Last updated on March 10th, 2021 at 11:30 am

This article about the Informed Consent Action Network’s petition to halt COVID-19 vaccine trials was written by Viridiana Ordonez, a J.D. candidate at the University of California, Hastings College of Law. 

This article summarizes the FDA’s response to Del Bigtree’s ICAN’s (petitioner) request regarding the Phase III trials for the COVID-19 vaccine.  The summary is divided into three parts:

1. Petitioner’s Request;
2. FDA’s description of vaccine process; and
3. FDA’s response to the petition.

ICAN’s request for COVID-19 vaccine trials

FDA’s response is based on ICAN’s four requests on his citizen petitioner (CP, in this case, ICAN) dated August 17, 2020, and the petition for an administrative stay of action (PSA), dated August 19, 2020. ICAN requested that: 

1.  any and all adverse events and reactions will be documented for the entire duration of the trial;
2. such documenting of adverse events and reactions shall last at least twelve months for adults, thirty-six months for children, and sixty months for infants and toddlers;
3. it uses an adequate sample size, appropriately powered, in order to (i) detect an increase in rare adverse events or, any untoward medical occurrence, whether or not considered vaccine-related, and (ii) determine that the rate of adverse events from the vaccine will not exceed the rate of adverse events known to occur from SARS-CoV-2; and
4. participants are tested for T-cell reactivity to SARS-CoV-2 pre-vaccination and post-vaccination. (see pages 1-2 of FDA response).

In his PSA, ICAN requested a stay on Phase III of the trial for mRNA-1273 until the study design implements the four requests on the CP for the duration of the trial.

The FDA denied the petitions because ICAN did not show any reasonable ground for the FDA to grant the requests.

FDA description of the process

I. Vaccines Are Safe

FDA has a strict regulatory process for licensing vaccines. First, the Public Health Service Act (PHSA) authorizes the FDA to license vaccines if the vaccines have demonstrated to be safe, pure and potent. In order to come to that determination, vaccines have to first be tested in non-clinical studies and on humans.

Sponsors of a vaccine must submit data before a vaccine can be licensed, including but not limited to:

1. data derived from nonclinical and clinical studies showing the product’s safety, purity, and potency;
2. a description of manufacturing methods for the vaccine;
3. data establishing the product’s stability; and
4. a representative sample of the product and summaries of results of tests.

After this data is submitted, the FDA reviews and evaluates the sponsor’s data and information to determine whether the vaccine is in fact safe, pure and potent. Only after that determination can a vaccine can be licensed.

The FDA continues to monitor vaccines to detect any “rare, serious, or unexpected adverse events” through the use of multiple surveillance methods. As a result, the United States has a very safe vaccine supply.

II. An EUA for A Vaccine Is Issued Only if It Meets Relevant Statutory Standards

The Secretary of Health and Human Services (HHS) determined that COVID-19 is a public health emergency with the potential to affect the health and security of U.S. citizens. The FDA then issued an emergency use authorization (EUA) for the Pfizer and Moderna vaccines under the Food, Drug and Cosmetics Act § 564 and 21 U.S.C. § 360bbb-3.

Before the FDA can issue a EUA, it must conclude the following requirements are met:

1. SARS-CoV-2 can cause a serious or life-threatening disease/condition;
2. Based on the totality of scientific evidence available, it is reasonable to believe that the product may be effective in diagnosing, treating, or preventing the disease or condition that can be caused by SARS-CoV-2;
3. the known and potential benefits of the product to treat the condition outweigh the known and potential risks of the product; and
4. there is no adequate, approved, and available alternative to the product for diagnosing, preventing, or treating conditions.

EUAs are governed under a different statutory framework than Biologics Licensure Application (BLA), but the FDA has made clear that issuance of a COVID-19 vaccine must demonstrate clear and compelling safety and efficacy throughout the Phase III clinical trial. A Phase III trial involves a large number of people that receive either an investigational vaccine or a control. The efficacy is studied by comparing both groups.

The FDA expects that after the submission of a EUA request and issuance of a EUA, sponsors will continue to evaluate the vaccine and work towards submitting a BLA.

III. Process for investigational dew drugs (IND)

Before a vaccine is approved by FDA for use by the public, the vaccine must undergo a rigorous and extensive development program to determine the vaccine’s safety and effectiveness.

This program includes preclinical research and clinical studies. During the preclinical stage, the sponsor collects data and information to establish that the vaccine does not expose humans to unreasonable risk.

Before starting the clinical studies, the sponsor must submit an investigational new drug application (IND) to the FDA. The IND must describe the proposed study as well as the protection and rights of the subjects and must also include information on the clinical protocols and investigators. This information is necessary to allow the FDA to assess whether the initial trials will expose humans to unnecessary risks.

After the IND is submitted, a sponsor must wait 30 days before initiating a clinical trial while the FDA reviews the application. Once the application is approved, the investigation is divided into three phases. Phase I studies focus on safety and immunogenicity studies performed in a small number of subjects; Phase II studies provide information about short-term side effects, and Phase III studies provide information and data on the effectiveness and safety measures required for licensing the vaccine.

At any point, the FDA may stop or request additional studies. The FDA can also issue a clinical hold to prohibit investigations if necessary.

FDA’S response to the petition

In its response to the petition, the FDA addresses each of the four requests the petitioner made as well as his request for a stay of action.

I. Both Petitioner’s Request for Documentation of All Adverse Events and Request for Documentation for Specified Periods of Time Are Denied.

The FDA determined that specified adverse event monitoring as Petitioner requests is not required. FDA has addressed this issue in its June 2020 Guidance where it provided advice on the safety evaluation of COVID-19 vaccines.

The FDA addressed the safety follow-up for the clinical trial which includes the monitoring and recording of:

• solicited local and systemic adverse reactions that occur during the 7 days following each injection using eDiaries;
• unsolicited adverse events observed or reported during the 28 days following each injection;
• adverse events leading to discontinuation from Day 1 through Day 759 or withdrawal from the study;
• medically-attended adverse events from Day 1 through Day 759 or withdrawal from the study.

This shows that the follow-up includes monitoring for certain adverse events for two years, not limited to situations where participant withdraws from study. Other types of data important to identify problems caused by the vaccine are also collected, including “data on all serious adverse events; data on non-serious adverse events that lead to dose modification, drug discontinuation, or withdrawal from the study; and data on unscheduled study visits, hospitalizations, and accidental injuries because these events may reflect serious adverse events of the drug.” Thus, extensive data is kept.

There are other protections that those stated above. For instance, data safety monitoring boards (DSMBs) play a role in the monitoring of safety signals in trials by accumulating data from ongoing trials on a regular basis. Additionally, comprehensive safety data, including all adverse events, are collected in the early stages of drug development.

Later, it makes sense to be more selective, since there is little value in collecting repeat data on common, non-serious adverse events (like mild headaches) or on events for which there is little reason to see a link to the vaccine. Collecting extensive unhelpful data may delay the identification of an important safety signal, and the selective approach is in line with FDA’s general approach to safety.

The FDA also denied the Petitioner’s request for specific time period follow-ups such as 24 months for adults after vaccination. FDA’s October 2020 Guidance recommends a median follow-up duration of at least 2 months after completion of the full vaccination regimen.

Moreover, there are safety measures already in place; in order to issue a EUA, FDA must determine that the known and potential benefits of a product outweigh its known and potential risks and that it may be effective in preventing, diagnosing, or treating COVID-19. Two months is sufficient because adverse effects typically appear within six weeks after vaccination.

Furthermore, this two-month period is based on extensive historical experience with vaccines and the current need for such vaccines. Thus, a follow-up for at least 24 months for adults, as requested by Petitioner is not necessary to support a EUA for a vaccine.

The FDA also denied the Petitioner’s request that the trial tracks adverse events for 36 months for children and 60 months for infants because ICAN did not identify scientific support showing that these time periods are necessary for vaccine trials. ICAN relied on a 2019 publication by researchers at FDA and Duke University describing the duration of drug therapy in completed drug trials that supported approval for use of the drugs in children with chronic diseases, but that publication excluded clinical trials from the study. Thus, it is not appropriate to use the results from that research and apply them to the clinical trials for the COVID-19 vaccine.

FDA also rejected the Petitioner’s request that all adverse events be documented for the entire duration of the COVID-19 vaccine clinical trial because collecting such data would be of no value in assessing safeness for several reasons. First, as more events occur throughout the trial, more events unrelated to the vaccine occur, which may complicate the FDA’s determination of safety. Second, excessive collection of data can negatively impact the trial. Thus, a structured collection of safety data for a scientifically informed period of time is recommended (as the two-month time period already in place). In addition, safety continues to be evaluated post-licensure for any vaccine, regardless of the length of pre-licensure safety studies, through monitoring systems such as VAERS, FDA’s BEST System, and CDC’s Vaccine Safety Datalink.

II. Petitioner’s Request for An Adequate Sample Size is Denied.

Petitioner argues that 15,000 participants in the vaccine arm (out of 30,000 total in the trial) is a small number and cannot provide an adequate safety profile.

Petitioner did not provide statistical analyses or other scientific evidence to support that the 15,000-sample size is too small. The size of the safety database to support licensure of the vaccine, in this case, should not be any different than that for other vaccines for infectious diseases.

The typical size of most clinical trials is 3,000 – 15,000 is substantially higher, and provides more data. The size is certainly enough to detect, for example, events that are at a rate of 1:1000.

All vaccines are associated with some risk, but the FDA authorizes vaccines after carefully assessing their safety profile and determining that the benefits of a vaccine outweigh its potential risks. That assessment does not simply require tabulating the rate of any adverse event but requires the FDA to take into account the severity of those events. Events that are not severe are not included, and Petitioner does not provide scientific justification for why comparing the rate of any and all adverse events would be appropriate.

III. Petitioner’s T-Cell Reactivity Request Is Denied

Petitioner’s third request is that phase III of mRNA-1237 be amended to provide that testing for T-cell reactivity before and after vaccination. Petitioner relied on an article stating that if subjects with pre-existing reactivity are not sorted out evenly during the trial, it might result in erroneous conclusions.

However, the authors of that article have stated that T-cell reactivity is not well understood. Thus, randomization is a better strategy because T-cell reactivity information could be a confounding variable that could bias the comparison between the two groups. Further, with randomization, both groups are balanced in regard to identified and unidentified confounders.

IV. Petitioner’s Request for Stay of Action is Denied

The petitioner requested a stay of action until the study design is amended to provide for all of the four requests described above. Under FDA’s regulations, however, the FDA has already set out standards to review petitions for stay of action.

The Commissioner can grant or deny in whole or in part based four main prongs:

1. the petitioner will otherwise suffer an irreparable injury;
2. the petitioner’s case is not frivolous and is being pursued in good faith;
3. the petitioner has demonstrated sound public policy grounds supporting the stay; and
4. the delay resulting from the stay is not outweighed by public health or other public interests.

All four must be met by the petitioner in order for the FDA to grant the petitioner a stay of action. Additionally, FDA’s regulation at 21 CFR § 10.35 also provides that the FDA may grant a stay of administrative action if the Agency believes it is in the public interest and in the interest of justice.

A. Petitioner Failed to Meet the Criteria for An Administrative Stay of Action.

First, the FDA determined that Petitioner has not demonstrated irreparable injury because the injury he claims is too remote. Petitioner argues that once the vaccine is out, states will mandate that all citizens are vaccinated; if the trial is not amended now, the petitioner will not be able to object to the vaccine based on deficient clinical trials.

However, the Petitioner failed to show that the continuation of the trial (if the stay is not granted) will in fact cause states to issue requirements that will cause the petitioner to receive the vaccine.

Second, Petitioner has not demonstrated sound public policy arguments for his request. The FD&C Act provides a “clinical hold” mechanism for prohibiting sponsors of clinical investigations from conducting the investigation for a vaccine during the clinical trials. The FDA can issue a stay by issuing a clinical hold, but the petitioner has not properly identified any basis under 21 CFR § 312.42 or section 505(i)(3) of the FD&C Act to justify his request. A stay is only warranted when the reasons provided satisfy both sections.

Finally, a delay, in this case, would be outweighed by public health or other public interests. Petitioner argues that having the requested safety review protocols will be in the best interests of all Americans, but the FDA points out three reasons why it is not.

First, the vaccine for COVID-19 is authorized based on FDA’s science-based decision-making process and met standards for safety and effectiveness; second, the vaccine has also met all regulatory requirements; and third, the current public health situation goes against any unnecessary delay. Thus, issuing a stay without justification or without showing that safety inadequacies exist is not in the public health or public interests.

The FDA does not address whether Petitioner’s case is frivolous and is being pursued in good faith. Nevertheless, the FDA found that Petitioner failed to satisfy three of the requirements to implement a stay.

B. Neither the Public Interest nor the Interest of Justice Support Granting a Discretionary Stay of Action

The Response also states that although the FDA may grant a stay of administrative action if the Agency believes it is in the public interests and in the interest of justice, it is not the case in this situation. In this case, it is in the public interests and in the interest of justice for the trials for COVID-19 to continue. Furthermore, the petitioner did not justify a clinical hold based on a basis under 21 CFR § 312.42 and section 505(i)(3) of the FD&C Act.

Conclusion

The FDA denies the four requests that Petitioner made after careful consideration. The Petitioner also failed to meet the criteria for a stay and did not prove that a delay was in the public’s interests. Furthermore, FDA reassured the public that its process for manufacturing a vaccine, including its clinical trials and data collection on safety, is thorough and careful. Petitioner failed to support his request with scientific evidence proving otherwise.