A recent story in Nature highlights a few important concepts in the conduct of placebo-controlled trials. This story is about a very small placebo-controlled trial involving only 15 children who were stung by bark scorpions in Arizona. The trial’s goal was to demonstrate effectiveness of a new antivenom, Anascorp. The bark scorpion is the only scorpion in the southwestern US thought to be potentially life-threatening for humans and, according to what I’ve read, is a very frequent and very unwelcome visitor in many Arizona homes.
Here’s a link to the story, from Nature: A tiny trial of 15 people helps convince the US to approve a drug that takes the pain out of scorpion stings
“It’s a rare, potentially fatal, emergency medical disease that predominantly affects rural children, and if you put all those adjectives together, it didn’t look possible to put [a placebo-controlled trial] together at all,” says Leslie Boyer, director of the Venom Immunochemistry, Pharmacology and Emergency Response (VIPER) Institute at the University of Arizona in Tucson, who led the supporting trial reported two years ago in the New England Journal of Medicine. “We started out with a daunting task.”
For one thing, trial investigators can’t enroll participants ahead of time because there’s no way of knowing who will get stung. Then there was the problem of getting hospitals to sign up to a placebo-controlled trial….”
This story is interesting because it demonstrates some of the difficulties with conducting placebo-controlled trials, and challenges with getting clear clinical research data about yet-to-be-approved treatments in the face of a life-threatening injury. It is also pretty unheard of for a trial involving such a small number of participants to be considered as clearly definitive as this one was.
First, it was difficult to think of using a placebo in the face of a potentially life-threatening scorpion sting. It would be unethical to agree to withhold any kind of treatment and to instead give a placebo to a child with the symptoms of a scorpion bite (which are described in the article as including “severe pain, extreme nausea, blurred vision and breathing problems”.) Children who experience such a reaction have difficulty, over time, coping with the pain and nausea, and extreme demands on the cardiopulmonary system can lead to more serious situations, including death. Faced with a child who has been stung by a scorpion, most parents would not wish to take the time to (a) go through an informed consent process in the face of such a potential emergency, and (b) go through a consent process when the end result might well be a placebo. As a parent, you’d want the antivenom and you’d want it fast, understandably. The researchers fully understood this dilemma and the difficulty with using a placebo in this case.
Second, there is another older antivenom that had been used between about 1965 and 2000. Produced at Arizona State University’s Antivenom Production Laboratory in Phoenix, this antivenom, while effective, was not highly purified, leading to anaphylactic reactions in many patients. Furthermore, the laboratory that produces it stopped making it. Some doctors and emergency rooms have stockpiles of the older antivenom drug and were, again understandably, very reluctant to withhold the old antivenom (which, while imperfect, did the trick) in order to enroll patients into a placebo-controlled trial.
So the researchers knew what they were up against, in terms of being able to conduct a placebo-controlled trial. And they also knew that, in many cases, a placebo-controlled trial is one of the necessary first steps in being able to make clear, quantitative claims about drugs in order to move forward to conduct larger trials investigating dosage, safety, side effects, etc. Once they got 2 hospitals to take part, they only needed 15 patients in order to demonstrate, quite definitively, that the new antivenom was, as the researchers say, “overwhelmingly effective.” The results were impressive: for all kids treated with Anascorp, symptoms resolved completely within 4 hours — compared to long, and more complicated recoveries for the kids who got a placebo.
Once word got out about the effectiveness of this new antivenom, a new ethical dilemma emerged. No one wanted to administer the old antivenom; nor did they want to be enrolled in yet further placebo studies. So Anascorp was made available, on an “open trial” basis, to all centres who might treat patients with bark scorpion stings. In a 6 year period, they effectively conducted the largest antivenom “trial” in history, with more than 1500 patients treated with the new antivenom, with only mild side effects. They then put together an FDA proposal to approve the use of the drug in treating scorpion stings.
Good news. As of August 4, 2011, the FDA has approved the use of Anascorp for use in scorpion stings. You can read about that here, if you’re interested (or live in Arizona!): FDA approves Anascorp for Use in Scorpion Stings.