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Vaccine safety: British are less sceptical than Europeans, but younger people need assurance

BMJ 2019; 365 doi: https://doi.org/10.1136/bmj.l4291 (Published 19 June 2019) Cite this as: BMJ 2019;365:l4291

Response 2 to Christopher Exley’s “Re: Vaccine safety: British are less sceptical than Europeans, but younger people need assurance” (2019 Jul 3)

Exley writes: “There has not been a single vaccine 'safety study' on any vaccine given to children (up to the age of 18) there have only been vaccine efficacy studies (Exley, 2019b).” TOTALLY WRONG. Clinical trials required for approval of vaccines require both efficacy and safety data. For the first vaccine for any particular disease, placebo-based double-blind randomized studies are usually required. Once a vaccine has been approved for a particular disease, then trials of a new vaccine are compared with the older one. It would be highly unethical to expose the control group, by giving them a placebo, to the disease.

Vaccine Approval Requires Efficacy AND Safety Data

UK: “The standard for testing and monitoring of vaccines is higher than it is for most other medicines, because they are one of the few medical treatments given to healthy people (mainly healthy children). This means that the level of acceptable risk is much lower than it might be for a cancer treatment, for example. . . Phase III study – a trial in a much larger group of people (usually several thousand). . . gather statistically significant data on the vaccine's safety and efficacy (how well it works). This means looking at whether the vaccine generates a level of immunity that would prevent disease, and provides evidence that the vaccine can actually reduce the number of cases. It also gives a better chance of identifying rarer side effects not seen in the phase II study . . . Licensing – expert review of all trial data by the UK government through the Medicines and Healthcare products Regulatory Agency or European regulator (European Medicines Agency). At this stage the regulators check that the trials show that the product meets the necessary efficacy and safety levels. They also make sure that, for most people, the product’s advantages far outweigh the disadvantages.(University of Oxford, 2018).”

USA: “Phase 3 trials typically enroll thousands of individuals and provide the critical documentation of effectiveness and important additional safety data required for licensing. At any stage of the clinical or animal studies, if data raise significant concerns about either safety or effectiveness, FDA may request additional information or studies, or may halt ongoing clinical studies.” (FDA, 2018) “One Phase III goal is to assess vaccine safety in a large group of people. Certain rare side effects might not surface in the smaller groups of subjects tested in earlier phases.” (College of Physicians, 2019)

WHO: “The safety of a vaccine and the frequency and seriousness of any adverse reactions that it can induce is a critical factor for countries to consider . . .The safety of a new vaccine is assessed in clinical trials before it can be licensed (WHO, 2014 p. 20).”

For additional info on placebo-based clinical trials: ICH Expert Working Group, 2000; Rid, 2014; Singh, 2016; WHO, 2013.

One example: “Gardasil was assessed in Double Blind Randomised Placebo Controlled Trials that used the fully formulated vaccine and compared it with two different placebos, the aluminium adjuvant and a saline solution.” (Block, 2010; FDA, 2006, pp 417-18; Harris, 2017; Markowitz, 2014, pp. 14,42). Note. no serious events were found for the placebo groups; but the aluminum group did have higher minor adverse events, e.g., pain at injection site.

For an example list of placebo-controlled randomized vaccine studies, check out: Kathy, 2018.

In addition, Exley and antivaccinationists are dead wrong about post-marketing surveillance. VAERS can and does pick up rare adverse events and is not the only post-marketing surveillance program used in the US, as well as post-marketing programs in the UK and WHO (Harrison, 2019a; University of Oxford, 2018; WHO, 2014). And, finally, numerous separate studies of vaccine safety have been carried out (Harrison, 2019b).

Exley seems not to understand that even well-done placebo-controlled double-blinded randomized clinical trials can’t guarantee a valid result. The randomization process is intended to equalize groups on all other variables that could influence the outcome; but this isn’t guaranteed, even with blinded randomization one group can end up with one or more “confounding” variables. This problem is with ALL epidemiological designs. However, when one does numerous studies, with different populations, with different designs, even in different nations, the probability that all will end up with the “confounding” variable(s) in one group becomes less and less, so if the results are similar, one can decide with confidence a public policy.

While nothing we are exposed to is without risks, e.g., e-coli, salmonella from food, oncogenic substances in environment, vaccines are the most highly regulated, both before being approved and once on the market, by far of anything else, including other drugs, medical devices, and food. From the history of infectious diseases, the current state of infectious diseases in the World (but a plane flight away), immunology (vaccinology is applied immunology), microbiology, epidemiology, and biostatistics, the benefit/cost ratio of vaccines is overwhelming. Yes, rare serious adverse events do occur; but compared to the suffering, hospitalizations, disabilities, and even deaths caused by the natural diseases, the choice should be obvious. As for other ingredients in vaccines, e.g., the trace amounts of aluminum are far less than the aluminum we get from our environment, even breast milk or formula. Yep, high doses of aluminum are dangerous; but, as a vegan and blood donor I take iron supplements. If I swallowed the entire bottle I would be in trouble. While I try to avoid any meds, I sometimes take a couple of aspirin. If I swallowed the bottle I would die an excruciating death. Just a couple other ingredients: albumin is the protein in egg whites and blood plasma, formaldehyde is a byproduct of our own bodies metabolism and the amount from this is far greater than the trace amounts in vaccines.

References:

Block SL, Brown DR, Chatterjee A et al. ( Clinical Trial and Post-Licensure Safety Profile of a Prophylactic Human Papillomavirus (Types 6, 11, 16, and 18) L1 Virus-Like Particle Vaccine. Available at: https://kpar.us/wp-content/uploads/2016/03/hpv-safety-2010.pdf

College of Physicians of Philadelphia (2019). Vaccine Development, Testing, and Regulation. History of Vaccines. Available at: https://www.historyofvaccines.org/content/articles/vaccine-development-t...

Exley C (2019a Jul 3). Re: Vaccine safety: British are less sceptical than Europeans, but younger people need assurance. BMJ Rapid Responses. Available at: https://www.bmj.com/content/365/bmj.l4291/rr-13

Exley C (2019c Jun 24b). Re: Vaccine safety: British are less sceptical than Europeans, but younger people need assurance. Available at: https://www.bmj.com/content/365/bmj.l4291/rr-0

FDA (2006 Jun 8). Clinical Review of Biologics License Application for Human Papillomavirus [GARDASIL]. Available at: http://wayback.archive-it.org/7993/20170723091811/https:/www.fda.gov/dow...

FDA (2018 Jan 30). Vaccine Product Approval Process. Available at: https://www.fda.gov/vaccines-blood-biologics/development-approval-proces...

Harris HP (2017 Feb 20). Was the Gardasil vaccine ever compared with a placebo? Sciblogs. Available at: https://sciblogs.co.nz/diplomaticimmunity/2017/02/20/gardasil-vaccine-co...

Harrison J (2019a Jul 1). Wrong About Post-Marketing Surveillance of Vaccine Adverse Events. Response to Jacob Puliyel, John Stone, Allan Cunningham, etc. BMJ Rapid Responses. Available at: https://www.bmj.com/content/365/bmj.l2268/rr-7

Harrison J (2019b ). Response to Christopher Exley’s “Re: Vaccine safety: British are less sceptical than Europeans, but younger people need assurance” (Exley, 2019 Jun 27). BMJ Rapid Responses. Available at: https://www.bmj.com/content/365/bmj.l4291/rr-11

Kathy (2018 Aug 6). There are no vaccine studies with saline placebo? Vaccinesworkblog. Available at: https://vaccinesworkblog.wordpress.com/2018/08/06/there-are-no-vaccine-s...

ICH Expert Working Group (2000 Jul 20). CHOICE OF CONTROL GROUP AND RELATED: ISSUES IN CLINICAL TRIALS: E10. INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE. Available at: https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Ef...

Markowitz LE, Dunne E F, Sariya M et al. (2014 Aug 29). Human Papillomavirus Vaccination: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR: 63(RR05): 1 - 30. Available at: https://www.cdc.gov/mmwr/preview/mmwrhtml/rr6305a1.htm

Rid A, Saxena A, Jacqui AH et al. (2014 Aug 20). Placebo use in vaccine trials: Recommendations of a WHO expert panel. Vaccine; 32(37): 4708-4712. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4157320/?report=printable

Singh K, Mehta S (2016 Jan). The clinical development process for a novel preventive vaccine: An overview. Journal of Postgraduate Medicine; 62(1): 4-11. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4944327/?report=printable

Tingle AJ, Mitchell LA, Grace M et al. (1997 May 3). Randomised double-blind placebo-controlled study on adverse effects of rubella immunisation in seronegative women. ABSTRACT Available at: https://www.ncbi.nlm.nih.gov/pubmed/9142061
University of Oxford (2018 Oct 29). How vaccines are tested, licensed and monitored. Vaccine Knowledge Project. Available at: http://vk.ovg.ox.ac.uk/vaccine-development

WHO (2013). Expert Consultation on the Use of Placebos in Vaccine Trials. Available at: https://apps.who.int/iris/bitstream/handle/10665/94056/9789241506250_eng...

WHO (2014 Apr). Principles and considerations for adding a vaccine to a national immunization program: From decision to implementation and monitoring. Available at: https://apps.who.int/iris/bitstream/handle/10665/111548/9789241506892_en...

Competing interests: No competing interests

17 July 2019
Joel A Harrison
Long-Retired Epidemiologist
NONE: I have NEVER worked for the FDA, NIH, CDC, any pharmaceutical company, nor ever purchased pharmaceutical stocks
U.S.A.