A clinical trial is a medical research study designed to assess whether or not a new drug or treatment is well-tolerated and effective in treating people with a particular disease. Careful regulations govern the development of new drugs. Prior to clinical trials, investigational drugs must be tested in the laboratory and in animals to assess its potential efficacy and safety. The results of these studies will determine whether it is appropriate to advance the drugs into clinical development.
All new drugs that reach this stage are required to go through an orderly series of clinical trial steps called phases. All clinical trial phases involve careful follow up and assessment of the effects of the new drug in human volunteer participants. Researchers design each phase to address a different question.
Early trial phases often involve assessment of the effects and the safety of the drug in healthy volunteers. In later phases, the effects of the drug are evaluated in patients with the disease which the drug is intended to treat. In some trials, the new drug is compared to a sham drug, called a placebo. In others, the new drug may be compared to existing treatments, to check whether the new drug offers advantages. In all clinical trial phases researchers monitor all participants carefully and regularly to gather data about the effects of the drug.
Some patients with serious diseases may be keen to try new drugs that offer them hope of improvement or cure and may find the carefully regulated process frustrating. But researchers and pharmaceutical companies are legally obliged to comply with these regulations in order to ensure that there is optimal patient safety at every stage and that new drug efficacy and safety is evaluated by rigorous scientific standards.
In Phase 1 trials the new drug is usually tested in a small group of healthy volunteers. The main goal is to evaluate how safe the new drug is in humans. Researchers gather data in order to learn about how the human body metabolizes the drug, to identify common side effects and to determine a tolerated dose range.
In Phase 2 trials the drug is tested in a small group of patients with the condition being studied. The goal is to further evaluate the safety and efficacy of the drug, and to determine the best dose and regimen for Phase 3 trials.
After a Phase 2 trial has shown that a new drug is effective and safe in small numbers of patients, Phase 3 trials test the drug in a larger group of patients. Hundreds or even thousands of participants may be recruited from several different places. When the disease studied is rare, like TTR amyloidosis, the drug development process may involve a single Phase 2/Phase 3 study due to the rarity of the disease and limited patient availability.
The goal of Phase 3 trials is to confirm the preliminary evidence that the drug is safe and effective. The large number of participants enable researchers to assess how common and how serious any side effects are, to gather more extensive information on the extent to which the drug benefits patients and to determine dose and regimen schedules.
The data gathered from Phase 3 trials can then be used to apply for marketing approval from the licensing authorities. If the application is successful, this data is then used as the basis for the official drug information.
After the licensing authorities have approved the marketing of a new drug, post-marketing trials called Phase 4 trials are carried out. The goal is continued safety and efficacy monitoring when the drug is used more widely, in order to identify long-term risks and benefits and to identify any rare side effects.
The guidelines determining who can take part in clinical trials are called eligibility criteria. These criteria are designed to ensure that the type of patients most likely to benefit from the new drug take part and to reduce the chance that participants are put at risk. Sometimes researchers conduct early trials in a group of patients who are relatively similar, so that the outcomes can be reliably compared. If the results are encouraging, later trials may include a more varied patient population.
IONIS-TTRRx Inclusion & Exclusion Criteria
Inclusion criteria state who may participate in a clinical trial. They may include a list of characteristics such as age, gender, diagnosis or disease stage.
Exclusion criteria state who may not participate in a clinical trial. For example, people who have taken a particular drug prior to the trial may be excluded. Pregnant women are often excluded from clinical trials because there is usually insufficient information available on possible risks the new drug may pose to the unborn baby. Patients with familial amyloid polyneuropathy (FAP) who have undergone liver transplantation are excluded from the ongoing Phase 3 IONIS-TTRRx trial.
The researchers who design clinical trials take great care to maximize the chances of benefits and to reduce the risks to participants. New drugs are always tested in the laboratory and in animals before they are tested in humans. Nevertheless, they may cause unexpected, unpleasant side effects. Before the trial starts, the researchers inform participants about any side effects that they know about, such as those that patients in earlier phase trials have experienced. All participants are monitored very carefully throughout the trial and sometimes also after the trial is completed. This enables the researchers to quickly identify any side effects and to take action to minimize them.
There may be some inconvenience to participants, including the need to attend the trial center regularly, to fill in questionnaires, keep a symptom diary or undergo extensive interviews and physical examination. Travel costs can usually be claimed back.
Benefits of participation in clinical trials include gaining access to potentially beneficial new drugs before they are widely available. In addition, patients may benefit from the extra medical attention as any changes in health status are picked up and acted on early. They may also feel empowered by the knowledge that they are taking an active role in their own health care and helping other patients by participating in the development of new treatments.
Each clinical trial is conducted according to a detailed study plan called a protocol. This is carefully designed by the researchers to ensure that participants’ health is safeguarded and that the trial will yield answers to specific research questions. The protocol includes the eligibility criteria, the proposed dosing and testing schedule and the trial duration.
Participants in RCTs are randomly assigned to two or more groups at the start of the trial. One group is given the trial drug and the other group is given an inactive treatment (placebo), an alternative treatment or no treatment. The group receiving the trial drug is called the experimental group and the other group is called the control group. Researchers follow both groups to compare the outcomes.
A placebo is a pill, powder or liquid with no treatment value (a “sugar pill”). It is given to patients in the control group of a controlled clinical trial. The placebo should have the same appearance as the active drug received by the experimental group, and should be administered in the same manner and with the same schedule.
In double blind trials neither the participants nor the researchers know who is receiving the trial drug and who is receiving a placebo. An independent third party codes the trial drug and the placebo materials and holds the code secretly until the study is completed or a significant adverse effect requires ‘unblinding’ where participants and researchers are informed as to which they received.
Participants and researchers all know what drug and what dose is being received.
Multi-center trials include patients and researchers in a number of different locations, often from different countries all around the world.
Before trials start, researchers are legally required to explain all the important information about the study to the participant. They must ensure that the participant understands the risks and benefits, that enrollment is voluntary and that if the trial is placebo controlled, they may not receive the active treatment. Once the participant agrees to participate in the study they would then sign an informed consent form.