Global contract research organization ICON ran the trial. It was able to draw on its experience in running trials on the ground during the Ebola pandemic – meaning it was able to adapt to difficult circumstances – but had to scale up this know-how into a global trial working with 150 sites across the US, Europe, South Africa and Latin America.
Digital innovations – such as remote monitoring – proved their worth in the pandemic and the learnings from COVID-19 trials will be able to help improve future clinical trial processes, says the company. And it notes that the pandemic has accelerated an existing trend towards decentralised and hybrid trials.
Taking the vaccine into the clinic
Clinical trials for the Pfizer/BioNTech vaccine began in May 2020: having brought a potential vaccine using new mRNA tech into the clinic in less than four months.
Here, the Phase 1/2 studies in Germany and the US - designed to determine the safety, immunogenicity and optimal dose level of a vaccine – were already deviating from the norm. At this point, Pfizer/BioNTech were still assessing four different candidates: with a novel design of the trial allowing for the evaluation of the various mRNA candidates simultaneously in order to identify the safest and most efficacious in a greater of number of volunteers, in a manner to facilitate the sharing of data with regulatory authorities in real time.
In July, the selected candidate – BNT162b2 – moved into a global Phase 2/3 trial.
Dublin-headquartered ICON had already been providing Pfizer with clinical trial services for some 30 years and formed a strategic relationship with the company in 2011 on the planning, execution, management and conduct on clinical trials.
In 2020 it stepped up to take on the COVID-19 vaccine trial. This ranged from providing site training, document management and operational support for patient Informed Consent Form review, coordinated eConsent in most countries, and assisting with clinical supply management services.
“The Pfizer/BioNTech clinical trial was one of the largest and fastest randomised trial ever conducted,” Nuala Murphy, president of ICON Clinical Research Services, told us.
“We recruited more than 44,000 patients and made our submission for emergency authorization in 248 days – for anyone familiar with clinical trial timelines, even considering vaccine trials generally have to move fast, this is unprecedented.
“We were able to draw on more than 20 years of experience in vaccine trials – ICON is the industry leader in vaccine development, and has run vaccine trials for every major pandemic of the last two decades, including SARS, MERS and Ebola. We were the only CRO to run trials on the ground during the height of the Ebola pandemic, so we are used to operating under difficult circumstances.
"Some of the lessons learned from this and other pandemic vaccine trials helped us understand and meet the challenges this time, but of course the COVID-19 trials are on a completely different scale, and truly global in nature. The trial itself reflected that.”
BNT162b2 trials: The stats
- A Phase 1/2/3, multicenter, multinational, randomized, placebo-controlled, observer-blind, dose-finding, vaccine candidate–selection, and efficacy study in healthy individuals.
- Assessed male and female participants aged 12 – 85.
- 155 global study locations including US, Germany, Brazil, Turkey and South Africa.
- Phase 1/2: The study was designed to determine the safety, immunogenicity and optimal dose level of 4 candidates. The dose level escalation portion (Stage 1) of the Phase 1/2 trial in the US enrolled up to 360 healthy subjects into two age cohorts (18-55 and 65-85 years of age). The first subjects immunized in Stage 1 of the study were healthy adults 18-55 years of age. Older adults were immunized with a given dose level of a vaccine candidate once testing of that candidate and dose level in younger adults had provided initial evidence of safety and immunogenicity.
- Phase 2/3: a 1:1 vaccine candidate to placebo, randomized, observer-blinded study to obtain safety, immune response, and efficacy data needed for regulatory review.
- The NCT entry can be found here and the study protocol here.
In the spotlight
While clinical trials are crucial in bringing any new biologic to market, the COVID-19 vaccine trial was very much in the spotlight as the most advanced of its type in the Western world.
There were also the logistics of managing the trial around a pandemic; and the drive from both within and outside the company to get the vaccine into arms as quickly as possible.
“From the beginning we were aware of the significance of what we were engaged in,” said Murphy. “All clinical trials are important, but on this particular trial, we knew the world was watching and waiting for the results. So we knew that the COVID-19 trials had to happen at the greatest speed and with the highest levels of safety, quality and rigour.
“To do this we implemented rolling data submission to the regulators — we would submit data over time, and be able to amend over time. This required sophisticated planning in setting up the trial, and designing an operational plan. We also played a key role in selecting suitable sites, and making sure each clinical setting was appropriate and that investigators were able to deal with the volume of subjects required from a trial of this size.
“Given the nature of vaccination programmes, we had to ensure we recruited a diverse and representative patient population. Again this was about selecting the right sites, and managing patient recruitment.
"There were also the operational considerations of conducting a trial in the middle of a pandemic – we had to ensure patient and staff safety, which we did through the use of PPE and other measures, for example.”
One of the challenges of the trial was the logistics of the vaccine’s need for special ultra-cold storage conditions at -80ºC to -60ºC (-112ºF to -76ºF).
“When you’re setting up a vaccine trial, you have to work with sites that have been trained to manage the vaccine and the administration,” said Murphy.
“Part of the set up allows for us to have coordinators on site to ensure that the investigators and nurses are following the plans around the vaccine, which has to be managed at a pretty low temperature.
"We had to ensure the site was set up to manage those low temperatures, and we had monitors out on site to really ensure that all of the trial protocols were followed to the letter and ensured compliance.”
'There are several digital innovations that have really proved their worth'
So what are the lessons and learnings that can be taken away from the clinical trials for the vaccine?
“There are many, many ways I think we can learn from this and make improvements to the trial process – it’s potentially one of the few positives to come out of this incredibly challenging time,” said Murphy.
“In many ways, the pandemic has sped up existing trends across the industry, innovations which already existed but may otherwise have taken years to gain wider acceptance among industry and regulators.
“In particular there are several digital innovations that have really proved their worth. A really significant one is remote monitoring. How do you decentralize trials so they are faster and easier to do for the patients, the investigators and the industry? Different sponsors have different levels of interest and tolerance to running trials remotely, but ICON has been at the forefront of this change and this trial proved beyond doubt that this is perhaps the best way to improve trial efficiency.
"For the Pfizer/BioNTech, approximately 90% of the trial monitoring was conducted remotely. For example, using a team in Japan to provide remote monitoring capabilities to cover sites in the Americas to make the most of different time zones. This was a significant step - working remotely allowed us to be much more agile with our resource assignment and technology has played an enormous role in making what we achieved possible.
"The pandemic has definitely accelerated the existing trend towards decentralised and hybrid clinical trials, and this is something ICON has long been championing, because it can both speed up drug development, and make research and development less costly – R&D is the single biggest cost involved in bringing new drugs to market and this cost has increased over the last ten years.”
The Phase 3 trial reached its primary analysis in November 2020: meeting all primary efficacy endpoints with 95% efficacy. The trial had 170 confirmed cases of COVID-19. Of these, 162 cases were seen in the placebo group compared to eight cases in the vaccine group. The study recorded 10 cases of severe COVID-19: nine of which occured in the placebo group and one in the vaccine group.
A request for Emergency Use Authorization in the US was submitted the same month; and the vaccine was then authorized in the US on December 11 (shortly after UK authorization on December 2).
The trial is not over, however: as all subjects are monitored for a further two year period. And the next step is to test the vaccine in groups that cannot currently receive the vaccine due to a lack of data – such as pregnant women and children (Pfizer has already started a trial in pregnant women and one in children is set to follow later this year).
And the company must also be ready for future variants of the virus. Pfizer and BioNTech have already started trialling a third booster shot of the vaccine in Phase 1 participants from the 2020 study (these participants received two 30μg doses from May onwards; and will now receive a 30μg booster of BNT162b2 6-12 months after their initial two-dose regimen).
There is also the question as to whether a modified vaccine will be needed against variants: which would again require trials to be constructed in the context of unknowns about the virus and the requirements for regulatory submission. Pfizer and BioNTech say a new vaccine could be produced in a matter of weeks: while new guidance from the FDA has started to clarify the regulatory process.
“Any new vaccine designed to provide protection against emerging new variants would be subject to a new trial," notes Murphy. "However, recently (in February) the FDA encouraged the pharmaceutical industry to begin work on modified vaccines designed to counter the new COVID-19 variants, but that such trials for modified versions of vaccines which had already received at least Emergency Use Authorisation (EUA) could be completed with just a few hundred people, over a shorter time period of two to three months.”
Vaccine development timeline
The vaccine, BNT162b2, is a nucleoside-modified messenger RNA candidate.
March 17: Pfizer and BioNTech announce they will co-develop a potential COVID-19 vaccine, using BioNTech’s mRNA-based vaccine candidate BNT162. The project starts with four potential vaccines: building on a 2018 mRNA vaccine partnership for influenza.
May: Clinical trials begin: with the novel design of the trial allowing for evaluation of various mRNA candidates simultaneously.
July 13: BNT162b2 is granted FDA fast track designation (along with BNT162b1). Later in July, BNT162b2 is selected as the lead candidate and starts Phase 2/3 safety and efficacy trials.
Oct 6: Pfizer and BioNTech initiate rolling submission to European Medicines Agency
November 18: Phase 3 study concluded with 170 confirmed COVID-19 cases in the 43,000 strong trial. The companies report 95% efficacy for the vaccine candidate; and obtain 2 months of safety data as required for a EUA request to the FDA.
November 20: Request for EUA submitted to the FDA.
December 2: The UK becomes the first country to authorize the vaccine
December 8: The first Pfizer/BioNTech vaccine shot is delivered to a member of the public in the UK.
December 10: In the US, the Vaccines and Related Biological Products Advisory Committee (VRBPAC) issues a positive endorsement of the vaccine.
December 11: Vaccine authorized for use in the US under an EUA
December 14: Vaccination starts in the US