The ethics of using of a reactogenic placebo in vaccine clinical trials
What is it about?
The main aim of our research was to examine Merck’s scientific rationale for using a reactogenic aluminum-containing “placebo” in Gardasil HPV vaccine pre-licensure clinical trials. What we found is that Merck made several inaccurate statements to trial participants in Denmark that compromised their right to informed consent. First, even though the clinical trial protocol for Gardasil listed safety testing as one of the trial’s primary objectives, the recruitment brochure distributed in Denmark emphasized that the trial was not a safety study, but rather, that the vaccine had already been thoroughly tested and 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 (amorphous aluminum hydroxyphosphate sulfate–AAHS), which does not appear to have been properly evaluated for safety. A reactogenic placebo is a pharmacologically active substance masquerading as a “placebo control”; its use in clinical trials nullifies the very concept of a placebo-controlled trial. Several trial participants experienced chronic disabling symptoms, including some randomized to the adjuvant “placebo” group. We also discovered that Merck was not transparent about the identity of AAHS, as the first vaccines in which AAHS was used as an adjuvant were described in journal publications and in documents apparently submitted to the U.S. and the European regulators as containing “aluminum hydroxide”. It thus appears that Merck represented to both the U.S. and the European regulatory agencies that the adjuvant that the company used in several vaccines licensed prior to Gardasil was not a novel aluminum compound, but rather, one of the conventional aluminum adjuvants that has been in use in human vaccines for many decades. The company may have done this because a disclosure that they had actually used a novel aluminum adjuvant might have triggered a request by the regulators for additional safety studies.
Why is it important?
Current animal and human research indicates that aluminum adjuvants may be associated with persisting and disabling systemic symptoms and neurological impairments. Moreover, the WHO acknowledges that, “since adjuvants have their own pharmacological properties, which might affect both the immunogenicity and the safety of vaccines, safety assessment is essential…as is the evaluation of the pharmacokinetics of the adjuvant alone.” It is therefore unclear why the drug regulatory agencies continue to endorse the use of aluminum adjuvant “placebos” in vaccine clinical trials. This practice is problematic for two reasons: first, it needlessly exposes trial subjects to risks only without any possible benefit, and is thus a clear violation of medical ethics guidelines which require that research involving human subjects be so designed as to minimize harms and maximize benefits. Second, administering a reactogenic compound with demonstrated systemic adverse effects as a placebo comparator will hinder the discovery of vaccine-related safety signals. Quite paradoxically, saline placebos are routinely used in animal studies of autoimmune disease induction that employ aluminum as the choice adjuvant for the purpose of breaking tolerance to co-injected protein or peptide antigens. It is thus further problematic that a saline placebo control is considered a standard of good research in animal studies, but not in clinical trial studies involving human subjects.