One shot

There is no denying the pharma industry’s traditional vaccine development has been completely upended by the urgency of the pandemic. Racing a virus that continues to cause thousands of deaths around the world on a daily basis, the industry is attempting to safely condense a process that typically can take a decade, down to a matter of months. Arthur points out that because the industry’s approach to vaccines is unique, the industry’s approach to addressing vaccine confidence during a pandemic should be unique as well.

“We’re in the middle of a major global infectious disease event. We can’t travel. We can’t go to work. These are very different times. And when you think of it that way, then you would think about the approach to explaining the vaccine differently,” she says.

Skepticism: Now available in many flavors

The new strain of vaccine skepticism that has emerged during the pandemic has multiple and varied points of origin.

“You have a variety of different flavors here; it’s not just all one thing contributing to vaccine hesitancy,” says John LaMattina, senior partner at PureTech Health, author and former president of Pfizer Global R&D. “And if each of those add up — to say 50 percent of the population — then it could really slow down progress.”

Why would people who generally support vaccines refuse one at a time when the need is so urgent?

For starters, the SARS-CoV-2 vaccine approval timeline has become an election flashpoint. While championing his administration’s aggressive vaccine push, President Trump has repeatedly promised the American people a vaccine before Election Day — a timeline that has been refuted by top level health officials and the majority of drugmakers involved in Operation Warp Speed.* Democratic leaders, including vice president nominee Kamala Harris, have responded by raising concerns about taking Trump’s “word for it” on the safety of a pre-election vaccine. Trump, in turn, has accused Democrats of spreading “reckless anti-vaccine rhetoric.”

While partisan divide alone is enough to dent vaccine confidence, the pandemic has dragged the U.S. Food and Drug Administration — the 100+ year old agency heralded for its gold standard work in protecting public health — into a political warzone. The perception of political interference has caused many to doubt the agency’s credibility when it comes to drug approvals.

“Another element that enters into this of course ties into the FDA, and what the FDA has been doing so far in terms of COVID-19,” says Stewart Lyman, who has worked as an independent biopharma consultant for more than 15 years. (Lyman is also known for voraciously and colorfully taking on Twitter trolls who spread false information about vaccines.) “Political interference in the process is only making things worse.”

At the center of much of the controversy has been the agency’s issuing of Emergency Use Authorizations (EUAs), a pathway that was thrust into the public eye during the pandemic after the agency issued two heavily debated EUAs — one for the malaria drug hydroxychloroquine, the other for blood plasma from recovered COVID-19 patients.

Hydroxychloroquine, for which the EUA was revoked two months after it was issued when the science didn’t hold up, was (and still is) ardently promoted as a COVID-19 treatment by President Trump and many of his supporters. The second controversial EUA decision, for convalescent plasma, was made on the eve of the Republican National Convention. President Trump and FDA Commissioner Stephen Hahn came under fire for what many interpreted as a misrepresentation of data during the press conference announcing the EUA.

For Lyman, the tipping point for FDA credibility actually came the day prior to the convalescent plasma EUA, when President Trump accused the FDA of being part of the “deep state,” directly calling out Commissioner Hahn.

“The deep state, or whoever, over at the FDA is making it very difficult for drug companies to get people in order to test the vaccines and therapeutics. Obviously, they are hoping to delay the answer until after November 3rd. Must focus on speed, and saving lives! @SteveFDA,” Trump tweeted.

While Commissioner Hahn later commented in press interviews that he had never seen anything that resembled the “deep state” at the FDA, Lyman — who doesn’t mince words — feels the agency head should have had a much stronger reaction, and that the credibility of the entire agency was tarnished because Hahn did not do so.

“When Trump accuses the FDA of being part of the deep state and says they are working to slow down the progress of making the vaccine … to not have the head of the FDA counter this clearly and vigorously — I thought this was disgraceful and unconscionable,” says Lyman.

“I think Stephen Hahn needs to step down,” he concludes.

If it’s possible to put politics aside, a vaccine made available under an EUA may also invoke concern that vaccines are being approved too quickly. While historically there has only been one vaccine issued under an EUA,** the possibility of using the pathway for a COVID-19 vaccine has not been ruled out by the FDA or drugmakers. Top officials at the FDA have repeatedly promised (via published op-eds and interviews) that no shortcuts will be taken, even if an EUA is granted.

“We don’t have any intention of using EUA to take a vaccine of sub-optimal effect or an unproven vaccine forward,” Dr. Peter Marks, director of the Center for Biologics Evaluation and Research (CBER), stated during a mid-August press event.

Yet, many health experts continue to voice concerns surrounding the perception that a vaccine is being “rushed” to approval. In an Aug. 26 letter to Commissioner Hahn and Marks, the Infectious Diseases Society of America (IDSA) and HIV Medicine Association (HIVMA) strongly recommended the full licensure of a vaccine rather than an EUA, stating that “meeting the requirements for full approval is the surest route to maximum public trust and vaccine uptake.”

“It’s interesting how the speediness of the approval works against buy-in from the public to take the vaccine. There’s already a lot of misinformation out there, and getting through that is going be difficult enough — but I think if vaccines do come out under EUAs, it could be difficult to convince the public at large to take them,” says Chad Landmon, who chairs Axinn, Veltrop & Harkrider’s IP and FDA Practice Groups, frequently counseling on food and drug law.

For the pharma industry and government agencies alike, addressing the issue of vaccine skepticism and its spiderweb of causes has become a complex problem with no easy solution.

Imagining what’s at stake

“What is at stake is beyond imagination,” said Pfizer CEO, Albert Bourla, in a recent interview about developing COVID-19 vaccines.

The gravity of the situation on the surface is serious enough: With the pandemic death toll recently reaching a somber one million lives lost, a return to some semblance of normalcy rests on safe and effective vaccines — and, more specifically, people willing to take these vaccines.

But the issue at hand is not about defending the merits of vaccination — the vast majority of those who are expressing hesitancy about COVID-19 vaccines support vaccination in general. Instead, the implicit danger of this situation comes in the prospect of potentially losing people who may only be hesitant in this one particular situation, to the “other side” — and once people fall down the rabbit hole of anti-vaccination, they may be lost to science forever.

With vaccine confidence already historically low, a misstep by vaccine developers this far into the game could be catastrophic — having a ripple effect beyond the current coronavirus pandemic.

“In my mind, the absolute worst outcome here — worse than having no vaccine — is to come up with a vaccine that turns out to be not safe or not effective — or even both,” says Lyman. “Because that is going to cause people to doubt vaccines big time and pharma big time. And you’re going to see a dip in the number of people who are vaccinating their kids for measles and other illnesses. And that is going to result in a much greater increase in sickness and death across the country.”

Arthur agrees with the potential for serious repercussions.

“I think everyone is worried about that. I worry about there being a blowback on regular vaccines that have lots of data to them. I certainly worry that it undermines public health in general,” says Arthur.

Although wavering trust in vaccines is creating a tenuous situation for pharma, it’s a situation that could also break in pharma’s favor.

“The pharma industry’s reputation has suffered and this is a golden time for them to reverse public opinion by coming up with something effective in record time. That would do a tremendous good to resuscitate the industry. But if they screw it up, well…it will just further trash a reputation that’s already struggling,” says Lyman.

Perhaps no one recognizes reputational inflection points for the pharma industry more aptly than John LaMattina. In 2013, after touring the country for his first book and coming across so many people filled with anger about the pharma industry, LaMattina wrote a second book, “Devalued and Distrusted: Can the Pharmaceutical Industry Restore its Broken Image?”

“When I wrote ‘Devalued and Distrusted,’ pharma’s reputation was really in the pits,” says LaMattina.

“And while they’ve been slowly improving, things seem to have really turned around for them last March when a lot of companies basically dropped what they were doing and devoted resources to COVID-19. And what was fascinating was people suddenly started to get it. In this crisis, who’s going to come up with the therapeutics and vaccines? When you really want to gear up and run a clinical trial of tens of thousands of people and manufacture a billion doses of vaccines, only one place does that. And that’s the pharmaceutical industry,” says LaMattina.

While he is a self-proclaimed cheerleader for pharma’s response to the pandemic, LaMattina is quick to acknowledge that the industry needs to continue to confront misconceptions if it wants to gain back public trust, and much of this can be accomplished through transparency.

Ask and you shall receive

In many ways, the pharma industry has exceeded expectations — in some cases even granting items on hypothetical wish lists opined by industry experts — putting forth historic levels of transparency when it comes to COVID-19 vaccine development.

For example, several industry veterans have penned articles urging COVID-19 vaccine developers to adhere to the strictest of scientific standards when it comes to vaccine safety and efficacy. LaMattina was among those to make this request publicly. In an opinion piece published in Forbes, LaMattina stressed that it was imperative that biopharma companies unite behind the mantra, “We will issue no vaccine before its time.”

Just days later, industry vets (including LaMattina) got exactly what they asked for when nine vaccine makers released a joint pledge to continue to make the safety and well-being of vaccinated individuals the top priority in the development of the first COVID-19 vaccines.

The media was quick to label the pledge as “historic,” and those in the industry agree with this assessment. “I don’t remember anything of this nature ever,” says LaMattina.

The pledge, which included a bulleted list of four specific promises, was intended to provide reassurance to both health professionals and the general public that vaccine makers are committed to science and safety.

“I’m sure people recognize this is unusual. Drug companies coming out and saying ‘We’re not going to cut corners here. We’re not going to be forced into getting approval on something before it’s ready.’ It’s kind of hard not to notice that — certainly with doctors it had to resonate pretty well,” says LaMattina. “And it was the right thing to do.”

In another example, BIO, the biopharma industry’s largest trade association, published an open letter from several biopharma CEOs calling on their peers and the federal government to commit themselves to transparency when it comes to clinical trial data. “We believe that public health, and the public’s trust in new medical products, are dependent upon the integrity, transparency and objective assessment of new data as they emerge,” the letter stated.

Pharma’s most dramatic response to these calls for transparency came in mid-September when Moderna and Pfizer/BioNTech — both of which are involved in the government’s Operation Warp Speed push to produce 300 million doses of vaccine by January 2021 — released their phase 3 clinical trial protocols to the public. Days later, two more drugmakers tapped into the OWS initiative, AstraZeneca/University of Oxford and then Johnson & Johnson, did the same.

The protocols, which are each over 100 pages long, reveal details about trial participant selection and monitoring, safety parameters, and the evidence researchers will use to determine efficacy. It is unusual for drugmakers to reveal these trial blueprints or share data before the study has concluded.

Dr. Tal Zaks, chief medical officer for Moderna, told The New York Times that Moderna had consulted an outside ethics expert who advised the company that the only way to win trust was to be “transparent to the point of discomfort,” prompting the company to be the first to release the trial protocols.

Thou doth advocate too much

Dr. Alejandro Cane, who serves as the vice president, North America Medical and Scientific Affairs, Pfizer Global Vaccines at Pfizer agrees that transparency is the path to take when it comes to communicating about vaccines.

“From the beginning, [Pfizer] committed to be as transparent as possible during the vaccine development process and we will continue to do that,” he says.

Like many of the drugmakers developing potential COVID-19 vaccines, Pfizer has made information about its vaccine process and progress, including the recently added clinical trial protocol, prominently available on its consumer website. The company hosts a vaccine-themed podcast that discusses the scientific, cultural and political elements of vaccination. Pfizer has also recently announced plans to launch a direct-to-consumer education campaign as part of its COVID-19 strategy.

“I think companies are thinking long and hard about what they can be doing now to better reassure and inform the public about the strict safety and efficacy standards for new vaccines,” says Landmon, clarifying that a pharma company can’t make evidentiary claims about a vaccine if the data doesn’t yet exist.

It’s a fine line for pharma companies to walk when it comes to being vocal and transparent about vaccines in development, without overtly marketing them — especially when the general public perceives much of pharma’s actions as profit-driven.

When Moderna released early results from eight volunteers enrolled in the phase 1 clinical trial for its mRNA vaccine in mid-May, the drugmaker’s stock valuation soared. But scientists said the readout lacked meaningful data and critics came down hard on Moderna, accusing the company overhyping the findings just to boost shareholder value.

“It’s interesting because I don’t know what companies can do. There’s such a hunger for information. So if a company releases information in order to help with the national dialogue about whether or not a vaccine is plausible, how do they do that in a way that doesn’t cause people to accuse them of being opportunistic?” says Arthur.

“If you’re a pharma company and you make too heavy of a push, you risk all the credibility you’ve earned,” says LaMattina.

Drugmakers have taken a more neutral approach by collaborating with industry peers and government agencies to share information about vaccines.

“Public education is critical, and [Pfizer] aims to increase awareness of the importance of vaccinations in collaboration with patient organizations, medical and public health institutions,” says Cane.

It was Pfizer’s Bourla who issued a five-point plan early in the pandemic, calling on the biopharma industry to join Pfizer in committing to “unprecedented collaboration to combat COVID-19.” The plan called for all members of the “innovation ecosystem” including pharma companies, government agencies and academic institutions to commit to working together in addressing the pandemic. Bourla has been particularly vocal about Pfizer’s vaccine journey, speaking out directly against the politicization of vaccines, as well as addressing vaccine safety and vaccine skepticism candidly in numerous media appearances.

But now, with many projecting Pfizer will “win” the vaccine race — or at least, be the first company to submit its vaccine data package to the FDA for review — the drugmaker that has been most outspoken may find itself in the hottest seat in the house.

Uncertainties remain

On Sept. 10, Commissioner Hahn tweeted the FDA’s plans to issue expanded guidance on EUA for vaccines to prevent COVID-19. This was seen as an effort to shore up public confidence in vaccine safety and the agency itself.

Even before the guidance was made public, the agency indicated that the EUA criteria would be more rigorous than outlined in the previous guidance. On the same day Hahn announced that new guidance was forthcoming, Marks said that the standards for a vaccine EUA will look more like those of a full biologics licensure.

“If we are going to issue an EUA, it’s going to be like an EUA plus,” Marks said during a virtual Duke-Margolis Center for Health Policy meeting.

One of the more notable new provisions — reported through anonymous sources before the FDA released the guidance on Oct. 6 — is that vaccine manufacturers seeking an EUA must follow trial subjects for a median of at least 60 days after the subjects receive the final dose (which in most cases is the second dose) of the vaccine. 

This has landed critics and enthusiasts alike on the doorstep of Pfizer — the drugmaker who has been the most optimistic about a vaccine timetable — with Bourla repeatedly saying that a conclusive readout from Pfizer’s phase 3 mRNA vaccine trial is possible by the end of October. [Editor's note: On Oct. 16, 2020 Bourla posted a letter on the Pfizer website stating that the company will not apply for EUA of its vaccine before the third week of November]

The debate over the feasibility of an October vaccine from Pfizer has played out intensely in the media. Some argue that if the new EUA guidance were to be implemented, the math doesn’t add up to an October EUA for Pfizer — because Pfizer’s vaccine trial, which requires a second dose 21 days after the first dose, had not enrolled subjects early enough to allow for two months of follow-up by October.

But Bourla has doubled and tripled down on his timeline, despite the potential ramifications of releasing a vaccine during the most politically charged time of the year, calling Election Day “an artificial day” and vowing to produce the data when it’s ready.

Some public health experts aren’t satisfied. More than 60 researchers and bioethicists sent a letter to Bourla and the Pfizer board of directors, urging the drugmaker to wait until late November before filing an application for an EUA, in order to make sure that all trial participants have been monitored for a minimum of two months following administration of the second dose.

“There is too much at stake,” the letter concludes. “Submission of an application for an EUA before this standard is met would severely erode public trust and set back efforts to achieve widespread vaccination. In short, a premature application would prolong the pandemic, with disastrous consequences. The reputation of Pfizer and the pharmaceutical industry would be severely damaged.”

President Trump has called the new EUA guidance a “political move” and initially said the White House “may or may not approve it.” At present, it appears as though the FDA intends on following its guidelines even without the White House’s blessing. But no matter how the plotline unfolds, the result is mounting uncertainty and skepticism about vaccine safety.

With infectious disease experts warning of a likely cold-weather surge of coronavirus infections and deaths, the need for a safe and effective vaccine — and public acceptance of this vaccine — is at the forefront of public health.

Pharma’s role in producing vaccines is clear, but the industry’s role in building trust surrounding vaccines is more complicated to define. Above all, science and safety must prevail. In a situation where trust is dangling precariously by a thread, there is little margin for error.

“If we blow this — if we approve a vaccine too soon, and things go south, we will kill any hope of people accepting a COVID-19 vaccine. And that vaccine is our one real hope of getting beyond all this,” says LaMattina. “We’ve got to get it right.” 

Footnotes

* Pfizer is the only drugmaker involved in the Operation Warp Speed program who has recently expressed the possibility of an October timeline. As of Sept. 28, 2020, Pfizer reported having enrolled 35,369 participants across four countries for its phase 3 coronavirus vaccine trial. CEO Albert Bourla says the company could have “a conclusive readout” in late October and that if the results are positive, the company will immediately seek FDA approval.
[Oct. 16, 2020 editor's note: In a statement posted on the Pfizer website, CEO Bourla said that the company will not apply for emergency authorization of its coronavirus vaccine before the third week of November]

** The first use of the EUA authority was in 2005, when an EUA was issued for the military to use an anthrax vaccine, Anthrax Vaccine Adsorbed.