A reactogenic "placebo" and the ethics of informed consent in Gardasil HPV vaccine clinical trials: A case study from Denmark

Abstract

Background: Medical ethics guidelines require of clinical trial investigators and sponsors to inform prospective trial participants of all known and potential risks associated with investigational medical products, and to obtain their free informed consent. These guidelines also require that clinical research be so designed as to minimize harms and maximize benefits.

Objective: To examine Merck's scientific rationale for using a reactogenic aluminum-containing "placebo" in Gardasil HPV vaccine pre-licensure clinical trials.

Methods: We examined the informed consent form and the recruitment brochure for the FUTURE II Gardasil vaccine trial conducted in Denmark; and we interviewed several FUTURE II trial participants and their treating physicians. We also reviewed regulatory documentation related to Gardasil vaccine approval process and the guidelines on evaluation of adjuvants used in human vaccines.

Results: It was found that the vaccine manufacturer Merck made several inaccurate statements to trial participants that compromised their right to informed consent. First, even though the study protocol listed safety testing as one of the study's primary objectives, the recruitment brochure emphasized that FUTURE II was not a safety study, and that the vaccine had already been proven safe. Second, the advertising material for the trial and the informed consent forms stated that the placebo was saline or an inactive substance, when, in fact, it contained Merck's proprietary highly reactogenic aluminum adjuvant which does not appear to have been properly evaluated for safety. Several trial participants experienced chronic disabling symptoms, including some randomized to the adjuvant "placebo" group.

Conclusion: In our view, the administration of a reactive placebo in Gardasil clinical trials was without any possible benefit, needlessly exposed study subjects to risks, and was therefore a violation of medical ethics. The routine use of aluminum adjuvants as "placebos" in vaccine clinical trials is inappropriate as it hinders the discovery of vaccine-related safety signals.

Keywords: Amorphous aluminum hydroxyphosphate sulfate; Gardasil; HPV vaccine; Merck; adjuvant safety; adverse events; aluminum adjuvants; clinical trials; informed consent; placebo; reactogenicity.

Fig. 1.

Excerpt from Merck’s informed consent form in Denmark for the FUTURE II Trial. Translation: “In Denmark there are 1750 women that will participate, between the ages of 18 and 23. One half of the participants will receive the active vaccine, while the other half will get the placebo vaccine (meaning a vaccine without active substance). It is decided by lottery, which group the participant will be in. The test is ‘double-blind’, meaning that neither you nor the doctor that vaccinates you, will know if you receive an active or inactive vaccine”.

Fig. 2.

Excerpt from Merck’s recruitment brochure in Denmark for the FUTURE II Trial. Translation: “How is the study conducted in practice? The study lasts four years total. Some get the vaccine, and others get a placebo preparation (saline). Who gets what is random, and neither you nor the doctor who vaccinates you knows if you get the vaccine or not. The first year you get vaccinated three times (an injection with a little, thin needle). At the start of the study, you additionally get a gynecological examination, a blood test, a urine test, and will be asked about previous illnesses and various lifestyle habits (including sexual habits)”.

Fig. 3.

Excerpt from Merck’s recruitment brochure in Denmark for the FUTURE II Trial. Translation: “FUTURE 2 is NOT a side effect study. The vaccine is already thoroughly tested and has no side effects, apart from what you otherwise experience with other vaccines: Slight redness and soreness, where you got the shot”.

Fig. 4.

Excerpts from the pre-licensure randomized double-blind placebo-controlled trial of Merck’s formalin-inactivated hepatitis A vaccine Vaqta. (A) Excerpts from the 1992 trial publication, pg. 453, 454 [114]. (B) Excerpts from Vaqta product information leaflet, pg. 7, 11 [115].