In early April, Pfizer and BioNTech (P/B) announced their request to the U.S. Food and Drug Administration to expand the emergency use of their COVID-19 vaccine to adolescents aged 12 to 15[i]; it was authorized mid-May. In late April, P/B revealed their intention to file a similar application in Europe.[ii] Studies of this vaccine in children aged 5-11 will complete in June 2021. Trials in children under 5 years are underway. This vaccine has consistently shown the highest published efficacy rates in adults, and so its availability for children is hoped to provide another step toward reaching “herd immunity.” However, this success may also bring a significant challenge for the future—developing the next generation of vaccines.
PRA’s US social listening data suggests that a sizable proportion of parents, although vaccinated themselves, would be reluctant to have their children vaccinated. Of those willing to have their children vaccinated, it seems likely that a significant proportion would consider a vaccine with an EUA that’s proven to work in children, such as the P/B vaccine. Both Moderna and Johnson & Johnson have already initiated pediatric trials with their vaccines. If pro-vaccine parents are inclined towards the approved P/B vaccine, one might expect the uptake to be significant in children. Pfizer has the production capacity to vaccinate the entire population of the US, so supply seems unlikely to be an issue. Given the rate of progression of the other programs, they seem likely to complete enrollment before the P/B vaccine is widely available for children, following which they will, presumably, seek the same approvals as P/B.
With three vaccines holding an EUA (US) or a conditional approval (EU, UK) for use in children, what would persuade parents to enroll their children in a clinical trial of a new vaccine, especially if that employs a placebo control? Arguably, such a design would no longer be ethical. So, how will the newer vaccines, which may prove necessary to fight newer strains of COVID-19, be developed? In June 2020, the FDA released industry guidance on the development and licensure of COVID-19 vaccines. This guidance presciently included a provision for a time when a safe, effective COVID-19 vaccine might be available. If a vaccine is available and “precludes ethical inclusion” of a placebo control group, that vaccine should serve as a control treatment in a study designed for efficacy evaluation via non-inferiority hypothesis testing. So far, the EMA has not issued guidance on this topic.
The P/B and Moderna adult studies were large, even by vaccine development standards (43,000 and 30,000 subjects respectively). Non-inferiority trials can require even more subjects than placebo-controlled trials. Placebo-controlled trials may still be possible in countries where vaccine availability is limited. These trials seem likely to be difficult to undertake elsewhere. In the US and UK, for example, adult vaccination rates already exceed 50% and are increasing rapidly. So where will the necessary participants come from?
The position for pediatric development is potentially worse, given the combination of parental reluctance to vaccinate and the likely availability of three vaccines with EUA for pediatric use. It seems probable that only children from underserved areas would be enrolled into a non-inferiority trial of two vaccines. This raises a serious ethical issue regarding fair selection of participants and safety. President Biden’s May 4th announcement that the HHS would meet the costs in such cases would seem to remove this option in the US, further complicating the issue. The socialised medicine model throughout almost all of Europe has a similar effect.
An alternative approach may be to conduct studies, possibly placebo-controlled, in countries where pediatric vaccines are not readily available, which raises two questions:
- Should agencies accept a trial using an unethical design in their own regions?
- Would agencies and the clinical community in the region be willing to accept data generated in an entirely “foreign” setting?
Traditionally, the FDA has required evidence of safety and efficacy in patients representative of those to whom the FDA owes a duty, i.e., patients who live and receive treatment in the US. Historically, the EMA has shown a greater willingness to consider “foreign” data—it is in the middle of conducting rolling reviews of Synovac and Sputnik V, neither of which undertook clinical trials within the EMA’s area of interest.
It would therefore seem that the impending success of the COVID vaccine efforts will require answering challenging questions. The key question is this: once we have shown a number of vaccines are effective against a deadly condition, how do we design trials to establish whether newer vaccines may be more effective or work better against a particular variant?
Placebo-controlled trials will be ethically unacceptable and almost operationally impossible to enroll. The FDA has already alluded to an active-comparator, non-inferiority design. Valneva recently registered a superiority trial comparing their vaccine to the AstraZeneca one, albeit with a biomarker primary endpoint (immune response as determined by the geometric mean titer (GMT) of SARS-CoV-2-specific neutralizing antibodies).[iii]
The willingness of the major agencies to grant authorisations based on such designs is currently unknown. COVID-19 is not likely to be the last pandemic—it has shown that our current development and approval processes, whilst successful in taking us to 1st generation vaccines, are ill-designed to lead us to the next generation.
i. Reuters (2021) Pfizer, BioNTech request expanded emergency use of Covid-19 vaccine for ages 12-15. Available at https://www.reuters.com/world/pfizer-biontech-request-expanded-emergency-use-covid-19-vaccine-adolescents-2021-04-09/
ii. Guardian UK newspaper (2021) Pfizer/BioNTech Covid jab may be offered to 12-year-olds in Europe from June. Available at https://www.theguardian.com/society/2021/apr/29/pfizer-biontech-covid-jab-12-to-15-year-olds-europe-from-june
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