Protecting and Promoting Public Health: Advancing the FDA’s Medical Countermeasures Mission

By Anna Abram

The U.S. Food and Drug Administration’s wide-ranging public health responsibilities include the vital role we play on the frontlines of national security by facilitating the development and availability of safe and effective medical countermeasures. These are the vaccines, diagnostics and therapeutics that are needed to protect our nation from chemical, biological, and radiological and nuclear threats, whether naturally occurring, accidental, or deliberate. As in so many areas of public health, our work here is critical, and we are ever-cognizant of its urgency.

One of the many areas in which the agency is continuing to take steps to facilitate the development of medical countermeasures to protect Americans is with respect to the threat of smallpox. The World Health Assembly declared naturally occurring smallpox eradicated worldwide in 1980, following an unprecedented global immunization campaign. However, small amounts of the variola virus – the virus that causes smallpox – still exist for research purposes in two labs; one of these labs is in the U.S. and the other in Russia. Despite the eradication of naturally occurring smallpox disease, there are longstanding concerns that the variola virus could be used as a weapon. Since routine vaccination was discontinued in the 1970s, many people would be at high risk of getting very ill or dying if exposed to this highly contagious virus.

Medical Countermeasures Against Smallpox

The development of medical countermeasures for smallpox presents complex and unique challenges. It is not possible to conduct clinical trials involving patients with naturally occurring smallpox and exposing humans to the variola virus would be ethically unthinkable. To address this challenge – which also applies to many of the high-priority threat agents for which medical countermeasure are being developed – the FDA in 2002 established the Animal Rule, which allows efficacy data to be obtained solely from studies in animals when studies in humans are not ethical or feasible, provided the results can be reasonably extrapolated to expected human use and plans can be made for follow-up study when appropriate. (The FDA finalized guidance on product development under the Animal Rule in 2015).

Anna Abram

Anna Abram is FDA’s Deputy Commissioner for Policy, Planning, Legislation, and Analysis

However, the variola virus poses additional issues for drug developers. Unlike other products studied under the Animal Rule, studies of smallpox countermeasures require not just a surrogate host but also a surrogate pathogen. Most pathogens are capable of infecting multiple host species and therefore can be studied in other, nonhuman, species. But the variola virus only infects humans, which means that variola virus animal models are unlikely to convincingly resemble the human disease. To help delineate a path forward, the FDA issued a draft guidance “Smallpox (Variola) Infection: Developing Drugs for Treatment and Prevention” in 2007 and brought these important issues to an FDA public workshop in 2009 and an FDA advisory committee meeting in 2011. The revised draft guidance issued last week incorporates this input, providing developers with additional clarity on the regulatory path for products intended to treat smallpox. It recommends that efficacy be demonstrated based on studies in two animal models infected with related viruses – such as a monkey model using monkeypox and a rabbit model using rabbitpox. This guidance underscores how the FDA is continually working to identify and apply efficient solutions based on the most up-to date science in its regulation of safe and effective medical products.

The ultimate testament to the success of these efforts is the approval on July 13 of TPOXX (teconvirimat), the first drug with an indication for the treatment of smallpox and the 14th medical countermeasure approved under the Animal Rule. In conjunction with this product approval, the sponsor was awarded the first Material Threat Medical Countermeasure Priority Review Voucher, established by the 21st Century Cures Act, to incentivize the development of certain medical countermeasures against some of the most serious threat agents.

The FDA’s Other Recent Work on Medical Countermeasures

Smallpox isn’t the only area of medical countermeasure work ongoing at the FDA. On July 10, we approved an autoinjector which provides a one-time dose of the antidote atropine to block the effects of a nerve agent or certain insecticide poisonings (organophosphorus and/or carbamate).

We also recently issued an Emergency Use Authorization (EUA) to the Department of Defense (DoD), permitting the emergency use of a specific freeze-dried plasma product manufactured to treat U.S. military personnel with severe or life-threatening hemorrhage or coagulopathy (a condition that affects the blood’s ability to clot) due to traumatic injuries sustained in the conduct of military operations in situations when plasma is not available or when its use is not practical. The use of plasma in combat settings is severely limited by logistical and operational challenges, such as the need for refrigeration and, in the case of frozen plasma, a long thawing period. In January 2018, the FDA and DoD announced a joint program to prioritize the efficient development of safe and effective medical products intended to save the lives of American military personnel.  We are working closely with our DoD colleagues in these important priority areas, including the goal of having a licensed freeze-dried plasma product as soon as possible.

These are just some of the ways in which the FDA has been hard at work to advance our medical countermeasure mission. But there is more work to do and the agency is committed to doing it. We are constantly reminded that chemical, biological, radiological, and nuclear threats – whether deliberate, naturally occurring or accidental – can, and often do, emerge with little to no warning. Emerging threats are often not deterred by geographical boundaries in our modern times. The recent Ebola outbreak in the Democratic Republic of Congo is a reminder of the need to remain ever vigilant in our work to advance medical countermeasures as part of protecting and promoting public health.

We are committed to doing all that we can to continue to facilitate the development and availability of medical countermeasures. The FDA’s Medical Countermeasures Initiative (MCMi), established in 2010, is focused on providing clear regulatory pathways for medical countermeasures, advancing regulatory science to support regulatory decision-making, and articulating important regulatory policies and mechanisms to facilitate the timely development and availability of medical countermeasures. These actions are translating into tangible results. Since 2012, the FDA has approved, licensed or cleared more than 120 medical countermeasures (including supplemental changes to already approved applications and modifications to diagnostic devices) for a diverse array of threats including anthrax, smallpox, botulinum toxin, plague, and pandemic influenza.

Under the MCMi, the FDA is taking key actions to address many of the challenges associated with countermeasure development. For example, we still do not have adequate animal models to support the development of medical countermeasures against many potential biothreats nor do we have sufficient biomarkers to assist in supporting the extrapolation of data generated in animal models to humans. Without such tools, it can be difficult to generate the data necessary to support regulatory decision-making.

Given the urgency inherent in our medical countermeasure work, addressing these regulatory science gaps remains a high priority for the agency. To help address these challenges, the FDA has established a broad and robust portfolio of cutting-edge research under the MCMi Regulatory Science Program and is working with our private sector and government partners, including DoD, to help facilitate the translation of discoveries in science and technology into safe and effective medical countermeasures. Congress has also provided vital support and our recent actions in this space underscore how we are fully leveraging the authorities Congress has given us, including measures enacted as part of the Pandemic and All-Hazards Preparedness Reauthorization Act of 2013 and the 21st Century Cures Act.

The FDA remains deeply committed to working closely with its partners to achieve our mission of protecting and promoting the public health, both at home and abroad, by doing our part to facilitate the timely development of safe and effective medical countermeasures to protect our nation.

Anna Abram is the FDA’s Deputy Commissioner for Policy, Planning, Legislation and Analysis.

Collaboration and Medical Countermeasures: Furthering Regulatory Science

By: Dr. Stephen M. Ostroff

“I hope no one ever needs these products,” isn’t something you hear too often, particularly from those developing drugs, biologics, or devices. That point of view—and a universal desire to protect the American public—is what sets biodefense professionals apart.

Stephen OstroffWithin FDA, our Medical Countermeasures initiative (MCMi) does things a little differently as well. Managed by the Office of Counterterrorism and Emerging Threats, in the Office of the Chief Scientist, MCMi thrives on collaborations. We work proactively with industry, academic and federal research centers, FDA product centers and offices, and other government entities in our mission to help protect the U.S. from chemical, biological, radiological, nuclear, and emerging infectious disease threats.

Collaborating is particularly important to advancing regulatory science: developing the tools, standards, and approaches needed to evaluate FDA-regulated products—in this case, medical countermeasures—for safety, efficacy, quality, and performance. When it comes to developing the necessary data for regulatory decisions, medical countermeasures often present unique and complex challenges since the diseases they target rarely occur naturally.

To support regulatory decision-making for medical countermeasures, FDA manages a robust research portfolio under the MCMi Regulatory Science Program. Working with other federal agencies to ensure alignment with U.S. priorities, we fund both intramural and extramural research programs to drive innovation in regulatory science.

Ongoing research projects include:

  • Developing models of radiation damage in lung, gut, and bone marrow organs-on-chips, and using these models to test candidate medical countermeasures to treat such damage;
  • Mapping immune responses to certain biothreat agents and medical countermeasures in humans and animal models to create species-specific immune function maps;
  • Assessing the feasibility of using electronic health record systems to conduct near real-time monitoring of health outcomes, including serious or unexpected adverse events associated with medical countermeasures used during public health emergencies.

For those interested in these and other medical countermeasure-related regulatory science developments, FDA will be hosting our 2014 MCMi Regulatory Science Symposium at FDA headquarters in Silver Spring, Maryland, June 2-3, 2014. The meeting is free and open to the public (pre-registration required).

We welcome poster abstract submissions until April 27, 2014, in topic areas including: animal models, biomarkers and correlates of protection, devices, diagnostics, emergency communication, new technologies, product quality, and surveillance.

I also encourage you to read more about MCMi in action in our Fiscal Year 2013 Program Update.

Stephen M. Ostroff, M.D., is FDA’s Acting Chief Scientist