With the 2020 American Diabetes Association (ADA) conference recently completed, we’re once again seeing a slew of headlines about new diabetes research. If you read the details on these clinical trials, you’ll find a lot of references to “randomized,” “controlled,” “double-blind,” and yada, yada, yada. It’s a lot of jargon to digest. What does it all mean?
We’ve put together the following primer to help you make sense of it all. Information is gathered from interviews with Boston endocrinologist Dr. Richard Jackson, an accomplished clinician and researcher, and in part from the book we co-authored together back in 2007, “Know Your Numbers, Outlive Your Diabetes.”
First, let’s have a look at the many terms used to describe research methods, using layman’s language to make things clear:
Prospective means that the studies were planned before the occurrence of the events that they measured, compared to “retrospective” studies, which are conducted to “look backward” and explore events that have already occurred.
Controlled means that there is a second group of subjects, similar to those who got the experimental treatment, but who didn’t receive the treatment. You need a second group so you can compare the results of the two groups to better understand what the effects of the treatment were.
For instance, if you followed a group of people treated with a pink pill for 10 years, you might find that they gained an average of 10 pounds. Is this weight gain a direct effect of the pink pill?
If you also followed a control group that didn’t receive the pink pill, you might find that their average weight gain was 20 pounds. Now your conclusion might be very different; it seems that the pink pill might help people keep their weight down.
Of course, for the control comparison to be most useful, the groups must be comparable in all risk factors that are important to the topic being studied. For example, here you would want to know that the same number of people in each group live next to a doughnut shop, or that equal numbers were active members of fitness centers.
Randomizing study groups means that a computer program randomly assigns individuals to either the treatment group or the control group. This compensates for any unknown risk factors that you might not have recognized. Perhaps people with blue eyes are more likely to gain weight than people with brown eyes, and since you are attracted to people with blue eyes, you might unknowingly assign more of them to the study group than the control group. (This is where unconscious bias against minorities often came into play historically). Randomizing eliminates this possibility.
Blinding (or sometimes called “masking”) adds another layer of protection from biased results. The idea is that research subjects do not actually know if they are receiving the treatment, or if they are part of the control group. In our example above, the control group also takes a pink-colored pill, but one that is a placebo (contains no active ingredient). In what is called a double-blind study, even the researchers don’t know who’s receiving the real treatment until the end of the trial when the “code” is broken, and the data is analyzed.
Adverse event is the Food and Drug Administration’s (FDA) term for the negative effects of a drug or device. This could range from side effects like heart health implications to the malfunction of a device like an insulin pump. Even after drugs and devices come to market, the FDA tracks adverse event reporting in a public
Next, let’s understand the phases of clinical research, with a little help from a national resource called CenterWatch:
This phase includes initial studies usually including just a small number of healthy volunteers (20 to 100). Testing can take several months and is designed to assess the safety of a drug or device, i.e. its effect on humans, including how it is absorbed, metabolized, and excreted. This phase also investigates any side effects that may occur.
Phase II is a second-round that focuses on “efficacy,” or the ability to produce the desired result, of the drug or device, lasting from several months to 2 years, and involving up to several hundred patients. Most phase II studies are randomized and blinded to provide the pharmaceutical company and the FDA with comparative information.
In this phase, randomized and blinded testing involves several hundred to several thousand patients. This large-scale testing can last several years, provides a thorough look at the effectiveness of the drug or device and the benefits, and the range of possible adverse events. Seventy percent to 90 percent of drugs that enter phase III studies successfully complete this phase of testing.
Phase III studies are often referred to as pivotal trials because once this phase is complete, the pharmaceutical company can move ahead with requesting FDA approval for marketing the drug.
The final phase is often called “Post Marketing Surveillance Trials” since they’re conducted after a drug or device has been approved for consumer sale. These studies help the manufacturer to compare a drug with competitors already on the market; monitor a drug’s long-term effectiveness and impact on patients’ quality of life; and determine the cost-effectiveness of a therapy relative to others in its class.
Depending on the findings, phase IV studies can sometimes result in a drug or device being taken off the market, or restrictions of use might be put in place.
Because it is difficult to perform a research study that hits every mark — a large-scale, long-duration, prospective, randomized, controlled, double-blinded clinical trial — lots of research uses less rigorous approaches.
This is one of the reasons why news reports of research seem confusing and contradictory. Does coffee hurt your health or help it? And what about alcohol?
Many studies suggest that moderate alcohol consumption may decrease heart problems. But no one really knows, and it is unlikely that we will soon be able to find large numbers of people in their 40s or 50s who don’t drink, and then randomly assign some to moderate alcohol consumption for the next 5 to 10 years, and others to total abstinence.
Blinding the study would be even more difficult: How could some people drink alcohol without knowing it?
You get the idea; some questions are difficult to answer with certainty through definitive clinical studies.
Regarding the impact of the five most basic and essential diabetes-related health tests — A1C, blood pressure, lipids, microalbumin, and eye exams — the answers are much more clear. There have been large-scale, long-duration, prospective, randomized, controlled double-blinded (with some exceptions where blinding was difficult) trials that confirmed the powerful effects of controlling these factors.
Moreover, Jackson points out that there weren’t just one or two or even three studies in each area, but multiple studies, all supporting the conclusion that keeping these five factors in a safe range will ensure that you have reduced or even eliminated your chance of developing diabetes complications.