What is a Double-Blind Study?
At some point or another in our lives, everyone has needed for a certain medicine. Is it a headache? – Here, pop an Aspirin! Do you have bad digestion?
An antacid! An antibiotic for your infection, and so on.
Hopefully, fewer people had more severe medical issues that required more aggressive treatment – immunosuppressants, cancer drugs, chemotherapy, and so many others.
But when you just take the medicine that the doctor prescribed, has it ever crossed your mind to wonder how did a pharmaceutical company came to a conclusion that that specific medicine works for that specific ailment?
Another thing that comes to mind is: why do doctors say that you should not use medicine X anymore, but that you should start to use medicine Y because it is better i.e. it has fewer side effects, it works quicker, it works better.
How do they know?
Well, it is obvious that they did not just randomly decide that.
Recommendations of the kind are a product of a carefully conducted process that starts with the creation of the new medicine that may include biotechnology, testing it in a lab and later on animals, after that comes the time for human testing, and finally, putting it out to be purchased off the counter or prescribed by a doctor.
In this text, we will focus on the third part of drug testing and that is human testing.
We will answer questions on how the studies/trials are conducted, what the types of studies are, are they ethical and so on.
WHAT IS A CLINICAL TRIAL?
A clinical trial is conducted when there is a potentially better, new drug or treatment for a specific ailment or disease.
It is usually the case with rare or difficult diseases or diseases that still do not have a treatment that works e.g. Alzheimer’s.
The trials also happen for cancer treatments, or any other condition people might develop to be it physical or psychological.
Clinical trials may observe the effects of the drug, the side effects, and behavioral changes. They are conducted with the advancement of medicine, and people’s overall wellbeing in mind.
For a clinical trial to be conducted in a way that gives significant and valid results, participants have to be chosen according to particular criteria that relate to the object of the clinical trial.
For example, if a new Alzheimer’s drug is being tested- a participant firstly has to have the disease, then they have to be at a preferred stage of the disease (e.g. starting to show symptoms, but the disease is not too far gone).
To determine whether a patient qualifies for the trial there is the participant screening process that is used as the baseline for potential improvement and data collection.
The participants, if they qualify, are then informed about the possible benefits, risks, outcomes and so on, and are required to sign an informed consent stating that they have understood all that will be happening during the trial.
If a person participating in a study is not able to make their own decisions, their medical proxy signs the informed consent.
If you have or know somebody who has a condition that might be improved by participating in a clinical trial, you should know that participants are randomly chosen, although the participation has to be voluntary.
The doctor may mention that a study is available, and you can choose to participate.
Patients choose to participate because they want to potentially be one of the first people to ever receive treatment for a condition.
In such a way they are actively contributing to the development of medicine, and without volunteers who are open to such participation, medical advancement would be thwarted.
TYPES OF CLINICAL TRIALS
There are various ways in which a clinical trial may be conducted and they are called study designs. In this text, we will focus on randomized trials and their subtypes.
The way in which you can conduct a randomized study is the blind studies.
In blind studies either the participants or the medical team along with the participants are not aware of the fact whether they have received the treatment which is being tested or not.
i. Single-Blind Study
In a single-blind study, the medical team knows which group has gotten medication that is being tested, but the participants do not know that.
It is used in treatments where patients’ bias can affect the results of the trials.
The issue with a single-blind study is that, since they have all the information, the medical team’s bias can harm the research.
They can subconsciously pay more attention to the subjects receiving the treatments as opposed to those who are not. This is avoided with a double-blind study.
ii. Double-Blind Study
In a double-blind study, neither the medical team nor the participants are aware of the treatment distribution.
It is considered a ‘go-to’ study design for many reasons that are mainly ethical and psychological, and it ensures the most valid results at the end of the research because both participant’s and team’s bias is eliminated.
A double-blind study is also used in many other types of scientific research besides medical research, such as psychological, behavioral, market research and so on.
HOW DOES A DOUBLE-BLIND STUDY WORK?
First of all, there has to be a sufficient number of study participants.
The double blind study happens in the second and third phase of a clinical trial. In the second phase the required number of participants is from 20 to 80.
The participants are usually healthy individuals. The data collected in this stage of the trial are usually related to the side effects that the drug may cause i.e. worsening in the subjects; condition.
The third stage of the trial is a second double blind study. The number of participants in this stage is usually at least 100, however more preferable one ranges from 100 to 300 participants. The participants are then randomly divided into 2 groups:
- The ones who receive the active treatment, new drug, supplement or anything else that could be tested in a trial
- The ones who get a placebo or an already standardized medication depending on the type of study
Optionally, there is the third group of participants a.k.a. the control groups whose members do not get any treatment whatsoever but are just used as a baseline.
For example, people with depression will naturally show improvement after some time that cannot be contributed to the effects of the medicine given in a trial which tests the new antidepressant.
Let us say here how important it is to understand depression, and to seek help where needed.
The difference between the improvements between groups with treatment (both actual medicine and placebo) is compared to the improvements of the control group and they show the actual effects of the new antidepressant.
In many cases, the placebo group can be considered the control group.
For example, if a new cancer drug is being tested, the control group will get standard treatment, and the other group of participants will get the new drug.
This type of a blind-study is called comparative blind study (as opposed to placebo-controlled study) as the premise is that you compare the effects and side effects of an old drug that is already in use to the (side) effects of a new one.
Having a third group of cancer patients as a control group here would be extremely unethical as they would be deprived of a medicine.
On the other hand, if, for example, you are testing a new supplement that is supposed to, say, improve athletic performance, then it will be completely okay to use three groups of participants and observe the effects of both the supplement and the placebo.
For the study to be correct, all three groups would have to be on the same workout regime, sleep management, and diet. So the study would look like this:
- Group one: training + supplement
- Group two: training + placebo
- Group three: training
After the two blind studies, if the effects of the substance are proven beneficial, the FDA approves its use and allows it to be used.
The effects and side effects are still followed, although in a non-controlled environment, on a larger number of people (3000+) and over a longer period of time.
For any type of blind study to give valid results, participants have to be unaware of whether they have received a placebo or an active substance that is being tested.
In a double-blind study the team, as was already mentioned, is also unaware of this.
This is important as people are highly susceptible to biases which can affect both the patient and the medical staff.
It is long known that a patient’s psychological state and motivation can highly influence the outcome of treatments or interventions – the ones with the will to fight the illness have a better success rate than those who lost their hope and have already given up regardless of the fact that they have received the exact same treatment for the exact same (level of) disease.
Keeping the participants ‘blind’ to the information what they have received eliminates both good and bad effects of motivation, and provides the conditions for objective results regarding the effects of the substance on trial.
On the other hand, there is something called the experimenter effect, the observer-expectancy effect or the Clever Hans effect.
The experimenter effect is characterized by the staff working on the trial subconsciously affecting the study rendering it invalid.
People are emotional beings so, if included in a trial as a part of the research team, you want the research to succeed either for the pure altruism- you wish to help people, or just because you want to be connected to a medical breakthrough and have a successful career.
If a doctor knows which patient got a placebo and which one got an active agent, they might subconsciously ask questions in a manner that will give out that information to the patient, who, again subconsciously picks up the cues that the doctor emits.
This psychological effect has been shown on a number of occasions, and it is very interesting to note that even animals can pick up such cues, so why not people?
A doctor may also tend to pay closer attention to the patients on the drug rather than those on placebo.
The people involved in collecting and comparing data might, under such biases, overlook the lack of valid data or the negative data, and read into the preferable data too much.
In any case, the results of the study are not valid enough to continue with the research knowing that there are real scientific benefits of the medicine.
The definition of the placebo is “a pharmacologically inert preparation prescribed for the mental relief of the patient, or used especially in controlled experiments testing the efficacy of another substance “. The origin of the word is Latin for “I shall please”.
The placebo can be a sugar pill of the same shape, taste, and size as the actual pill, a saline solution for intravenous infusions such as chemotherapy, or any other form which corresponds to the active substance.
The reason behind it is that a patient should not be able to deduce that they may get a placebo instead of the active medication.
In clinical studies, as well as in life in general, a placebo can have really powerful effects on the human psyche and it is called the placebo effect.
The placebo effect is based on the premise that the human brain is capable of convincing the body to heal itself (or harm itself as we will see later in the text).
It is about getting real results with fake input. It is already well known that this happens but it is still not understood how this happens.
Placebos have been proved to alleviate depression, anxiety, pain, insomnia, improve your mood and sharpen thinking. It is based on the belief that you are taking an actual medication.
Here is an example of a placebo in a less serious and formal environment. Namely, in the tv series “The Big Bang Theory” a character named Raj has a disorder that manifests as his inability to speak to women unless he has had some alcohol.
In this scene, he drinks a beer and manages to have a conversation with a girl on the train, only to stop when it is pointed out to him that the beer was a non-alcoholic beer (start at 2:20).
However, it is more than just positive thinking and auto-suggestion that make you feel better.
There have been studies that show that people still show signs of improvement after they have been informed that what they got was, in fact, a placebo.
This improvement is said to come as a consequence of the ritualistic behavior of visiting a doctor and the trust we put in them. It has to do with the expectations – we expect to feel better after we consult with a doctor.
It is pretty much the same thing as when a mother kisses a child’s knee after he has fallen and injured himself.
The kiss does not really heal the hurt knee, but the very action and attention that the child receives help him feel better.
Even adults sometimes use this as a very “open placebo”. Remember the origin of the word? “I shall please”.
And even this is not all. It is not only our mental perception but also our physiological reaction to that anticipation, which actually activates immune responses that limit the secretion of damaging stress hormones.
Studies have linked the placebo effect with the body’s natural production of pain-relieving endorphins.
So the expectation of feeling better, in reality, causes the brain to secrete endorphins that naturally make you feel better.
The power of thought, however, can work against you, too.
The nocebo effect is completely the opposite of the placebo effect, and it is characterized by human brain creating negative effects on the body and the psyche.
For example, when you are in a fun park and want to go in a haunted house, your belief that something scary awaits is what actually makes you scared, even though there are just dolls, spider webs and surprises inside. Your body expects something negative and reacts accordingly.
Another drastic example is of a butcher who accidentally locked himself in a cold room.
He started to panic and caused himself to freeze although the cold room was out of order at the time, and the temperature inside was as in any other room in the shop.
The nocebo effect in the clinical trials is seen in the manifestation of the drug’s side effects. Namely, participants who are given the active agent may feel some side effects, although they are more likely to experience them if they were previously informed about what they may be.
If the side effects are not communicated to the participants they are less likely to experience them.
Proof of this lays in the fact that a certain percentage of participants on placebo experience the same side effects like the ones on the active agent, even though there is absolutely no physical or physiological reason for the side effects to appear.
This could be avoided by keeping the side effects from the participants but that action would not be in ethical or legal accordance with the informed consent.
The other issue with the nocebo or the lack of placebo is directly related to how the patients are given the medicine in a double-blind study.
The doctor essentially says “you may be given a real medicine or you may be given a placebo. You don’t know, and I don’t know.”
This action may create doubt and thus, the nocebo effect, not just about the side effects of the medicine but its general effectiveness.
BALANCED PLACEBO DESIGN
A possible solution for the issues that arise in the double-blind study regarding the placebo and nocebo effects can be solved by implementing the balanced placebo design.
This design would consist of four groups of participants – two placebo groups and two active agent groups.
The effects of the medicine, as well as expectancy, would be more realistically measured because, in this design, the groups are differently informed about what has been given to them. For example placebo:
- Group 1 – is given a placebo and is informed that what they have received is placebo
- Group 2 – is given placebo and is informed but they have received the active agent
- Group 3 – is given the active agent but is informed that they have received placebo
- Group 4- is given the active agent and is informed that they have received the active agent
So this is a trial that simultaneously tracks the efficacy of the substance, and the psychological effects of the placebo.
Although balanced placebo design provides the solution for the statistical issues that arise and the psychological effects on the drug’s success, it is arguable how ethical it is to deliberately misinform the participants on what they are actually getting from the trial.
With the constant advancement of medicine and the appearance of new drugs for diseases and illnesses that have been a serious problem for many people all over the world, the need for double-blinded studies is ever-present.
Thanks to them, and their volunteer participants medical breakthroughs are happening more often in this day in age than ever before.
Yes, the risks are great, as great as the benefits, but without those risks medical and pharmaceutical progress would be stunted, leaving many people without hope of a cure.
Considering ethical, legal and medicinal aspects of a double-blind study, we can say that, although not perfect, it is still the best choice for such a type of research.
Well, at least until the technology comes up with ways to test new substances without experimenting on animals and people.