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Guest post by Jeremy Howick\u00a0<\/em><\/strong><\/p>\n Trials show that drugs called \u2018interferon alpha\u2019 extend life<\/a> in people with advanced skin cancer (by a bit). If we invented a new drug to treat advanced skin cancer, most patients would want to know whether the new drug was better than interferon alpha. It would be less useful to know that the new drug was better than a sugar pill (a placebo). So in our study<\/a> it surprised us to find that Eggermont<\/a> and colleagues gave some advanced skin cancer patients placebos when testing their new drug called ipilimumab. Was this ethical?The answer depends on which version of the World Medical Association (WMA) ethical guidelines (codified in the \u2018Declaration of Helsinki\u2019) we look at. The original Declaration was published in 1964 as a response to the horrific Nazi experiments with humans in World War II. According to this original version, it was unethical to give people placebos if there was an established treatment. This makes sense to doctors and patients. If doctors could have<\/em> provided a treatment they knew worked, they risk doing relative harm by prescribing placebos, and harming patients is unethical. And most patients want to know which treatment option is the best one, not whether a new treatment is better than a placebo.<\/p>\n It\u2019s not that the original Declaration banned placebos in trials altogether\u2014they were allowed if there was no alternative. For instance there is no cure for the common cold. So testing a new treatment for the common cold against a placebo would be okay. There were also two other kinds of cases where they could be okay.<\/p>\n The revised Declaration states:<\/p>\n a placebo controlled trial may be ethically acceptable even if proven therapy is available \u2026 Where for compelling and scientifically sound methodological reasons its use is necessary to determine \u2026 efficacy or safety <\/em><\/p>\n A problem was that they didn’t explain what the \u2018compelling and scientifically sound methodological reasons\u2019 are. I searched for them and found two, and neither makes much sense<\/a>. The first is that placebo controlled trials are supposedly better at telling us whether a new treatment works or not. The geek word for this is \u2018assay sensitivity\u2019. Promoters of placebo controlled trials use the example of selective serotonin reuptake inhibitors (SSRI) antidepressants to make this point. While SSRI antidepressants are quite effective for people with severe depression, they barely beat placebos for people with mild depression.<\/p>\n This means that (at least in trials) SSRI antidepressants are not always better than placebos for people with mild depression. So if we compared a new antidepressant drug against an SSRI in people with mild depression. If the new drug were just as good as the SSRI we wouldn\u2019t know if the new one was better than a placebo or not.<\/p>\n But if the reason we need a placebo-controlled trial is because the old drugs aren\u2019t that good, then why not demand that the new drug be better than the old one? Many promoters of placebo controlled trials<\/a> think it is okay for a new drug to be as good as an old one, rather than better. You might believe this is okay if the new drug has fewer side effects. But the best way to prove that the new drug has fewer side effects than the old one is to do a trial in which we compare the new drug with the older one. (An option is to conduct a trial that has three groups: one group would get a placebo, the other would get the new drug, and the third would get the old drug.) Financial interests could also play a role here. If we compare the new drug with an older one, the new one might come out as a loser even if both are better than placebo. This could explain why Eggermont\u2019s placebo controlled trial was funded by industry, whereas trial<\/a> funded by the National Cancer Institute is currently underway that compares the new drug (ipilimumab) with the old one (interferon alpha).<\/p>\n The second \u2018methodological and scientific\u2019 reason to prefer placebo controlled trials is that they supposedly give us a measure of \u2018absolute effect size\u2019<\/a>. Basically this means that if we compare a new drug with an old one, we don\u2019t know how much better the new one is compared to a placebo. But why does this matter? Patients and doctors want to know how the new one compares to what they already have, not what it does compared with a placebo. There is another reason why this is wrong: placebos don\u2019t provide a \u2018baseline\u2019 against which an \u2018absolute\u2019 measure can be obtained. For example in ulcer drug trials, the placebo effects ranged from 0% and 100%<\/a> of the drug effect. Like with \u2018real\u2019 drugs, we don\u2019t always know why placebo effects vary, but they do.<\/p>\n Besides not making much sense, our recent study suggests that real doctors or patients don\u2019t agree with them. If real doctors and patients believed there were good \u2018methodological\u2019 or \u2018scientific\u2019 reasons, then we would expect to see lots of placebo controlled trials used where there was an established therapy. But we don\u2019t. We found that just four (6% of our sample) of trials used placebo controls even though they could have used an established treatment. The Eggermont trial of ipilimumab described above was one of them.<\/p>\n I\u2019ve tried contacting Eggermont to ask whether patients in the trial knew about the existence of interferon alpha but haven\u2019t had a response. And our study shows that real doctors and patients don\u2019t seem to agree with the WMA revision to the Declaration of Helsinki. The confusing arguments about the supposed \u2018methodological\u2019 advantages of placebo controls seem controversial at best. This means the WMA\u2019s policy on the ethics of placebos in trials is unethical.<\/p>\n","protected":false},"excerpt":{"rendered":" Guest post by Jeremy Howick\u00a0 Trials show that drugs called \u2018interferon alpha\u2019 extend life in people with advanced skin cancer (by a bit). If we invented a new drug to treat advanced skin cancer, most patients would want to know whether the new drug was better than interferon alpha. It would be less useful […]<\/p>\n\n