This article about the Informed Consent Action Network’s petition to halt the JNJ COVID-19 vaccine trial was written by Viridiana Ordonez, a J.D. candidate at the University of California, Hastings College of Law.
This is a summary of the FDA’s response to a citizen petition dated October 16, 2020, filed on behalf of the petitioner, Del Bigtree’s Informed Consent Action Network (ICAN), relating to the clinical trial of Ad26.COV2S, a Janssen Biotech, Inc. (a subsidiary of Johnson & Johnson, JNJ) COVID-19 vaccine.
Like a previous ICAN petition about COVID-19 vaccine trials, the FDA denied the petition in its entirety. FDA concluded that the vaccine trials were thorough, vaccine safety was carefully tested and monitored, and ICAN’s requests are not well-founded.
This summary is divided into three parts: (1) ICAN’s specific requests; (2) FDA’s description of the vaccine process and safety; and (3) FDA’s response to six specific requests.
Petitioner requests to end JNJ COVID-19 vaccine trial
ICAN made six specific requests in its petitioner regarding Phase III of the JNJ Janssen COVID-19 vaccine clinical trial:
- any and all adverse events and reactions will be documented for the entire duration of the trial;
- such documenting of adverse events and reactions shall last at least twenty-four months for adults, thirty-six months for children and sixty months for infants and toddlers, or such longer duration as appropriate, and in no event end prior to the subject reaching eight years of age;
- the JNJ COVID-19 vaccine trial will have an adequate sample size, appropriately powered, in order to
- detect an increase in rare adverse events or any untoward medical occurrence, whether or not considered vaccine-related, and
- 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 in the group under review;
- participants should be tested for T-cell reactivity to SARS-CoV-2 pre-vaccination and post-vaccination;
- germline transmission tests should be conducted for male participants; and
- HIV incidence will be “monitored at the end of the study and for an appropriate follow-up period” and the trial will “evaluate the levels and distribution of both vector and insert responses in target tissues where HIV acquisition is known to occur.”
(See pages 1-2 of the FDA response).
The FDA denied every single request in ICAN’s petition because it found that the petition does not demonstrate any reasonable grounds for the specific requests made.
FDA’s Description of the Process
FDA set out the process of licensing vaccines, and also the process leading up to the granting of an Emergency Use Authorization, or EUA.
I. Licensed Vaccines Are Safe
The Biologic Control Act (BCA) and Public Health Service Act (PHSA) authorized the FDA to license vaccines if the vaccines are shown to be safe, pure, and potent. To determine that, vaccines have to first be tested in non-clinical studies and then, in addition, on humans.
Further, sponsors of a vaccine must submit data before a vaccine can be licensed, including but not limited to:
- data derived from nonclinical and clinical studies showing the product’s safety, purity, and potency;
- a description of manufacturing methods for the vaccine;
- data establishing the product’s stability through the dating period; and
- 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 finally be licensed. Finally, vaccines continue to be safe even after licensure because the FDA continues to monitor vaccines to detect any “rare, serious, or unexpected adverse events” through the use of multiple surveillance methods.
II. An EUA for a COVID-19 Vaccine is Issued Only If It Meets Statutory Standards.
On February 4, 2020, the Secretary of Health and Human Resources (HHS) determined that COVID-19 is a public health emergency with the potential to affect the health and security of U.S. citizens. Thus, the Secretary determined that the EUA was appropriate and justified. Before issuing a EUA, the FDA concluded that the following requirements were met:
- SARS-CoV-2 can cause a serious or life-threatening disease/condition;
- based on the totality of scientific evidence, it is reasonable to believe that the vaccine may be effective in diagnosing, treating, or preventing the disease or condition;
- the known and potential benefits of the vaccine to treat the condition outweigh the known and potential risks; and
- there is no adequate, approved, and available alternative to the vaccine.
The FDA has made clear that issuance of a COVID-19 vaccine requires a demonstration of clear and compelling safety and efficacy throughout Phase III of the clinical trial. Phase III involves a large number of participants that receive either an investigational vaccine or a control.
The efficacy is studied by comparing both groups and the FDA has recommended that the vaccine should be at least 50% more effective than the control. Participants are monitored for safety events during the entire study, and if evidence from the clinical trial’s safety profile is acceptable, then the results can then be submitted to the FDA in support of the EUA. Following the submission and issuance of a EUA, the FDA expects that the vaccine sponsor will continue to evaluate the vaccine and work towards submitting a Biological License Application (BLA).
III. Process for Investigational New Drugs (IND)
Before the FDA approves a vaccine for public use, the vaccine must undergo a rigorous and extensive development program to determine safety and effectiveness including preclinical research and clinical studies. Before a clinical investigation can even begin, the sponsor must submit an Investigational New Drug (IND) application to the FDA. The application must describe the proposed study, the protection and rights of the subjects, and must also include information on the clinical protocols.
After the submission of the IND, there is a 30-calendar day waiting period in which the FDA reviews the application. Only after this review can the sponsor conduct a clinical investigation divided into three phases.
Phase I focuses on immunogenicity studies performed on a small number of subjects; Phase II includes several hundreds of individuals to determine any short-term side effects; Phase III requires a sample size of thousands or tens of thousands of people and provides data on the effectiveness and safety of the vaccine. If at any point there is a significant concern about safety or effectiveness, the FDA can request additional studies or stop the clinical trials.
FDA’s Response to the Petition
In its response to the petition, the FDA addressed each of the six specific requests the petitioner made in regard to Phase III of the clinical trials.
I. Petitioner Requests for Documentation of Any and All Adverse Events and Request for Documentation for Specified Periods of Time Are Denied.
The FDA determined that documentation of any and all adverse events as requested by ICAN is not required. The FDA has already addressed this issue in its June 2020 Guidance where it specifically provides advice on the safety evaluation of COVID-19 vaccines. Additionally, the FDA recommends that safety assessments of a vaccine include
- Solicited local and systematic adverse events for at least seven days after vaccination.
- Unsolicited adverse events in all participants for at least 21-28 days after vaccination.
- Serious and other medically attended adverse events for at least six months after completion.
The FDA points out that Janssen has made other protocol information available to the public, which includes the recording of all serious events for up to two years from vaccination for all participants, as well as all adverse events leading to the discontinuation until completion of the last study and medical attended adverse events until six months after vaccination.
The FDA agreed that comprehensive data is necessary, but comprehensive data is gathered at the early stages of the trials and it is best to adopt a more selective approach in data collection for common, non-serious adverse events later in the process.
Since most adverse events have already been characterized by these later stages of the trial gathering the same information would minimally enhance the current data value. It could also lead to complications or delays in the FDA’s ability to detect important safety signals.
Further, selective data collection in the late stages of the investigation is consistent with the FDA’s general approach. Using a selective data method later in the process prevents losing important information, facilitates participation in clinical studies, and allows for more efficient use of the clinical resources. Thus, the FDA does not believe that ICAN’s request should be part of the criteria for a EUA.
Additionally, before issuing a EUA, the FDA must determine if the known and potential benefits of a vaccine outweigh its known and potential risks and whether the vaccine would be effective in preventing, diagnosing, or treating COVID-19.
In order to make this analysis, data from Phase III studies have to include a follow-up duration of at least 2 months after completion of a vaccine series, which would allow for the identification of potential adverse events that were not identified at earlier stages. The FDA decided to issue a EUA for this vaccine since it is supported by an analysis of safety data collected from 43,783 participants enrolled in an ongoing randomized, placebo-controlled study. The FDA states that the eight-week follow-up after vaccination for this trial is right based on the need for the COVID-19 vaccine and the effectiveness demonstrated.
The FDA also denies ICAN’s request to track adverse events for 36 months for children and 60 months for infants and toddlers. ICAN relies on a 2019 publication by researchers at FDA and Duke University, which describes the duration of a drug therapy in a complete trial that supported a drug for children with chronic diseases.
However, the FDA explains that it is not scientifically appropriate to extrapolate the results or conclusions from that study to the current vaccine trials because both are very different; vaccines for bacterial or viral infectious diseases are not chronically or frequently administered like the drugs mentioned in that publication. Thus, ICAN has not demonstrated that the specific time period requested is necessary.
Documenting all adverse events for the entire duration of the clinical trial would not be of value in assessing safety. Excessive safety data collection may have negative consequences for vaccine development and the FDA has determined that the design of the current trial provides enough useful information for the issuance of a EUA. Further, safety continues to be evaluated even after licensure; the FDA has advised that follow-up of outcomes should continue after licensure for COVID-19 vaccines for ideally one to two years.
II. ICAN’s Request as to Sample Size is Denied
Because the FDA evaluated the sample size of Phase III trials during its review of an IND, a EUA request, or a BLA, the FDA has necessarily already performed this evaluation for the JNJ COVID-19 vaccine trial. The FDA determined that the size of the safety database to support licensure for a COVID-19 vaccine should not be different than that for other preventive vaccines.
For vaccines of infectious diseases, the typical pre-licensure safety database consists of at least 3,000 study participants who are vaccinated. For this particular study, the sample sizes are 20,000 subjects in the active group, and 20,000 in the control group. The FDA finds that this size is adequate to support authorization. ICAN did not provide any statistical or scientific evidence that demonstrates that this study size is inadequate.
III. Petitioner’s Request as to T-Cell Reactivity is Denied.
ICAN requested that Phase III of the JNJ COVID-19 vaccine clinical trial be amended to provide testing for T-Cell reactivity before and after vaccination. The FDA concedes that the implications of T-cell reactivity are not well understood, and it does not know how it would affect the results of this clinical trial.
However, T-cell reactivity could be a confounding variable that could bias the comparisons between the placebo and the active groups. Thus, participants in this study are randomized, ensuring that the groups are balanced with regard to identified and unidentified confounders. Further, the FDA is not currently aware of any basis to find that there is a preexisting T-cell reactivity among the participants. Thus, this request is also denied.
IV. ICAN’s Request for Germline Transmission Tests Is Denied.
ICAN requested that Phase III of the JNJ COVID-19 vaccine clinical trial be amended to provide for germline transmission tests to be conducted for male participants, relying on a 2006 guideline published by the European Medicines Agency’s Committee for Medicinal Products for Human Use, Guideline on Non- Clinical Testing for Inadvertent Germline Transmission of Gene Transfer Vectors (2006 EMA Guideline). However, the FDA points out that not all medical products should be assessed for germline transmission, especially where the properties of the product are notassociated with such risk, as is the case with the JNJ Janssen COVID-19 clinical vaccine trials.
Further, the 2006 EMA Guideline states that a decision to assess potential germline transmission should be determined on a case-by-case basis. The vector, dose, route of administration, and proposed clinical indication are all factors that need to be taken into consideration.
In this case, the Janssen COVID-19 vaccine is composed of a recombinant adenovirus serotype 26 (Ad26) vector. For this vector, the genome that encodes the protein required to replicate the virus is deleted, so the vector cannot replicate. Additionally, the Ad26 vector “is classified as a non-integrating vector, in that any integration into the host genome, if it occurs at all, occurs at low frequency.” These characteristics of the vector used in the Janssen COVID-19 Vaccine are not associated with a risk of vertical germline transmission of vector DNA. Thus, no testing is warranted.
V. ICAN’s Request for HIV Incidence Monitoring Is Denied.
ICAN requested that Phase III be amended to provide HIV incidence monitoring at the end of the study and to evaluate the levels and distribution of both the vector and insert responses in target tissues where HIV acquisition is known to occur. Petitioner bases this request on the fact that Ad26.COV2.S is a recombinant viral vector vaccine, and in past viral vector vaccine clinical trials the HIV incidence was higher in vaccinated participants than in the placebo group.
However, ICAN’s support relied on the STEP Study which was designed to evaluate an investigational HIV vaccine that consisted of three adenovirus serotype 5 (Ad5) vectors. That study indicated that the acquisition of HIV was higher in the vaccine recipients than in the participants receiving the placebo with prior evidence of Ad5 infection.
This does not mean that the increase rate is applicable to all adenovirus vector vaccines, especially those that express other proteins such as the JNJ Janssen vaccine, which is based on the Ad26 vector. The increased risk in the STEP Study appeared to require the presence of both the HIV antigen and the use of an Ad5 vector, and current data does not suggest that the increased infection rate would be expected with vaccines that do not contain Ad5 vectors.
Additionally, the results of the STEP Study were replicated in a 2012 study using simian immunodeficiency virus (SIV) in macaques, which serves as an animal model of HIV infection. In this study, there was evidence of a greater risk of infection only in Ad5-seropositive animals immunized with an Ad5 vaccine similar to that used in the STEP Study.
The authors of that study hypothesized that vaccine-induced vector-specific immune responses did not contribute to susceptibility to SIV. Therefore, there is evidence to support the view that the use of an adenovirus vector in a vaccine does not require monitoring for the effects of a non-HIV vaccine on HIV acquisition.
ICAN has not provided evidence to show that the Ad26 vector in the Janssen vaccine is linked to enhanced susceptibility to HIV infection. Thus, this request is also denied.
The FDA considered each of the six requests ICAN included in its petition and rejected each one because ICAN failed to support its requests.