Placebo

What was in that placebo during clinical trials? You might ask.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2831649/

Vaccine. 2009 May 26; 27(25-26): 3291–3294. Published online 2009 February 20. doi: 10.1016/j.vaccine.2009.02.031PMCID: PMC2831649
NIHMSID: NIHMS179347

Testing vaccines in pediatric research subjects

3. Placebos and children

While most recognize the need for research to advance medical care for children, those not closely familiar with the field might pause or even involuntarily recoil at the notion of randomizing children as research subjects to receive placebos. This is even more of an issue than in vaccine trials, where one usually injects vaccines rather than give them orally.

While 45 CFR 46 never mentions placebos specifically [3], the U.S. Food and Drug Administration has however provided specific guidance regarding placebos [7]. The FDA encourages the use of placebos and provides a conceptual basis for the practice. The FDA however does not specifically address placebos in children or other vulnerable subjects.
Unlike the FDA, the Declaration of Helsinki implicitly discourages placebos by articulating exceptions when placebos may be used in research rather than a general endorsement [5]. It specifically addresses the need for the investigator to take extreme care when using placebos and to limit the use of placebos to situations where there is an absence of existing proven therapies. The ICH GCP also specifically addresses the use of placebos but neither encourages nor discourages their use [6].

None of these regulations excludes placebos and their use for children. In fact, the American Academy of Pediatrics (AAP) in its “Guidelines for the Ethical Conduct of Studies to Evaluate Drugs in Pediatric Populations” specifically states, “In general, placebos should be used when data cannot be obtained by comparing the efficacy and safety of the drug under study with either a commonly used therapeutic agent for that condition or the natural course of the disease as described from clinical studies.” [8] The AAP guidelines list five situations when placebos in pediatric research are ethically acceptable. These include (1) when no intervention is currently accepted, (2) when the current intervention lacks proven benefit, (3) when the current intervention is unsafe, (4) when the addition of the proposed therapy to a standard therapy might prove unsafe, and (5) when the course of the condition under treatment varies widely in severity in a given individual.

For intramuscular and subcutaneous vaccinations, injections of sterile normal saline may serve as placebos, but researchers frequently choose other comparative agents. A review of the most recently published trials involving vaccines for children found a variety of comparators that took the place of placebos in children. For example, a recent study of pneumococcal conjugate vaccine with nine serotypes (PCV-9) used as its comparator an active vaccine [9]. Specifically, the PCV-9 was reconstituted with the DTP-Hib vaccine. The comparator was vaccine-diluent mixed with the same DTP-Hib vaccine. In another study, a novel, bivalent, heat-killed, whole-cell oral cholera vaccine is compared to a similarly manufactured, heat-killed Escherichia coli K12 vaccine-a vaccine of no therapeutic benefit [10]. In a third, recent study of a pneumococcal conjugate vaccine with seven stereotypes paired serially with a 23-valent, pneumococcal polysaccharide vaccine, the investigators used as the comparator hepatitis A or B vaccines [11]. In a fourth study, the study vaccine consisted of a Pseudomonas aeruginosa flagellar protein combined with aluminum hydroxide and thimerosal [12]. The comparator consisted of just aluminum hydroxide combined with thimerosal.