MS Research

There are many reasons that people participate in research studies of multiple sclerosis. Each person must weigh these issues and decide what is best for them.

Some of the benefits of research include:

• Helping others by advancing knowledge about MS and MS treatments
• Gaining access to new treatments or diagnostic tests that are not otherwise available
• Obtain medical care from healthcare professionals who are on the cutting edge of MS treatment
• Actively participate in their healthcare
• Participants in research often have a higher level of monitoring of their health

Some of the risks of research include:

• Experimental treatments may not be as effective as currently available treatments
• Experimental treatments may have side effects
• Many studies have placebo controls, meaning that there is a chance of not being on real treatment
• The research may be time-consuming and inconvenient

Prior to the introduction of the scientific method, knowledge was based on beliefs. Without proof, beliefs were determined by tradition, untested theorizing or even the social status of the believer. This led to many beliefs that we would consider odd today. For example, that the earth was the center of the solar system rather than the sun, or that most diseases were due to an imbalance of hot or cold in our bodies. In the case of multiple sclerosis, this has led to some very unusual, and potentially dangerous, treatments over the past few centuries. These have included poisons like strychnine and mercury, removal of large quantities of blood, shaving the head and electrical shocks.

The scientific method requires that the researcher state a hypothesis. This hypothesis must be something that can be put to the test to determine whether it is correct. An experiment is then designed to answer the question of whether the hypothesis is correct. Since it is difficult to design a "perfect experiment," this testing must often be repeated by several researchers with differing methods before a hypothesis can be widely accepted. This process of testing and retesting provides many opportunities for the hypothesis to be altered and refined before it is accepted.

Research is the only method of determining whether a treatment for multiple sclerosis is truly effective. The development of a treatment for multiple sclerosis normally required years of study in animals, and then three phases of studies in humans. These studies require that new treatments be compared to an older existing treatment, or to a placebo (a "sugar pill") to prove their effectiveness. Without rigorous study designs, it cannot be certain that a new treatment is truly effective.

The first medication to slow multiple sclerosis was released to the market in 1993. There are now several medications available with many more in development. Though there is still no cure for multiple sclerosis, in the future, we expect better treatments that are more convenient and safer.

There are several layers of oversight to assure that people participating in research are treated safely and ethically.

Protocol
Research studies are required to have a written protocol of what is going to be done. These documents are often over 100 pages in length and describe in detail all of the study procedures, medications that will be used, what outcomes will be measured and what safety precautions and tests are to be used. The protocol must be carefully followed. It assures that the study design has been carefully considered, and that things will not be forgotten during the course of the research.

Investigator’s Brochure
The investigator’s brochure (IB) is a description of what is known about a potential medication. It describes in detail the animal studies that have been done with a new medication, and also any human studies available. This is used to help determine whether there are any issues regarding safety with a medication.

Principal Investigator
The principal investigator (PI) is responsible for the safe and ethical conduct of the study. Their first responsibility is to the patient and the patient’s safety. They are responsible for assuring that participants are aware of the benefits and risk of a study as well as alternative treatments available outside of the study.

When a new medication is studied for multiple sclerosis, it must be compared to something. Most commonly, it is compared to a placebo. The placebo does not contain any real medication. Some people call them "sugar pills" though they are not often made of sugar.

Placebos are usually made to look just like the real medication. If pills are being studied, the size and shape of the placebo look just like the real medication. The binders and fillers of the real medication and the placebo are often the same. If injections are being studied, the color and volume of the placebo and real medication are the same.

Many people improve after taking a placebo. This is because the mind has a powerful influence on the way our bodies function. For example, 30-40% of patients have decreased pain with placebos. 79% of patients with depression improved with placebo, though 93% improved with antidepressants.

The procedures done during a multiple sclerosis research study can also influence how a person feels. These patients have many visits and tests; they have frequent contact with physicians and research staff from the study; they are excited about a possible new medication for multiple sclerosis.

If there is no comparison group for a new treatment, it is impossible to determine whether patients improved due to the medication or due to the placebo effect. The expectations of having an exciting new treatment, the relationship between the patient and the research staff, and the desire to get better and not disappoint others all make it difficult to evaluate treatments without a comparison group. Placebo groups are, by far, the best comparison group. Because all of the other research procedures are the same between the two groups, any difference in effectiveness can be attributed to the medication.

Some have suggested that historical controls can be substituted for placebo groups. This strategy has not worked. There are many differences in today’s multiple sclerosis patients compared to those even a few years ago. Advances in MRI technology have led to current multiple sclerosis patients being diagnosed much earlier than those in the past. The availability of treatments has caused a shift in those willing to enroll in research studies towards those with earlier disease and less disability. There are even shifts towards increased numbers of females and increased minorities in recent years that make comparisons to historical controls impossible to evaluate.

Some claim that results from uncontrolled studies are so impressive that further testing is not required. These claims are not justified. There are innumerable examples of past treatments that claimed astounding results, but which later disappointed with further study. There is no amount of testimonial claims that can substitute for a well design study.

Finally, another issue is whether a new medication can be compared to an older medication rather than to a placebo. This study design is now commonly used in multiple sclerosis trials. The weakness of this type of study is that it can only succeed if the new medication is better than the older treatment. If it is not as good as the older treatment (even though it might have some positive effect) it will be rejected. For this reason, the FDA generally required that at least one placebo-controlled study be included.

There are several phases of studies used to bring a medication to market.

Preclinical Studies
This phase consists of the laboratory studies of a medication. The medicine must be produced and the production process standardized so that a reliable product can be created. Also, the medication must be tested in animals for safety and dose. This is usually tested in at least 3 species of animals for safety (commonly mice, rats and rabbits). The safety of the medication in pregnant animals is also usually tested. The safety testing ranges from low doses to very high doses. It is also important to determine the dose. This is usually done in an animal model of multiple sclerosis called experimental allergic encephalomyelitis (EAE). EAE is not an animal model of multiple sclerosis, but it does represent a good system to study the effects of a treatment in an immune disorder of the nervous system. At the end of the preclinical studies, a medication must show some benefit in EAE, at achievable doses with acceptable safety.

Phase I Trials
Phase I trials are the first time that a medication has been given to humans. The phase I study has 2 purposes: safety and dose finding. Oftentimes, the medication is started at a low dose. After several patients have successfully received the low dose, the dose is increased. The dose continues to be increased until a target is reached. This target can be a target level that worked in the animal studies, or it can be based on some marker of the medication’s activity such as a blood level of the drug. This allows the dose to be determined. There are many tests for safety including blood tests, ECGs and other measurements. MRIs are usually done to assure that the medication dose not worsen the multiple sclerosis. For multiple sclerosis studies, 10-80 patients are usually included in phase I studies.

Phase II Trials
Phase II trials include larger numbers of patients and the introduction of a comparison group (usually a placebo). The primary purpose of the phase II study is to obtain additional safety data. This again includes blood tests, ECGs and other measures of safety. If there were any areas of concern identified in the phase I study, then additional testing in this area will be included. The other purpose of the phase II study is to collect information needed to design the phase III study. This means that various measures to determine effectiveness must be included. In multiple sclerosis, this commonly includes measures of MRI as well as measures of multiple sclerosis attacks and physical function. The phase II study is not large enough to prove that a medication is successful, but the data from this study can be used to calculate the size of the phase III study that will be required. For multiple sclerosis studies 80-200 patients are usually included in phase II studies.

Phase III Trials
Phase III trials are the final study used to prove that a medication is successful. If these studies are positive then the medication can be released to the market by the FDA. The phase III study must have one primary outcome measure that is the primary endpoint, and this endpoint must be clinically important (for multiple sclerosis usually attacks or disability). Many secondary endpoints may be included such as various MRI measures. The secondary endpoints help confirm the findings of the study, but the primary endpoint is the one that will determine whether the study is a success. MRI cannot be used as a primary endpoint because it is not clear whether a change on the MRI will be relevant to the person’s day-to-day life. Phase III studies also collect safety data. In multiple sclerosis, phase III studies have 250 to over a thousand patients. The FDA also usually requires that at least 2 phase III studies be conducted for a medication to come to market.

Phase IV Trials
Phase IV trials occur after a medication is on the market. These are also called post-marketing studies. These are required to look for additional safety data as larger numbers of patients are treated with the medication. In addition, studies may be done to expand the types of patients treated with the medicine, or the diseases it is used for. The safety studies in phase IV involve tens of thousands of patients.