Operation Warp Speed: A Legal Analysis of the Vaccine Development Process and How We Got Here

3.1 Exploratory Stage

The exploratory stage typically consists of development of vaccine candidates and in vitro testing.^[19] Here, researchers are identifying natural or synthetic molecules that may show promise in developing immunogenicity.^[20] This stage’s length will vary, but will generally take several years.^[21] Once a vaccine candidate has been identified and tested through various lab methods, the process will progress to the preclinical trial stage.^[22]

3.2 Preclinical Stage

In this stage, more experimentation and animal testing is done to ensure enough data is gathered to file an Investigational New Drug Application (IND).^{[23] [24]} While it is not necessary to notify the FDA of preclinical testing at this point, the preclinical testing is governed by FDA regulations known as the Good Laboratory Practice (GLP) regulations.^[25] The GLP regulations set out minimum standards for laboratory work and facilities for nonclinical studies that will be used to support an IND.^[26] Areas governed by the GLP include personnel, facilities, equipment, operating procedures, animal care, study protocols, record keeping, and reporting.^[27] The GLP regulations also allow the FDA to inspect the facilities and records to ensure compliance.^[28] If the regulations are not followed, the FDA can impose sanctions, disqualify testing facilities, disregard preclinical studies, and may even withdraw the application’s approval.^[29]

3.3 Clinical Trial Stage

After preclinical testing is completed, the next step is to conduct clinical trials in humans.^[30] However, to be allowed to test vaccines in humans, the sponsor must apply for an IND. The IND application includes data from preclinical studies and lays out the sponsor’s plan for conducting the clinical trials.^[31] The FDA will evaluate the data based on how sound it is, whether the methods used were adequate, and whether the vaccine is safe enough for use in humans subjects.^[32] If the FDA finds issues with the application, they may issue a clinical hold to prevent the sponsor from beginning clinical test trials.^[33] If the FDA does not object to the IND within 30 days of submitting the application, the sponsor may begin clinical tests.^[34]

Once the IND has been approved, the clinical testing of the vaccine may begin.^[35] The clinical testing stage is generally split into three phases called Phase 1, Phase 2, and Phase 3, respectively.^[36] These phases may overlap, and Phase 1 and 2 trials may have to be repeated as new data becomes available.^[37] Phase 1 trials are typically designed to determine the safety and tolerability of the vaccine to obtain preliminary immunogenicity data.^[38] These trials are conducted with around 20 to 80 human subjects that are closely monitored for adverse effects.^[39] Phase 2 trials are used to further evaluate immunogenicity, provide rates of common adverse effects, and obtain data needed to design Phase 3 studies.^[40] Phase 2 trials are conducted with several hundred human subjects.^[41] Phase 3 trials are large in scale and can involve several thousand human subjects.^[42] The goal of Phase 3 trials is to obtain critical safety and efficacy data needed to support licensure.^[43] Efficacy should be shown in randomized, double-blind, and well-controlled studies that may involve up to tens of thousands of human subjects.^[44]

3.4 FDA Review and Approval

Once clinical test trials are completed, the next step is to file a Biologics License Application (BLA).^[45] A BLA is a request to introduce a biological product to interstate commerce.^[46] The BLA will contain data from clinical and nonclinical studies that show that the vaccine meets the requirements for safety, purity, and potency.^[47] The BLA will also contain information regarding manufacturing, compliance of GLP regulations, data regarding the stability of the vaccine through a dating period, samples representing the vaccine, and information regarding the equipment and facilities used for manufacturing.^[48] A CBER review team will review the BLA and determine if the vaccine is safe and effective.^[49] The review team may also request that the sponsor present the data to the Vaccines and Related Biological Products Advisory Committee (VRBPAC).^[50] The VRBPAC is an FDA advisory committee that is made up of scientific experts and clinicians, consumer representatives, and nonvoting members from industry.^[51] The role of the VRBPAC is to evaluate the clinical data and comment on the data’s adequacy.^[52] CBER’s decisions are strongly influenced by the VRBPAC’s findings.^[53]

4.1 Fast Track Designation

Fast Track designation was implemented by Congress in the Food and Drug Administration Modernization Act of 1997 because they were concerned about the length of time that a new drug or therapy may take to develop and review, particularly in emergencies.^[59] A sponsor may request Fast Track designation if the new therapy demonstrates the potential to address unmet medical needs or a serious condition.^[60] The amount of data needed will depend on the stage of development.^[61] If the therapy is in an early stage of development, then evidence of activity in nonclinical models, mechanistic rationale, or pharmacological data may be considered to show the therapy’s potential.^[62]

Fast Track Designation allows or more frequent opportunities of interaction with the review team of the fast track therapy.^[63] These interactions could include meetings with the FDA, pre-IND meetings, end of Phase 1 meetings, end of Phase 2 meetings, meetings to discuss study design, meetings regarding the safety data required to support approval, etc.^[64] If the FDA determines that the fast track product may be effective, then the Fast Track designation allows for rolling review of portions of the marketing application before the sponsor completes and submits the BLA.^[65] The FDA will analyze the protect’s benefit and safety using a qualitative benefit- risk assessment pictured below (Figure 2).^{[66] [67]}

Figure 2:

FDA benefit-risk assessment framework.⁶⁷

There is a question however, of whether Fast Track designation would be “speedy” enough for a situation such as the COVID-19 pandemic, where a vaccine may have to be developed and approved in a matter of months. The issue would lie with the fact that while Phase 3 clinical trials may not be necessary at the time of BLA approval, Phase 1 trials and at least one Phase 2 trial will be necessary for the therapy to be approved.^[68] While this may drastically speed up the timeline when compared to the traditional process, approval may still take too much time in scenarios such as a pandemic involving an easily transmittable disease.

4.2 Breakthrough Therapy Designation

Breakthrough Therapy designation was created by the Food and Drug Administration and Safety and Innovation Act of 2012 as another method of decreasing the time for drug development and review.^[69] A sponsor must show substantial improvement over existing therapies in one clinically significant “endpoint” during early development in order to request breakthrough therapy designation.^[70] A clinically significant end point is “an endpoint that measures an effect on irreversible morbidity or mortality (IMM) or on symptoms that represent serious consequences of the disease.”^[71] This designation requires preliminary clinical evidence; however, the standard for reviewing the evidence is not as high as in the traditional process.^[72] In this case, preliminary clinical evidence is defined as “evidence that is sufficient to indicate that the drug may demonstrate substantial improvement in effectiveness or safety over available therapies, but in most cases is not sufficient to establish safety and effectiveness for purposes of approval.”^[73] While not as stringent of a standard, the FDA will still focus on ensuring that the therapy is safe and has the appropriate level of efficacy.^[74] If the FDA notes that subsequent data no longer shows the therapy as providing a substantial improvement, then the FDA may withdraw the designation (Figure 3).^[75]

Figure 3:

Breakthrough therapy designation process/timeline.⁷⁶

Achieving Breakthrough Therapy designation allows the sponsor to begin receiving advice from the FDA as early as Phase 1 of clinical trials as well as guidance from a proactive collaborative team of reviewers.^{[76] [77]} In addition, the designation allows for rolling review of marketing application as well as assistance in obtaining priority review at the time the BLA is submitted.^[78] While the Breakthrough Therapy Designation may decrease the time it would normally take to get a therapy approved, timelines show that the approval process is cut down by a couple of years at most, resulting in a process that would still take several years to complete.^[79]

4.3 Accelerated Approval

Accelerated approval was implemented under the original Prescription Drug User Fee Act of 1992 (PDUFA) and was a response to criticism of the lengthy approval process timeline for drugs and biologics.^[80] Accelerated Approval is used for circumstances where the approval process for a promising therapy should be expedited so that patients with serious conditions may access the treatment.^[81] Accelerated Approval is based on a surrogate endpoint which is a sort of marker such as “a laboratory measurement, radiographic image, physical sign or other measure that is thought to predict clinical benefit, but is not itself a measure of clinical benefit.”^[82] It may also be based on intermediate clinical endpoints which are measurements of therapeutic effect that can be measured earlier than an effect on IMM and is considered to be reasonably likely to predict the drug’s effect on IMM or other clinical benefit.^[83] Whether the endpoint would reasonable predict clinical benefit depends of the biological plausibility of the relationship between the endpoint, the disease, the desired effect, and the evidence to support the relationship (Figure 4).^{[84] [85]}

Figure 4:

Accelerated approval process/timeline.⁸⁵

4.4 Priority Review

In addition to Accelerated Review, the PDUFA also established a two tiered system of review times consisting of Standard Review and Priority Review.^[86] If an application is designated under Priority Review, then the FDA’s must take action on the application within six months instead of 10 months as is with Standard Review.^[87] An application will receive this designation if the therapy treats a serious condition and would provide a significant improvement in safety or effectiveness.^[88] Once the designation has been given, attention and resources will be directed towards the speedy evaluation of the therapy.^[89]

A significant improvement in safety or effectiveness against a serious condition can be shown through evidence of increased effectiveness in treatments, prevention or diagnosis of the condition, the elimination or substantial reduction of treatment-limiting adverse reaction, the documented enhancement of patient compliance that would lead to improvement in serious outcomes, or evidence of safety, and effectiveness in a new subpopulation.^[90]

4.5 Fast Enough?

While the programs the FDA has in place for expediting drugs and vaccines may help to get a new therapy out to the public a few years sooner that initially expected, an unprecedented event, such as a pandemic, may require a much quicker timeline than the current programs would be able to provide, even if working in conjunction with one another. In 2001, the European Commission held a conference in Brussels called “Pandemic Preparedness in the Community” in which the commission concluded that the next pandemic was imminent, and that the world was not prepared for it.^[91] Vaccine availability being one of the factors for that conclusion.^[92]

5.1 FDA Emergency Use Authorization

EUA allows for temporary FDA authorization for unapproved emergency uses of a medical product.^[127] The Pandemic and All-Hazards Reauthorization Act of 2013 (PAHPRA) added sections that describe the use of EUAs in response to a chemical, biological, radiological, or nuclear (CRBN) agent.^[128] When the Secretary of Health and Human Services issues an emergency declaration regarding a CRBN, EUA may begin to take place.^[129] To be granted EUA, the FDA must making the following findings: The CBRN threat is able to cause serious or life-threatening disease or condition; the EUA candidate may be effective to prevent, diagnose, or treat the condition; the known and potential benefits of the product seeking the EUA outweigh the known and potential risks; and there are no adequate, approved, and available alternative to the product to be authorized.^[130]

Previously, EUAs were established for the Zika Virus, Ebola Virus, Middle East Respiratory Syndrome Coronavirus (MERS-CoV), H1N1 Influenza, and Anthrax Vaccine Adsorbed (AVA).^[131] The FDA may issue EUAs for as long as the PAHPRA emergency declaration is active.^[132] The EUA will be considered terminated once the HHS Secretary has declared that the PAHPRA emergency has ended, the FDA approves a marketing application for the EUA which renders it moot, or the FDA revokes the EUA (Figure 6).^[133]

Figure 6:

Emergency use authorization with OWS.¹³⁴

In October 2020, the FDA published a nonbinding guidance document called Emergency Use Authorization for Vaccines to Prevent COVID-19: Guidance for Industry.^{[134] [135]} Once a vaccine candidate has been reviewed by the FDA, the sponsor may then request an EUA for the vaccine.^[136] The issuance of the EUA would hinge on a determination by the FDA on whether the vaccine’s benefits outweigh the risks based on the data collected from at least one well-designed Phase 3 trial.^[137] The data would have to demonstrate, in a clear and compelling manner, that the vaccine is safe and effective.^[138] Additionally, the sponsor would have to show an adequate plan for the collection of safety data of people vaccinated under the EUA, as well as show a plan for ongoing clinical trials to assess long-term safety and efficacy.^[139] At this point, a BLA has not been issue, therefore, the sponsor would also have to apply for the BLA.^[140] As of November 18, 2020, there are currently no vaccines that have been issued an EUA, but there are some vaccine candidates reporting satisfactory safety and efficacy data that may be applying soon.^[141]

7.1 Automatic Integration of FDA Guidance and Review throughout Clinical Trial Phases

The integration of FDA guidance and review throughout the entire vaccine development process in OWS is a huge reason that vaccine development for a COVID-19 vaccine has been able to maintain standards for safety and efficacy while remaining speedy. Although in a non-pandemic situation such a quick turn around would not be necessary, automatic, early integration of FDA guidance and review would likely greatly decrease the time frame for the development of needed vaccines and drugs so that they could be put out to the public more readily. Although it would not be feasible to have early FDA intervention with every therapy candidate, a higher standard of evidence showing potential to treat conditions could help with prioritizing which therapies the FDA chooses to guide through the process.

7.2 Increased Funding for Conducting Clinical Phase Trials

Another reason why OWS has been as successful as it has is due to the funding available for conducting trials, which removes the financial hurdle of being able to complete the trials. For therapies that show high promise in drastically changing the outcome of a serious condition, the FDA should more readily offer funding so that trials can be conducted seamlessly without the burden of waiting for financial backing from outside sources. The FDA could provide an application process to request funding similar to how the application processes are for the current expedited programs.

7.3 Provide Incentives for Development of Accelerated Vaccine and Drug Approval Plans for Different Scenarios

OWS was started from the ground up as a novel plan for major expedition for vaccine development in a pandemic scenario. While OWS provides a good groundwork for other situations, the FDA should incentivize scientists and experts to come up with thorough plans for other events that may occur, such as a biological attack or a radiation attack. Having multiple fleshed out plans for different scenarios could greatly increase the chance of mitigating huge economic and human loss simply because the United States would be prepared and would have ideas for development, manufacturing, and distribution already in place.

7.4 Increasing Time for Vaccination Injury Compensation

In the case of injury from a COVID-19 vaccine, the deadline for filing a claim should be increased from one to several years. This is because of long-term, adverse side effects would not be known because the vaccine was delivered so quickly, so people would not have fair notice of possible long-term effects until it happens to them, and by then it would be too late to file. While post market surveillance and use of the Vaccine Adverse Event Reporting System may help to mitigate the effects of an adverse event, it would not be equitable to only allow people a short time to be compensated for injury, especially since manufacturers, distributors, healthcare providers administering medical countermeasures, state and federal government, and their agents are given further broad liability protection from the PREP Act.^[158] Under the PREP Act, an actor would only be liable if willful misconduct that caused death or serious injury is shown.^[159]