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Randomized Clinical Trials

October 14, 2013

There has been a lot of controversy about a recent clinical trial of an oxygen treatment for premature babies. However, I found the reporting of the issue very confused. This article from the AP demonstrates the difficulty in communicating the issues surrounding randomized clinical trials (RCTs). There is a general misunderstanding – and frequently, misrepresentation – of what clinical trials are all about. It is all too easy to get the impression that these are just experiments on humans. The truth is that the evidence gathered from clinical trials is essential in deciding which treatments and medicines work, and which might be harmful. Without them medicine would not have come nearly as far.

My point here is not to give a full review of the controversy. For a good explanation see here.  Rather, I would like to use this as an example to explain some misconceptions about RCTs.

The following statement from the article demonstrates how it is easy to misunderstand the issue:

“… the debate is about one of modern medicine’s dirty little secrets: Doctors frequently prescribe one treatment over another without any evidence to know which option works best. There’s no requirement that they tell their patients when they’re essentially making an educated guess, or that they detail the pros and cons of each choice.”

I fully agree with this statement. But the writer never follows up to explain that this is precisely why we need clinical trials – to provide the evidence that will help decide which option is best.

It is easy to be reminded of the horrors of the past when reading about RCTs (like the Tuskegee syphylis experiment). I am not saying that we are living in a wonderful world in which medical researchers always do what is best for their patients – far from it. However, RCTs are the very tools that allows doctors to offer provenly better medical care.

If you read the beginning of the article, it remains unclear whether in the study premature babies were hurt (perhaps even on purpose) in order to test new medical approaches. Of course, this would be truly horrific if true. As you read further the picture becomes more confusing. The article states that

“Oxygen has been a mainstay of treating them [premature babies], but doctors didn’t know just how much to use. Too much causes a kind of blindness called retinopathy of prematurity. Too little can cause neurologic damage, even death. So hospitals used a range of oxygen, with some doctors opting for the high end and some for the low.”

This is exactly the point: Before the study was performed, a range of treatments was prescribed (85%-95% oxygen saturation levels). Doctors knew that oxygen treatment helped. They did their best to guess how much to use. But before the study was performed they were just guessing what treatment will lead to the best outcome. They did not know whether they could be doing more harm than good by administering too much or too little oxygen. In the absence of evidence, they essentially gambled.

This was a very important issue to resolve, and that is precisely why the trial was performed. Doctors could not have guessed that the higher oxygen levels both reduced mortality and improved outcomes. Now that the answer is known future generation of premature babies will receive better care.

But would this be ethical if it came at the expense of the babies involved in the study? Of course not! We cannot pay for progress in medicine by knowingly harming patients – indeed, the very thought of it evokes the darkest chapters of medical history.

So the question is if the babies in the study received the best medical care known at the beginning of the study. In clinical trials patients are split into groups that are given different treatments. One treatment cannot be known to be worse than the other(s) — this is what the trial is designed to resolve. However, if one treatment turns out to be better, then one of the groups will have received better (more effective) medical care. But this will be known only after the study is completed.

This is an essential point: Before the trial is performed, nobody knows for certain which treatment is better. Indeed, babies that did not participate in the study received a range of treatments, according to the best guess of their doctor. If the trial was not performed, the range of treatments — including the worse one — would still be administered.

What may be difficult to accept is that sometimes, perhaps more often than we realize, doctors simply do not know what the best treatment is. We laugh at the medieval use of leaches, bloodletting, and remedies that would help balance the humors. But doctors today still often guess about what works (how much is a matter of debate) – and I am not even talking about nutritional supplements almost all of which are completely unproven, if not known to be harmful.

I think this is where scientists in general – and mathematicians and statisticians in particular – need to better explain, and keep on explaining why we think certain things are true. Clinical trials offer a way forward in situations where we simply cannot base decisions on experience, but need to look at data and use statistics.

Returning to the case of the premature babies, the stories are heartbreaking

“I unknowingly placed my son in harm’s way,” said Sharissa Cook of Attalla, Ala., who wonders if vision problems experienced by her 6-year-old, Dreshan Collins, were caused by the study or from weighing less than 2 pounds at birth. “The only thing a mother wants is for her baby to be well.”

Dagen’s mother, Carrie Pratt, was more blunt with reporters: “Why is omitting information not considered lying?” she said. “We were told they would give her the best care every day.”

I cannot imagine what these families have gone through. But I do believe that what they suffered was not a consequence of a participation in the study. The babies in the study on average had lower mortality, and better outcomes than babies that were not in the study (perhaps due to the “inclusion benefit”). Had they not participated, it is impossible to know what treatment their physician would have chosen. It may have been any of the ones used in the studies, since the entire range of treatments offered was used in practice.

Explaining the need and the reasoning behind RCTs is not easy. It is far easier to write a story about premature babies harmed by a heartless group of faceless scientists and doctors in white coats. There are many example of people who do misuse evidence knowingly or unknowingly and harm patients by doing so: from the anti-vaccine fantasies of Andrew Wakefield to the cancer therapies of Dr. Burzynski. However, the people in this clinical trial have not done anything of the sort.

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