Why Are There So Few Clinical Trials for People with Primary Progressive Multiple Sclerosis?I have to say that I am shocked and dismayed by the relative lack of information available on primary progressive multiple sclerosis (PPMS), which is diagnosed differently than relapsing-remitting multiple sclerosis (RRMS) and has different symptoms. When you hear about research in to multiple sclerosis, it is almost always on RRMS, rather than PPMS.
You can try this yourself: Go to Clinical Trials Database at clinicaltrials.gov and type in "PPMS." Now try typing in "RRMS." See what I mean?
Part of this difference in numbers of studies has to do with the prevalence of the different types of multiple sclerosis (MS). Eighty-five percent of people with MS are initially diagnosed with RRMS, while only 10 to 15% of people start with a diagnosis of PPMS (about a quarter of these eventually get diagnosed with PRMS, the rarest form of the disease. There are other big challenges to running trials to test medications specifically for PPMS, though. In order to discuss these problems, it first helps to have an understanding of what an “easy” clinical trial design would look like. (Note: "Easy” here is a misleading term, as all clinical trials are fraught with difficulties in recruitment, follow-up, unexpected side effects, adherence, etc., which make any clinical trial a huge and expensive undertaking.)
Quick and Dirty Clinical Trials Primer
An example of an ideal clinical trial may be that for a vaccine for a very common infection, where participants are divided into two groups. One group receives vaccines and one group (the control group) does not. All participants can be tested at the end of a given time period for antibodies. The number of people who received vaccines who test “positive” can then be compared with the number of positive people who did not receive the vaccines. If the number of positive people who received vaccines is lower than those who did not receive the vaccine (by a certain percentage), then researchers can be pretty assured that the vaccine works. Of course, other things need to be assessed, such as differences in levels of exposure to the infection, as well as potential side effects and safety issues with the vaccine, but that is the general design of a basic trial.
Using this as an illustration of a very straightforward clinical trial design helps illustrate some of the obstacles to conducting a clinical trial to test therapies for PPMS. Some specific points are outlined below:
DisabilityMany studies require people to be ambulatory (able to walk) in order to be included in a study. This is so that the effect of the study drug on walking ability, energy level and other physical abilities can be studied by having people walk a certain distance within a certain time. In this way, researchers can use scores on the Expanded Disability Status Scale (EDSS) as an outcome measure. Many people with PPMS are no longer ambulatory.
AgePeople with PPMS tend to be older. This means that they often have additional age-related health problems, such as cardiac issues, diabetes, high blood pressure, vision problems and others. This makes it more difficult to determine which disease (MS or the other ones) is causing or contributing to disability. It also makes it difficult to determine which symptoms are side effects from the study drug and which are due to underlying health problems. In addition, people with other conditions may need to take other medications, which would exclude them from the study, as interactions between medications would not be known or could interfere with results.
Side Effects May Affect People with PPMS MoreIt may be harder for people with PPMS to tolerate side effects from the study drug, both due to MS-related symptoms, other health issues and age.
PPMS Is UnpredictablePPMS behaves differently in different people — some people experience a very quick progression to disability and others progress very slowly, often experiencing “plateaus” of several months or even years where symptoms remain stable. This variability makes it very difficult for researchers to compare placebo groups to treatment groups. It is also impossible to estimate predicted decline, so that the status of people taking a study drug cannot be compared with even an idea of where they may have been had they not taken the drug.
People whose PPMS progresses very slowly may have to be eliminated from the study so that researchers could figure out if the drug is doing anything (otherwise the study would have to continue for many years). That would leave only the people with quickly-progressing PPMS, though, which would also not be a good test of a drug, as these cases may not be representative of all (or even most) cases of PPMS.
Too Big, Too Long, Too ExpensiveWhile all of the above obstacles illustrate that the lack of clinical trials for PPMS is not all about money, there is always a financial factor. Given the above problems in finding just the right patients with the appropriate levels of disability and rate of progression and overall health, any study seeking to prove the effect of a drug to statistical significance would have to be very large. It would have to recruit many participants, meaning it would have to be spread out geographically over many locations (there just aren’t that many people with PPMS in one place).
Participants would also have to be followed for a very long time, as the rate of progression in some people is subtle and variable (as mentioned above).