Understanding how RA drugs are tested for effectiveness and safety
Over the past decades, remarkable strides in our understanding and treatment of RA have been made. There are more effective treatments for RA now than ever before, and, if you have the disease, you stand a better chance of leading a full, normal life than ever before.
As the central star of your RA care team, one of the most important and powerful things you can do is to get accurate information about the many treatment options available to you. There is a lot of truth to the old saying “knowledge is power.” Understanding the basics about how the effectiveness and safety of treatments for RA are tested will help you make informed decisions and participate more fully in your care. When you take an active role in your care, supported by your doctor, nurses, and other health professionals, you will be part of a truly unbeatable team.
Basics about clinical trials
The gold standard in testing the effectiveness and safety of any medication used to treat a disease, including treatments for RA, is the randomized, controlled trial (RCT, for short). Typically, an RCT compares a medicine or treatment with a control, typically something called placebo (this is often just a pill that contains no medicine or, in the case of an injection or infusion, a liquid, such as a saline solution, with no medicine). An RCT study can also compare one test treatment to another active treatment. This active treatment is called an active control and is typically a treatment that is already proven to be effective. In some cases, RCTs will include both an active control and placebo. The key is to set up a comparison that will tell us something meaningful about the effectiveness and safety of the test treatment.
In an RCT, the comparison is made in a group of patients who are randomly assigned (randomized) to receive either the test drug or the placebo. If the group is large enough and the effects of the medication being tested are strong enough, there may be what is called a statistically significant difference between the effect of the medication and placebo.
This statistical difference between an active treatment and placebo, or between two active treatments, is what tells us that a medication works. Just to make sure that the results of one study are not a fluke, it is typically necessary to replicate or repeat the results in multiple RCTs.
We need RCTs to tell us that there is a real difference between a medication and placebo, to avoid the placebo effect. Placebo effect is something that is seen in clinical trials, where a certain percentage of patients who get placebo instead of active treatment will experience an improvement. It may be their belief that they are receiving real treatment, or their confidence in their doctor, or just the power of positive thinking, but results from studies show that placebo treatments often result in a real, measurable health improvement in some patients.
Understanding the language of clinical trials
As you start to read about results from clinical trials of treatments for RA, you will encounter a number of terms that are commonly used and have special meanings within the world of clinical research. We’ll try to cover the most important of these terms.
Key components of a randomized, controlled trial
Clearly defined study question
Appropriate control group
Adequate sample size
Selection of appropriate study population
Sufficient duration to show treatment effect
Defined outcome measures
Appropriate statistical plan
Appropriate randomization plan
Adapted from Simon L, Boers M. Design of trials for new therapies in patients with rheumatoid arthritis. In: Hochberg MC, Silman AJ, Smolen JS, Weinblatt ME, Weisman MH, eds. Rheumatoid Arthritis. Philadelphia, Penn: Mosby Elsevier; 2009:387-393.
Study design and methods. In addition to RCTs, there are other types of trials or studies that use different design features. When you look at an article or report describing a study, usually you can find information about the design of the study in a section labeled “study design” or “methods.” Every well-designed study starts out with a primary question (and secondary questions) that it seeks to answer or test. The primary study question is sometimes called the study hypothesis. An example might be “Does treatment X result in improvement in RA symptoms (compared with placebo)?”
The study then details the steps that will be taken to answer the question. These steps will include the criteria for selection of participants for the study. Selection criteria are sometimes called inclusion and exclusion criteria. The study design will also clearly spell out the way it will measure results, defining what are called efficacy and safety outcomes or endpoints. Examples of efficacy endpoints typically used in RA drug studies include disease activity score (DAS) and American College of Rheumatology (ACR) 20/50/70 responses (the numbers here refer to a 20%, 50%, and 70% improvement from baseline or when the study starts).
The study design or methods will also include the statistical plan, which will spell out how the study will determine the significance of comparisons and lay out how it came up with the required number of study participants (also called sample size) for making meaningful comparisons. It will also define other important parameters of the study, such as duration and means of testing the safety of the test treatment.
Why is randomization so important? Some studies do not involve randomization. In other words, there is no effort to randomly assign patients to one treatment or another. One reason randomization is so important in studying the effects of a treatment, is that when an investigator takes it upon him or herself to decide who will receive a study treatment, results of the study become subject to the bias of the investigator. Randomization in an RCT is typically done using a computer, which removes all human bias from the decision of who will receive the test treatment and the control substance. Some studies lack any control, either placebo or active. These studies are sometimes called uncontrolled. Other studies may involve a historical control, a group of patients from an earlier study who received placebo or another active treatment.
We already know that RCTs involve the random assignment of participants to the active test treatment and a control, either placebo or another active treatment or both. The best RCTs will also use what is called blinding to make sure that study participants and/or investigators (the scientists that conduct the study) do not know who is receiving the test treatment and the control.
Studies where both patients and investigators are unaware of who is receiving the test treatment and the control are called double-blind studies. Studies where only patients are unaware of whether they are receiving the test treatment or the control are called single-blind studies. Studies where there is no effort to disguise who is receiving the test treatment or control are called unblinded or open-label studies. In many cases, an RCT will include an initial double-blind stage and transition into an open-label phase where participants are given the option of switching to the test treatment, usually to generate long-term treatment results.
The important thing to understand about blinding is that it is used so that the biases and preconceptions of participants and investigators alike do not interfere with the results of the comparison being made in the trial. If an investigator knows that he or she is giving a patient an active treatment, that knowledge may affect the way they care for the patient, which may have an influence on the results of the study.
How are the results of clinical trials used?
Clinical trials of new treatments for RA and other diseases are required for regulatory approval by agencies responsible for ensuring the safety and efficacy of treatments, including drugs and medical devices.
In the US, the Food and Drug Administration (FDA) is responsible for approval of new treatments and requires manufacturers to conduct a number of different clinical trials in humans to evaluate the efficacy and safety of treatments. Before these human trials can begin, the manufacturer conducts preclinical studies (including both animal and in vitro studies) to demonstrate the potential therapeutic effect of a new product. The regulatory agency responsible for drug approvals in Europe is the European Medicines Agency (EMA).
Clinical studies required for FDA approval consist of Phase 1 through Phase 3 trials. Phase 4 trials are typically conducted after a drug is on the market. Other specialized studies of new drugs are conducted to examine the pharmacokinetics and pharmacodynamics of drug products. Each clinical trial phase has a defined focus in terms of the regulatory approval process.2
- Phase 1 trials: treatment is evaluated for safety in a small group of patients (20 to 80). For drug treatments, a safe dosage is determined.
- Phase 2 trials: treatment is tested in a larger group of patients (100 to 300) to further evaluate safety and to test efficacy.
- Phase 3 trials: treatment is evaluated in a large group of patients (1,000 to 3,000) to confirm efficacy, evaluate safety and side effects, and compare it to the standards of care in a specific disease.
In the US, the FDA reviews all study protocols (the documents that define the methods for clinical trials) for experimental treatments, stipulating trial objectives and requirements along the entire approval process, from Phase 1 through Phase 3 trials. The FDA also will review all clinical trial data as part of an application for regulatory approval of a treatment. In terms of the FDA approval process, results from Phase 3 trials are of key importance. Phase 3 trials that are used for regulatory approval are often termed “pivotal trials.”