Losing Control of the Controlled Clinical Trial in These Times of Emergency Use Authorization (EUA) Vaccines
Do you remember your high school science teacher explaining what a controlled experiment is? It is when just one thing is changed in the group receiving the experimental intervention (compared to the “control” group receiving standard or no treatment), then one waits to see if there is a difference in the outcome between the two groups. In controlled clinical trials, the “standard” treatment is often a marketed product with an already well-known safety profile, and the “no treatment” is placebo. https://www.fda.gov/patients/clinical-trials-what-patients-need-know/glossary-terms
Merriam-Webster defines a “controlled experiment” as “an experiment in which all the variable factors in an experimental group and a comparison control group are kept the same except for one variable factor in the experimental group that is changed or altered.” https://www.merriam-webster.com/dictionary/controlled experiment
What does the Food and Drug Administration (FDA) say about this basic tenet of science? In a 2014 draft guidance, they acknowledge that “the simultaneous use of more than one investigational product may confound the results of the clinical investigations” and voice concern for subjects “exposed to more than one investigational product for which the safety profile may not be well understood.” https://www.fda.gov/regulatory-information/search-fda-guidance-documents/informed-consent
In study protocol documents, such as those found on https://clinicaltrials.gov, one might see such language prohibiting administration of two investigational products during a single time period in either the eligibility criteria or concomitant medications sections. Just a few examples:
- Exclusion Criteria: Patients who have received any other investigational agent ≤ 28 days prior to registration are not eligible. https://clinicaltrials.gov/ProvidedDocs/43/NCT02808143/Prot_SAP_000.pdf
- Exclusion Criteria for enrollment: Prior/Concomitant therapy: Use of any investigational or non-registered product (drug, vaccine or medical device) other than the study vaccine during the period beginning 30 days before the dose of study vaccine, or planned use during the study period. https://clinicaltrials.gov/ProvidedDocs/98/NCT04657198/Prot_000.pdf
- Concomitant Medications: Restricted Treatments: Investigational agents
Note: prohibited within 4 weeks prior to https://clinicaltrials.gov/ProvidedDocs/94/NCT04173494/Prot_000.pdf
Early on in the initial COVID-19 vaccine rollout, a very reasonable question was posed to the FDA regarding receipt of an unplanned, additional investigational product (such as an EUA vaccine) during a controlled clinical trial. The FDA responded with the following guidance:
Q27. Certain clinical trial protocols have an exclusion criterion for receipt of another “investigational medical product.” If a participant receives a vaccine or other medical product for the prevention or treatment of COVID-19 authorized under an Emergency Use Authorization (EUA), would FDA consider this receipt of an investigational medical product?
When a medical product is being used under an EUA, it is an authorized (though not an approved or cleared) medical product for use in clinical care that has met the statutory criteria under section 564 of the FD&C Act. The product is not being studied under an IND or IDE when used pursuant to an EUA, and FDA therefore does not consider receipt under an EUA as receipt of an investigational product.82 In contrast, when the same product is used in a clinical investigation under an IND or IDE, the product’s safety and/or effectiveness is being studied for investigational uses, and FDA would consider receipt in this situation to be receipt of an investigational product.
As always in the design of a clinical investigation, there may be valid scientific reasons to have an exclusion (and even a discontinuation) criterion for a medical product—a monoclonal antibody or vaccine, for example—whether that product was used under an EUA or not. These scientific reasons may include risks to an individual if they enroll or continue to participate in a clinical trial after receiving (or having received) the excluded product, or the potential impact of the use of the excluded product on trial objectives, such as confounding the determination of effectiveness of the product under investigation. [https://www.fda.gov/media/136238/download]
To me, this recommendation did not jibe with the tenets of modern drug development. Concerned, I wrote to the FDA that it was not “acceptable for an experimental medical product to be randomly introduced into a proper clinical trial if in the setting of an ’emergency.’” Receipt of an EUA COVID-19 vaccine by a clinical trial subject already taking the trial’s investigational agent would result in exposure “to more than one investigational product,” regardless of regulatory pathway. https://www.pandata.org/a-second-letter-to-dr-peter-marks-food-and-drug-administration/
For your reference, the FDA’s response back to included below.1
The FDA guidance above (“Q27”) is “intended to remain in effect only for the duration of the public health emergency related to COVID-19 declared by the Secretary of Health and Human Services (HHS) on January 31, 2020, effective January 27, 2020, including any renewals made by the HHS Secretary in accordance with section 319(a)(2) of the Public Health Service Act (PHS Act) (42 U.S.C. 247d(a)(2)).”
Someday, when all “declarations” are over, will we return to the controlled clinical trial as I once understood it?
References:
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May 27, 2021, 5:18 AM |
Dear Dr. Taccetta –
Thank you again for your March 22, 2021 correspondence regarding the Emergency Use Authorization for COVID-19 vaccines. The following information addresses the topics conveyed in your letter to Dr. Peter Marks.
Please refer to FDA’s January 2017 Guidance for Industry and Other Stakeholders titled, Emergency Use Authorization of Medical Products and Related Authorities (https://www.fda.gov/media/97321/download). Section III of this guidance document states:
“The EUA authority under section 564 allows FDA to facilitate availability and unapproved uses of MCMs needed to prepare for and respond to CBRN emergencies. The EUA authority is separate and distinct from use of a medical product under an investigational application (i.e., Investigational New Drug Application (IND) or Investigational Device Exemption (IDE)), section 561 expanded access authorities, and section 564A emergency use authorities discussed in section IV of this guidance.”
For your convenience, we have underlined the relevant sentence of the paragraph that pertains to your statement, “As all COVID-19 vaccines are products under EUA, thus “investigational vaccines,” by allowing patients in any non-designated trial to randomly receive these vaccines, we are essentially altering the general investigational plan of said trial by adding an additional investigational agent(s).” In summary, each vaccine that FDA makes available by EUA authorizes use of an unlicensed product based on criteria set out by statute and when used according to the conditions of the EUA, the IND regulations are not applicable.
We have restated your topics below and addressed them accordingly:
Subject Participation in More Than One Clinical Investigation
As stated above, each vaccine that FDA makes available by EUA authorizes use of an unlicensed product based on criteria set out by statute and when used according to the conditions of the EUA, the IND regulations are not applicable. In addition, please refer to FDA’s January 2021 Guidance for Industry, Investigators, and Institutional Review Boards titled Conduct of Clinical Trials of Medical Products During the COVID-19 Public Health Emergency (https://www.fda.gov/media/136238/download). Specifically, Question and Answer #27 states:
Question– Certain clinical trial protocols have an exclusion criterion for receipt of another “investigational medical product.” If a participant receives a vaccine or other medical product for the prevention or treatment of COVID-19 authorized under an Emergency Use Authorization (EUA), would FDA consider this receipt of an investigational medical product?
Answer– When a medical product is being used under an EUA, it is an authorized (though not an approved or cleared) medical product for use in clinical care that has met the statutory criteria under section 564 of the FD&C Act. The product is not being studied under an IND or IDE when used pursuant to an EUA, and FDA therefore does not consider receipt under an EUA as receipt of an investigational product. In contrast, when the same product is used in a clinical investigation under an IND or IDE, the product’s safety and/or effectiveness is being studied for investigational uses, and FDA would consider receipt in this situation to be receipt of an investigational product. As always in the design of a clinical investigation, there may be valid scientific reasons to have an exclusion (and even a discontinuation) criterion for a medical product—a monoclonal antibody or vaccine, for example—whether that product was used under an EUA or not. These scientific reasons may include risks to an individual if they enroll or continue to participate in a clinical trial after receiving (or having received) the excluded product, or the potential impact of the use of the excluded product on trial objectives, such as confounding the determination of effectiveness of the product under investigation.
Muddying of Safety Signals
Under FDA regulations at 21 CFR 312.32, an IND sponsor must report to FDA any serious adverse event (SAE) that is both unexpected and for which there is a reasonable possibility that the drug caused the serious adverse event, i.e., there is evidence to suggest a causal relationship between the drug and the adverse event.
For an individual who has received an FDA-authorized COVID-19 vaccine (i.e., not as a participant in a COVID-19 vaccine clinical trial) and is participating in a clinical trial that is investigating another medical product, the sponsor of the trial or the participant may report a suspected vaccine adverse event to the Vaccine Adverse Event Reporting System (VAERS).
In addition, regarding the COVID-19 clinical trials, the general safety evaluation of COVID-19 vaccines, including the size of the safety database to support vaccine licensure, have not been different than for other preventive vaccines for infectious diseases. Furthermore, a comprehensive surveillance system is in place to monitor the safety of COVID-19 vaccines post authorization. The details of the safety surveillance system are available on the FDA website at https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/covid-19-vaccine-safety-surveillance.
For each of the COVID-19 vaccines that have received Emergency Use Authorization, the Fact Sheet for Healthcare Providers Administering Vaccine (Vaccination Providers) includes information on adverse reactions that were reported during clinical trials.
In the design of any clinical investigation, consideration should be given to potential confounding of the evaluation of safety of the investigational product that may be introduced by receipt of another medical product, including COVID-19 vaccines or other vaccines – whether under an EUA or not.
Please note that the circumstances of each clinical trial are different, and sponsors are encouraged to discuss any questions with FDA.
No Communication of Risk
Please refer to page 24 of FDA’s January 2017 Guidance for Industry and Other Stakeholders titled, Emergency Use Authorization of Medical Products and Related Authorities.
“Although informed consent as generally required under FDA regulations is not required for administration or use of an EUA product, section 564 does provide EUA conditions to ensure that recipients are informed about the MCM they receive under an EUA.”
FDA must ensure that recipients of the product are informed, to the extent practicable given the applicable circumstances, that FDA has authorized the emergency use of the product, of the known and potential benefits and risks, and of the extent to which such benefits and risks are unknown, that they have the option to accept or refuse the product, and of any available alternatives to the product. Typically, this information is communicated in a “fact sheet.” Each COVID-19 vaccine authorized by FDA for Emergency Use has a Fact Sheet for Healthcare Providers Administering Vaccine (Vaccination Providers) and a Fact Sheet for Recipients and Caregivers and these are available on the FDA website at:
Absence of Cohesive and Collaborative Safety Reporting
Please refer to our response in the section titled “Muddying of Safety Signals.”
In addition, as a condition of the EUA, each EUA holder (Pfizer Inc. Moderna TX and Janssen Biotech) is required to report the following to the Vaccine Adverse Event Reporting System (VAERS) for their vaccine:
•Serious adverse events (irrespective of attribution to vaccination), •Cases of Multisystem Inflammatory Syndrome in children and adults; and •Cases of COVID-19 that result in hospitalization or death that are reported to the EUA holder
Furthermore, it is mandatory for healthcare providers administering COVID-19 vaccines (vaccination providers) to report the following to VAERS: •Vaccine administration errors whether or not associated with an adverse event, •Serious adverse events* (irrespective of attribution to vaccination), •Cases of Multisystem Inflammatory Syndrome (MIS) in adults and children, and •Cases of COVID-19 that result in hospitalization or death.
As you are likely aware, anyone can submit a report to VAERS.
Questions about Liability
Please refer to page 41, section VII, Liability Protection of FDA’s January 2017 Guidance for Industry and Other Stakeholders titled, Emergency Use Authorization of Medical Products and Related Authorities for information pertaining to your question.
In addition, the Fact Sheet for Healthcare Providers Administering Vaccine (Vaccination Providers) for each COVID-19 vaccine that has been made available by EUA includes the following information:
The Countermeasures Injury Compensation Program
The Countermeasures Injury Compensation Program (CICP) is a federal program that has been created to help pay for related costs of medical care and other specific expenses to compensate people injured after use of certain medical countermeasures. Medical countermeasures are specific vaccines, medications, devices, or other items used to prevent, diagnose, or treat the public during a public health emergency or a security threat. For more information about CICP regarding the <name> COVID-19 Vaccine used to prevent COVID-19, visit www.hrsa.gov/cicp, email cicp@hrsa.gov, or call: 1-855-266-2427.
Please be assured that each vaccine authorized for emergency use by FDA has met FDA’s rigorous, scientific standards for safety, effectiveness, and manufacturing quality needed to support emergency use authorization.
We hope that you have had the opportunity to receive one of the three COVID-19 vaccines.
Best regards –
Lorrie
Lorrie H. McNeill
Office of Communication, Outreach and Development Center for Biologics Evaluation and Research U.S. Food and Drug Administration
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Dr. Carol Taccetta is a U.S.-licensed physician, board-certified in pathology, with a career in drug development spanning 25 years. Key agency interactions include Dr. Taccetta’s co-drafting of a chapter in the 1989 U.S. Surgeon General’s Report (CDC), as well as serving as Sponsor’s Responsible Medical Officer for a successful New Drug Application (NDA) to the FDA.
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