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Research / Innovation / Development


Non-clinical Safety Evaluation of Vaccine: Strategic Considerations to Accelerate Clinical Development Vaccines are medicinal products intended to elicit an immune response(s) that can prevent (prophylactic vaccine) and / or lessen the severity (therapeutic vaccine) of a given disease. Vaccination involves priming the immune system of a host with an infectious agent or components of an infectious agent, modified in a manner to ensure that the vaccine does not cause any harm or disease to the host, but ensures that when the host is confronted with that infectious agent, its immune system can respond adequately to control the invading organism before it causes any ill effect1. Like other non-vaccine pharmaceuticals, the development of vaccine is also a step-wise process comprising preclinical proof of concept, non-clinical development (efficacy, quality, and safety), and clinical development; the data generated in the initial stages guides the strategy for the next stage, until it is proven efficacious and safe in the well conducted clinical trials in the target human population.

Special Features of Vaccines from a Safety Perspective The decision to approve a drug is taken after careful weighing of the potential risk that the product may pose to the patients and the benefits that the products provide in terms of preventing or treating a disease. Therefore, a drug product may get approval even if it is known to cause some harm, provided that the relief that patient gets will far outweigh the risk, taking into consideration other existing medical options.

effects. There cannot be a single strategy that can meet requirements of every type of vaccine under development. With the advancement in science, new types of vaccines are being developed, for example DNA vaccine, mRNA vaccine, vaccines involving recombinant viral vectors and recombinant proteins, etc. To complicate the matter further, various types of adjuvants, antigen combinations, cytokines, complex excipients, etc. are included, and different delivery methods are explored with an intent of developing more efficacious and safer vaccines. Therefore, vaccines represent the most diverse class of product candidates in the pharmaceutical industry. While the basic principles laid out for the safety evaluation of non-vaccine pharmaceuticals apply to vaccines, there are fundamental differences between vaccine and other pharmaceuticals, which necessitates a careful tailor-made strategy that suits the individual type of vaccine being developed. A checklistbased study conduct using standard study design is unlikely to satisfy either the scientific or the regulatory requirements; rather the strategy should be designed, taking into account the type of vaccine being developed, nature of the antigen, type and duration of intended immune response, potential similarity / dissimilarity in the immune response between non-clinical species and human, route and method of administration, qualitative and quantitative composition of vaccine product, including adjuvants, excipients, and potential impurities.

Therefore, the safety evaluation strategy, both non-clinical and clinical, should be robust enough to identify the potential risk and to show sufficient evidence of safety.

Regulatory Expectations and the Study Requirements Guidelines with respect to development of different vaccines are available from agencies such as EMA, US FDA, ICH, and WHO (see Table 1). These guidelines provide a general framework for evaluation, and it is not necessary that all studies included in the guidelines would be needed for the candidate vaccine. It is also true that studies / investigations not listed in these guidelines may also be warranted depending on the issues specific to the vaccine being developed. Regulatory agencies also stress more a case-by-case and science-based approach when it comes to identifying the studies needed, their design and timing. Therefore, engaging the concerned regulatory agency in a timely manner, and seeking their feedback and concurrence on the proposed strategy early in the development, avoids delays in the development / approval due to concerns raised by the agencies that may require additional investigations. Fundamental principles and the studies needed for non-clinical safety evaluation of any pharmaceuticals are laid out in ICH M32. Certain concepts described in ICH M3 do apply to vaccines; however, due to the unique features of vaccines, there are considerable differences with respect to type of studies needed and their design, as summarised in Table 2.

How do I Plan my Non-clinical Safety Evaluation Strategy? Potential safety concerns associated with vaccines include general systemic toxicity, (paradoxical) enhancement of the intended disease, induction of local toxicity, pyrogenicity, adverse immunological effects such as autoimmunity or sensitisation, and in some cases teratogenicity / reproductive

Pharmacodynamic End points are Critical to Enhance the Study Value and Acceptance As the vaccine is inherently designed to act on the immune system, evaluation of effects on immune organs and / or functions are invariably included as part of any toxicological studies. These evaluations are important from a safety assessment perspective.

With respect to safety evaluation of vaccines, especially preventive vaccines, two important things need to be kept in mind: •

Firstly, the safety bar is very high as it is given to healthy people (at least at the time of vaccination) as opposed to patients, and is given to millions of people in a short time-span.


Secondly, some sections of the general public still hesitate to get vaccinated, partly due to the misconceived notion about their potential to cause an adverse effect.


Summer 2020 Volume 3 Issue 2

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IBI V3 I2  

International Biopharmaceutical Industry

IBI V3 I2  

International Biopharmaceutical Industry

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