. Also see: Impact Story: Evaluating the Potential of Microengineered Human Cellular Systems to Predict Drug Effects in the Clinic
- CDRH's work on virtual population (ViP) models - A set of detailed high-resolution anatomical models created from magnetic resonance image data of volunteers. Since their inception, the ViP models have become the gold standard for in silico biophysical modeling applications. These models have been cited and used in over 600 premarket applications at CDRH.
- Expanding next-generation sequencing tools to support pandemic preparedness and response - FDA-ARGOS database updates may help researchers rapidly validate diagnostic tests and use qualified genetic sequences to support future product development. Researchers can use the FDA-ARGOS database—a validated source of reference datasets—along with bioinformatics tools to validate the performance, sensitivity, and specificity of diagnostic tests with computer modeling (in silico).
- Cross-Species Immune System Reference - In an FDA-funded project, researchers collected data on human and animal immune responses, and used this data to create species-specific immune function maps. They overlaid the maps to highlight differences and similarities and mapped immune responses to certain biothreat agents and possible medical countermeasures in humans and animal models.
- Alternative Methods for Evaluating Locally Acting, Non-systemically Absorbed Drugs in Canine Disintegrating or Chewable, Single Layer Combination Drug Products - This non-terminal research study is designed to gather data needed to support reducing or eliminating the use of dogs in certain studies that lead to the approval of medicines that are used to treat certain illnesses in dogs. The dogs involved in this study were retired for adoption into pet homes at the conclusion of the study.
- Centers of Excellence in Regulatory Science and Innovation (CERSI) Project – Leveraging Human Brain Organoids for Mixture Neurotoxicity and the Understanding of Individual Susceptibilities
National Center for Toxicological Research (NCTR) projects highlighted in NCTR 2022 Annual report. NCTR alternative methods-related projects include:
- Evaluating the developmental neurotoxicity of inorganic arsenic exposure in zebrafish for regulatory risk assessment
- Evaluation of drug toxicity on placenta immunity using a microphysiological human placental barrier model
- Advance microphysiological system based study of Zika virus infection in testes, viral transmission and antiviral countermeasures
- Evaluation of new alternative models of folliculogenesis for assessing drug/chemical toxicity
- Integrating pharmacokinetics and adverse effects data from the agency approval documents with the rule-of-two model to improve the assessment of hepatotoxicity risk
- Development of an artificially intelligent virtual pregnant woman modeling suite to support regulatory decisions
- Performance of 3D-bioprinted human skin equivalents for in vitro dermal absorption testing of FDA-regulated drugs and cosmetic ingredients used for dermal and transdermal applications
- Establishment of a liver-chip system to predict individual susceptibility and adaptation to drug-induced liver injury
- Examining ethnic and racial disparities in critical care delivery to heart failure patients with artificial intelligence and real-world data
- Comprehensive evaluation of drug-induced cardiotoxicity with induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs)
- Development of artificial intelligence methods for food safety
- Also, see the list of Publications Co-authored by FDA on Alternative Methods.
- How Simulation Can Transform Regulatory Pathways (FDA Grand Rounds lecture recording, August 2018)
- Virtual Family
- Catalog of Regulatory Science Tools to Help Assess New Medical Devices
- Regulatory Science Research Tools for Medical Countermeasure Development
- What are medical countermeasures?
- Animal Testing & Cosmetics