Measuring Vaccine Efficacy The right endpoints are key to success

Authors:

Paul Gillard, Vice President, Medical and Scientific Strategy, Vaccines Therapeutic Area

Delphine Saragoussi, Executive Director, Epidemiology and Scientific Affairs, Post-Approval Studies and Real-World Evidence

Sarah Rosen, Senior Director Project Management, Peri- and Post-approval Studies and Real-World Evidence PPD clinical research business of Thermo Fisher Scientific

Endpoints are needed throughout the vaccine development life cycle. Their selection is critically important and impacts study outcomes. Each development stage needs a careful assessment of fit-for-purpose endpoints. In this article, we will discuss how to develop, assess and select endpoints at each development step.

The development of pharmaceutical products requires the generation of data that enable a comprehensive evaluation of benefit against potential risks. Prophylactic vaccines are no exception. The benefit component must be accurately measured throughout the product development life cycle to determine vaccine efficacy (VE). Measuring VE is accomplished with disease- and/or pathogen-specific clinical study endpoints. These endpoints are carefully tracked, captured, evaluated in detail and sometimes adjudicated to assess if study efficacy objectives are being met. This comprehensive approach is critical for regulators, public health experts, prescribers and patients to make informed decisions on licensing, guideline recommendations, clinical use, and patient adoption and adherence.

A vaccine benefit-risk profile relies on conclusions drawn from the analysis of VE endpoints.

Identifying appropriate and valid endpoints

Measuring efficacy endpoints is required for all novel vaccines and for existing vaccines used in new target populations, unless there are established and validated surrogates of efficacy.

From polio and influenza—against which the first vaccines demonstrated their efficacy decades ago—to more recent disease targets such as SARS-CoV-2 and RSV, the use of carefully defined endpoints is a fundamental part of assessing VE in both large, prospective, randomised, placebo-controlled and real-world studies.

The type of endpoints of interest varies throughout the clinical development life cycle.

Epidemiologists and clinicians are instrumental in assessing the key medical needs that a novel vaccine intends to address, as well as the targeted outcomes it hopes to achieve. Endpoints are typically considered across four dimensions:

1. Clinical triggers—the symptoms of the disease or ailment that will trigger further diagnostic procedures (clinical trial setting) or may form the basis for a diagnosis based on clinical judgment or other circumstantial evidence (real-world setting).

2. Pathogen identification—Currently dominated by high-throughput polymerase chain reaction (PCR) based on assays but, depending on the pathogen, other lab tests may play an important role, such as virological and microbiological cultures.

3. Geography and seasonality—Factors that influence when and where a disease outbreak is likely and how this impacts the positive and negative predictive values of any assays.

4. Population specifics—How different populations (e.g., infants vs. the elderly) express signs or symptoms differently, and how acceptability and application of diagnostic procedures may vary between these populations.

Throughout a clinical development plan, endpoints must be refined to strike the right balance between diagnostic sensitivity and specificity (Figure 1). When a test’s sensitivity is high, it is more likely to give a true positive result and correctly detect the presence of disease or illness. When specificity is high, it is more likely to give a true negative result and correctly identify the lack of disease or illness. Each has its place in the vaccine development life cycle, so both sensitivity and specificity should be assessed and their roles defined at the outset. Phase III studies require the highest sensitivity to ensure the entire disease burden is assessed for efficacy but also specificity, as the vaccines are pathogen-specific and sometimes restricted to strains or serotypes. (Figure 1)

Pre-clinical phases

The preclinical phase requires that experts assess the epidemiology of the disease in terms of incidence, prevalence, severity, risk factors, outcomes and other elements. Where feasible, disease burden and medical need are measured or assessed across different health care systems and geographies. These are typically assessed in non-interventional epidaemiologic studies, often called natural history or descriptive studies. The main objectives of a natural history study are to describe the following

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