Placebo-Controlled Trials: Why They Are Key for Reliable Clinical Research

When enrolling in a clinical trial, it’s important to understand every element so you can make an informed choice. One such part of many clinical trials is the placebo. In this article, we’ll help you understand placebo-controlled trials, including their benefits, challenges, and what participants can expect when they agree to take part.

What are placebos?

Placebos, also known as “dummies” or “sugar pills”, are inactive substances or treatments that have no real therapeutic effect on the condition the new drug is intended to treat. A placebo might look and taste the same as the testing drug, but it contains no active ingredients.

Participants who have taken a placebo may experience “the placebo effect” which is a well-known phenomenon where patients feel better after consuming, although it is not the real drug containing the active ingredients. Scientists aren’t completely clear on how the “placebo effect” works, but it’s thought that it’s caused by endorphins (happy hormones) being released in the brain.

How placebos affect the body's biological mechanisms

When the body experiences something, whether it’s a drug, placebo, or even a feeling, it can cause a biological mechanism. These biological mechanisms can be defined as casually interacting parts and processes that result in one or more effects. Placebos can affect two main biological mechanisms - psychological and neurobiological.

Psychological mechanisms

Psychological mechanisms are responsible for changes in psychological outcomes. Several psychological mechanisms can impact our thoughts and behaviors, and they’re usually divided into three categories: cognitive, emotional, and motivational.

Cognitive mechanisms are concerned with how we process information. Emotional mechanisms involve the way we feel about things, and motivational mechanisms are responsible for our drives and desires.

In terms of the placebo effect, this has typically been attributed to conscious cognition or awareness. As an example, participants in a clinical trial may already have expectations of how they will feel after taking the testing drug, so could effectively experience it without consumption of the real thing. Additionally, the placebo effect could occur due to the action of automatic basic learning mechanisms, like Pavlovian conditioning - learning through association.

Neurobiological mechanisms

Neurobiological mechanisms refer to happenings in the brain, of which many can cause reactions in the body, this can include taking a placebo. Even without an active substance, placebo treatments induce real responses in the brain.

When a participant believes a treatment will work, the brain can trigger neurotransmitter release, hormone production, and immune response. These can help to ease symptoms of pain, inflammatory diseases, and mood disorders.

There can be adverse effects too. For example, even without taking an active substance, consuming a placebo can cause neurobiological mechanisms that result in addiction or other tendencies.

What is a placebo-controlled trial?

A placebo-controlled trial refers to a clinical study in which one group of participants receives a placebo, and the other receives the new treatment or drug being tested. Scientists and researchers compare the results of each group to establish whether the new treatment or drug is effective, and how effective it is.

How do placebo-controlled trials work?

In a placebo-controlled study, participants are randomly assigned to their group, either the placebo group or the new treatment. Medical professionals monitor and record the results of each group throughout the study. They seek to determine whether the observed effects of the new treatment are due to its specific therapeutic properties, or whether they are caused by psychological factors, like the patient’s belief in the efficacy of the treatment.

Placebo-controlled trials are highly valuable in clinical research, working to allow researchers to isolate and quantify the particular effects of treatment beyond any psychological or contextual influences.

Protocol and consent requirements for use of placebos in clinical trials

When researchers use a placebo in a clinical trial, they will be bound to fixed protocols and stringent consent requirements to ensure ethical standards and participant well-being are maintained.

In the development of protocols, researchers will rigorously design elements of the trial to minimize bias and confounding variables. They must also adhere to predetermined guidelines for placebo administration, dosage, and monitoring. Ethical review boards also support researchers at this stage, evaluating and approving protocols to make sure the potential benefits of the trial outweigh any participant risks.

Informed consent is also a key feature of placebo-controlled clinical trials. It’s crucial that participants are provided comprehensive information about the trial, including the potential use of a placebo, and the nature of its inert properties. These consent forms should clearly describe the random assignment process and emphasize that participants may receive either the experimental treatment or a placebo. They should also highlight the fact that participants are volunteers, and they can leave the study at any time without consequence.

The benefits of a placebo-controlled study

There are many advantages of placebo-controlled trials, both for medical researchers and participants. Here, we’ve listed some of the key benefits for researchers and the wider scientific landscape:

• Determining treatment efficacy - By using placebos, researchers can establish the true efficacy of a new treatment or drug. By comparing the results of each test group, medical professionals can isolate specific effects of the treatment beyond any potential placebo effect or other psychological factors.
• Minimizing bias - Placebo-controlled trials usually use randomization in participant grouping to ensure the participants are comparable at the beginning of the study. Blinding is also commonly used to reduce the risk of bias when collecting and interpreting the data.
• Placebo effect quantification - While researchers are keen to explore the effects of the experimental treatment, using a placebo in a clinical trial can also help them quantify the placebo effect itself. Understanding the scale of the placebo response is vital for interpreting the study’s results and distinguishing the placebo from the actual therapeutic effect of the treatment.
• Enhancing causality interference - By using a placebo in a trial, researchers can confidently make causal interferences regarding the relationship between the treatment and outcomes. This means they can establish a clear picture of whether the observed changes are due to the treatment or other factors.
• Regulatory approval - Many regulatory agencies, like the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), require placebo-controlled trials as evidence to approve new drugs or treatments. Forming part of the rigorous study design, this adds to the credibility and reliability of the data submitted for regulatory review.
• Identifying adverse effects - To enable a more thorough assessment of the overall safety profile of a new treatment, researchers use a placebo group to help identify and attribute adverse effects to the experimental treatment or drug.
• Resource efficiency - Using a placebo in a clinical trial can also be more resource-efficient than other study designs. They often require smaller sample sizes compared to clinical trials that use multiple active treatment arms or those that compare standard care or existing treatments.

Limitations of a placebo-controlled trial

Although placebo-controlled clinical trials provide valuable insights, they can also come with limitations, challenges, and ethical considerations, including:

• Ethical concerns - When a study includes the use of a placebo, ethical concerns can arise, particularly when effective treatments already exist for the condition being investigated. Withholding a proven treatment from participants could be considered ethically unacceptable, particularly when the condition is severe or life-threatening.
• Patient expectations - If participants go into a clinical trial expecting to potentially experience a beneficial treatment for their condition, this can influence their psychological and physiological responses - the placebo effect. Unfortunately, this could complicate the interpretation of results because any improvements observed in the treatment group could be influenced by both the treatment itself and the participant’s expectations.
• Limited generalizability - Results from clinical trials using a placebo don’t always generalize well to real-world clinical settings. The strict inclusion and exclusion criteria and the controlled clinical trial environment don’t always represent the diversity and complexity of patients in routine medical practice.
• Compliance and attrition - As study participants have the right to withdraw from a study at any time, there is a risk that participants in the placebo group could be more likely to leave the study if they suspect or experience no benefit from the intervention. This could result in biased data and affect the overall validity of the study.
• Unblinding issues - Ensuring blinding is maintained throughout a study can be difficult, particularly if the active treatment’s side effects are different from the placebo. Unblinding could occur if participants or researchers can deduce group assignments and potentially introduce bias into the trial.
• Placebo response variability - The response from the placebo can differ greatly across individuals and various conditions. The impact of the placebo effect could be influenced by factors including patient expectations, the nature of the condition, and the study environment.
• Practical constraints - Sometimes, it’s logistically challenging or impractical to design a placebo that is indistinguishable from the experimental treatment, especially for interventions that have noticeable side effects or impacts.

Types of placebo-controlled trials

Just like other types of clinical trials, placebo-controlled trials can also have various forms, with their designs depending on the specific research questions being investigated. When researchers are deciding on placebo-controlled trial designs, they will consider other factors including the nature of the condition being studied, ethical considerations, and practical constraints.

Carefully considering these elements enables researchers to design and conduct their clinical trials in a way that ensures the validity and generalizability of their findings. Here, we’ll look at some common types of placebo-controlled trials.

Parallel-group design

In this type of placebo-controlled trial, participants are randomly assigned to either the experimental treatment group or the placebo group, also known as the control group. This design is commonly used in all types of clinical trials thanks to its straightforward nature, but it is particularly effective for researchers seeking to compare the efficacy of a new treatment with a placebo.

Crossover design

With a crossover design, participants receive both the experimental treatment and the placebo, albeit at different times during the life of the study. There is commonly a “washout period” between the two phases which minimizes any carryover effects.

This type of placebo-controlled study is effective when the primary interest is participant comparisons. Researchers can also increase the efficiency of the study with this type, by reducing the required sample size.

Add-on or augmentation design

This design involves participants in both groups receiving a standard treatment, with the experimental group also receiving an additional treatment - the experimental treatment or drug. In contrast, the other group receives a placebo or no additional treatment.

Add-on designs are typically used to determine whether adding a new treatment to an existing routine would provide additional benefits beyond standard care.

Dose-response design

With the dose-response design, participants are assigned to either different dosage levels of the active treatment or a placebo. This helps researchers investigate the relationship between the treatment dose and its efficacy. This type of placebo-controlled trial is effective when determining the optimal therapeutic dose, or understanding how the treatment’s effectiveness could change with different doses.

Enrichment design

In this type of study, participants are first treated with the experimental treatment. After a predetermined period, those who respond positively will be randomized to continue with either the active treatment or a placebo. Those who didn’t are removed from the trial.

Enrichment designs are beneficial in identifying subgroups or patients more likely to benefit from the new treatment. This allows for a more targeted and efficient use of scientific resources.

Withdrawal design

Participants in a withdrawal design will initially receive the experimental treatment or drug. Following this, they will be randomized to either continue with the treatment or switch to a placebo, with the outcomes of both groups compared. This type of study can help researchers assess whether the observed benefits are sustained or primarily due to the ongoing active treatment.

Provocation design

In a provocation study, participants with a condition that can be temporarily provoked or exacerbated will receive both the experimental treatment and a placebo at different times. This is useful when the outcome of interest can be objectively measured before and after the active treatment or placebo has been given.

Phases of placebo-controlled trials

When it comes to phases, a placebo-controlled study is no different from any other clinical trial and will typically progress through different phases. The common phases in a clinical study, including those that involve a placebo control group are:

• Phase 0: Exploratory trials
• Phase 1: First-in-human trials
• Phase 2: Pilot trials
• Phase 3: Confirmatory trials
• Phase 4: Post-marketing surveillance

When a placebo is used in a clinical trial, it is most commonly found in the earlier phases, such as phases two or three. This is because researchers are specifically assessing the efficacy of the treatment in these phases.

Ethics of placebo-controlled clinical trials

As we’ve already mentioned, placebo-controlled clinical trials often stir up several ethical considerations or concerns. Researchers need to carefully balance the benefits of the study design with the protection of its participants, especially when investigating conditions with existing treatments. In trials like these, it may not be ethical to include a placebo group and an alternative study design will be required.

Ensuring placebo-controlled trials are ethical

When making sure that placebo-controlled clinical trials are ethically sound, researchers, trial sponsors, and other staff must adhere to three key considerations:

• Consent - Participants need to be fully informed about the chance they could receive a placebo, the reasons why a placebo is being used, and any uncertainties surrounding treatment allocation. Ensuring participants have a comprehensive understanding is vital for respecting the autonomy of participants and obtaining genuinely voluntary consent.
• Adhering to review boards - Without adhering to the requirements of medical review boards like the FDA or EMA, clinical trials cannot be approved. The pivotal role that these boards play is crucial for ensuring the potential benefits of placebo use outweigh any participant risks.
• Communication - To uphold the ethical standards of placebo-controlled clinical studies, researchers must ensure they offer transparent communication, regular and ongoing monitoring, and a commitment to minimizing participant harm. This also helps to foster and improve public trust in the research process.

Participating in a placebo-controlled clinical trial

If you’re unsure whether you want to participate in a clinical trial, it’s vital to get all the facts before committing. You need to fully understand the difference between a placebo-controlled trial and a non-placebo-controlled trial so you can make a fully informed decision. You should also be aware that you have the right to withdraw from a study at any time, due to any reason.

Before you enroll in a clinical trial, no matter what condition you have, you need to also consider the potential risks and benefits, ensuring you have a clear understanding of the study requirements.

Benefits of participating in a placebo-controlled trial

There are several benefits to participating in a placebo-controlled trial as a participant, including:

• Contributing to medical knowledge - By participating in a clinical trial of any kind, you are actively contributing to medical knowledge and developing new treatments. This means your involvement may not only help your condition but could also help improve healthcare options for future patients.
• Access to cutting-edge treatments - If you’re in the active treatment group of a placebo-controlled clinical trial, you could have access to potentially innovative treatments that may not be available outside of the trial.
• Close medical monitoring - When you participate in a clinical trial, you will be closely monitored with care from experienced medical professionals. This is often more intense and regular than standard care which is beneficial whether you’re part of the active group or placebo group.
• Possibility of personal benefit - Although it’s not always guaranteed, as is the nature of clinical trials, participants within the active treatment group have the potential to experience personal therapeutic benefits.
• Ethical oversight and informed consent - Placebo-controlled clinical trials are bound by ethical oversight and a thorough informed consent process, which ensures participants are fully aware of the study details. This includes any potential risks and benefits that will allow participants to make the best decision for them.

Risks of participating in a placebo-controlled trial

Like any type of trial, participants in a placebo-controlled trial could also be exposed to risks, including:

• Potential for no treatment benefit - If you are placed in the placebo group of your trial, you are likely to receive an inactive substance which could result in no therapeutic benefit being experienced.
• Exposure to unknown risks - With experimental treatments, the full safety profile may not always be known, which could lead to the possibility of participants being exposed to unexpected side effects or risks. However, this is typically explained in the informed consent process.
• Psychological impact - If participants in a placebo-controlled clinical trial discover or believe they have been part of the placebo group, they may experience psychological distress which can cause them to lose trust in the research process. This is especially the case if they believe they are taking the experimental drug.
• Lack of immediate access to effective treatments - If a clinical trial is investigating a condition that already has treatments available, those in the placebo group could be foregoing immediate access to those therapies. This could lead to withdrawal from the process.

How to participate in a clinical trial that uses a placebo

There are several steps to participating in a placebo-controlled clinical trial. You first need to identify clinical trials that are both relevant to your condition and actively recruiting participants.

Once you’ve found a suitable clinical trial, you will need to undertake a screening process to ensure you are eligible for the trial. The criteria for acceptance will be outlined in the study protocol, which you should have access to.

If you are eligible, you will be sent detailed information about the trial, including whether placebos are used and the informed consent process. You may also have a comprehensive discussion with the research team where you’ll learn about the purpose of the trial, and any risks and benefits.

Where to find placebo-controlled clinical trials

Once you’ve decided you want to participate in a clinical trial, you will need to find one. There are several ways to find relevant trials for your condition.

• Online resources - The internet is often the first place people look for information about clinical trials. Some online resources you can use to find a relevant clinical trial include ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), the European Union Clinical Trials Register, and the National Institutes of Health (NIH) website.
• Disease-specific organizations - Several disease or condition-specific organizations or patient advocacy groups hold databases about clinical trials related to their focus. They may also be able to provide information on relevant clinical trials. It’s a good idea to check with organizations that are relevant to your health condition.
• Research institutions and hospitals - Reaching out to research institutions, academic medical centers, and hospitals in your local area is a good way to learn about upcoming clinical trials. These places often hold clinical trials, so will likely have information about studies you could participate in.
• Clinical research networks - Many countries have established clinical research networks that support the facilitation of clinical trials, which means they could be good places to look for upcoming or ongoing trials.
• Healthcare providers - If you have regular visits with your healthcare provider concerning a specific condition, it could be worth talking to them about the possibility of participating in a clinical trial. They might be aware of ongoing or upcoming clinical trials and can guide you in deciding which trial would be suitable for you.

Conclusion

Placebos are often a crucial element in clinical trials and offer many different benefits for both participants and researchers. A key advantage of placebo-controlled trials is that they provide the opportunity to better isolate treatment efficacy and ensure any adverse effects are identified thoroughly and quickly. Whether you’re just starting to educate yourself on clinical trials or you’re ready to sign up, understanding how placebos work is vital.