A Second Letter to Dr Peter Marks, US Food and Drug Administration

A drug safety physician's alert to Dr. Peter Marks (U.S. Food and Drug Administration) regarding the need for clear guidance or regulation concerning COVID-19 vaccines as default investigational products in non-vaccine clinical trials.

By Carol Taccetta, M.D., F.C.A.P
Read Dr Taccetta’s first letter here

A drug safety physician’s alert to Dr. Peter Marks (U.S. Food and Drug Administration) regarding the need for clear guidance or regulation concerning COVID-19 vaccines as default investigational products in non-vaccine clinical trials

Originally emailed 22 March 2021. Please note: the views expressed here are my personal opinions and do not reflect the views of former or current employers or any professional organizations to which I belong.

Dear Dr. Marks,

As a drug safety physician with a pharmaceutical industry career spanning 25 years, I have discovered what I believe to be gaps in the COVID-19 vaccine Emergency Use Authorization (EUA) process which require immediate clarification for industry (or other responsible sponsors) regarding all ongoing clinical trials.

Per 21CFR312.3, “an experiment is any use of a drug except for the use of a marketed drug in the course of medical practice.”1

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). 2,3,4

This creates:

1. Subject Participation in More Than One Clinical Investigation

a. Clinical trial (interventional) protocols under an Investigational New Drug (IND) application normally prohibit other investigational therapies during the study. In the FDA’s “Subject Participation in More Than One Clinical Investigation,” the FDA “strongly discourages these practices as enrollment in more than one clinical investigation could increase risks to subjects, particularly because they may be exposed to more than one investigational product for which the safety profile may not be well understood.” 5 “Moreover, there may be potential drug or device interactions, and the simultaneous use of more than one investigational product may confound the results of the clinical investigations.”5

b. Exclusion criteria typically prohibit recent participation in another investigational study involving other investigational products, be they study drug, biologic (such as licensed or unlicensed vaccine), or device. Protocol deviations would ensue as most protocols will not allow simultaneous trial enrollment.

c. When an additional investigational agent has been introduced outside the general investigational plan, all IND efficacy and safety data is made useless.

2. Muddying of Safety Signals

a. Potential and identified risks that normally would be attributed to the investigational agent under study may now be ascribed to the COVID-19 vaccine (and vice versa).

3. No Communication of Risk

a. Patients have not signed an Informed Consent Form (ICF) for their studies with the knowledge that an additional investigational agent will be introduced; they are only told of the potential “side effects” of the original investigational agent under study.

b. This same risk information has not been provided to the investigator via the Investigator Brochure.

c. The combination of investigational agent and COVID-19 vaccine would not have been institutional review board (IRB)-approved.

4. Absence of Cohesive and Collaborative Safety Reporting

a. As the COVID-19 vaccine would be treated as a concomitant medication in a clinical trial, there is no mandated avenue for industry to report the vaccine as a suspect medication either to the FDA or to the vaccine manufacturer.

b. There is a not even a COVID-19 vaccine term in the WHO drug dictionary by which the vaccine could be captured in a data field for later signal detection. 6

c. The Investigator and vaccine manufacturer are currently responsible for independently reporting any Serious Adverse Event (SAE), for which they become aware, to the Vaccine Adverse Event Reporting System (VAERS), but there is no process for collaboration or coordination of SAEs and follow up information between the non-vaccine IND Sponsor, the IND Sponsor of the vaccine and the Agency.

d. Patient information is kept confidential within a study environment. Others cannot access this protected health information. This coded information will not be able to “link up” with the VAERS data.

e. As the CDC has noted that, in certain situations, the mixing and timing of COVID-19 vaccines from different manufacturers could be considered, there may be three or more investigational agents being studied at the same time.7 Usually, if a patient is administered a single treatment outside the protocol (an investigational agent not specified by the protocol), the study would be terminated for that patient.

5. Questions about Liability

a. The ICF often states that if a patient is injured during the trial, the sponsor will cover medical expenses. Will there be an issue regarding coverage of expenses for an adverse event attributed by both the Investigator and Sponsor to the vaccine?

Dr. Marks, I had the pleasure of meeting you several years ago at a Drug Information Association (DIA) conference. There, we briefly discussed some of the challenges in causality assessment of adverse events during a clinical trial. Specifically, we discussed the difficulty in assigning causality between an adverse event and a single study medication when two or more investigational products were being studied: one investigational early in its clinical development and one marketed with a better understood safety profile. For example, how could one assume an immune-related adverse event (irAE) was attributed to the marketed drug with a known safety profile of irAEs? Could the new drug with the emerging safety profile reasonably be excluded as a culprit? The phenomenon of potential drug interaction between the two drugs could essentially even create a “third” investigational agent. This level of complexity of causality assessment currently exists in many trials within the boundaries of an appropriate IND application. The introduction of an experimental vaccine outside the limits of an IND general investigational plan will result in the adverse conditions cited above.

For the sake of thoroughness, I will note here the FDA’s guidance, Conduct of Clinical Trials of Medical Products During the COVID-19 Public Health Emergency, in which the FDA states: “Certain clinical trial protocols have an exclusion criterion for receipt of another “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. 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.”8

What I believe the guidance is saying is that it is acceptable for an experimental medical product to be randomly introduced into a proper clinical trial if in the setting of an “emergency,” not based on the foundations of modern drug development upon which I was trained and by which we’ve all grown to value and practice since the early 60s. 9

The next paragraph of the guidance seems to reinforce a few of my concerns, but leaves me more confused, i.e., is it up to the sponsor to determine if the COVID-19 vaccine is an investigational agent?:
“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.”

I look forward to your immediate response and action to shed light on these critical issues.

Carol Taccetta, M.D., F.C.A.P.


  1. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=312.3
  2. https://www.fda.gov/media/144412/download
  3. https://www.fda.gov/media/146303/download
  4. https://www.fda.gov/media/144636/download
  5. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/informed-consent#morethanone
  6. https://www.who-umc.org/whodrug/whodrug-portfolio/
  7. https://www.cdc.gov/vaccines/covid-19/info-by-product/clinical-considerations.html
  8. https://www.fda.gov/media/136238/download
  9. https://www.fda.gov/consumers/consumer-updates/kefauver-harris-amendments-revolutionized-drug-development

Image by torstensimon from Pixabay

Dr Taccetta is a U.S. licensed physician, board-certified in pathology, with a career in drug development spanning 25 years. Key agency interactions include Carol’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.


Publisher’s note: The opinions and findings expressed in articles, reports and interviews on this website are not necessarily the opinions of PANDA, its directors or associates.

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