Introduction
Politicization of a COVID-19 vaccine may be causing a long-term safety issue for the U.S. public health. A poll administered by the Kaiser Family Foundation indicates that Americans are fearful of political influence on the development of a COVID-19 vaccine which may jeopardize the safety of any vaccine brought to market. More than half of poll participants said they would not be willing to take a free COVID-19 vaccine if it were available before the November presidential election. Another poll from Gallop similarly showed that more than one-third of poll participants would be unwilling to take a free FDA-approved vaccine if it were currently available.
The discourse in politics and media on the subject of a COVID-19 vaccine has created a reality where an individual’s point of view on a COVID-19 vaccine is directly tied to their political ideology; 85% of Democrats surveyed said they were worried about the FDA rushing a COVID-19 vaccine, while less than 35% of Republicans held the same viewpoint. President Trump recently claimed on Twitter that the FDA is delaying the development of a COVID-19 vaccine until after the November 3rd election. For many Americans, anti-mask and anti-quarantine rhetoric has further devalued the severity of the current outbreak. On the other side of the political spectrum, Vice Presidential candidate Kamala Harris recently questioned the safety of a pre-election COVID-19 vaccine developed through President Trump’s Operation Warp Speed during an interview she had with CNN. Internationally, a hastily approved COVID-19 vaccine in Russia was met with backlash from experts for its rush to market.
The result of these stories has been confusion among the general population about the validity of a COVID-19 vaccine. Notwithstanding the political debate, in comparison to past vaccine development initiatives, the COVID-19 timeline does appear to be extraordinarily fast. Does this mean corners are being cut for political gain? Is this an example of approval speed coming at the price of safety, or is the fear an unfounded result of continued politicization of the vaccine issue? Any unresolved questions of political considerations affecting the safety or efficacy of a COVID-19 vaccine should be quelled by examining the intensive safety data, regulatory oversight, and public scrutiny on this vaccine development process.
Government Approach to COVID-19 Vaccine Development – Operation Warp Speed
The Different Approach: A Public-Private Development Partnership
The government has taken a much different approach in response to COVID-19 compared to past outbreaks, and, as a result, is set for the timely distribution of vaccines. During the current COVID-19 outbreak, some experts have cited past vaccine development cycles to determine that a COVID-19 vaccine would likely not be ready in time to significantly help the current outbreak. On the other hand, the U.S. government’s top infectious-disease expert, Dr. Anthony Fauci testified before Congress in June that he was optimistic about a vaccine being available by the end of 2020 or early 2021. Since past outbreak vaccines have taken years to produce, how could Dr. Fauci confidently offer his testimony that a COVID-19 vaccine was achievable with less than one year of development?
Historically, vaccines have not been a lucrative investment for pharmaceutical companies. Cost margins are thin, risk is high, and prices are relatively low. This has often led to difficulties in motivating private pharmaceutical companies to even consider attempting to produce vaccines. However, the new approach, taken in part by the CDC, FDA, and HHS, for COVID-19 drastically mitigates the risk inherent in vaccine production for companies and properly incentivizes private research, development, and rapid production capacity.
The Goal
Rather than relying exclusively on the private sector for production on its own accord, as has been the case in the past, the CDC, FDA, NIH, DoD, and BARDA (the Biomedical Advanced Research Development Authority, an office of the Department of HHS which provided the development and distribution funding to private companies for vaccine development) have connected with private industry to fund massive development and distribution efforts for a COVID-19 vaccine. The stated goals of this initiative, known as Operation Warp Speed, included funding and streamlining the research, development, and testing of a COVID-19 vaccine. Though perhaps the most important goal is to accelerate manufacturing and distribution for products prior to gaining FDA approval. The timeline aims for delivery of 300 million doses of a COVID-19 vaccine by early 2021, with newer estimates expecting 700 million doses by March 2021. This plan required the U.S. government to take a calculated risk, as did other governments across the world, by pre-purchasing massive quantities of COVID-19 vaccines and absorbing development costs and risk of pharmaceutical companies.
The Execution
The U.S. government made several $1 billion purchases of 100+ million vaccine doses (with the option to buy hundreds of millions more doses) from several of the top companies researching a COVID-19 vaccine. The U.S. government has also taken the lead on the distribution of vaccines. The industry norm would be to wait for full FDA approval before setting up a supply chain, a time consuming and costly endeavor for a private business. But the new joint corporate-government venture should help facilitate getting vaccines to market as efficiently as possible. Governmental involvement in the distribution of a COVID-19 vaccine should reduce the need for profit-conscious private companies to extend the research and development stages for cost considerations. While, in most cases, a company would focus on getting their product to be as inexpensive as possible prior to bringing it to market, governmental pre-purchasing and assistant in distribution of vaccines will alleviate those considerations. A common example of this is the distribution of cold-chain needy vaccines which would normally cause companies to prolong development to make further adjustments (like accounting for room temperature stability). Now, they can bring a refrigerated vaccine to market without concern for the additional infrastructure requirements or the additional storage costs that eat away at margins. This approach, though incurring significant costs to the government, allows for dramatically streamlined development and distribution capabilities unlike anything this industry has seen before in order to get vaccines to market as soon as possible.
Pre-purchasing of vaccines by the government allows a supply chain ramp-up without having to wait until FDA approval is won. Products that are in the late stages of clinical trials (meaning they have not yet gained FDA approval) are already being manufactured at risk in anticipation of FDA approval. In most circumstances, getting a supply chain set up would require waiting until after FDA approval is won and would then take months to even begin seeing significant distribution capacity. Here, supply chains are already up and running for the frontrunning COVID-19 vaccines entering the final stages of clinical trials. AstraZeneca, who has a Phase III product (final stage), already has the capacity for 1 billion doses to be manufactured (with initial orders of 300 million and 100 million already placed by the U.S. and U.K., respectively). That supply chain capability, spurred by the U.S. government’s investments (and other world governments for international distribution), will be a major reason that a COVID-19 vaccine may get to market much faster than many historical examples of vaccines. Once a vaccine receives proper FDA approval, it can be distributed almost immediately.
“The deep state, or whoever, over at the FDA” is managing the FDA approval process
The question of FDA approval of a COVID-19 vaccine has been at the center of political turmoil. Terms like “fast-tracking” and “emergency use authorization” have been swirling around without an actual idea of whether that means that corners are being cut on the safety aspects of clinical trials. However, when it comes to safety, the answer is an emphatic no; safety standards will not have to be lowered. “Fast-tracking” from the FDA primarily focuses on waiving some of the time constraints of the drug approval process. For example, the FDA Director, Dr. Stephen M. Hahn, has stated that the FDA is willing to take in trial data before the completion of the final phases of clinical trials in an effort to expedite the approval process. He made clear that it is not a blind rubber-stamping of the vaccine. Instead, the data must show the necessary efficacy and safety metrics for approval, or else the FDA will require the producers to wait to collect all of the data in their trials and reassess.
The ongoing FDA oversight of COVID-19 clinical trials, in this case, is a significant factor that may aid speedy approval. Trials have FDA monitors investigating the safety of the products on an ongoing basis. Safety data can be (and, in the industry, commonly is) submitted to the FDA on a rolling basis with the final metrics on efficacy coming after the data is completely collected. The FDA issued specific guidance, to that end, on what data could be provided early. The “fast-tracking” of a vaccine is a result of the resources that the FDA, other governmental departments, and private companies are putting into this development. Data collection and analysis that, in other circumstances, could take months may take mere weeks because of the resources that companies are utilizing in an effort to get their data to the FDA. The FDA approval timeline, which, in a normal case, has waiting periods of 90 days before scheduling a conference with FDA reviewers could be reduced significantly for a COVID-19 vaccine. A review conference could occur quickly after data submission since the FDA will have dedicated many of its resources to analyzing COVID-19 vaccine data. Though the FDA may not be able to provide full approval in such a short time period, emergency use authorization could likely aid in the speedy rollout of COVID-19 vaccines for the most at-risk populations.
Emergency use authorization would allow the FDA to grant limited uses of medical products and treatments “to the extent feasible and appropriate given the applicable circumstances.” For COVID-19, this could mean the most at-risk populations for COVID-19—first responders, hospital personnel, adults aged 50 and over, or other populations—could receive the vaccine before it is available to the general public. Emergency use authorization is not a novel issue. Since being implemented as part of the Project BioShield Act of 2004 (and the subsequent bipartisan expansion under the Pandemic and All-Hazards Preparedness Reauthorization Act of 2013), many devices and therapies have been given emergency use authorization where a clear need is shown (especially during the 2009 H1N1 flu outbreak). Congress intended this act to streamline FDA approval, expand the treatments that can receive this authorization, and grant latitude to the FDA testing requirement in order to prepare the country to weather a pandemic.
The factors being examined by the FDA will require them to weigh the public health need (and the efficacy of the product in treating that need) with the safety concerns. Emergency use authorization will not require the FDA to accept any lower safety standard than is normally acceptable. Extremely large clinical studies (i.e., n=30,000+) looking at safety and efficacy from companies like AstraZeneca may be the most valuable information the FDA will receive when determining statistical significance for safety and efficacy and the value it will have for certain at-risk populations. Though this initial approval might not be available for all patient populations, these studies will be valuable for companies developing strategies to immediately distribute a COVID-19 vaccine to some of the most at-risk populations. When looking at the clinical trial data for the major players in the vaccine race, it is clear that stringent safety procedures are still in place.
Are the clinical trials for a COVID-19 vaccine subpar compared to other clinical trials?
The notion that the actual clinical trials for a COVID-19 vaccine are lacking in some regard does not hold any weight. The AstraZeneca Phase III trial, for example, is a double-blinded, quadruple-masked, placebo-controlled trial with 30,000 participants. The study obviously must garner results of safety and efficacy to present to the FDA for approval, but is this trial going to have any real value despite all of the criticisms that are swirling?
As with any statistical data interpretation, the conclusion must be backed up by a high level of statistical certainty. One easy way to decrease the overall variation in the trial and increase certainty in a result is by increasing the trial base (in statistical terms, your “n” value). With massive trial participation, the data will be able to clearly show both safety and efficacy to a high degree of statistical certainty because of the lower likelihood of results by random chance (or, in statistical terms again, your p-value)such a large patient population will produce.
Comparing some other contemporary examples of trials that led to FDA approval for vaccines and other treatments proves the scientific normalcy and validity of the COVID-19 vaccine trials:
Sanofi Pasteur’s 2005-06 vaccine for the common flu was a non-randomized 120-person trial (study start date to primary completion spanned September 2005- February 2006).
The Novartis 2009-10 vaccine for H1N1 (importantly, another novel virus) completed its single-blind study (started in September 2009 and with a primary completion date of November 2009) and submitted that data to the FDA with approximately 2,700 adult participants.
In the non-vaccine area, the FDA recently approved Remdesivir (a drug originally meant to treat Ebola) for the treatment of COVID-19. Their trial was completed through an open-label trial of approximately 5,000 participants (with a start to primary completion timeline of just over one month).
The FDA itself recently stated that pre-licensure clinical studies typically use a population of approximately 3,000 participants. After approval, the populations may expand to important subpopulations (pregnant women, children, individuals with comorbidities, etc.). With the trials being conducted for a COVID-19 vaccine by companies like AstraZeneca, Moderna, Pfizer, and Johnson & Johnson, the FDA should be able to make a clear judgment on the data despite the consolidated approval process. All of the listed companies plan to (or have already begun) enrolling between 25,000-60,000 participants in late-stage trials that should enable determinations of the efficacy and safety of a large population. Once these trials lead to a vaccine’s approval for limited uses, more trials on expanded subpopulations will soon follow.
Conclusion
The timelines for the concluding clinical trials seem to indicate a vaccine may not be hitting the market before the election in November, but it is likely not far behind. The public pressure on the COVID-19 vaccine development is unprecedented. One clinical trial participant’s illness (out of 30,000 total participants) became international news several weeks ago and caused a swarm of regulators and independent examiners to intensely investigate whether or not it was a vaccine-related complication. With the number of ongoing clinical trials that are in all stages of development (upwards of 130), many independent review boards and safety boards have already begun examining the safety of these products. Ultimately, there is no need for a tradeoff between rapid development and safety. The factors that allow a speedy getting-to-market process should not, in any way, compromise the safety of a COVID-19 vaccine. As top execs from many biopharma companies emphasized after President Trump tweeted about a perceived FDA conspiracy to stop vaccine production, politics need not, and should not, come into play in the conduct of clinical trials for the evaluation of a safe and effective COVID-19 vaccine.
Matthew Gallotto is a second-year student at Northeastern University School of Law. Matthew holds a bachelor’s degree in finance from the University of Massachusetts Amherst, where he also worked for a legal services office that aided students in a variety of legal matters. Matthew’s legal interests include the biotech and finance industries and matters relating to emerging companies. At Northeastern, Matthew is a member of the Business Law Society and an associate editor on the Northeastern University Law Review.