Section 7. Facilitate Development of Medical Countermeasures to Protect Against Threats to U.S. and Global Health and Security: Strategic Plan for Regulatory Science
Medical countermeasures, or MCMs, are drugs, biologics (including vaccines), devices (including diagnostic tests and personal protective equipment), and other equipment and supplies for response to public health emergencies involving chemical, biological, radiological, or nuclear (CBRN) threat agents or naturally-occurring infectious disease outbreaks. The range of MCMs required to rapidly and effectively respond to these types of public health emergencies is not yet fully developed. Moreover, there is limited capability to rapidly develop a new MCM in response to a new or emerging threat, and only limited capacity to ramp up production of existing MCMs once an event is detected.
An extensive review of the U.S. processes and infrastructure for developing, approving, and stockpiling MCMs, released in August 2010, identified FDA as one of the most critical components of the nation’s Public Health Emergency Medical Countermeasures Enterprise (PHEMCE). Because FDA is responsible for evaluating product safety and efficacy, it has significant understanding of the steps required for successful product development. Harnessing FDA knowledge and expertise in the form of a comprehensive MCM initiative will help establish regulatory pathways based on the most advanced scientific foundations available, accelerate MCM development, and realize the promise of new technologies for faster development and flexible, rapidly scalable manufacture of MCMs.
To attain these goals, in 2010, FDA launched the Medical Countermeasures Initiative (MCMi) which consists of three pillars to establish regulatory pathways and accelerate MCM development toward approval: 1) enhancing the regulatory review processes for MCMs; 2) advancing regulatory science for MCM development and evaluation; and 3) modernizing the legal, regulatory, and policy framework for effective public health response. The second pillar, advancing regulatory science, is critical for realizing the promise of multiyear investments by the nation to develop MCMs, since development of many MCMs is impeded by the lack of key scientific information, animal models, or methods needed to assess their safety or efficacy. In particular, when efficacy studies in humans are unethical or infeasible, studies in animal models 1 will typically be needed to provide the efficacy data required to support approval, licensure, clearance, or emergency authorization. Alternatively, in those cases where no freshly collected human specimens are available for development and validation of diagnostic assays, well-characterized archived specimens or, in some instances, even contrived or simulated specimens, may be used to assess assay performance. To facilitate development of safe and effective MCMs against diseases or conditions caused by CBRN threats or emerging infectious diseases 2 , FDA will work closely with the federal government’s PHEMCE partners, as well as academia and industry, to focus its scientific agenda on four overarching areas: develop, characterize and qualify animal models for MCM development; modernize tools to evaluate MCM product safety, efficacy, and quality; develop and qualify biomarkers of diseases or conditions; and enhance emergency communication. In addition, FDA will conduct product needs assessment in collaboration with the clinical community, academia, industry, and Biomedical Advanced Research and Development Authority (BARDA) to identify products that can be delivered efficiently and applied easily without requiring advanced skill or expertise, and furthermore have potential for broadest impact.
In close alignment with priorities identified by the PHEMCE, FDA will facilitate development of safe and effective MCMs through both intramural research and collaboration with external partners (e.g., academia, U.S. government agencies, non-governmental organizations, and industry) to address, for example, the following needs:
- Develop, characterize, and qualify animal models for MCM development:
- Develop and evaluate animal models for the ability to demonstrate a response to the countermeasure that will be predictive for humans, including the ability to extrapolate pharmacokinetic/pharmacodynamic (PK/PD) data from animals to humans to determine appropriate dosing in humans; and
- Develop a database of non-clinical efficacy models to support development of biomarkers and endpoints, and inform decision-making on feasibility of certain animal models to support approval or licensure of MCMs (also see section 1).
- Modernize tools to evaluate MCM product safety, efficacy, and quality:
- Partner with the Department of Health and Human Services (HHS) and Department of Defense (DOD) to support and facilitate development of advanced manufacturing approaches and facilities, including rapid, scalable, platform approaches;
- Identify and evaluate methods to improve availability and reuse of personal protective equipment;
- Continue to develop electronic data standards and report forms to facilitate rapid assessment of the safety and efficacy of deployed MCMs;
- Develop reference materials related to relevant threat agents to facilitate development of preventive vaccines, therapeutics, and detection and diagnostic methods; and
- Develop and evaluate high throughput, sensitive, specific, cost-effective methods to detect threat agents, diagnose the disease or condition, and perform broad-based pathogen detection.
- Develop and qualify biomarkers of diseases or conditions:
- Improve knowledge of natural history of pathophysiology of human diseases or conditions caused by CBRN agents;
- Identify and develop biomarkers that enhance the understanding of the mechanism of action of MCMs, and may provide measures of MCM product efficacy; and
- Determine pathogenesis in relevant nonclinical models and evaluate for predictive value to human condition.
- Enhance emergency communication:
- Evaluate past risk and emergency communications to identify and improve the effectiveness of communications in a public health emergency;
- Improve quality and health literacy level of FDA communication about FDA-regulated products; and
- Enhance FDA’s capabilities and develop new strategies to collect, monitor, and track during emergencies real time data on adverse events associated with the use of drug, biologic, and device MCMs.
Each year, the influenza vaccine is slightly different due to accumulated genetic changes in circulating influenza viruses. In order to develop a protective vaccine, the strain for the vaccine needs to be matched to the expected strains circulating. Once produced, the manufacturer needs to be able to accurately measure the potency of each strain component in the vaccine, which requires the production of reagent standards, including a strain-specific antiserum. This is typically done by purifying the hemagglutinin (HA) protein from the flu vaccine strain, immunizing sheep with the purified protein, and then using the resulting antisera to analyze the manufactured vaccine. HA purification is time-consuming and often unsuccessful, and can become a rate-limiting step in the final lot release testing on the vaccine strain if the antisera are not available. CBER scientists have shown that they can use recombinant DNA techniques to generate the HA protein without having to culture the virus in eggs or cell culture as an alternative and more rapid method for preparation of pandemic influenza strain-specific antibody for vaccine potency determination. The resulting antisera from sheep immunized with the recombinant HA have shown identical sensitivity and specificity to those sera obtain from HA purified from the virus. This approach has the potential to help make influenza vaccines available more quickly, particularly for a pandemic.
Public Health Impact:
Advancing regulatory science in the areas above will provide enhanced preparedness by establishing more flexible and nimble manufacturing processes and by creating data, tools, and methods to speed development and evaluation of MCM product safety, efficacy, and quality. Improved scientific data will facilitate development of safer, more efficacious products to respond to threats — should that become necessary — thus mitigating the morbidity and mortality of an attack or outbreak fostering resilience and recovery.
The MCM regulatory science program will bring the nation a step closer to the preparedness and response capabilities articulated in the HHS Public Health Emergency Medical Countermeasures Enterprise Review, where the nation’s MCM Enterprise is equipped to respond to any attack or threat, known or unknown.
Ultimately, the output of MCM regulatory science will have substantial implications for improving the health and security of the U.S. population beyond CBRN and emerging infectious disease threats. Advancing regulatory science to support development of MCMs will contribute directly and indirectly to development of safer, better products for other diseases and conditions.
1. For more on requirements for approval or licensure under these conditions see “The Animal Rule”: New Drug and Biological Drug Products; Evidence Needed to Demonstrate Effectiveness of New Drugs When Human Efficacy Studies Are Not Ethical or Feasible; Final Rule”, 5/31/2002.