How Health Professionals Conceptualize and Represent Placebo Treatment in Clinical Trials and How Their Patients Understand It: Impact on Validity of Informed Consent

<div><p>Context</p><p>Previous studies suggested that many patients, who have given their informed consent to participate in randomized controlled trials (RCT), have somewhat limited understanding of what a placebo treatment is. We hypothesized that the relationship between patients and their health professionals plays a central role in this understanding.</p><p>Methods</p><p>We interviewed 12 patients included in RCTs (nine suffering from Parkinson’s disease and three from Huntington’s disease) and 18 health professionals involved with RCTs (eight principal investigators, four associated physicians and six clinical research associates). Semi-structured interviews were conducted after the RCTs had ended but before the treatment allocation was revealed.</p><p>Results</p><p>Only two patients clearly understood the aim of placebo-controlled RCTs. Only one principal investigator said she asks all her patients whether they agree to participate in RCTs. The seven others said they only ask patients who seem more likely to be compliant. Their selection criteria included docility and personality traits associated in other studies with enhanced placebo responses. According to 13 of the 18 health professionals, their relationship with patients may influence the amplitude of the placebo response. All but one clinical research associates added that the placebo response could result from a “maternal” type of care. All principal investigators said they have a strong influence on their patient's decision to participate. Finally, when interviewees were asked to narrate a memory of a medically unexplained healing, in eight of 11 physicians' narratives the beneficiary was a child while in 10 of 12 patients' narratives it was an adult.</p><p>Conclusion</p><p>Our observations suggest that the interrelationship between health professionals and patients involved in RCTs could be compared to that between parents and children. Therefore, adherence to formal rules regarding informed consent does not ensure a balanced relationship between patients and health professionals.</p></div

List of questions asked to interviewees.

<p>List of questions asked to interviewees.</p

Interviewees.

<p>Interviewees.</p

Conceptualization of the placebo response.

<p>Conceptualization of the placebo response.</p

Analysis of personal memories of unexplained healings.

<p>Analysis of personal memories of unexplained healings.</p

Opinion of principal investigators about patients' inclusion in RCTs.

<p>Opinion of principal investigators about patients' inclusion in RCTs.</p

General influence of PI and CRA on placebo response.

<p>General influence of PI and CRA on placebo response.</p

Specific influence of APs on treatment response of their patients.

<p>Specific influence of APs on treatment response of their patients.</p

Retrograde labeling of A11 neurons projecting to the spinal cord.

<p><b>A.</b> Schematic representation of the hypothalamic A11 area in which TH-IR neurons were reached by FluoroGold. The dots represent the localization of TH-IR A11 neurons. The red frame represents the area where representative micrographs were taken. <b>B.</b> Representative micrograph showing a reconstructed overview of the TH immunopositive and FG retrograde labeled cells in the A11 group. Immunoreactivity was revealed with Novared kit for TH neurons (Red) and with SG kit for FG neurons (Blue). Double-stained neurons (TH-FG) were labeled in a blue-red combination (i.e. black). The black arrows point to typical double-stained cells. The round heads arrows point to TH-stained neurons. Note that no single FG-stained neurons were found and that the majority of double-stained neurons are located on the ipsilateral side of spinal injections (right) <b>C–H</b>: Representative double-fluorescent immunostaining of TH (green) and FG (red) obtained under a confocal laser-scanning microscope in the A11 posterior hypothalamic group. The white arrows point to typical double-stained cells. Note the colocalization between the TH-positive and FG-positive neurons within the A11 region. Abbreviations: cp = Cerebral Peduncle; FG = FluoroGold; MM = Medial Mammillary nucleus; LHA = Lateral Hypothalamic Area; TH = Tyrosine Hydroxylase; TM = Tuberomammillary nucleus; V3 = Third Ventricle; ZI = Zona Incerta.</p

Absence of dopamine transporter expression in the diencephalospinal pathway.

<p><b>A–C</b>: Immunohistochemistry targeted against the DAT. <b>A.</b> Representative micrograph of DAT labeling positive neurons in the ventral tegmental area. The arrows point to typical immunopositive neurons. <b>B.</b> Representative micrograph showing the absence of DAT labeling at the posterior hypothalamus level. <b>C.</b> Representative micrograph showing the absence of DAT labeling in a lumbar spinal section. <b>D–F</b>: Representative DAT binding autoradiographs in the substantia nigra (<b>D</b>), posterior hypothalamus (<b>E</b>) and lumbar spinal cord (<b>F</b>). Note the absence of DAT expression in the posterior hypothalamus and spinal cord, in contrast with the intense expression in the substantia nigra and striatum (positive controls). The arrow points to the approximate location of A11 area. <b>G–I</b>: Film autoradiograms after radioactive i<i>n situ</i> hybridization targeting the DAT mRNAs in the substantia nigra (<b>G</b>), posterior hypothalamus (<b>H</b>) and lumbar spinal cord (<b>I</b>). Note the absence of DAT mRNA expression in the posterior hypothalamus and spinal cord, in contrast with the intense expression in the substantia nigra (positive control). The arrow points to the approximate location of A11 area. Abbreviations: Hcd = Head of Caudate nucleus; Mfb = Medial forebrain bundle; MM = Medial Mammillary nucleus; mtg = Mammilotegmental fasciculus; Pu = Putamen; SN = Substantia Nigra; V3 = Third Ventricle.</p