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Incorporating Alternative Approaches in Clinical Investigations for New Animal Drugs Public Meeting Materials

Incorporating Alternative Approaches in Clinical Investigations for New Animal Drugs Public Meeting Materials

The purpose of this public meeting is to facilitate discussion and obtain input from stakeholders about the use of complex adaptive and other novel investigation designs, data from foreign countries, real-world evidence, and biomarkers and surrogate endpoints in animal drug development and regulatory decision making.

The meeting is expected to include four sessions that focus on the following topics: (1) complex adaptive and other novel investigation designs; (2) data from foreign countries; (3) real-world evidence; and (4) biomarkers and surrogate endpoints. Within each session and following all sessions there will be an opportunity for public comment. You may also submit comments to the public docket. To facilitate the development of guidance on these topics, please consider the following questions. When responding please identify the topic and question in your response.

Topic 1: Complex adaptive and other novel investigation designs

  1. In September 2018, the FDA published draft Guidance for Industry: Adaptive Designs for Clinical Trials of Drugs and Biologics, which applies to human drugs and biologics. How should these apply to study designs for animal drugs? What are the potential study adaptation features that could be applied to animal drug investigations? What are the challenges and possible solutions to apply these adaptations to studies for animal drugs? To what type of studies for animal drugs would these study designs be most applicable?
  2. How does complex adaptive design differ from adaptive design? What constitutes other novel investigation designs? What examples are directly applicable to animal drug development?
  3. Are there partnerships that can be formed between the FDA and the regulated industry, academia, or other groups to facilitate the development or use of these novel investigational designs for animal drug development? What strategic work is needed to enable the regulated industry to make full use of these novel investigational designs for animal drug development? What methods are needed, such as the use of simulations or modeling, to facilitate the use of these novel investigational designs for animal drug development?

Topic 2: Data from foreign countries

For the purposes of this meeting, the FDA considers data from foreign countries to be data from investigations or studies conducted outside the United States (U.S.). The FDA can accept data from studies conducted outside the U.S. to support a new animal drug application, provided the applicant demonstrates that the data are adequate under applicable standards to support approval (Section 569B of the Food, Drug, and Cosmetic Act (21 U.S.C. 360bbb-8b)). The FDA can also accept data from studies conducted outside the U.S. to support a food additive petition. While the regulatory standards for approval differ between animal drugs and animal food additives, data from foreign countries can be used to support either approval if the data meet the appropriate regulatory standards.

  1. What challenges and potential solutions do you have in meeting the requirements of substantial evidence of effectiveness, as defined in 21 CFR 514.4, when using data from foreign countries for an animal drug?
  2. Typically in the U.S. when we wish to show a test drug is no worse than an active control, that active control is an approved animal drug in the U.S. A non-inferiority analysis is used to statistically demonstrate this relationship. In studies conducted outside the U.S., an active control may be used that is not approved for that use in the U.S. In the absence of a U.S. approval for the active control, the FDA cannot interpret non-inferiority to the unapproved active control. What challenges exist in utilizing these studies? What criteria should the FDA use to accept a study where the active control is not approved in the U.S.? What are potential options or solutions to enable the FDA to use these studies?
  3. What challenges exist in demonstrating that data from foreign countries were generated under conditions representative of typical conditions in the U.S. for an animal drug or food additive? What are potential solutions to these challenges?
  4. What challenges exist in designing studies for an animal drug or food additive to meet the approval requirements of different jurisdictions? What are possible solutions to these challenges?
  5. What challenges exist in study conduct and the collection and interpretability of data from foreign countries (both manual and electronic) that may influence study quality and data integrity to support the approval of an animal drug or food additive? What are possible solutions to these challenges?
  6. What other challenges have you encountered and what potential solutions would you propose with regard to providing data from foreign countries to the FDA?

Topic 3: Real-world evidence

There is significant activity within the Agency aimed at clarifying how to determine if real-world data (RWD) are sufficient to generate real-world evidence (RWE) that could be used for regulatory decision making by the FDA. In August 2017, the FDA published Guidance for Industry and Food and Drug Administration Staff: Use of Real-World Evidence to Support Regulatory Decision-Making for Medical Devices and, in accordance with the 21st Century Cures Act, released “A Framework for FDA’s Real-World Evidence Program” in December 2018 for human drug and biological products.

  1. How should the FDA define RWE for making regulatory decisions for animal drugs? What sources of RWD should the FDA consider to generate RWE for animal drugs?
  2. What challenges exist for the use of RWE for animal drug approvals? What are possible solutions to these challenges?
  3. In what contexts might RWD/RWE be used to generate clinical evidence for regulatory decision making for animal drugs?
  4. What factors should the FDA consider when evaluating RWE for animal drugs?

Topic 4: Biomarkers and surrogate endpoints

Biomarkers have long been a part of veterinary medicine. Examples include routine tests such as body temperature, heart rate, complete blood cell count and clinical chemistry, radiographs, and intraocular pressure. Numerous technological advancements have greatly increased the number of available biomarkers while reducing their cost. Unfortunately, many potential biomarkers are not validated for their use and interpretation in clinical investigations. The FDA’s Center for Drug Evaluation and Research (CDER) has a formal Biomarker Qualification Program, related guidance, and affiliated consortia to support the development and use of biomarkers in regulatory decision making for human drugs. The FDA is seeking stakeholder feedback on how to best support the identification and development of new biomarkers for new animal drug applications and on ways to better incorporate biomarkers and surrogate endpoints into animal drug development.

  1. What are the expectations of sponsors, researchers, veterinarians, and producers for the use of biomarkers in the context of animal drug regulation and how might biomarkers be used in addition to surrogate endpoints in the design and conduct of clinical studies?
  2. Biomarkers are commonly used for diagnosing disease to enroll patients, sample size estimations, and pilot/proof-of-concept studies. What information should be provided to the FDA to support their use in these contexts (e.g., analytical validation, clinical validation, establishing clinical utility, companion diagnostics etc.)?
  3. What are the major challenges in translating potential biomarkers and/or surrogate endpoints into practical tools in clinical trials? What are possible solutions to these challenges?
  4. How do we determine the evidentiary criteria for evaluating biomarker use?
  5. Should the FDA develop a biomarker qualification program like CDER’s? Would such a program be beneficial, and is it something that stakeholders (e.g., drug sponsors) would use? Are there other approaches to the development and acceptance of biomarkers for animal drugs?