United States Government Accountability Office Report to Congressional Committees PUBLIC HEALTH June 2022 PREPAREDNESS Medical Countermeasure Development for Certain Serious or Life-threatening Conditions GAO-22-105248 June 2022 PUBLIC HEALTH PREPAREDNESS Medical Countermeasure Development for Certain Serious or Life-threatening Conditions Highlights of GAO-22-105248, a report to congressional committees Why GAO Did This Study What GAO Found Past bioterrorist attacks, such as the The Department of Health and Human Services' (HHS) Food and Drug anthrax attacks of 2001, highlight the Administration (FDA) established the Animal Rule in 2002 to allow for the threat of widespread illness and death approval of medical countermeasures based on animal efficacy studies when posed by CBRN agents and the human clinical trials are not ethical or feasible. Medical countermeasures are importance of medical medical products that may be used to prevent, treat, or mitigate potential health countermeasures. GAO has previously effects of exposure to chemical, biological, radiological, and nuclear (CBRN) reported on the challenges of agents. GAO found that FDA has undertaken efforts to provide information and developing medical countermeasures. feedback to developers to support medical countermeasure development under Medical countermeasures may need to the Animal Rule. For example, in 2015 FDA issued guidance clarifying the types be developed and approved under of studies and data needed to demonstrate product efficacy. FDA has approved FDA's Animal Rule. 16 medical countermeasures under the Animal Rule, 14 of which were approved The Pandemic and All-Hazards over the past decade. Preparedness and Advancing Innovation Act of 2019 included a Research of Biological Agents in a Clinical Laboratory provision for GAO to review medical countermeasure development under the Animal Rule. In this report GAO describes (1) FDA efforts to support medical countermeasure developers under the Animal Rule, and (2) the extent of animal model qualification under FDA's Animal Model Qualification Program, and the effect of qualified models on medical countermeasure development. GAO reviewed FDA documentation, including agency medical countermeasure development guidance. GAO also interviewed or FDA established the Animal Model Qualification Program in 2011 to provide obtained written responses from FDA publicly available animal models to support efficacy testing under the Animal officials; other federal agencies Rule for multiple medical countermeasures for a given disease or condition. involved in medical countermeasure Researchers and developers can submit models to the program for qualification, development; and a nongeneralizable and, once qualified, a model can be used by other developers when appropriate. selection of six developers, three For example, an animal model for inhalation anthrax would include protocols, contract research organizations and such as exposure timing and dosage, to produce disease manifestations that four academic research and policy adequately reflect inhalation anthrax manifestations in humans. As of April 2022, organizations. GAO selected FDA has qualified one animal model under the program. FDA officials and many interviewees based on their developers GAO spoke with attributed the limited number of qualified models to a involvement in or knowledge of lack of an incentive to pursue qualification. Specifically, submitting a model for medical countermeasure development qualification is voluntary, and FDA officials said the qualification process is under the Animal Rule. rigorous and resource intensive, which may deter submissions. However, many HHS and the Department of Defense developers reported that the limited number of qualified animal models has not provided technical comments, which impeded product development, citing other ways to identify animal models that GAO incorporated as appropriate. can be used for product development. FDA officials and others that GAO spoke with, including some developers and contract research organizations, said the View GAO-22-105248. For more information, contact Mary Denigan-Macauley at (202) 512- program may still be beneficial. For example, FDA officials said the program 7114 or DeniganMacauleyM@gao.gov. could help further future development of medical countermeasures, particularly for CBRN agents that currently do not have approved medical countermeasures. United States Government Accountability Office Contents Letter 1 Background 5 FDA Efforts and Information Sharing with BARDA to Support Medical Countermeasure Developers under the Animal Rule 11 FDA Has Qualified One Animal Model, but FDA Officials and Stakeholders Said Medical Countermeasure Development Has Not Been Impeded by Lack of Qualified Models 18 Agency Comments 21 Appendix I Interview Selection Methodology 23 Appendix II GAO Contact and Staff Acknowledgments 25 Table Table 1: Products Approved by FDA under the Animal Rule as of April 2022 9 Figures Figure 1: Responsibilities for Medical Countermeasure Development, by HHS Office or Agency 7 Figure 2: FDA Animal Rule Product Approvals by Year 13 Figure 3: Challenges Inherent to Developing Medical Countermeasures under the Animal Rule 15 Page i GAO-22-105248 FDA Animal Rule Abbreviations ASPR Office of the Assistant Secretary for Preparedness and Response BARDA Biomedical Advanced Research and Development Authority CBRN chemical, biological, radiological, and nuclear DOD Department of Defense FDA Food and Drug Administration HHS Department of Health and Human Services NIH National Institutes of Health This is a work of the U.S. government and is not subject to copyright protection in the United States. The published product may be reproduced and distributed in its entirety without further permission from GAO. However, because this work may contain copyrighted images or other material, permission from the copyright holder may be necessary if you wish to reproduce this material separately. Page ii GAO-22-105248 FDA Animal Rule Letter 441 G St. N.W. Washington, DC 20548 June 16, 2022 The Honorable Patty Murray Chair The Honorable Richard Burr Ranking Member Committee on Health, Education, Labor and Pensions United States Senate The Honorable Frank Pallone, Jr. Chair The Honorable Cathy McMorris Rodgers Republican Leader Committee on Energy and Commerce House of Representatives Recent experiences with emerging infectious diseases as well as concerns regarding past bioterrorist attacks, such as the anthrax attacks of 2001, highlight the threat of widespread illness and death posed by chemical, biological, radiological, and nuclear (CBRN) agents. 1 These threats underscore the importance of medical countermeasures-medical products, including drugs and biologics such as vaccines-that may be used to treat, prevent, or mitigate potential health effects of exposure to CBRN agents. Medical countermeasure development can be a lengthy, complex, and expensive process. We have previously reported on the challenges and extensive resources required to research, develop, and seek marketing approval for such products. 2 The Department of Health and Human Services' (HHS) Food and Drug Administration (FDA) typically grants marketing approval for drugs and biologics based on human clinical trials that demonstrate the products are 1InSeptember and October 2001, letters laced with anthrax were mailed through the U.S. postal system to two U.S. senators and members of the media. 2See GAO, Public Health Preparedness: HHS Has Taken Some Steps to Implement New Authority to Speed Medical Countermeasure Innovation, GAO-20-601R (Washington, D.C.: July 29, 2020) and National Preparedness: HHS Is Monitoring the Progress of Its Medical Countermeasure Efforts but Has Not Provided Previously Recommended Spending Estimates, GAO-14-90 (Washington, D.C.: Dec. 27, 2013). Page 1 GAO-22-105248 FDA Animal Rule safe and effective for their intended use. 3 However, it would be unethical or infeasible to conduct human clinical trials when developing certain medical countermeasures. For example, it would be unethical to expose healthy individuals to harmful CBRN agents, such as cyanide, to conduct human clinical trials for products that treat the disease or condition associated with the CBRN exposure. For such medical countermeasures, FDA issued regulations commonly known as the Animal Rule in 2002. This Rule generally allows FDA to approve a medical countermeasure for serious or life-threatening conditions based on evidence from animal efficacy studies-studies that measure the effectiveness of a product in preventing or treating a condition-if the product is reasonably likely to produce a clinical benefit in humans. 4 In part due to the complexities and challenges of developing medical countermeasures under the Animal Rule, both FDA and HHS's Biomedical Advanced Research and Development Authority (BARDA) support and advise medical countermeasure product developers (hereafter referred to as developers). For example, FDA often provides feedback to developers developing products under the Animal Rule to help ensure that their animal efficacy studies generate sufficient evidence to support approval under the Animal Rule. BARDA, which funds and helps oversee the advanced research and development of certain medical countermeasures, also advises developers working on products 3See 21 U.S.C. § 355(b) (drugs) and 42 U.S.C. § 262(a) (biologics). See also 21 C.F.R. Part 312, Subpart B (investigational new drug applications); § 314.50 (new drug applications); and § 601.2 (biologics license applications) (2021). Drugs are chemically synthesized, while biologics-which include vaccines, blood products, and proteins, among other things-are derived from living sources such as humans, animals, and microorganisms. FDA approves drugs that are safe and effective and licenses biologics that are "safe, pure, and potent," which is widely interpreted to mean safe and effective. For the purposes of this report, we use the term "approve" for both drugs and biologics. 4See 67 Fed. Reg. 37988 (May 31, 2002) (codified at 21 C.F.R. Parts 314, Subpart I, and 601, Subpart H (2021)). Only drugs and biologics can be approved under the Animal Rule. Other medical products regulated by FDA, such as medical devices, cannot be approved under the Animal Rule. In order for a product to be approved under the Animal Rule, its safety must be established in humans. While the Animal Rule has predominantly been used for the development of medical countermeasures to address potential public health emergencies, the Animal Rule is not exclusive to medical countermeasures and could be used for other products, such as antitoxins for snake bites, in which human clinical trials may not be ethical or feasible. While preliminary product studies that explore the potential of a product to have the desired effect are often performed in animals as part of early product development to help provide a basis to proceed to clinical trials in humans, the Animal Rule allows FDA to grant approval for products for use in humans based on animal efficacy studies. Page 2 GAO-22-105248 FDA Animal Rule under the Animal Rule. This includes providing feedback on navigating FDA regulatory processes. FDA also established the Animal Model Qualification Program in 2011 to help facilitate medical countermeasure development under the Animal Rule. The program is intended to provide publicly available information on potentially useful animal models for developers to use during product development and when seeking marketing approval. Animal efficacy studies use animal models-a specific combination of an animal species, specified CBRN agent, and the manner of the agent's exposure in the animal-that reflect key elements of the human experiences with the disease or condition associated with the CBRN exposure. For example, an animal model for inhalation anthrax would include protocols for the timing, delivery method, and dosage of exposure to produce disease manifestations in an animal species that adequately reflect key elements of the disease manifestations of inhalation anthrax in humans. 5 A single, qualified animal model may be used to develop multiple medical countermeasures for a single condition caused by a CBRN agent, potentially streamlining medical countermeasure development. 6 The program is also intended to help developers reduce redundancy and conserve resources. The Pandemic and All-Hazards Preparedness and Advancing Innovation Act of 2019 includes a provision for us to review and report on medical countermeasure development under the Animal Rule. 7 In this report we describe 1. FDA efforts and information sharing with BARDA to support medical countermeasure developers under the Animal Rule; and 2. the extent to which FDA has qualified animal models under the Animal Model Qualification Program and the effect, if any, of these models on medical countermeasure development under the Animal Rule. To answer these objectives, we reviewed agency documentation, including FDA product development guidance, meeting minutes, advisory 5Exposure to the CBRN agent Bacillus anthracis causes the condition of inhalation anthrax. 6For the purposes of this report, we use "qualified model" to refer to an animal model qualified through the Animal Model Qualification Program. 7Pub. L. No. 116-22, § 604, 133 Stat. 905, 957-58. Page 3 GAO-22-105248 FDA Animal Rule committee proceedings, and product approval documentation for products approved under the Animal Rule, and a BARDA contract with a product developer. 8 We also reviewed articles published from 2009 through 2021 on animal models and animal efficacy studies for products approved under the Animal Rule. We interviewed officials from FDA and BARDA, along with other stakeholders. Specifically, we interviewed officials or obtained written responses from the National Institutes of Health (NIH) and the Department of Defense (DOD); six of 10 developers that have had a product approved under the Animal Rule since 2012; three clinical contract research organizations that have conducted animal efficacy studies for approved Animal Rule products; and four academic research and policy organizations with knowledge of medical countermeasure development under the Animal Rule. 9 Among the four remaining developers we were unable to interview, two declined to speak with us, citing issues identifying staff with relevant institutional knowledge, and two were acquired by other companies. 10 We selected the other stakeholders to interview based on their involvement in or knowledge of medical countermeasure development under the Animal Rule (for additional information on our interview selection, see app. I). What we found through our interviews with developers, contract research organizations, and academic research and policy organizations is not generalizable to all such developers and organizations; however, the interviews provide insight into the development of animal models and medical countermeasures under the Animal Rule. 8Advisory committees provide independent advice and recommendations to FDA on scientific and technical matters related to the development and evaluation of products regulated by the agency. 9NIH's National Institute of Allergy and Infectious Diseases, along with DOD's Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense and Defense Threat Reduction Agency are involved in and have conducted medical countermeasure research and product development related to the Animal Rule, including having conducted work to develop animal models for CBRN agents. We obtained written responses from NIH and one developer. 10We focused our interviews on developers that developed medical countermeasures after implementation of the Animal Rule. Two medical countermeasures, pyridostigmine bromide and Cyanokit, were approved under the Animal Rule prior to 2012 but had been developed before the Animal Rule's implementation. Pyridostigmine bromide was used during the Persian Gulf War in 1990 and 1991 as a pretreatment for nerve agents, and the active pharmaceutical ingredient in Cyanokit received marketing approval in France in 1996 for cyanide exposure. Page 4 GAO-22-105248 FDA Animal Rule As part of our work, we examined FDA and BARDA efforts to share information to help develop medical countermeasures under the Animal Rule in the context of federal internal control standards. 11 We determined that the information and communication component was significant to our objective, including the underlying principle that management should externally communicate necessary information to achieve the agency's objectives. We conducted this performance audit from May 2021 to June 2022 in accordance with generally accepted government auditing standards. Those standards require that we plan and perform the audit to obtain sufficient, appropriate evidence to provide a reasonable basis for our findings and conclusions based on our audit objectives. We believe that the evidence obtained provides a reasonable basis for our findings and conclusions based on our audit objectives. Background HHS Offices and Agencies HHS offices and agencies are responsible for helping to develop and Involved with Medical oversee medical countermeasures to address CBRN threats. This responsibility involves a range of activities, from prioritizing and Countermeasure supporting the development of medical countermeasures to addressing Development under the identified CBRN threats, reviewing and granting marketing approval for Animal Rule medical countermeasures, and stockpiling medical countermeasures for use in public health emergencies. In January 2022, we placed HHS's leadership and coordination of public health emergencies on our high risk list in part due to concerns related to the stockpiling and management of medical countermeasures. 12 HHS offices and agencies support the development of medical countermeasures to address CBRN threats in part by engaging with and providing research and development support to developers. Several offices and agencies within HHS have specific responsibilities for public health preparedness and response activities related to furthering the 11Internalcontrol is a process effected by an entity's oversight body, management, and other personnel that provides reasonable assurance that the objectives of an entity will be achieved. GAO, Standards for Internal Control in the Federal Government, GAO-14-704G (Washington, D.C.: Sept. 10, 2014). 12GAO, COVID-19: Significant Improvements Are Needed for Overseeing Relief Funds and Leading Responses to Public Health Emergencies, GAO-22-105291 (Washington, D.C.: Jan. 27, 2022). Page 5 GAO-22-105248 FDA Animal Rule development of medical countermeasures, including those developed under the Animal Rule (see fig. 1). • The Office of the Assistant Secretary for Preparedness and Response (ASPR). This office leads the federal medical and public health response to public health emergencies, including prioritizing medical countermeasures for development. 13 • NIH. This agency conducts and funds early development research that can be used for medical countermeasure development. For example, NIH conducts research to better understand CBRN agents and human and animal responses to the agents. NIH's National Institute of Allergy and Infectious Diseases supports the development of animal models that can be used for medical countermeasure development. • BARDA. As a component of ASPR, BARDA oversees the advanced research and development of certain medical countermeasures for CBRN threats. BARDA contracts with and funds the work of developers developing products under the Animal Rule and often provides product development feedback based on BARDA officials' product development and regulatory expertise. In addition, BARDA contracts with clinical contract research organizations that provide technical support for developers. BARDA also works with contract research organizations to develop animal models that can be used to help develop medical countermeasures under the Animal Rule. These contract research organizations have specialized laboratory facilities and trained staff to execute animal efficacy studies under the Animal Rule. While BARDA provides financial and technical support to developers, BARDA does not have any regulatory authority to approve medical countermeasures for marketing in the United States. 14 • FDA. As part of its overall role to assess the safety and effectiveness of medical products, this agency ensures and assesses the safety and effectiveness of medical countermeasures by regulating their development, granting marketing approval, and conducting postmarket surveillance. FDA also provides technical assistance to 13ASPR is also responsible for managing the Strategic National Stockpile, the repository for drugs, biologics, medical devices, and other supplies, for use in a bioterrorist attack or other public health emergency. 14Although a component within ASPR, we refer to BARDA as an agency throughout this report. Page 6 GAO-22-105248 FDA Animal Rule developers to help ensure that their product development meets FDA's regulatory requirements and supports the development of product development tools, such as animal models that can be used to develop products under the Animal Rule. 15 Figure 1: Highlighted Responsibilities for Medical Countermeasure Development, by HHS Office or Agency FDA Review and Approval The Animal Rule includes four key requirements that must be met for of Medical FDA to approve a product under the Animal Rule. Countermeasures under the Animal Rule 15These HHS offices and agencies, along with other federal agencies and departments, such as DOD, are partners in HHS's federal interagency decision-making body, the Public Health Emergency Medical Countermeasures Enterprise, which, among other responsibilities, provides recommendations to the Secretary of Health and Human Services regarding CBRN medical countermeasure research, development, and procurement. See 42 U.S.C. § 300hh-10a. Page 7 GAO-22-105248 FDA Animal Rule 1. The mechanism of toxicity of the CBRN agent (i.e., how it causes the disease or condition) and the product's mechanism of action (i.e., how the product produces its effect to prevent or treat the disease or condition caused by the CBRN agent) are reasonably well understood. FDA Human Clinical Trials 2. The product's effect is demonstrated using animal models for more than one animal species expected to react with a response that is predictive for humans (unless the effect is demonstrated in a single animal species that represents a sufficiently well-characterized animal model for predicting the response in humans). 16 3. The animal study outcome is clearly related to a desired benefit in humans, such as in the enhancement of survival. 4. The data or information allows for the selection of an effective dose in humans. 17 Typically, before drug developers may apply to FDA for approval to market a drug or There are several additional requirements a medical countermeasure biologic in the United States, they must must meet to obtain approval under the Animal Rule, including that conduct human clinical trials to test the safety and efficacy of their products. Generally, in medical countermeasures developed under the Animal Rule need to clinical trials, one group of trial participants- demonstrate that they are safe for their intended human use. 18 The the experimental group-is given the product, while a separate control group does not Animal Rule also requires developers to submit plans for conducting receive the product. The clinical trials follow a human studies after product approval, in the event that individuals are typical series from early, small-scale studies exposed to the CBRN agent and develop associated conditions that the to late-stage, large-scale studies. The data and outcomes associated with the product is intended to prevent or treat. The purpose of these human experimental and control groups are studies is to verify the medical countermeasure's safety and effectiveness compared with one another to determine whether the product achieves its intended effect, and to assess any potential safety risks. Source: Food and Drug Administration (FDA) (information, photo). | GAO-22-105248 16A "sufficiently well-characterized animal model" means the model has been adequately evaluated for its responsiveness for predicting and reflecting the key elements of the human experiences with the disease or condition associated with the CBRN exposure. 17In assessing the sufficiency of animal data for product approval, FDA may also take into account other data, including human data, available to the agency. For example, some products developed under the Animal Rule had been previously approved for other, relevant non-countermeasure indications and had available relevant data from prior human clinical trials. 18There are no product safety requirements particular to the Animal Rule. Developers seeking product approval under the Animal Rule need to provide appropriate safety data and information similar to drugs and biologics developed outside the Animal Rule, such as data from human clinical trials. Page 8 GAO-22-105248 FDA Animal Rule when used in humans who have been exposed to the CBRN agent, when such studies are feasible and ethical. 19 As of April 2022, FDA had approved 16 medical countermeasures under the Animal Rule. See table 1. Table 1: Products Approved by FDA under the Animal Rule as of April 2022 Product (proprietary FDA approval BARDA- name) Developera Indicationb year funded Pyridostigmine bromide U.S. Army Soman nerve agent 2003 Noc poisoning Cyanokit EMD Pharmaceuticals Cyanide poisoning 2006 Noc Levaquin Janssen Plague 2012 No Raxibacumab Human Genome Sciences Anthrax 2012 Yes BAT Cangene Botulism 2013 Yes Cipro Bayer Healthcare Pharmaceuticals Plague 2015 No Anthrasil Cangene Anthrax 2015 Yes Neupogen Amgen Acute radiation 2015 Yes exposure Avelox Bayer Healthcare Pharmaceuticals Plague 2015 No Neulasta Amgen Acute radiation 2015 Yes exposure BioThrax Emergent BioSolutions Anthrax 2015 Yes Anthim Elusys Therapeutics Anthrax 2016 Yes Leukine Sanofi-Aventis Acute radiation 2018 Yes exposure TPOXX SIGA Technologies Smallpox 2018 Yes Nplate Amgen Acute radiation 2021 Yes exposure Tembexa Chimerix Smallpox 2021 Yes Source: GAO analysis of Food and Drug Administration (FDA) and Biomedical Advanced Research and Development Authority (BARDA) documentation. | GAO-22-105248 a Refers to the original entity that submitted the medical countermeasure for FDA approval under the Animal Rule. For several products, the developer listed has since been acquired by another company or has transferred the rights to the product to another company. b The indication generally describes the disease, condition, or symptoms that the product is intended to treat, prevent, or mitigate. The indications listed in the table are abbreviated references to more specific and detailed indications. 19Inaddition, products approved under the Animal Rule are required to include patient labeling that explains product approval was based on efficacy studies conducted in animals alone, and products may also be subject to postmarketing restrictions to ensure safe use. See 21 C.F.R. §§ 314.610(b)(2) and (3) and 601.91(b)(2) and (3) (2021). Page 9 GAO-22-105248 FDA Animal Rule c Products approved by FDA prior to BARDA's establishment in December 2006. Animal Model Qualification FDA established the Animal Model Qualification Program to provide Program publicly available animal models to support efficacy testing for multiple products under the Animal Rule for a given disease or condition caused by a CBRN exposure. 20 Under the program, FDA may qualify an animal model for a specific context of use if the agency determines that the model reflects key elements of the human experiences with the relevant disease or condition associated with the CBRN exposure and is appropriate for use in animal efficacy studies. For example, if FDA qualified a particular animal model for the treatment of pneumonic plague through the Animal Model Qualification Program, developers could use the qualified model to develop and test multiple medical countermeasures for pneumonic plague under the Animal Rule instead of developing their own models, if the model was appropriate for use in testing the specific medical countermeasures. When a developer uses a qualified animal model within its stated context of use, FDA does not have to reevaluate the appropriateness of the model as a model of key elements of the human disease or condition, but it will still need to evaluate the model for its appropriate use with the product. For example, if a developer working on a pneumonic plague product uses a qualified animal model within its stated context of use, FDA would not have to reevaluate the appropriateness of the model's use in efficacy studies for the product. Other federal agencies involved in developing animal models, such as NIH, BARDA, or DOD, along with academic researchers and developers, can submit models for qualification under the Animal Model Qualification Program. While developers need to use animal models that are expected to be predictive for humans for their animal efficacy studies to have their products approved, submitting a model for qualification under the Animal Model Qualification Program is voluntary-the use of a qualified model is not needed to obtain product approval under the Animal Rule. 21 20Information on qualified animal models is available on FDA's website. See Food and Drug Administration, CDER & CBER Drug Development Tool Qualification Project Search, accessed April 25, 2022, https://fda.force.com/ddt/s/. 21FDA officials told us they do not have any staff solely dedicated to the Animal Model Qualification Program and do not have funding data specific to the program. Page 10 GAO-22-105248 FDA Animal Rule FDA Efforts and Information Sharing with BARDA to Support Medical Countermeasure Developers under the Animal Rule FDA Support for Medical Based on our review of agency documentation and interviews with Countermeasure agency officials and stakeholders, we found that FDA undertook efforts to support the development of products under the Animal Rule. These Developers under the efforts included issuing clarifying guidance and sharing other information Animal Rule to help developers through the approval process. NIH and DOD officials, developers, clinical research organizations, and academic research and policy organizations we interviewed told us that these efforts helped further the development of medical countermeasures. In particular, these stakeholders said that the following FDA practices helped further the development of medical countermeasures under the Animal Rule. • Ongoing engagement and feedback. Many developers and academic research and policy organizations reported that FDA had constructive, ongoing communication with developers to provide input and feedback on animal models, animal efficacy study designs, and preliminary results. For example, one developer noted that FDA helped identify the appropriate animal models to use for its product efficacy studies and provided input on the dosing protocols for the CBRN agent. FDA officials noted that early engagement with developers to obtain consensus on animal models is particularly important before initiating the animal efficacy studies. • FDA advisory committee meetings. Many developers, contract research organizations, and a policy organization cited FDA advisory committee meetings as helpful in furthering medical countermeasure development. These stakeholders told us the meetings helped bring forward useful external expert perspectives and helped to generate consensus on animal efficacy study designs. For example, one developer noted that an advisory committee helped generate scientific consensus on relevant animal models to use for animal efficacy studies for a given CBRN agent. Page 11 GAO-22-105248 FDA Animal Rule Some stakeholders attributed recent positive experiences with medical countermeasure development under the Animal Rule in part to FDA addressing challenges in the years after the Animal Rule's implementation in 2002. According to BARDA and DOD officials, developers, and academic research and policy organizations, during the early years of the Animal Rule's implementation, there was limited data and information on how to best use animal studies to demonstrate efficacy. According to these stakeholders, FDA's initial expectations for conducting studies were not clear. In addition, these stakeholders explained that, because few products had yet been approved under the Animal Rule, there were limited precedents regarding the level of data and information required by FDA to demonstrate efficacy for approval. FDA, BARDA, and DOD officials, developers, and academic research and policy organizations generally described the initial challenges with the Animal Rule as early program "growing pains." These stakeholders told us that, over the past decade as FDA approved more medical countermeasures under the Animal Rule, the agency clarified the types and nature of animal efficacy studies and data needed to demonstrate efficacy under the Animal Rule (see fig. 2). In particular, the approvals established precedents that clarified product approval requirements and helped guide later development. For example, one developer we spoke with noted that it used product approval information from a previously approved medical countermeasure to inform its approach to seeking product approval for its product. Page 12 GAO-22-105248 FDA Animal Rule Figure 2: FDA Animal Rule Product Approvals by Year In addition, NIH and DOD officials and a developer told us FDA guidance issued in 2015 on the Animal Rule helped better define the agency's expectations for conducting animal efficacy studies under the Rule. 22 To help ensure developers understand how to meet the Animal Rule's requirements, the guidance describes the essential elements of an appropriate animal model and animal efficacy study design considerations for generating sufficient evidence of product efficacy, and includes product review checklists for developers. 23 DOD officials noted that additional CBRN-specific guidance has also helped provide clarity on FDA's expectations. For example, FDA issued guidance on developing products under the Animal Rule for the treatment or prevention of 22Food and Drug Administration, Product Development under the Animal Rule Guidance for Industry (Silver Spring, Md: Oct. 2015). FDA previously issued draft guidance for developing medical countermeasures under the Animal Rule in 2009. We reported in 2011 that medical countermeasure developers faced difficulty in applying the draft guidance, which presented challenges for product development. See GAO, Public Health Preparedness: Developing and Acquiring Medical Countermeasures against Chemical, Biological, Radiological, and Nuclear Agents, GAO-11-567T (Washington, D.C.: Apr. 13, 2011). 23The guidance also provides information on FDA's expectations about human safety data, among other additional regulatory considerations. Page 13 GAO-22-105248 FDA Animal Rule smallpox, which, among other things, provides information on smallpox animal models and smallpox-specific considerations for conducting animal efficacy studies. 24 Anthrax NIH officials, several developers, and several contract research The Food and Drug Administration has organizations, also cited the development of animal models for approved medical countermeasures conducting animal efficacy studies under the Animal Rule as having developed under the Animal Rule for anthrax. Anthrax is a disease caused by bacteria further aided the development of medical countermeasures. According to known as Bacillus anthracis that can lead to these stakeholders, early after implementation of the Animal Rule, few severe illness in humans. Bacillus anthracis is found naturally in soil, though it can also be animal models that could support medical countermeasure research and used as a biological weapon. In 2001, development had been developed. Since then, federal agencies, contract powdered Bacillus anthracis spores were research organizations, and developers have invested resources in and mailed through the U.S. postal system, leading to five deaths and illness in 17 others. worked to study and develop many animal models that have supported medical countermeasure product development. For example, according to NIH officials, there are now small animal and non-human primate animal models that are considered relevant and appropriate for studying a wide range of conditions stemming from CBRN agents, including anthrax, smallpox, plague, tularemia, and conditions associated with acute radiation exposure. (See sidebar for information about anthrax.) DOD officials, a developer, and an academic research organization noted that it may be more difficult to develop and obtain FDA approval for certain medical countermeasures because of differences in how the products are developed or used. (See fig. 3 for information on the challenges developing medical countermeasures under the Animal Rule.) Letter sent to a U.S. Senator during the 2001 In particular, they noted that preventive products, such as vaccines, may anthrax attacks. Source: Centers for Disease Control and Prevention be more difficult to develop. Such products often involve demonstrating (information), Federal Bureau of Investigation (photo). | GAO-22-105248 that animal immune responses reflect expected human immune responses, which these stakeholders said may involve greater complexity than demonstrating the efficacy of treatments. In addition, FDA and DOD officials noted that developers of medical countermeasures for prevention and prophylaxis (pretreatment) may have to provide greater evidence of product safety for approval under the Animal Rule. In particular, these products are subject to a different risk-benefit analysis since they would be given to healthy individuals and those not experiencing symptoms 24Food and Drug Administration, Smallpox (Variola Virus) Infection: Developing Drugs for Treatment or Prevention Guidance for Industry (Silver Spring, Md: Nov. 2019). Other FDA guidance documents for developing products under the Animal Rule include Food and Drug Administration, Guidance for Industry, Internal Radioactive Contamination - Development of Decorporation Agents (Rockville, Md: Mar. 2006) and Anthrax: Developing Drugs for Prophylaxis of Inhalational Anthrax Guidance for Industry, (Silver Spring, Md: May 2018). FDA plans to issue additional guidance in 2022 on developing medical countermeasures for acute radiation syndrome under the Animal Rule. Page 14 GAO-22-105248 FDA Animal Rule from CBRN exposures, as opposed to treatments given to those actively experiencing symptoms. Figure 3: Challenges Inherent to Developing Medical Countermeasures under the Animal Rule Page 15 GAO-22-105248 FDA Animal Rule FDA and BARDA FDA and BARDA efforts to better share information between one another Information Sharing to have helped support developers under the Animal Rule, according to agency officials and some stakeholders. 25 Because both agencies are Support Medical providing feedback to developers, it is important that the agencies have a Countermeasure shared understanding of the relevant information and issues affecting Developers product development to avoid providing conflicting or misaligned feedback. According to FDA and BARDA officials and a policy research organization, in the initial years after implementation of the Animal Rule in 2002, the agencies did not always provide aligned feedback to developers. They attributed this in part to the previously noted early lack of clarity regarding FDA's expectations for product approval. However, FDA, BARDA, DOD, and NIH officials; developers; clinical research organizations; and academic research and policy organizations cited steps that the agencies took to improve their information sharing efforts and processes for supporting developers, including the following: 26 Sharing FDA feedback with BARDA. To help ensure FDA and BARDA have a consistent shared understanding of developers' issues, BARDA officials said that the agency's contracts with developers were updated in 2010 to include provisions that require developers to share all of the developers' communications with FDA with BARDA officials. Previously, developers were not required to update BARDA officials on FDA's feedback, and FDA officials told us developers did not always fully or accurately relay FDA's feedback to BARDA officials. However, BARDA officials said that, beginning in 2010, their contracts have specified that developers are required to provide BARDA with information about scheduled meetings with FDA and minutes from formal and informal meetings with FDA. BARDA is also able to review all developer materials before submission to FDA under the updated contracts. Several developers told us they found BARDA's feedback on their FDA submission materials relevant and helpful in preparing for interactions with FDA. For example, one developer noted that BARDA officials helped prepare submission data according to FDA preferences. FDA officials said that they encourage 25FDA can share certain information with BARDA under the ASPR-FDA Memorandum of Understanding. See Food and Drug Administration, Memorandum of Understanding Between Food and Drug Administration and Office of the Assistant Secretary for Preparedness and Response (Apr. 16, 2019), accessed June 6, 2022, https://www.fda.gov/about-fda/domestic-mous/mou-225-19-013. 26We determined that FDA and BARDA information sharing practices were generally consistent with the information and communication component of federal internal control standards. See GAO-14-704G. Page 16 GAO-22-105248 FDA Animal Rule product sponsors to practice full transparency with relevant federal agencies. • BARDA attendance at meetings between medical Ebola Virus countermeasure developers and FDA. A couple of developers Ebola virus disease is highly lethal and can noted that having BARDA officials attend developer meetings with cause illness and death in humans from FDA has helped ensure that BARDA officials receive information on severe hemorrhagic fever. Case fatality rates FDA's feedback and that all parties hear FDA's expectations. For average 50 percent and can reach 90 percent. People can contract Ebola virus example, one developer told us BARDA officials attended meetings disease through direct contact with wild the developer had with FDA to listen to the discussions and remain animals, a sick or dead person infected with aware of any updates. One academic research and policy the Ebola virus, or through contact with contaminated surfaces and materials. organization said that BARDA is generally involved with meetings From 2014 through 2016, there was an Ebola between developers and FDA to help ensure developers receive virus disease outbreak in West Africa. Eleven consistent feedback from both agencies. people, mostly medical workers who became ill in West Africa, were treated for the disease • BARDA participation in FDA advisory committee meetings. in the U.S. Another outbreak occurred in the Democratic Republic of the Congo from 2018 Developers, contract research organizations, and an academic through 2020. research and policy organization noted that FDA advisory committee The Food and Drug Administration (FDA) has meetings have helped establish a better shared understanding of approved two treatments and a vaccine for relevant research and issues, and have helped identify the Ebola. Early product studies were conducted under FDA's Animal Rule, which allows the appropriate animal models for animal efficacy studies. BARDA agency to approve products based on officials attended and have presented at several advisory committee evidence from animal efficacy studies when it would be unethical or infeasible to conduct meetings held by FDA. For example, in 2011 and 2013 respectively, human clinical trials. However, the outbreaks subject matter experts from BARDA presented at FDA advisory in West Africa and the Democratic Republic of committee meetings about the development of medical the Congo allowed for human clinical trials to demonstrate the effectiveness of the Ebola countermeasures to treat smallpox and the approval of Botulism products. Antitoxin Heptavalent, a medical countermeasure for the treatment of botulism. • Interagency working groups. FDA, DOD, and NIH officials cited interagency meetings and working groups as helping with efforts to share and disseminate information about animal models and medical countermeasure development. For example, DOD and NIH agency officials told us that an interagency working group focused on medical countermeasure development for filoviruses, such as Ebola virus disease, has served as a helpful forum for sharing information about filovirus animal models. 27 (See sidebar for information about Ebola A view of a bleeding intravenous site of a patient infected with Ebola virus. virus disease.) Source: FDA (information), Centers for Disease Control and Prevention (information, photo), World Health Organization • Hosting interagency medical countermeasure development (information). | GAO-22-105248 workshops. A few developers, a contract research organization, and an academic research organization cited public interagency workshops hosted by FDA, BARDA, and NIH focused on various 27Filoviruses, including the Ebola and Marburg viruses, can cause illness and death in humans from severe hemorrhagic fever. Page 17 GAO-22-105248 FDA Animal Rule CBRN agents as helpful in obtaining perspectives from subject matter experts involved in medical countermeasure development and for sharing information about the logistical challenges with animal model research. For example, FDA and BARDA officials participated in a 2017 NIH workshop on the ability to repurpose existing products as medical countermeasures for conditions stemming from acute radiation exposure. One contract research organization said that workshops helped further the development of medical countermeasures for anthrax. 28 (See sidebar for information about anthrax.) One developer also noted that the ability to hold informal discussions with FDA officials during interagency workshops helped clarify the agency's guidance and regulatory expectations. FDA Has Qualified One Animal Model, but FDA Officials and Stakeholders Said Medical Countermeasure Development Has Not Been Impeded by Lack of Qualified Models FDA Has Qualified One Our review of FDA documentation shows that, since FDA's establishment Animal Model Since 2011 of the Animal Model Qualification Program in 2011, the agency has qualified one animal model. According to FDA, DOD, and NIH officials and several developers, a variety of reasons have contributed to the limited number of qualified models, including the investment of time and resources needed to submit the necessary information for qualification. According to FDA officials, since the program's inception in 2011, the agency had accepted 11 animal model submissions, with the majority submitted between 2011 and 2014. FDA officials told us the majority of 28For example, FDA and BARDA hosted a workshop in November 2007, and FDA presented at a workshop in July 2011 on the development of medical countermeasures for anthrax. Page 18 GAO-22-105248 FDA Animal Rule these were submitted by federal agencies involved in animal model development, including NIH, BARDA, and DOD, and two were submitted Tularemia by academic researchers. FDA had qualified one of the 11 submissions The Food and Drug Administration has qualified an animal model under the Animal as of April 2022-a cynomolgus macaque model for pneumonic tularemia Model Qualification Program to help develop developed by NIH that FDA qualified in October 2021. 29 (See sidebar for products for tularemia. Tularemia is an infectious disease caused by the bacteria information about tularemia.) Francisella tularensis. Found widely in nature in animals, it could be isolated and used for FDA officials told us they had not qualified the other 10 submissions for bioterrorism, likely by being made airborne for exposure by inhalation. various reasons. One submission is currently under review by FDA for People who inhale dust or aerosols qualification, while the other nine had not progressed to the qualification contaminated with Francisella. tularensis stage. FDA officials told us that several submissions included only basic bacteria could experience sudden fever, chills, headaches, muscle aches, joint pain, and descriptions of the animal models and lacked additional supporting progressive weakness and, if left untreated, information, such as proposed animal model data collection and analysis may experience severe respiratory illness, including life-threatening pneumonia and plans. systemic infection. According to officials from FDA and other federal agencies-such as NIH, BARDA, and DOD-that develop animal models and many developers we interviewed, there are several reasons why there are not more qualified models under the Animal Model Qualification Program. FDA officials stated the agency's qualification determination process under the program is rigorous. Developers and federal agencies that develop animal models need to submit sufficient animal modeling data, among other evidence, to meet FDA's qualification standards. FDA bases its qualification on determining both that the animal model reflects key A close view of a patient's left thumb from the lateral perspective, revealing an ulcerative elements of the human experiences with the relevant disease or condition skin lesion, which was diagnosed as associated with the CBRN exposure, and that it can be appropriately tularemia. used in animal efficacy studies to develop medical countermeasure Source: Centers for Disease Control and Prevention (data, photo). | GAO-22-105248 products. 30 Officials from federal agencies that have submitted animal models for qualification noted this rigor and the resources required to pursue qualification. NIH officials told us that pursuing qualification of an animal model is resource-intensive because it involves conducting well- controlled and well-documented studies and providing FDA with extensive data and analyses. DOD officials reported that FDA requires a stringent level of evaluation to qualify a model, including requiring a wide range of animal modeling data. For example, DOD officials told us they considered pursuing FDA qualification of an Ebola animal model but determined not 29In October 2021, FDA qualified a cynomolgus macaque model of pneumonic tularemia submitted by NIH's National Institute of Allergy and Infectious Diseases. According to NIH officials, NIH has submitted three additional models to FDA's Animal Model Qualification Program that are in various stages of the qualification process. 30FDA, Product Development under the Animal Rule Guidance for Industry. Page 19 GAO-22-105248 FDA Animal Rule to expend the likely resources needed to meet the program's rigorous requirements. FDA, BARDA, and DOD officials and many developers told us the resource investment required to pursue qualification under the Animal Model Qualification Program may deter developers and federal agencies from pursuing model qualification. For example, they noted that, even when animal models are used to support product approval under the Animal Rule, there is little financial or other incentive for medical countermeasure developers to pursue qualification of the models, because they would need to voluntarily expend additional time and resources to do so. One developer told us it did not have any incentives to pursue qualification once the FDA had approved its product, since obtaining qualification under the Animal Model Qualification Program was so resource-intensive. BARDA and DOD officials and some developers also noted developers' and agencies' competing priorities and resource constraints as reasons not to pursue qualification. For example, DOD officials noted that a developer's priority was to focus on product development and achieve product approval from FDA, rather than to spend time and money obtaining a qualification under the program. According to BARDA, NIH, and DOD officials, many developers, and contract research Stakeholders, Medical organizations told us the limited number of animal models qualified through FDA's Animal Model Qualification Program has not impeded their Countermeasure product development work. FDA's approval of medical countermeasures Development Has Not under the Animal Rule does not require the use of a qualified model, and Been Impeded by Lack of developers have used existing animal models to perform animal efficacy Qualified Models studies for their products. Many developers reported obtaining subject matter expertise on which animal models to use from FDA and contract research organizations. In particular, FDA officials and many developers said they met iteratively prior to conducting animal efficacy studies to discuss and determine the appropriate animal models to use. BARDA, NIH, and DOD officials, some developers, and contract research organizations also reported sharing information about animal models with the close-knit scientific community working on animal models and medical countermeasure product development for their collective benefit. This is done, for example, when developers publish articles on their animal efficacy studies. 31 These articles include information about the specific 31These articles may be written in collaboration with contract research organizations that conduct animal studies. Page 20 GAO-22-105248 FDA Animal Rule protocols and combinations of animal species used, the method of exposure and dose of the CBRN agent, and the resulting efficacy study data. Although the use of qualified animal models to develop medical countermeasures has thus far been limited, FDA officials, NIH and DOD officials, some developers, and contract research organizations told us the Animal Model Qualification Program can still provide benefits to future medical countermeasure development. Despite the rigor associated with pursuing animal model qualification, they said having additional animal models qualified could be beneficial to future medical countermeasure development. In particular, they envision that qualified animal models could help reduce medical countermeasure product development time, as having existing animal models to access could limit the time developers spend designing animal models and animal efficacy studies. Having additional animal models qualified could also help clarify FDA expectations early in the product development process. For example, DOD officials told us they found the qualified animal model for tularemia provided efficiencies for their product development work. FDA officials told us that publicly disseminating detailed information about qualified animal models will make the models easier to replicate in other studies. They also said having qualified animal models for high-priority CBRN threats without approved medical countermeasures could help encourage future product development for those threats. Further, there may be little risk in maintaining the program, as FDA officials told us that the program requires limited agency resources to administer and does not have dedicated staff. We provided a draft of this report to HHS and DOD. HHS and DOD Agency Comments provided technical comments, which we incorporated as appropriate. We are sending copies of this report to the Secretary of Health and Human Services, the Secretary of Defense, appropriate congressional committees, and other interested parties. In addition, the report is available at no charge on the GAO website at https://www.gao.gov. Page 21 GAO-22-105248 FDA Animal Rule If you or your staffs have any questions about this report, please contact me at (202) 512-7114 or DeniganMacauleyM@gao.gov. Contact points for our Offices of Congressional Relations and Public Affairs may be found on the last page of this report. Mary Denigan-Macauley Director, Health Care Page 22 GAO-22-105248 FDA Animal Rule Appendix I: Interview Selection Methodology Appendix I: Interview Selection Methodology To review the development of medical countermeasures under the Food and Drug Administration's (FDA) Animal Rule, we interviewed officials from federal agencies that support the development of medical countermeasures under the Animal Rule. These includes FDA and the Department of Defense (DOD). We also interviewed officials from the Office of the Assistant Secretary for Preparedness and Response's Biomedical Advanced Research and Development Authority (BARDA), and obtained written responses from the National Institutes of Health (NIH). We also interviewed representatives from six of the 10 medical countermeasure developers (developers) that have received approval for products under FDA's Animal Rule since 2012. 1 We interviewed Amgen, Chimerix, Elusys Therapeutics, Emergent Biosolutions, and SIGA Technologies. We obtained written responses from Janssen. Five of the six developers we interviewed had approved products that were supported by BARDA. For the four developers we were unable to interview, two declined to speak with us citing issues identifying staff with relevant institutional knowledge, and two were acquired by other companies. 2 We interviewed the three contract research organizations that conducted animal studies for approved Animal Rule products. We selected these three contract research organizations for interviews based on a contractual relationship with BARDA to develop animal models for Animal Rule product development and for having conducted animal efficacy studies for approved Animal Rule products. We interviewed representatives from Battelle, Lovelace Biomedical, and Southern Research. We interviewed four academic research and policy organizations with knowledge of medical countermeasure development under the Animal 1We focused our interviews on developers that developed medical countermeasures after implementation of the Animal Rule. Two medical countermeasures, pyridostigmine bromide and Cyanokit, were approved under the Animal Rule prior to 2012 but had been developed before the Animal Rule's implementation. Pyridostigmine bromide was used during the Persian Gulf War in 1990 and 1991 as a pretreatment for nerve agents, and the active pharmaceutical ingredient in Cyanokit received marketing approval in France in 1996 for cyanide exposure. 2Human Genome Sciences, Inc., developer of Raxibacumab, was acquired by another pharmaceutical company in 2012, and Emergent Biosolutions later acquired the rights to the product in 2017. Cangene, developer of BAT and Anthrasil, was acquired by Emergent Biosolutions in 2014. Page 23 GAO-22-105248 FDA Animal Rule Appendix I: Interview Selection Methodology Rule. We selected the four academic research and policy organizations based on Internet searches on the Animal Rule, a review of journal and academic articles on medical countermeasure development under the Animal Rule, and a snowball approach of asking interviewees about relevant organizations. We interviewed representatives from the Biotechnology Innovation Organization, Bipartisan Commission on Biodefense, Johns Hopkins Center for Health Security, and University of Maryland School of Medicine Medical Countermeasure Program. Page 24 GAO-22-105248 FDA Animal Rule Appendix II: GAO Contact and Staff Appendix II: GAO Contact and Staff Acknowledgments Acknowledgments Mary Denigan-Macauley, (202) 512-7114 or GAO Contact DeniganMacauleyM@gao.gov In addition to the individual named above, Kelly DeMots (Assistant Staff Director), Michael Erhardt (Analyst-in-Charge), Christina Lee, and Marie Acknowledgment Suding made key contributions to this report. Also contributing were Kaitlin Farquharson, Diona Martyn, Laurie Pachter, and Ethiene Salgado- Rodriguez. (105248) Page 25 GAO-22-105248 FDA Animal Rule The Government Accountability Office, the audit, evaluation, and investigative GAO's Mission arm of Congress, exists to support Congress in meeting its constitutional responsibilities and to help improve the performance and accountability of the federal government for the American people. GAO examines the use of public funds; evaluates federal programs and policies; and provides analyses, recommendations, and other assistance to help Congress make informed oversight, policy, and funding decisions. GAO's commitment to good government is reflected in its core values of accountability, integrity, and reliability. The fastest and easiest way to obtain copies of GAO documents at no cost is Obtaining Copies of through our website. 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