The U.S. Food and Drug Administration (FDA) on Oct. 29, 2021, approved emergency use authorization (EUA) of the Pfizer-BioNTech COVID vaccine for children aged 5 to 11 and adults, signing off on a new formula that contains tromethamine, without having completed animal or human clinical trials to assess safety or efficacy. In continuation of an accelerated effort, the FDA only reviewed Pfizer’s “analytical comparability assessments” to evaluate if Pfizer’s COVID vaccine formulations containing Tris and phosphate-buffered saline (PBS) buffers were “analytically comparable.”
Pfizer and BioNTech submitted a request on Oct. 7, to amend its EUA to include use of a 2-dose primary series of the Pfizer-BioNTech COVID-19 vaccine — 10 μg each dose, administered 3 weeks apart — in individuals 5 to 11 years of age for active immunization to prevent COVID-19 caused by SARS-CoV-2.
On page 14 of the FDA’s briefing document, it states “authorization is being requested for a modified formulation of the Pfizer‐BioNTech COVID-19 Vaccine.”
Under “vaccine formulation,” it further states, “to provide a vaccine with an improved stability profile, the Pfizer-BioNTech COVID-19 vaccine for use in children 5-11 years of age uses tromethamine (Tris) buffer instead of the phosphate-buffered saline (PBS) as used in the previous formulation and excludes sodium chloride and potassium chloride.”
The document continues, “authorization and future licensure of the modified formulation is based on analytical comparability to the currently authorized PBS containing formulation.”
Formula change not validated by human or animal trials
Pfizer said the “change in buffer is not considered clinically significant,” and is used to simplify administration and increase storage times in pharmaceutical products. The new formula is authorized for use in individuals 5 to 11 and in those 12 years of age and older, according to the Pfizer-BioNTech EUA letter of authorization (LOA) reissued by the FDA on Oct. 29.
Yet, Pfizer’s COVID vaccine containing PBS — the formula actually used in the clinical trial for children aged 5 to 11— was not authorized for use in the 5 to 11 age group.
According to Cleveland Clinic, Tris is commonly used for the prevention and treatment of metabolic acidosis associated with various clinical conditions such as heart bypass surgery or cardiac arrest. It is also used in other vaccines like dengue, smallpox and Ebola vaccines — none of which are routinely used in children — and a diabetes medication, Humalog. We note that the doses used for the vaccine are much smaller.
The FDA categorizes tromethamine as a category C drug and suggests using tromethamine only if clearly needed. It is not known whether tromethamine will harm an unborn baby, but animal reproduction studies have shown an adverse effect on the fetus, and “there are “no adequate and well-controlled studies in humans.”
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“The new formulation contains tromethamine, which is known as Tris buffer, and it’s commonly used as a buffer in a variety of other FDA-approved vaccines and biologics, including products for use in children,” Dr. Peter Marks, director of the Center for Biologics Evaluation and Research, said during a press briefing. “The FDA-evaluated manufacturing data [to] support the change in this inactive ingredient, and concluded it did not impact the safety or effectiveness of the product.”
However, no human or animal trials were conducted to determine the safety or efficacy of the new formula. According to the FDA’s Letter of Authorization (LOA), reissued on Oct. 29, “analytical comparability assessments” revealed that the Pfizer-BioNTech COVID vaccine formulations containing Tris and PBS buffers were “analytically comparable.” The burden of proof is on Pfizer to show that the new formula does not change the safety and efficacy profile.
“Analytical comparability assessments use laboratory testing to demonstrate that a change in product formulation does not impact a product’s safety or effectiveness,” the LOA states.
In conducting its assessment, the FDA said it compared the modified formulation inclusive of the Tris buffer to the originally-authorized formulation containing the PBS buffer — evaluating product appearance, size of the lipid-nanoparticle (LNP), the integrity of the mRNA in the product, product composition and purity.
“The combination of release testing and characterization testing demonstrated that the modified formulation is analytically comparable to the original formulation,” the FDA concluded.
In an emailed statement to USA Today, an FDA spokesperson said any major changes made to a vaccine or drug require “the submission of data, based on adequate and well-controlled clinical studies demonstrating safety and effectiveness.” The FDA must then approve any such changes.
Generally, changes to vaccine formulas need to be validated. Once a COVID-19 vaccine has been granted EUA or is formally licensed and distributed for human use, there really is no changing its ingredients or formulation,” Dr. Paul Offit, director of the Vaccine Education Center at the Children’s Hospital of Philadelphia and member of the FDA’s COVID vaccine advisory panel, told USA Today.
“Every lot has to be exactly the same as the next lot, exactly the same,” Offit said explaining this consistency is baked into the vaccine’s approval process, which also involves how the vaccine is manufactured.
Any change or addition to a vaccine for whatever reason would require vaccine developers to have their product reassessed by the FDA. “If a company ever decides to make a change … they have to essentially get a new license,” Offit said.
Scientist raises concerns over lack of data
During a meeting of the Vaccine and Related Biological Products Advisory Committee (VRBPAC) on Oct. 26, Dr. Steven Pergam, associate professor of vaccine and Infectious disease and clinical research at Fred Hutch, asked Dr. William Gruber, Senior Vice President of Pfizer Vaccine Clinical Research and Development [2:55:24] whether the “actual study” done in the 5 to 11 age group used the new Tris buffer.
Gruber responded, “the studies were done using the same volume 0.2 ml that is in the final presentation in terms of the dose but contained the PBS buffer. We obviously had extensive consultations with the FDA and it was determined that clinical studies were not required — again because the LNP and the mRNA are the same and the behavior in terms of the reactogenicity and efficacy are expected to be the same.”
Dr. David Wiseman, a research scientist with a background in pharmaceutical research and product development, said in an interview with TrialSite News, the FDA’s approval of Pfizer’s new formula is “simply outrageous,” without adequate studies to determine the safety or efficacy of the new formula.
Wiseman said Pfizer’s new formula was tested “using analytical chemistry methods,” and the FDA declares the new formula containing the Tris buffer is “analytically comparable to the old formula.”
During the VRBPAC meeting, Pfizer’s representative [Gruber] said “all of the studies that were done to support the use of the vaccine in children were done using the old formula,” Wiseman said. “They were not done using the new formula, and they said this explicitly.”
Wiseman further explained:
“Whenever you’ve got an FDA regulated product — whatever the product is that the FDA regulates — and now they want to make even a minor manufacturing change, you have to justify to FDA why the proposed change you want to make does not impact safety or efficacy. That’s the basic rule.
“Potentially, it must go through all the kinds of testing you did with the old product. The company’s objective is to get away with as little as possible. The FDA’s objective, if they’re being honest about it, is to do a reasonably good job and to ask the company to do A, B or C types of studies in order to have some sort of assurance the proposed change doesn’t affect the safety and efficacy of the product.”
Wiseman emphasized the two formulas be analytically comparable, but the issue is whether they’re biologically compatible — which Wiseman said would at least require animal studies to determine if the products are biologiclaly equivalent.
“If I were changing the formula, I would be prepared to present animal studies or other types of tests, supporting biological equivalence, not just analytical equivalence,” Wiseman said. “All the FDA did was evaluate the manufacturing data. They did not inquire for any other data, and Pfizer apparently didn’t provide it if they’ve done it.”
Wiseman said one might argue this is just a minor change, but “they would have needed to do animal toxicity studies, look at how the product affects the reproductive system and conduct a biodistribution study — studying how the drug moves around the body, in addition to possible clinical studies.”
“When people say it’s a minor change, I’ve seen minor changes turn out to be not so minor,” Wiseman said. “We could be very clever and make all sorts of theories but at the end of the day I want to see it — and there could be chemical changes that weren’t measured in a lab.”
What about the risks?
Wiseman told TrialSite News issues could arise from changing the PBS buffer to a Tris buffer:
“Here’s the scenario. Look at the storage conditions for the old vaccine with -80 degrees and so on. And you have to maintain this temperature. There’s a lot of quality control involved here, and there’s a lot of opportunity for temperature storage conditions to not meet specifications. So, what could actually happen or may have been happening up to now — the 30 microgram dose people think they were getting may actually have only been effectively a 20 or a 10 microgram dose for some people.
The consultant noted Moderna’s COVID vaccine also contains tromethamine, which in addition to Moderna’s higher nominal dose, could possibly associate with a poorer safety profile. For example, this vaccine has been paused in Germany, France, Denmark, Sweden and Finland to people over the age of 30 due to an increased risk of myocarditis.
The buffer changes also create the possibility of further confusion and errors. For example, Pfizer-BioNTech inventories associated with the old formulation containing the Phos buffer will be depleted over the next period of time — we estimate a quarter or so. Confusion may ensue because of variable roll-out of the new formulation with different storage conditions. The prospect for administration errors also materializes. Tracking adverse events while linking them to old, or new formulations could be challenging.
Conclusion
FDA authorization of this formulation change extends an ever-growing list of lapsed but long-standing regulatory practices established to assure the public of the safety and efficacy of medical products during this pandemic. Most recently this includes FDA’s admitted lapse to verify Pfizer’s efficacy analysis for the children’s vaccine as well Janssen’s efficacy analysis for its second dose.
Traditionally the burden of proof rests with the vaccine manufacturer to demonstrate biologically comparable safety and efficacy. During this pandemic, the FDA appears to have relaxed its standards possibly in the name of efficiency and expediency. Vaccine manufacturers and regulators that seek to overcome vaccine hesitancy may consider following traditional regulatory practices to send a signal to the market that both quality and patient safety are of paramount concern.