Acknowledging the Dynamic Epidemiology of Infectious Diseases During Clinical Trial Planning

Knowledge of infectious disease epidemiology is essential to clinical trial planning, as this information is needed to identify for which populations a vaccine or treatment will be most effective. This knowledge includes analysis of demographic, geographic, social, seasonal and other risk factors. When combined with situational awareness of local site capacity, clinical operations and other site-specific enrollment indicators, an understanding of the epidemiology can help determine site locations and strategies for optimal participant engagement.

Given globalization, infectious diseases are spreading further and faster, making epidemiology more challenging, yet ever more important, to track. Throughout a trial, information from monitoring the changing epidemiology of an infectious disease guides appropriate adjustments to site selection, recruitment and data analysis.

Emerging diseases require agile responses.
COVID-19 has emphasized the need to rapidly understand and monitor characteristics of a new infectious disease on a global scale. In response to the new coronavirus, the scientific community quickly responded, using learnings from previous regional outbreaks; however, the scientific community was initially at a disadvantage—although part of the coronavirus family, COVID-19 exhibited novel transmissibility and durability of immunity response.1 In addition, susceptibility of specific subpopulations and effectiveness of existing treatments were unknown.
Although it is fundamentally understood that a new infection will follow a set pathway (emergence, local-scale transmission, movement beyond borders and possible global spread2), it remains challenging to predict where and when (or even if) the infection will spread, who will be most affected, which new variants will emerge and even how the public will respond to public health strategies.
When developing and testing new therapies and vaccines for an emerging disease, surveillance of the following provides valuable information during the study design phase:
We previously discussed the challenges of recruiting COVID-19 patients for therapeutic trials; rapid onboarding of sites is essential to ensure the patient population will remain available, and there has been fierce competition for patients as multiple therapies are being tested within the same site. It became necessary for researchers to stay two steps ahead of where the outbreak would migrate—to identify which sites should be recruited next—as discussed by Loice Magaria, Clinical Research Project Manager at FHI Clinical, in this video:
At the same time, vaccine development can be complicated by increasing seroprevalence, from vaccination, previous infection or both. A systematic review of SARS-CoV-2 seroprevalence studies conducted by a World Health Organization (WHO) collaboration of researchers showed that true COVID-19 infections exceeded reported cases globally, based on data from January 2020 to October 2021 across 92 countries.3 Key findings included:
The need for vaccines has not ended. As new waves of infection sweep the world, immunity wanes, and some countries still don’t have access to a reliable supply. Robust and representative epidemiological data, including seroprevalence, helps identify where vaccine trials can be conducted in seronegative populations and data sources that might require statistical adjustment due to increasing seropositivity. Proactively and consistently monitoring this information can inform the planning phases and allow swift counterplanning when needed.
Outbreaks have ripple effects on other infectious diseases.
For clinical trials, COVID-19-related public health policies also affected investigations of vaccines and treatments for a number of additional illnesses—not only because of delayed trials but also because there were fewer opportunities for exposure to pathogens due to social distancing and mask requirements and potentially fewer diagnoses related to fewer visits to clinics. Collectively, these realities contributed to decreased incidences of new infections4-8 of influenza, measles, tuberculosis (TB), rotavirus gastroenteritis, dengue fever, whooping cough, varicella-zoster, typhoid and respiratory syncytial virus (RSV).
The same policies restricted access to preventative and therapeutic health care services, thereby increasing the spread of some diseases, impacting vaccination rates and exacerbating existing illnesses, again changing the epidemiological characteristics of certain diseases.
Then, as restrictions are lifted, there has been a resurgence of infections such as other respiratory infections and some gastrointestinal infections, as documented among children aged 0 to 3 years in Israel.4 Interestingly, in Germany, influenza activity remains suppressed, while rhinovirus infections have risen, particularly in children.9 RSV infections are peaking at a high level,10 in a greater number of older children10 and during the spring and summer,10,11 all of which is atypical. In other locations, younger infants are experiencing more severe RSV-related disease, potentially due to lack of exposure (and therefore diminished immunity) in the previous season.11
Another concern is the effect of SARS-CoV-2 infection on the characteristics of other diseases. We’ve had multiple discussions with sponsors about the potential need to modify study designs for TB, HIV and other infectious diseases based on current or previous SARS-CoV-2 infection.
Diligent surveillance is crucial to endemic disease control.
In addition to recognizing how outbreaks are affecting other diseases, continuous surveillance of vaccination rates, seroprevalence, concurrent prevalent diseases and the effect of public health policies for endemic and persistent infectious diseases is also essential in the absence of an outbreak, as our team recently discussed in a plenary discussion about TB.
Many regions have higher prevalences of multiple infectious diseases, bringing into focus the need to account for simultaneous infections in clinical trials or new locations to conduct studies. The decision about when and where to base a research program might depend on where the investigational product is in its development cycle—does it need to be tested in isolation, or is there interest in how it performs in real-world situations of greater infectious disease burden? Strategies may be needed to operate within that real-life environment. For example, populations with high prevalence of HIV, and the associated impact on immunity, tend to also be susceptible to TB,12 malaria,13,14 hepatitis B14 and other infectious diseases. Antiretroviral therapies can interfere with treatments for other infectious diseases and should be considered during trial planning.
Other considerations include existing public health priorities. For example, the WHO’s End TB Strategy, which drove the updated WHO consolidated guidelines on tuberculosis in 2020,15 states that TB preventive therapy (TPT) “should be considered a human right for individuals who are at increased risk for TB” and emphasized the role of TPT as standard of care. In the guidelines’ 18 recommendations, preventive care is prioritized for HIV-positive individuals, household contacts of someone with TB and children. Therefore, overlap exists between those eligible for TPT as standard of care and eligible individuals for TB vaccine trials, and the population of treatment-naive individuals is also decreased. In a roundtable discussion, we asked participants how we proceed with TB vaccine development in the midst of increasing uptake of TPT, especially when withholding TPT is potentially unethical. The following strategies were discussed:
We also have the opportunity to learn from previous infectious disease priorities, such as HIV, for which vaccination development is learning to co-exist with increasing use of pre-exposure prophylaxis (PrEP) therapy to prevent HIV infection in high-risk individuals.

Multidrug resistant (MDR) strains of common pathogens are also the cause of dynamic epidemiology in many parts of the world. MDR-TB is a current concern, with increasing prevalence and poorer treatment outcomes with existing first-line treatments, while second-line treatments are limited, often toxic and expensive.16,17

Robust surveillance data are vital to appropriately plan clinical trials for infectious disease vaccines and therapies.
The ability to follow the epidemiology of a given infectious disease depends on the surveillance system in place, including case detection and tracking, local and national reporting systems, and government support for data sharing. Tapping into local resources with intimate knowledge of their populations, health systems, government policies and available resources can help identify areas that are best suited for a trial’s disease of interest and intervention.

To take advantage of this localized knowledge, we’ve developed and applied a unique method of site feasibility involving biosurveillance methodologies and epidemiological evaluation, which allows us to proactively assess sites and anticipate changes in epidemiology that should be considered in the study design. To hear more, watch our plenary presentation from the 6th Global Forum on TB Vaccines.



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