Understanding vaccine safety and efficacy in clinical trials

The different stages of vaccine development and testing

Before a new vaccine becomes available to the public, it usually goes through many different stages of testing to ensure it is safe and effective in people.1

Phases of clinical trials

4 orange  circles  with silhouettes. Pre-clinical stage. Phase 1. Phase 2. Phase 3.

Preclinical stage: During this phase, different vaccine candidates are initially tested in animals to find out what kind of immune response they might trigger. A vaccine candidate must also be tested for immunogenicity and toxicity, at different doses, to make sure it can be further tested in humans.2

Phase 1: The next step is a clinical trial in a small number of healthy human volunteers during which a vaccine is tested to determine if it causes any side effects and whether it causes any undesirable effects.3 These trials may also determine the appropriate dose and/or formulation to elicit an effective response.3,4 Medical staff collect samples like blood or urine at regular intervals to measure how the body metabolizes (ie, gets rid of) the drug, whether it works as intended, and what the side effects may be.4

Phase 2: In the next stage, hundreds of people are recruited to test whether the investigational vaccine works well enough to minimize the risk of getting ill (phase 2a), and if it does, what the right dosage should be (phase 2a/2b).3 To do this, participants are given either the vaccine or a placebo. Researchers then measure the efficacy of the vaccine by calculating the number of vaccinated people who got sick with the disease under the study compared to those who received a placebo.3

Phase 3: In the final stage of clinical trial evaluation, the vaccine is tested for how effective it is in even more people, often thousands of volunteers, and sometimes includes specific patient groups (eg, those who are more vulnerable to developing the disease or people who have a weak immune system).3 During this phase, researchers try to determine if the vaccine is effective and safe to use in a much broader population. Dosages and any side effects are also monitored during these trials.3

Immunogenicity trial: These clinical studies take place in all phases of vaccine development and are conducted in people for whom a specific vaccine is intended. Immunogenicity is a measure of the immune response that a vaccine produces and how strong it remains over time.5 The aim of these studies is to measure and then select which vaccine formulations work best and compare the immune responses (eg, in vaccinated vs unvaccinated people).5 An immunogenicity trial may then lead to an efficacy trial or may stand alone.

What happens when trials meet their endpoints

The results and data from phases 1, 2, and 3 form part of the submission package that is submitted to regulatory authorities, such as the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), for review. It is up to them to decide whether or not to approve a new vaccine. But this is not the end of the process.

Even after a vaccine or drug becomes available for real-world use, it continues to be monitored for safety and effectiveness and may have to undergo phase 4 studies.1 These trials may be mandated by a regulatory body, such as the FDA, or chosen to be carried out by the pharmaceutical company to monitor a pharmaceutical product in a wider or different population to assess real-world effectiveness or possible long-term side effects.6

Phase 4: These trials, also called post-marketing surveillance studies (PMS), may take place after a vaccine or drug has been approved for use in the general population. They are not carried out for every new drug or vaccine, but when phase 4 studies are conducted, they involve many more people than in the phase 3 study and are used to continue to monitor the product for safety and effectiveness in the real world.3,7 The main objective of a phase 4 study is to observe the product’s performance in real life, to study the long-term risks and benefits of using it, and to discover any rare side effects, which will only become apparent as the drug or vaccine is studied in a very large population over a long period of time.7

When clinical trials fail: an opportunity to learn

Clinical trials may fail for a number of different reasons, for example, if the drug or vaccine being tested does not demonstrate acceptable levels of safety or efficacy. In the earliest phases, the immune response generated by a vaccine may not be as good as that generated in animals in the preclinical stage, the dose may not be appropriate, or it may cause severe side effects. Sometimes phase 3 studies are underpowered, which means there aren’t enough people taking part in the study to measure the desired outcomes.8 If a study isn’t designed well, this can also distort the results and make it harder to determine whether a drug or vaccine is truly effective or not.

While failed trials can be frustrating, there is much to be learned from them. Every trial provides the scientific community with more insight and information, such as which specific drugs or vaccines work and which don’t, that will help future drug research and development.

  1. What are clinical trials and studies? National Institute on Aging. Available at: https://www.nia.nih.gov/health/what-are-clinical-trials-and-studies [Accessed 27 Aug 2021].
  2. Cunningham AL, et al. Vaccine. 2016;34(52):6655–6664.
  3. Singh K, et al. J Postgrad Med. 2016;62(1):4–11.
  4. When are phase 1 clinical trials done? Verywellhealth. Available at: https://www.verywellhealth.com/what-are-phase-1-clinical-trials-2249152 [Accessed 27 Aug 2021].
  5. Guidelines on clinical evaluation of vaccines: regulatory expectations. World Health Organization. Available at: https://www.who.int/publications/m/item/WHO-TRS-1004-web-annex-9 [Accessed 27 Aug 2021].
  6. Center for Drug Evaluation & Research - Post-Approval Safety Monitoring. FDA. Available at: https://www.fda.gov/about-fda/fda-track-agency-wide-program-performance/fda-track-center-drug-evaluation-research-post-approval-safety-monitoring [Accessed 27 Aug 2021].
  7. What is a phase 4 clinical trial? News Medical. Available at: https://www.news-medical.net/health/What-is-a-Phase-4-Clinical-Trial.aspx [Accessed 27 Aug 2021].
  8. Fogel DB. Contemp Clin Trials Commun. 2018;11:156–164.
Additional reading

Additional reading

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