Careful preparation is key to success in any crisis. But how can a country ensure that it is ready to respond rapidly, effectively and cost efficiently to a naturally-occurring or manmade public health emergency? Value-focused Model-Informed Drug Discovery and Development (MID3) and precision public health models are being employed to prepare Medical Countermeasures (MCMs), determine the most appropriate MCM dosing, and support pandemic planning and response decisions.
What are MCMs? MCMs are regulated products that can be used in a public health emergency. The emergency could be due to a terrorist attack with Chemical, Biological, Radiological, Or Nuclear (CBRN) material, a naturally-occurring emerging disease, or a natural disaster.
MCMs can be used to prevent, diagnose or treat conditions resulting from those natural or manmade threats. MCMs can include biological agents, such as vaccines, blood products and antibodies; therapeutic, antimicrobial and antiviral drugs; and a broad range of devices, for example diagnostic tests to identify threat agents, and personal protective equipment, such as gloves, face masks, and ventilators.
By way of context, the US Food and Drug Administration (FDA) has approved, licensed or, cleared more than 120 MCMs (including supplemental changes to already approved applications and modifications to diagnostic devices) since 2012, for a diverse array of threats including anthrax, smallpox, botulinum toxin, plague, and pandemic influenza.
To protect their citizens from these potential threats, many countries have created MCM programs, which are public-private partnerships focusing on the development of advanced technologies to support their national preparedness strategy. In this way, bespoke virtual advanced MCM product development teams are formed with partners for each MCM technology. Such collaborations are usually between the country’s national departments of health and defence and various industry and academic partners. The most effective MCM programs harness expertise and resources from across civil and military domains, academia and industry to maximise in-country capabilities. Often advanced MCM technology projects also leverage the capability and capacity of international collaborators.
With the dramatic growth in global travel comes a similarly dramatic increase in the risk of naturally-occurring or manmade public health emergencies. It now takes only hours for an infectious disease to travel between continents. Furthermore, as citizens grow older, their immune system gradually deteriorates and become less effective. This process, known as immunosenescence, means that older populations are less well equipped to mount a defence against, and as such are at much greater risk from, an influx of infectious diseases to which they have not been previously exposed.
That effect is of particular concern in Japan where more than 26 per cent of the population is older than 65 years of age, and that percentage is expected to rise to 45 per cent by 2050. Furthermore, Japan is preparing to receive a massive influx of international visitors when it hosts the Rugby World Cup in 2019 and the Tokyo Olympic and Paralympic Games in 2020.
Further illustrating the need for ongoing MCM research, and the importance assigned to it by global regulatory agencies, the US FDA approved TPOXX (tecovirimat), the first drug with an indication for treatment of smallpox on July 13, 2018.
“To address the risk of bioterrorism, Congress has taken steps to enable the development and approval of countermeasures to thwart pathogens that could be employed as weapons. Today’s approval provides an important milestone in these efforts. This new treatment affords us an additional option should smallpox ever be used as a bioweapon,” said FDA Commissioner Dr. Scott Gottlieb. “Today’s action reflects the FDA’s commitment to ensuring that the U.S. is prepared for any public health emergency with timely, safe and effective medical products.”
Although the World Health Organization (WHO) declared naturallyoccurring smallpox eradicated in 1980, following an extensive global immunisation campaign, small amounts of the virus remain in research labs and there have been concerns expressed for many years that it could be used as a bioweapon. Since routine vaccination against smallpox was discontinued in the 1970s, many people would be at high risk of getting very ill or dying if they were exposed to this highly contagious virus.
Smallpox is caused by the variola virus and spread by direct contact between people. Symptoms include fever, exhaustion, headache and backache. A rash initially consisting of small, pink bumps progresses to pus-filled sores before finally crusting over and scarring. Smallpox complications can include encephalitis, corneal ulcerations, and blindness.
TPOXX was developed by SIGA Technologies Inc. together with the U.S. Department of Health and Human Services’ Biomedical Advanced Research and Development Authority (BARDA).
The FDA granted TPOXX Orphan Drug status and both Fast Track and Priority Review. In addition, TPOXX was awarded the first Material Threat Medical Countermeasure Priority Review Voucher. This voucher program was established under the 21st Century Cures Act to incentivise the development of certain MCMs against some of the most serious threat agents.
The establishment of MCM programmes in particular countries often begins with a capability and capacity audit, during which an independent, experienced third-party assesses the country’s MCM preparedness. This assessment includes an evaluation of the country’s MCMs on market and under development, and a review of its national MCM stockpile and deployment strategies. It also features an evaluation of the country’s manufacturing capability and capacity for advanced MCM product development.
The auditing company can also examine and pressure-test the country’s emergency response strategies. For example, it can review questions such as: How would the government respond if the only potential treatment or protective vaccine available during a public health emergency had not yet received regulatory approval? What would the accelerated approval process look like? How would medical personnel be trained to administer the new product? What would be the most appropriate dose to use? And how would the new product be distributed efficiently to the citizens who need it?
MCM experts generally recommend the development of virtual R&D teams, which can quickly leverage pertinent strengths and experience irrespective of the experts’ geographical location. For example, Medicines Development for Global Health (MDGH), an Australian not-for-profit bio pharmaceutical company, successfully employed a virtual R&D team to develop moxidectin for onchocerciasis (river blindness). Drug development was driven by a small, core in-house MDGH team that served as project leader/project manager. Certara contributed drug development expertise in clinical pharmacology, translational medicine, and regulatory science to the program. When the US FDA approved moxidectin as an oral treatment for river blindness on June 13, 2018, it was the first new drug approved for that disease in 20 years. In the process, MDGH became the first not-for-profit company to achieve FDA approval of a drug as a sole sponsor, and the first not for profit to be awarded a priority review voucher by the FDA. It also created a new model for developing medicines for neglected tropical diseases.
This virtual R&D team approach has proven to be the most efficient way to develop advanced MCM products identified as requirements during the audit.
It is also critically important that each country develops an agile, sovereign, advanced MCM manufacturing capability. It is not practical or prudent to rely on MCM supplies from allies during an international health crisis during which their primary focus will be on protecting their own citizens.
Value-focused model-informed drug discovery and development (MID3) and agent-based modelling – which combine computer modelling and simulation with deep drug development expertise and real-world data – have been used effectively for assessing, developing and deploying MCMs in countries around the world. We call this MID3-Precision Public Health or MID3-PPH.
MID3-PPH provides a quantitative decision support framework for public health officials and other stakeholders to discuss and evaluate the impact of potential pandemic scenarios, evaluate various response scenarios, review the country’s stockpiling strategies for pertinent vaccines and medications, and inform supply logistics decisions for the deployment of MCMs.
The Australian Defence Science and Technology Group commissioned national MCM capability and capacity audits in 2012 and 2017. Those audits employed the quantitative Technology Readiness Level (TRL) system used by BARDA and US Department of Defense to assess Australia’s MCM preparedness. The audit results were then used to inform the Australian Departments of Health and Defence MCM policy. The Australian Departments of Health and Defense have also used MID3 and deep knowledge of drug and vaccine development to develop an evaluation process for including experimental drugs and vaccines in the national stockpile prior to regulatory approval, and create co-development strategies to combat specific threats.
Among the more difficult decisions to make during a public health emergency involve determining the most appropriate dosing regimen to use for a new MCM.
MID3, especially physiologicallybased pharmacokinetic (PBPK) modelling, can be an enormous help in this regard. It can be used to determine firstin-human dose selection and evaluate new drug formulations.
In fact, MID3 is used extensively to evaluate drug safety and efficacy for different patient populations. It has the advantage that only a small amount of clinical data is required for the PBPK model to be able to accurately predict a drug’s impact across different patient populations.
MID3 can accurately determine a drug’s effectiveness in virtual patient populations in instances where it is not possible to recruit patients for clinical trials. MID3 is invaluable, for example, when researchers need to accurately bridge from adult clinical trial data to determine paediatric drug dosing.
This is a difficult exercise because paediatric patients are not simply small adults. There are numerous physiological changes that occur in children, such as maturation of metabolic capacity, immune system, and renal and hepatic function, which can have an impact on drug disposition, especially in those under two years of age. Changes in body composition can alter distribution volumes, and changes in gastrointestinal function can impact absorption. Furthermore, the number and quality of drug-related receptors present as a function of age can also be important.
Fortunately, MID3 is able to take all those factors into account. In fact, Certara has a paediatric PBPK simulator that was specifically developed to inform on drug performance for children (and neonates) from 28 weeks through to two years of age.
MID3 using this paediatric simulator helped the developer of Tamiflu (oseltamivir), an antiviral used to treat and prevent influenza, to obtain dosing approval from both the US FDA and European Medicines Agency (EMA) for treating infants as young as two weeks.
MID3 can also be used to test new drug combinations, and predict drugdrug interactions (DDIs) in virtual patient populations.
This is particularly important for elderly people, who tend to have a higher incidence of comorbidities, often requiring polypharmacy, which can result in DDIs and potential adverse reactions. Certara also has a simulator that models elderly populations, ensuring that health authorities can develop PPH strategies tailored to meet the needs of its senior citizens, too.
MID3 can similarly be used to determine the most appropriate drug dose for other vulnerable patient populations such as pregnant women, and patients with impaired liver or kidney function in realworld situations. This in silicomodelling and simulation approach allows many more drug combinations to be tested than could ever be achieved using real patients in clinical trials. It also spares patients and animals from unnecessary exposure to experimental drugs.
Furthermore, MID3 is already accepted by all major health authorities. These include Japan’s Pharmaceuticals and Medical Devices Agency, the Australian Therapeutic Goods Administration, the US FDA, EMA, and the China National Drug Administration.
“FDA’s Center for Drug Evaluation and Research (CDER) is currently using modelling and simulation to predict clinical outcomes, inform clinical trial designs, support evidence of effectiveness, optimise dosing, predict product safety, and evaluate potential adverse event mechanisms,” said Dr. Gottlieb in July 2017.
In fact, 95 per cent of novel new drug approvals by the US FDA in the first half of 2018 were supported by Certara software or services. This approach has also led to new regulatory precedents and policies being defined.
Pandemic influenza represents a significant seasonal threat globally. Government policy makers and pandemic planners wrestle with forecasting the influenza season every year. They never know how an emerging virus’ features may change during a pandemic, altering the optimal antiviral, its dose and deployment strategy.
Pandemic influenza is difficult for health authorities to manage for the aforementioned reasons. In addition, while it is spread by direct contact between individuals, there are a number of variables that affect its population impact its degree of infectivity and virulence, patient resistance, the antiviral, dose and timing used, and preventative measures taken such as closing schools or wearing face masks.
Oseltamivir (Tamiflu) is a major component of national stockpiles and pandemic influenza planning worldwide.
By coupling MID3 methodology with epidemiology, viral characteristic and healthcare utilisation measures, an agent-based model has now been developed that can show officials how an influenza virus infection can propagate through a community and nation. This model can demonstrate how a drug can influence an individual’s disease burden directly or a population’s disease burden indirectly via a reduction in viral shedding which can lead to decreased virus transmission. The proof-ofconcept model was based on oseltamivir. Such an approach can be used to develop a PPH model for any infectious disease.
This model also provides a quantitative framework that enables public health officials, physicians, pharmacologists, pharmacometricians, epidemiologists and health economists to all speak the same language and engage in meaningful dialogue with industry regulators and payers.
As a result, this type of model allows health authorities to make informed realtime decisions when responding to a public health emergency.
MID3 provides valuable insights that allow governments and public health authorities to be appropriately prepared and enables them to make objective,informed decisions when faced with manmade and naturally-occurring public health emergencies.