Research Explained

Approximately 2,000 MS-related research papers are published every year - that's about seven studies each day.

Often the results of one study seem to contradict another study. How do you make sense of these scientific findings? The following information is to help put the scientific findings you encounter in context.

Whether or not a study can be considered credible and scientifically sound depends on many factors, including the type of study conducted, the expertise of the researchers, the statistical analyses used and the rigour and quality of the external independent review of the results.

Basic Research Phase

Many hypotheses regarding possible treatments for MS begin in the lab. In these studies, the treatments are often assessed at a very basic level through the use of cells and cultures as well as an experimental, animal model of MS called experimental allergic encephalomyelitis (EAE) in laboratory rodents. These studies allow for a preliminary evaluation of the possible benefits of a treatment, as well as some idea of the safety and risks of that treatment. If the study is promising, it might move after further study into clinical trials. The study of CCSVI is currently in an early phase in which the aim is to detemine whether abnormalities of veins are associated specifically with MS and if so, what types of MS. Should the current studies indicate that CCSVI is a scientifically-verifiable condition, and that it is related to MS, the testing of CCSVI-related procedures would then move quickly into clinical trials.

Clinical Trials

Clinical trials are research studies that involve testing or studying a treatment in people to see if it is safe and effective. Each phase of a clinical trial follows a protocol and has a specific goal. The information gathered in a trial is used to build knowledge about the new treatment and support the subsequent phases of the research process. Read more about steps to launching a clinical trial.

What is a protocol?

All clinical trials are based on a set of rules or an action plan called a protocol. A protocol describes what will be done in the study, how it will be conducted, what types of people are eligible to participate in the study, and why each part of the study is necessary. All protocols in Canada are conducted according to Good Clinical Practices (GCPs). Good Clinical Practices (GCPs) is an international ethical and scientific framework for the design, conduct, monitoring, auditing, recording, analyses, and reporting of clinical trials that ensures that the data results are credible and accurate, and that the rights of trial participants are protected. Before a protocol can be put into practice, it must obtain two levels of approval: Health Canada (national regulatory agency) and that of an independent ethics committee.

Phase I Study

Phase I trials test the experimental treatment in a small group of people (20-80 people). The purpose is to determine a treatment's safety, learn about a safe dosage range and treatment application, identify side-effects and answer a few initial questions about the way the treatment works in the human body. Phase I trials are usually open-label trials (both the researcher and the participant know what the participant is taking as a medication).

Phase II Study

Phase II trials look more closely at safety and efficacy, and how a treatment affects the human body. Phase II trials usually involve a slightly larger number of people (100-300) who have the disease or condition for which the treatment was developed. Most Phase II trials have a control group; a group that receives either a conventional, existing treatment, or they may receive a placebo. The non-control group receives the treatment under study. The two groups can then be compared. Phase II trials are often double-blind, meaning, neither the person taking the treatment nor the researcher supplying it knows whether it's the real treatment or the placebo. This way neither the patients' nor the doctors' expectations about the experimental treatment can influence the observations and results.

Phase III Study

Phase III trials are the last step before a treatment is submitted to Health Canada. Because of the natural history of the disease, Phase III studies in multiple sclerosis are conducted on large populations of study participants (1,000-3,000), and can last up to five years or more. Phase III trials are large, multi-centre (at many different geographic locations), randomized (subjects randomly chosen to receive treatment or placebo), double-blind and placebo-controlled trials. The purpose is to confirm the treatment's efficacy, monitor side effects, compare it to commonly used treatments and learn more about its safety.

From Trial to Established Treatment

The results from the Phase I to Phase III studies are compiled and the data assessed and presented as an application (with the goal of approving the treatment) to Canada's health regulatory agency, Health Canada. The process of data analysis can take many months or years. The review process by Health Canada likewise takes many months.

The pace of research can seem slow, especially when you have a chronic or progressive disease. It may not seem like a comfort, but this process was designed to minimize harm to patients. There are numerous examples of treatments which were not adequately studied and which caused serious harm. A well-documented example of this is a medication called Thalidomide which was prescribed for pregnancy-related nausea before it had been studied sufficiently, and which resulted in serious birth defects. The research process is long, but it is in place to help ensure that when a treatment is available, it will be proven to be safe and effective, or should it have risks or side-effects, these will be clearly identified.

In some diseases or conditions, physicians can access experimental treatments on compassionate grounds through Canada's Special Access Program. This access is limited to patients with serious or life-threatening conditions on a compassionate or emergency basis when conventional therapies have failed, are unsuitable, or are unavailable.

MS is a progressive disease for many, and it can make life very challenging, but it is not generally considered a life-threatening condition. That is, people with MS can die from MS-related complications, but thankfully, this is very rare, and most people with MS live very close to a 'normal' life span (Kalb, "Multiple Sclerosis: The Questions you have, the answers you need").

Phase IV Study

Once a treatment has received approval from Health Canada, a phase IV study is often done. These post-marketing trials seek to identify further information about the treatment's risks, benefits, side-effects and optimal use. Several hundred to several thousand people may take part in a phase IV study.

Types of Clinical Trials

Observational:

A type of study in which individuals are observed or certain outcomes are measured. The researcher has no influence over the study, and no attempt is made to affect the outcome (for example, no treatment is given).

Prospective:

Participants are identified before the study begins and then followed over time.

Meta-analysis:

is a statistical technique for combining, summarizing, and reviewing existing research studies.

Randomized:

Participants are grouped by chance, usually by computer. Participants are typically divided into the treatment group that receives the treatment being evaluated and a placebo or control group that receives either the current standard treatment or no active treatment.

Cross-Over:

Each participant receives both the treatment and a placebo at different times during the study

Double-Blinded:

Neither the participants nor the researchers know whether a participant is receiving the treatment or the placebo

Open Label:

These are studies in which both the individual participant and the researcher know that the participant is receiving the treatment and not a placebo.

What is a control or control group?

A control is the standard against which experimental treatments are evaluated. In Phase II and III clinical trials, one group of patients will be given an experimental treatment, while the control group is given either a standard treatment for the illness or a placebo. A control is part of the criteria of evidence-based medicine. In the case of CCSVI, control group participants would receive a sham procedure.

What is a placebo?

A placebo is an'inert' pill, liquid, or powder with no active ingredients. In phase II and III trials, experimental treatments are compared with placebos to assess the experimental treatment's efficacy and safety.

What is a 'sham' procedure?

A sham procedure is a placebo form of a procedure. A trial participant may receive a 'sham' or 'fake' surgery, injection or other medical procedure, so that there is a control group. For example, a sham procedure was done in a study on coronary artery disease and angina. The majority who received the sham surgical procedure reported their pain was gone, even though their heart function continued to deteriorate on all objective measures. In potential CCSVI clinical trials, a sham procedure might mean inserting a catheter without using the balloon or stent, so the person does not know whether or not they have actually undergone the procedure.

What is the placebo effect?

The placebo effect is a scientifically recognized, measurable reality. There are measurable changes that occur in the brain when someone is given a placebo that they expect or hope will benefit them. The effect tends to be the greatest in symptoms with a subjective component, such as pain, but it can affect physical function too. The placebo effect is well-documented in many diseases and conditions. For example, a landmark study in Parkinson's disease was able to show an increase in the release of the neurotransmitter dopamine (which is deficient in Parkinson's disease) in patients given a placebo. In MS, studies have indicated that 70% of individuals treated for a recent worsening of their disease will improve, at least temporarily, with placebo. For this reason, treatment of a recent exacerbation in MS can only be considered effective if it leads to long lasting improvement in significantly more than 70% of people who are given it (Kalb, Rosalind C. Multiple Sclerosis: The questions you have, the answers you need. Demos, New York: 2008. Herndon, Robert "How Multiple Sclerosis Treatments are Developed).

The placebo effect is stronger with injections/infusions and surgical procedures than pills and in some studies the placebo effect can last months, even up to a year, although very often it has less durability and starts to fade more quickly. In some cases, it can take time for a study to separate the placebo response from a true benefit.

So as not to deprive trial participants from receiving an effective therapy, many studies now compare a new therapy against one that has been approved for the condition for which the new therapy is being tested. In this type of study, the existing therapy serves as a baseline instead of an inactive placebo. This method is also useful when a high percentage of people with the condition being studied are taking an approved therapy.

How does this relate to the proposed procedure for CCSVI? For one thing, the timing and nature of the benefit that many people are reporting is consistent with a placebo effect. That doesn't mean that the placebo effect is all that accounts for reports of improvement, only that it should be kept in mind. For any treatment to be considered scientifically sound, there needs to be a placebo controlled trial done to rule placebo out.

All existing MS therapies (not to mention symptom management medications) have gone through rigorous studies to ensure an appropriate balance of safety and efficacy in treating MS. The process from basic research phase to approval in Canada can take approximately 20 years.

The Challenge of Studying MS

It's important to note that multiple sclerosis is a particularly challenging disease to study. It can be difficult to determine whether a trial participant has spontaneously improved as occurs in relapsing-remitting MS, or whether the treatment being studied is producing benefit. When studying MS, enough time must be taken to see a difference in the frequency and severity of relapses - this is a statistical measure that must be based on a large number of people and a significant amount of time.

What is Evidence-Based Medicine?

Evidence-based medicine (EBM) is a term that has become common in health-care contexts. It aims to apply the best available evidence gained from the scientific method to clinical decision-making. It is, "the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients" (Haynes and Haines, 1996). It is a systematic approach to patient care that takes into consideration scientific evidence, the expertise of your health provider(s), and the patient's choice and perspective.