Learn about clinical trials

Description

Clinical trials are research studies that are conducted in several phases (0-4) and used to determine the appropriate dose, safety and efficacy of a medicine, procedure or device in humans. Clinical trials may also evaluate behaviour, trends in diagnosis of disease, or ways to prevent a specific health condition. Not all clinical trials test a specific medicine or intervention, some may observe or collect data over a specific period to learn about a disease or patient population. All medical devices, medicines and procedures must undergo rigorous testing in the clinical trial setting before being widely distributed to the general population.

Prior to testing a medicine or procedure in humans, animal or lab research is conducted to determine the efficacy and safety of a medicine or procedure. This is called the preclinical stage of testing. Then, once the medicine or procedure is considered safe for testing in humans, according to regulatory and ethics authorities, the clinical trial can progress to phase 1 testing in a small number of patients. The medicine or procedure must be tested in phase 1 to then progress to phase 2 and onward. Once a medicine or procedure has successfully progressed through the preclinical stage and phases 1, 2 and 3, the researchers can apply for regulatory approval with the European Medicines Agency (EMA) to make the medicine available in the European Union. If the medicine or procedure is approved by the EMA, it is then up to the regulatory authorities in each country in the European Union to decide if the medicine or procedure will be available and reimbursed in that country. See the sections clinical trial phases and regulation of clinical trials for further information.

Regulation of clinical trials

Clinical trials take place worldwide and are sponsored by the pharmaceutical industry, universities, various organisations, foundations, scientific societies and governments. Before a clinical trial takes place, the investigators must create a comprehensive clinical trial protocol (study plan) and undergo ethics approval in all countries where the clinical trial is planned. Also, before a clinical trial can progress to the next phase, it must undergo approval. The clinical trial protocol usually includes information on the following aspects of the study:

Background and rationale of the research
Research questions
Research objectives and endpoints
The length of the study
The study’s criteria for inclusion and exclusion of participants
Assessments
Dosage and method of administration of the medicine
Safety protocols and risks
Methods of analysis

While the ethics approval process varies depending on the country, it often includes submission of a dossier to an ethics committee who then takes into consideration the following:

The relevance of the clinical trial and trial design
The risks and benefits of the clinical trial
The clinical trial protocol
The suitability of the investigator to conduct the clinical trial
The quality of the facilities where the clinical trial will take place
The written informed consent document
Liability insurance and payment policies and amounts for patients who experience death or injury related to the clinical trial
The investigator’s plans for recruitment of patients for participation in the clinical trial

The ethics committee consists of a combination of people such as researchers, clinicians, lawyers/judges and laypeople such as patients or carers.

In the European Union, in the past, clinical trial sponsors had to submit clinical trial applications separately to national competent authorities and ethics committees in each country to gain regulatory approval to run a clinical trial. Since January 2025, sponsors have had to submit one online application via a single online platform known as the Clinical Trials Information System (CTIS) for approval to run a clinical trial in several European countries. However, there are issues that are deemed specific to each country and are assessed separately by national ethics committees. Therefore, approval can still be denied by in some member states.

After a clinical trial has started, a data and safety monitoring committee often monitors the risks, benefits and adverse events in a clinical trial. These individuals are often statisticians, ethics experts, clinicians and researchers. The committee can recommend the study sponsor pause or stop the clinical trial entirely due to safety or other concerns. Often the committee is looking at:

The ability for the patient to adhere to the study requirements
Patient withdrawal from the trial
Safety (death, adverse events)
Efficacy (the committee helps decide if the trial should continue if the medicine is ineffective in the preliminary data analysis)
Regulation of medicines, devices and procedures in the European Union

Once a medicine has completed phases 1, 2 and 3 of clinical development, the researchers submit a dossier to the European Medicines Agency for regulatory approval of a medicine or procedure. The European Medicines Agency (EMA) and European Commission (EC) make decisions for approval of the medicine based on the safety and efficacy data.

Once the EMA and EC approve the medicine or procedure, it must undergo evaluation at a national level to receive approval for reimbursement in a specific country. This is called health technology assessment (HTA) and investigates the following:

The effectiveness of the medicine or procedure compared to what is available in the country
The financial and economic impact of paying for the medicine or procedure
The health policy, social and ethical impacts of the procedure or medicine at the national level

This is a complex process that results in decisions at a national level whether to make the medicine or procedure available in a specific country. It is important to remember just because a medicine is approved by the EMA, it does not mean it is available to every patient in the European Union due to decisions made at the national level. Furthermore, pharmaceutical companies sometimes choose to not bring a medicine or procedure to market in a specific country and undergo the HTA process, resulting in inequalities throughout the European Union with access to medicines.

Furthermore, countries outside of the European Union may have their own approval bodies and procedures.

Risks of a clinical trial

Adverse events (AEs)

One of the main risks of participation in a clinical trial is experiencing an adverse event. An adverse event is the development of a symptom related to the treatment or procedure being tested in the clinical trial. Some adverse events can be temporary and do not require treatment, or some can be permanent and even require hospitalisation or result in death. Examples of adverse events often seen in myeloma and AL amyloidosis clinical trials are:

Haematological (relating to the blood e.g. low white and red blood cells or low platelets)
Infections
Neuropathy
Cytokine release syndrome (CRS)
Neurotoxicity
Nausea/vomiting
Diarrhoea
Bone pain
Visual problems, keratopathy
Changes in skin
Changes in taste
Anxiety or aggression (often related to steroid use)
Loss of appetite
Heart failure
Infusion reactions or allergic reactions to treatment
Decrease in quality of life

Blinding and randomisation

In some clinical trials, patients are unaware of their type of treatment, which is called blinding or a single-blinded study. Sometimes both the patients and treating clinicians are not aware of the treatment being given (this is a double-blinded study). In other cases, the investigators, treating clinicians and patients are unaware of the treatment received (a triple-blinded study).

Furthermore, some patients are randomly assigned to receive either the investigative treatment or the placebo (dummy treatment) or standard of care treatment already available on the market. Therefore, enrolment in this type of clinical trial does not guarantee you will obtain access to the investigative treatment. You must first understand the trial’s design before choosing to participate. The use of placebos or standard of care comparators is important in research experiments as it helps the investigators understand how the new medicine compares in safety and efficacy to what is already available to patients.

However, for patients with myeloma and AL amyloidosis, a placebo is never used to completely withhold medical intervention. In accordance with the World Medical Association Declaration of Helsinki, placebos are only permissible under highly controlled conditions. In trials for these conditions, a placebo is almost always used as an “add-on” therapy. This means every patient in the trial receives the full, proven standard of care treatment (one group receives standard care plus the investigative treatment, while the comparator group receives standard care plus a placebo).

For conditions like MGUS and smouldering myeloma, where the current standard medical practice is “watchful waiting” (active observation without immediate therapy), a trial might compare a new preventive treatment against a pure placebo. However, regardless of the condition being studied, if a patient's lab results or symptoms show signs of change, strict safety protocols ensure they are immediately switched to active, proven treatments.

Some clinical trials have multiple parts or groups (known as “arms”), of which patients may be a part of and receive either the study treatment or placebo. Randomisation and blinding can happen either at the beginning or during the clinical trial, depending on the trial design and what arm a patient is assigned.

Blinding and randomisation are used in research to reduce the potential introduction of unintentional bias (from either the researchers or participants) and to therefore improve the validity of the results.

Dose and route of administration

A dose is a specific amount and the route of administration is the way a medicine is given to a patient. Clinical trials investigate medications in various forms such as intravenous, subcutaneous or oral. Often in the early stages of the clinical trial, medicines are given at low doses that are progressively increased to measure their safety, efficacy and tolerance (step-up dosing). It is important to know that if you are enrolled in an early phase clinical trial, you may potentially be given lower doses of a medicine that are not considered effective yet and are used to assess tolerability.

Newer myeloma treatments have different administration methods, such as chimeric antigen receptor T-cell therapy (or CAR-T), which requires taking a patient’s blood cells, adapting them and then reinfusing them intravenously.

Often, myeloma treatments are given in cycles, meaning you receive the treatment, or a combination of treatments, often at the beginning of the month and are then given some time to rest. This time allows your body to recover and usually happens over several weeks. For example, some patients will receive treatment at the beginning of the month and then 21 or 28 days later.

Clinical trial phases

A new medicine, device, or procedure is tested in several phases in a stepwise fashion. Researchers must receive regulatory approval based on efficacy and safety data to progress through each phase of a clinical trial before they can seek approval from the European Medicines Agency (EMA).

Phase 0 (pre-clinical) or early phase 1: this phase of development includes the testing of a medicine, device or procedure in a laboratory setting on animals
Phase 1: this phase of development includes the testing of a medicine, device or procedure in a small (20 to 80) group of people for the first time, often to evaluate the appropriate dose, safety and efficacy
Phase 2: this phase of development often lasts several years and includes the testing of a medicine, device or procedure in more people (100 to 300) to evaluate the efficacy and safety further
Phase 3: this phase of development often lasts several years and includes testing a medicine, device or procedure in a large group of patients (300 to 3,000) and often tests the medicine in combination with other treatments or in comparison to treatments already available on the market. The primary goal of this phase is to obtain enough evidence of safety and efficacy to get approval from regulatory authorities
Phase 4 (post-marketing approval): this clinical trial phase occurs after the medicine, device or procedure is on the market and accessible to the general population. During this phase, drug developers continue to monitor the efficacy and safety of the medicine, device or procedure in the general population.
Sometimes a researcher can design a clinical trial that combines multiple phases or has multiple parts. These studies are often labelled as a phase 1a, phase 1b, phase 2a, phase 2b, or phase 1/2 clinical trials
- A phase 1a clinical trial is often evaluating a medicine at a single dose in a small group of patients for safety and tolerability
- A phase 1b clinical trial is often evaluating a medicine at multiple doses in a small group of patients for safety and tolerability
- A phase 2a clinical trial focuses on the efficacy of the medicine at the target dose
- A phase 2b clinical trial focuses on the safety of the medicine at the target dose
- A phase 1/2 study combines phases 1 and 2 of research
- A phase 2/3 study combines phases 2 and 3 of research

How to enrol in a clinical trial?

First, you must discuss your options with your treating clinician. They have the most detailed information about your condition and can help you determine your eligibility for a clinical trial.
Some clinical trials only select participants from a specific group of patients and these individuals are usually decided in advance. These studies are therefore not available to everyone, despite eligibility. These clinical trials are known as “enrolment by invitation” studies.
Recruitment is defined as the method used to find patients to participate in a clinical trial. Recruitment of patients is often a complex process that occurs via previously developed community networks (hospitals, doctors, patient organisations, patient registries, clinical trial registries, pharmacies and recruitment agencies), advertising and other methods. Frequently clinical trial sponsors partner with large hospitals to support the recruitment of patients. Yet, this often leads to clinical trial access gaps for patients that do not live close to or in a country where these facilities are located.

Logistics

Before enrolling in a clinical trial, you must first discuss your eligibility with your clinician
Once you are deemed eligible, you will be given information about the study design and asked to complete an informed consent document in writing. This document provides you with a comprehensive list of the clinical trial’s risks, anticipated benefits and participation requirements. Before signing and agreeing to participate, take time to review the informed consent document and discuss it with your carers, clinicians and the study team to ensure you understand the complete document, including the study’s risks, anticipated benefits and requirements. This time is important to clarify doubts you may have.
You will then go through a screening process to confirm your eligibility. It often includes a consultation with the study doctor, lab work, imaging and potentially a bone marrow biopsy. No clinical trial procedure can be performed without a doctor first explaining to you the clinical trial and before the informed consent is signed.
Once you enrol in the clinical trial, you will have multiple visits for treatment administration and disease response measurements. During these visits, you may have blood work taken through a needle in your arm, a bone marrow biopsy, imaging, vital sign measurements or urine tests taken.
Clinical trials visits can last from a few hours to several days. Some visits may occur in the hospital (inpatient), where you will be observed for several days after receiving treatment. Or they can take place in an office (outpatient) where you go for potentially several hours to receive the treatment. Some clinical trials, although rarely, allow for you to administer treatment at home with nursing support.
In addition to receiving the treatment and tests, you and your carer will need to monitor for symptoms or adverse events. This may require at-home monitoring, such as blood pressure or temperature measurements and completion of a diary or documents to report this information to the study team.
In addition to monitoring, you may be required to complete a patient-reported outcome (or PRO) questionnaire at treatment or follow-up visits. These are very important to complete. The results of these questionnaires are often reported to regulators to provide the patient perspective on treatment tolerability and effects on your quality of life. These questionnaires often ask about your pain, depression, sleep, mood, physical mobility, satisfaction, symptoms you are experiencing and general questions about how you feel. This information will be collected in several ways, such as through phone interviews, on a tablet or electronic device or on paper and may take several minutes to complete. If you ever have trouble completing these, ask the study team for assistance. Some examples of questionnaires often used in clinical trials are the following:
- European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30) or the myeloma specific EORTC QLQ-MY20 questionnaire
- The Functional Assessment of Cancer Therapy (FACT/GOG-Ntx) or the myeloma specific FACT-MM questionnaire
- The MD Anderson Symptom Inventory for Multiple Myeloma (MDASI-MM)
- The Myeloma Patient Outcome Scale (MyPOS)
The treatment being studied in the clinical trial and any medical tests or procedures specifically required for the trial should normally be provided at no cost to you. However, the arrangements and costs for other medicines, supportive care, hospitalisation and treatment of adverse events may vary depending on the trial and country.
You will have more frequent visits and/or hospital stays during a clinical trial than during typical treatments. Therefore, it is essential to consider the logistics and need for reliable transportation and assistance to and from appointments. Some patients require more extended hospital stays at treatment centres that are not close to home or must remain close to the treatment facility. Therefore, it is crucial to consider the costs and feasibility of transportation (such as the location of the treatment centre relative to your home) and hospital stays during the clinical trial. Some clinical trial sponsors may reimburse transportation and hotel costs for carers and patients. Yet, this is not always guaranteed and there may likely be some out-of-pocket costs associated with the clinical trial.
In addition to the out-of-pocket costs for transportation and housing, you must clarify further potential out-of-pocket expenses with the study sponsor. This may include expenses related to the study treatment, hospitalisation and management of adverse events. Also, you must be aware of potential compensation if you were to die or become injured due to taking part in the clinical trial.

Clinical trial eligibility

To be eligible for a clinical trial, you must meet various strict criteria to start the enrolment process. Research has shown that, on average, the use of strict eligibility criteria eliminates 56.8% of patients from participating in a cancer clinical trial. These criteria are called inclusion and exclusion criteria and are often related to your laboratory results, previous treatments, fitness level and overall health. Inclusion and exclusion criteria are used to ensure the safety and validity of the clinical trial design and results. While there are some concerns about too strict inclusion and exclusion criteria, it is necessary to restrict some participants entry into a clinical trial to prevent unexpected side effects or even death in some severe cases. Also, inclusion and exclusion criteria work to ensure that the general population will have the same, if not similar, experience as those in the clinical trial and the presence of other diseases or cancers could potentially bias the clinical trial results.

Some examples of standard inclusion criteria in myeloma and AL amyloidosis clinical trials are:
- Patients older than 18 years of age (and often times younger than 75 years of age)
- Patients with a diagnosis of myeloma (often medicines are initially tested in patients with relapsed/refractory myeloma who have exhausted all their treatment options)
- Patients with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 indicating they are functional enough to tolerate treatment
- The presence of measurable myeloma cancer cells or paraproteins
Some examples of standard exclusion criteria in myeloma and AL amyloidosis clinical trials are:
- A history of, or current presence of, other cancers
- Moderate to severe neuropathy
- Prior treatment with a specific myeloma treatment
- Severe heart, kidney or liver failure
- Infection with HIV or hepatitis C
- Substance abuse concerns
- Mental health concerns
- A history of failure to take treatments appropriately or many missed appointments
- Presence of myeloma cancer cells outside of the bone marrow (often in the form of a tumour) known as extramedullary disease or a plasmacytoma

What should I consider before enrolling in a clinical trial?

Logistical considerations

Are there any expenses for myself and/or my carers? Such as taking time off from work, travel, hotel stays, insurance or medical costs. Are these expenses reimbursed? Am I willing to travel or be hospitalised for days or weeks at a time?
Do I have the proper support at home and during visits to assist with monitoring or other requirements associated with the clinical trial?

Physical/treatment considerations

What are the risks? Do I feel like I am willing to take a chance at this point in my life/disease process?
Are there any alternative options available for treatment?
Looking at the possible side effects, do I feel like these are tolerable? Have I experienced these before?
How often do I need invasive procedures or tests during the trial? Am I willing to deal with the potential discomfort associated with these?

Clinical trial design considerations

Will I have access to the medicine after the trial ends if I can tolerate and benefit from it?
What are the chances of receiving the study treatment (i.e. will I be randomised)? Will I know what medicine I am going to receive (i.e. will I be blinded)?
How will my data (disease and personal information) be handled and reported to me?
Are there any risks of losing eligibility during the trial, meaning I will not get the study treatment?

Personal considerations

Have I shared my wishes with my family in case something happens to me before or during the trial?
Have I completed any advanced directives?
What is most important to me, and how do I define quality of life?

Who can answer these questions? Ask your healthcare team about logistics, the need for a carer, risks and alternative options and trial details. Nurses and/or doctors should be able to answer these questions. Carefully read the informed consent. It can be very long and overwhelming, but it contains valuable information about the trial. Regarding your personal considerations, think about these questions and talk with your family and/or friends.

Command Palette

What are clinical trials?

1Description

2Regulation of clinical trials

3Risks of a clinical trial

Adverse events (AEs)

Blinding and randomisation

Dose and route of administration

4Clinical trial phases

5How to enrol in a clinical trial?

6Logistics

7Informed consent

8Clinical trial eligibility

9What should I consider before enrolling in a clinical trial?