Allowing someone with schizophrenia to remain in a psychotic state is cruel and harmful to the person, but that is what happened in a recent drug trial.
Canadian psychiatrist, David Laing Dawson, pointed out that "the longer our brains remain in an altered state...the longer it will take to return to a normal state." In addition, he said that it is painful to the person and dangerous. American psychiatrist, E Fuller Torrey, said that "common sense would suggest that individuals with active psychosis should not be deprived of antipsychotic medication." Dr. Torrey is the head of the Stanley Medical Research Institute and both comments were made to me via e-mail.
But that is what happened in a trial conducted by Otsuka Pharmaceutical and Lundbeck Pharmaceutical to gain approval from the Food and Drug Administration (FDA) in the United States earlier this year.
In a study called Efficacy and Safety of Brexpiprazole for the Treatment of Acute Schizophrenia: A 6-Week Randomized, Double-Blind, Placebo-Controlled Trial, 636 patients were recruited at 65 study centers in the United States (35.8 per cent of randomly assigned patients), Ukraine (18.1 per cent), Romania (17.1 per cent), Serbia (11.8 per cent), Latvia (4.9 per cent), Malaysia (3.3 per cent), Japan (3.0 per cent), Poland (2.5 per cent), South Korea (2.4 per cent), and Canada (1.1 per cent). Patients were assigned to either one of three doses of the experimental drug or to placebo.
All of the patients were recruited because they had an acute exacerbation of their schizophrenia and, as the study authors stated, "would benefit from hospitalization or continued hospitalization for treatment." Now, while the experimental drug did prove beneficial enough from this study for the FDA to approve its use in the U.S., the dropout rate was quite high. Only 410 of the 636 patients (64 per cent) were able to complete the six week trial. Needless to say, the largest number of dropouts were in the placebo arm (59 per cent). As the authors described it, "Most treatment-emergent adverse events with placebo were related to the underlying condition." In other words, their schizophrenia got worse!
What I would have expected along with many others, is that the experimental drug would be compared to an already existing and proven treatment drug. That way, no one is left untreated to suffer. We would expect the experimental agent to do as well as or better than an already proven treatment.
The ethical research guidelines outlined in the Declaration of Helskinki and developed by the World Medical Association state that "The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the best proven intervention(s)." (Section 33). It adds that "Where no proven intervention exists, the use of placebo, or no intervention, is acceptable."
The World Health Ogranization writes "As a general rule, research subjects in the control group of a trial of a diagnostic, therapeutic, or preventive intervention should receive an established effective intervention." (P30). The Government of Canada stipulates that "A new therapy or intervention should generally be tested against an established effective therapy."
This study was approved by an ethics board and it did comply with one of the medical research protocols -- the Guidelines for Good Clinical Practice -- which says nothing about use of placebos. According to Margaret Somerville, the Founding Director, Centre for Medicine, Ethics and Law and the Samuel Gale Chair in Law at McGill University in Montreal, "Some ethicists believe it is unethical to include a placebo limb in such trials, others that it can be justified under certain conditions. What those conditions are all depends on the facts."
She added that "I know that in the past some pharmaceutical companies wanted to and did run trials of new antipsychotic medications against placebos and not standard treatment, as they hoped for a more statistically significant result, but in my opinion that is not a valid ethical justification for placing subjects at additional risk of harmful events if they are taken off medication, that is for including a placebo arm rather than a standard treatment arm as the comparator."
However, when she read the journal article she had this to say:
It's impossible to judge the ethics of placebo use on the basis of the information reported in the paper, but the burden of proof that it is ethical is on the researchers so in the absence of evidence to that effect use of the placebo is not ethically justified in my opinion. And placebo use is not the only issue. I note this statement " the 0.25-mg dosage was hypothesized to be ineffective on the basis of preclinical data", which I would understand to mean that the requirements of "clinical equipoise" were not fulfilled for that limb.
Clinical equipoise means "that a state of genuine uncertainty (exists) on the part of the clinical investigator regarding the comparative therapeutic merits of each arm in a trial." In other words, the investigator is not sure which arm of the trial will or won't be effective. In this case, the investigators knew that the low dose of the experimental agent was of no value. To give the subjects that dose is, therefore, unethethical.
According to Kristofer Baumgartner, a spokesperson for the FDA, "Because a high rate of placebo response is common in psychiatric clinical trials, use of placebo is necessary to prevent the approval of products that are not actually effective. It is only by showing that a drug performs better than a placebo that we are able to differentiate a "true" drug effect from the placebo effect. This is the methodological reason supporting use of placebo."
He added that patients in this trial were hospitalized so they could be closely monitored.
According to Dutch researcher, Erik Claver, the FDA has not followed the Declaration of Helsinki since 2008, although Kristofer Baumgartner did mention that a placebo is allowed under specific condition under the Helsinki protocol. Claver added that not having a placebo benefits the pharmaceutical industry in two ways:
"It is easier to show that a drug is better than placebo than existing therapies. Active comparator trials require more patients and consequently more time and money.
If the existing treatment turns out to be more efficacious, it enforces the market position of the competitors product."
And so, those who were in the placebo group suffered more than they should have for the sake of a drug approval.
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