Expediting a COVID-19 Vaccine: FDA Approval Process
By Kristin Brooks, Managing Editor | 09.09.20
The pressures of the pandemic are pushing sponsors and FDA to look at both efficacy and speed in developing a vaccine.
While the usual time it takes to develop a vaccine is roughly 10 years, an unprecedented effort is underway to develop a COVID-19 vaccine within a year to address the global pandemic. Chad Landmon of Axinn, Veltrop & Harkrider LLP walks us through the typical FDA approval process and how the processes for a coronavirus vaccine may differ due to the global pressure to develop and approve one quickly. He also discusses considerations that may go into the FDA disclosing certain details around the approval process.
Contract Pharma (CP): How does the FDA approval process typically work for vaccines?
Chad Landmon (CL): Vaccines follow an approval pathway that is similar to that of biologic drug products. The vaccine sponsor first submits an Investigational New Drug (IND) application to FDA. As with drugs, the IND incudes information about the vaccine, such as vaccine excipients, safety data from preclinical testing in animals, labeling, and protocols for the proposed clinical trials. The IND application also includes efficacy data, which evaluates the vaccine’s ability to raise the desired immune response.
The next step is to conduct three phases of clinical trials in humans. Phase 1 studies are small studies to demonstrate safety and immunogenicity; Phase 2 studies are somewhat larger dose-ranging studies; and Phase 3 studies are very large with thousands of subjects with researchers evaluating safety and efficacy. If the study data supports efficacy and safety, the vaccine sponsor submits a Biologics License Application (BLA), which includes the safety and efficacy findings from the clinical trials. FDA then evaluates the data and may approve the vaccine for marketing. Sponsors will generally conduct Phase 4 studies once the vaccine is approved, and these studies are larger and longer to gather data about long-term safety and efficacy.
CP: How are the processes for a coronavirus vaccine different due to the global pressure to develop and approve one quickly?
CL: COVID-19 has pushed fast-forward on the vaccine approval process. Although the steps should be the same, everything has been accelerated due to the need to get a safe and effective vaccine on the market quickly. The normal timeline from preliminary research to vaccine approval is about a decade, and the fastest development has been about four to five years. It is clear that the world can’t wait that long, so we’re seeing several sponsors combine Phase 1 and 2 trials to speed up the process.
In addition to the complexity and time it takes to complete the studies, sponsors are also facing difficulties caused by the pandemic itself. For example, supply chains across the industry have been disrupted and some sponsors might be having difficulty enrolling a sufficient number of people in the studies.
FDA guidance states that the primary efficacy endpoint should be at least 50%, i.e., that the coronavirus vaccine is effective in at least 50% of individuals who have had the vaccine. For comparison, the efficacy of a flu shot is about 40-60%, whereas the MMR (measles, mumps, rubella) vaccine is highly efficacious and protects about 99% of vaccinated individuals. But we aren’t looking for perfection here. We’re looking for a vaccine to be used as a tool in a multifaceted approach to controlling the pandemic, which also includes mask wearing and physical distancing. The pressures of this pandemic are pushing sponsors and FDA to look at both efficacy and speed in developing the vaccine to find an appropriate balance.
CP: What additional hurdles might the FDA face in the approval process?
CL: It is possible that FDA will reassess the 50% primary efficacy endpoint in the guidance. If a flu vaccine is 40-60% effective, it might still be worth pursuing a coronavirus vaccine that fails to meet the primary endpoint but is able to meet a secondary endpoint that is slightly lower. For a first-generation vaccine, FDA will likely need to ask some difficult questions about the cost-benefit of a vaccine that might not hit the required efficacy endpoints. This is where an emergency use authorization might come in, which is distinct from the standard approval. For example, with a vaccine that doesn’t quite meet an efficacy endpoint, FDA might grant an emergency use authorization and suggest that the sponsor go back to the drawing board if it wants to try for a second-generation vaccine that is more efficacious. Although such an approach may be beneficial because we would have a vaccine on the market that works in some percentage of inoculated individuals, we do have to worry whether having a less effective vaccine on the market may further undermine the public’s confidence in taking vaccines.
Safety is a less flexible consideration. FDA will likely stick to strict safety requirements, especially because this vaccine will need to be quickly administered to millions of individuals. There won’t be much time, however, to evaluate if there are any adverse events that weren’t identified in the smaller studies before rolling out the vaccine to millions or hundreds of millions of individuals. Monitoring for adverse events could be difficult as well, particularly because fever is a common side effect of vaccines and is also a common symptom of COVID-19 (and many other viruses).
Of course, if there are significant side effects, but they’re less serious than complications of COVID-19, FDA might have to make some difficult decisions to determine whether the benefits outweigh the risks, especially if FDA considers granting an emergency use authorization for a particular vaccine.
CP: What considerations may go into the FDA disclosing certain details around the approval process?
CL: One of the most important features of a vaccine is that the public trusts its safety and efficacy. Without trust, the public is going to be apprehensive about taking a coronavirus vaccine, especially considering the expedited approval process. With that in mind, it is likely that FDA will strive to be as transparent as possible to assuage the public. On the other hand, some of this information will be confidential, and the vaccine sponsor might not want to reveal certain information, especially relating to manufacturing processes and other trade secrets. The sponsor will also have to evaluate whether releasing confidential information might be beneficial, especially as it relates to the public’s trust.
To a certain extent, however, the approval process is known to the public. Vaccines must pass Phase 1, 2, and 3 studies, and data from post-approval Phase 4 studies is also routinely evaluated. Additionally, the public has access to certain information about clinical studies on ClinicalTrials.gov. But regarding information that is not normally available to the public, we might see coordination between FDA and the vaccine sponsor in deciding what information to release.
It has been said many times about COVID-19, but is worth repeating: we are in unprecedented times. With a modern global pandemic and coordination among many public health entities, the scientific community has the opportunity to advance innovation and discovery in a way we really haven’t seen before. As a regulatory agency, FDA plays a crucial role by interfacing not only with vaccine producers but also with the public at large to create confidence that any vaccine hitting the market will be an effective and safe tool in the fight against COVID-19.
Chad Landmon chairs Axinn, Veltrop & Harkrider LLP’s Intellectual Property and Food and Drug Administration Practice Groups and focuses his practice on patent litigation and counseling and food and drug law, with an emphasis on pharmaceuticals, biologics, medical devices, and human tissue products. He maintains a particular focus on patent trial work and FDA litigation, having served as a first chair trial lawyer on multiple cases and having litigated over 50 cases during the past 10 years alone, many of which have included products with billions of dollars in annual sales.
Contract Pharma (CP): How does the FDA approval process typically work for vaccines?
Chad Landmon (CL): Vaccines follow an approval pathway that is similar to that of biologic drug products. The vaccine sponsor first submits an Investigational New Drug (IND) application to FDA. As with drugs, the IND incudes information about the vaccine, such as vaccine excipients, safety data from preclinical testing in animals, labeling, and protocols for the proposed clinical trials. The IND application also includes efficacy data, which evaluates the vaccine’s ability to raise the desired immune response.
The next step is to conduct three phases of clinical trials in humans. Phase 1 studies are small studies to demonstrate safety and immunogenicity; Phase 2 studies are somewhat larger dose-ranging studies; and Phase 3 studies are very large with thousands of subjects with researchers evaluating safety and efficacy. If the study data supports efficacy and safety, the vaccine sponsor submits a Biologics License Application (BLA), which includes the safety and efficacy findings from the clinical trials. FDA then evaluates the data and may approve the vaccine for marketing. Sponsors will generally conduct Phase 4 studies once the vaccine is approved, and these studies are larger and longer to gather data about long-term safety and efficacy.
CP: How are the processes for a coronavirus vaccine different due to the global pressure to develop and approve one quickly?
CL: COVID-19 has pushed fast-forward on the vaccine approval process. Although the steps should be the same, everything has been accelerated due to the need to get a safe and effective vaccine on the market quickly. The normal timeline from preliminary research to vaccine approval is about a decade, and the fastest development has been about four to five years. It is clear that the world can’t wait that long, so we’re seeing several sponsors combine Phase 1 and 2 trials to speed up the process.
In addition to the complexity and time it takes to complete the studies, sponsors are also facing difficulties caused by the pandemic itself. For example, supply chains across the industry have been disrupted and some sponsors might be having difficulty enrolling a sufficient number of people in the studies.
FDA guidance states that the primary efficacy endpoint should be at least 50%, i.e., that the coronavirus vaccine is effective in at least 50% of individuals who have had the vaccine. For comparison, the efficacy of a flu shot is about 40-60%, whereas the MMR (measles, mumps, rubella) vaccine is highly efficacious and protects about 99% of vaccinated individuals. But we aren’t looking for perfection here. We’re looking for a vaccine to be used as a tool in a multifaceted approach to controlling the pandemic, which also includes mask wearing and physical distancing. The pressures of this pandemic are pushing sponsors and FDA to look at both efficacy and speed in developing the vaccine to find an appropriate balance.
CP: What additional hurdles might the FDA face in the approval process?
CL: It is possible that FDA will reassess the 50% primary efficacy endpoint in the guidance. If a flu vaccine is 40-60% effective, it might still be worth pursuing a coronavirus vaccine that fails to meet the primary endpoint but is able to meet a secondary endpoint that is slightly lower. For a first-generation vaccine, FDA will likely need to ask some difficult questions about the cost-benefit of a vaccine that might not hit the required efficacy endpoints. This is where an emergency use authorization might come in, which is distinct from the standard approval. For example, with a vaccine that doesn’t quite meet an efficacy endpoint, FDA might grant an emergency use authorization and suggest that the sponsor go back to the drawing board if it wants to try for a second-generation vaccine that is more efficacious. Although such an approach may be beneficial because we would have a vaccine on the market that works in some percentage of inoculated individuals, we do have to worry whether having a less effective vaccine on the market may further undermine the public’s confidence in taking vaccines.
Safety is a less flexible consideration. FDA will likely stick to strict safety requirements, especially because this vaccine will need to be quickly administered to millions of individuals. There won’t be much time, however, to evaluate if there are any adverse events that weren’t identified in the smaller studies before rolling out the vaccine to millions or hundreds of millions of individuals. Monitoring for adverse events could be difficult as well, particularly because fever is a common side effect of vaccines and is also a common symptom of COVID-19 (and many other viruses).
Of course, if there are significant side effects, but they’re less serious than complications of COVID-19, FDA might have to make some difficult decisions to determine whether the benefits outweigh the risks, especially if FDA considers granting an emergency use authorization for a particular vaccine.
CP: What considerations may go into the FDA disclosing certain details around the approval process?
CL: One of the most important features of a vaccine is that the public trusts its safety and efficacy. Without trust, the public is going to be apprehensive about taking a coronavirus vaccine, especially considering the expedited approval process. With that in mind, it is likely that FDA will strive to be as transparent as possible to assuage the public. On the other hand, some of this information will be confidential, and the vaccine sponsor might not want to reveal certain information, especially relating to manufacturing processes and other trade secrets. The sponsor will also have to evaluate whether releasing confidential information might be beneficial, especially as it relates to the public’s trust.
To a certain extent, however, the approval process is known to the public. Vaccines must pass Phase 1, 2, and 3 studies, and data from post-approval Phase 4 studies is also routinely evaluated. Additionally, the public has access to certain information about clinical studies on ClinicalTrials.gov. But regarding information that is not normally available to the public, we might see coordination between FDA and the vaccine sponsor in deciding what information to release.
It has been said many times about COVID-19, but is worth repeating: we are in unprecedented times. With a modern global pandemic and coordination among many public health entities, the scientific community has the opportunity to advance innovation and discovery in a way we really haven’t seen before. As a regulatory agency, FDA plays a crucial role by interfacing not only with vaccine producers but also with the public at large to create confidence that any vaccine hitting the market will be an effective and safe tool in the fight against COVID-19.
