People sometimes use the term ‘research’ in a very loose way for almost any kind of information-gathering about a topic of interest – finding out information about your Multiple Sclerosis, by reading this book for example. However,
‘scientific research’ involves a very particular way of acquiring information, where a specific question – called a hypothesis – is devised and tested, to find out whether, under particular conditions, that question is answered negatively or positively. To be treated as scientifically correct (valid), the same answer must be repeated under exactly the same conditions by other researchers.
There are broadly five kinds of scientific research being undertaken in relation to MS:

• The systematic study of the distribution and patterns of MS in different communities and countries – usually known as epidemiological research – might involve asking questions about whether Multiple Sclerosis is more common in one geographical area than another, or is decreasing or increasing in a particular population over time, and what factors might explain these differences.
• Laboratory-based research focuses on questions related to the development of MS, for example why and how it affects specific nervous system tissue, where researchers often work at the level of individual cells; or what are the possible genetic differences between people with and without MS where blood or tissue types are examined.
• Clinical research on patients seeks to answer questions about what is often called the ‘natural development’ of Multiple Sclerosis in individuals, through the investigation of particular symptoms and signs that develop in those individuals over time, and what consequences these have for people’s ability to function in everyday life.
• Other research concentrates on questions about the effectiveness of potential therapies for MS, commonly undertaken through clinical trials – often after extensive safety testing in the laboratory. People with MS may be asked if they wish to participate in a clinical trial, for example to test a new drug.
• More research is increasingly taking place in what is called applied science in relation to MS. In the absence of a cure, much of this research is investigating how, for example, physiotherapy or speech therapy can reduce the impact of symptoms, or how far psychological support or counselling can help people to manage their symptoms better.

Each of these approaches uses scientific methods to understand Multiple Sclerosis, and assist people with the disease. However, the most common form of scientific method you are likely to come across personally is the clinical trial.

Epidemiological research

As we have said, epidemiological research primarily focuses on the distribution of MS in specific populations and countries. In Chapter 1 we talked about some distribution patterns that had led to important lines of inquiry about possible causes of the disease. Thus the facts that MS is found largely in temperate regions of the world and more amongst women, and that there appear to be geographical ‘hotspots’ of the disease, all seem to explain something about Multiple Sclerosis. The problem with epidemiological research is that there are many, many reasons why such patterns could occur. Most patterns are misleading in that they either disappear when subjected to detailed investigation, or are explained by another factor not related to MS. Quite a number of people with MS have found several others with the condition in their area, or have had some job or other life experience in common. It is tempting to jump immediately to the conclusion that there must be some link that has caused the MS. Usually such patterns occur just by chance – even when very odd things happen, such as two or three unrelated people with MS living in the same street. In such cases the findings of epidemiological research are primarily suggestive, and must be supported by other kinds of research.
At present two of the most interesting, although very time-consuming, types of epidemiological research, are those trying to detect and assess all people with MS in a particular area, and those measuring the distribution in the population of certain genetic ‘markers’ linked with MS. In the former studies, findings are indicating that there are more people with MS than we had previously thought, and the latter findings are suggesting increasingly firm associations between particular genetic markers and types of Multiple Sclerosis.

Laboratory research

There is a very wide spectrum of research in this area; it is usually undertaken on individual cells or cellular processes, often in animals. Much of this research is linked to understanding how the body’s immune system in Multiple Sclerosis seems to attack itself. Many scientists believe that the body’s failure to distinguish between ‘foreign invaders’ in the form of bacteria, viruses and so on (which it should attack), and its own tissue (which it should not attack), is the root explanation of why MS occurs. This kind of research has identified many of the different types of cell in the immune system, how they work, and what happens when they fail or become disrupted. Studying how immune systems work both in animals and in people with MS, who also have other diseases thought to be immune related (such as rheumatoid arthritis), gives a clearer idea of what is happening in people with MS. However, such work is not always directly transferable to MS. For example, in the late 1980s, research on a disease model in animals (called EAE – experimental allergic encephalomyelitis), thought to be similar to Multiple Sclerosis in humans, revealed promising clues to therapies that might prevent EAE in animals, and thus possibly prevent MS in humans. However, it turned out that the human immune system was far more complicated than that of laboratory animals. As a parallel development a number of fierce immunosuppressant therapies were devised, in the hope that, by suppression of the activities of the immune system, then at least no further ‘autoimmune’ attacks would occur on the body’s own tissue. However, many of these therapies suppressed all immune system activity, and so led to major infections and complications, in which often the intended ‘cures’ produced worse symptoms than those of the disease they were supposed to help.
Nevertheless, from these studies have come some interesting develop- ments – and one of these developments is work on what are called
‘cytokines’. These are chemical messengers associated with the regula- tion of immune system activity; understanding these cytokines has already proved rewarding. For example ‘interferons’ are one kind of cytokine and, of course, ‘beta-interferons’ have proved to give consider- able therapeutic benefit in MS. However, the position is still complicated, for some cytokines seem to make MS worse and some seem to help con- trol it; whilst beta-interferons seem to help MS, other types of interferon do not. The lesson from this particular kind of research, just as in much scientific research, is that there are many disappointments as well as new developments, and often the disappointments lead to new approaches to Multiple Sclerosis.

Clinical research

Clinical research directly involves studying people with Multiple Sclerosis and their symptoms on an individual basis. Although it may sound strange after many years of research on MS, what is called the ‘natural history’ of the disease is still not entirely clear, although major studies in Canada have revealed much about the long-term outcome of MS. As we discussed in Chapter 1, it is still not really possible to give anyone a clear idea of how their disease will develop over time, so much clinical research is still devoted to assessing people with MS over long periods of time – several decades – to chart as carefully as possible how their disease develops, especially in relation to early symptoms and signs. Such information is very important, in order to judge, for example, whether early inter- vention will af fect the later course of the disease. As people with the condition know, the effects of MS appear to be very fickle on a day-to-day basis, let alone a longer term one, so it is one of the most difficult research tasks to determine the specific effects of MS, as against those occurring from other, perhaps unrelated, conditions, and the effects of natural ageing processes. Other clinical research is focused on improving and developing diagnostic techniques to try and ensure that such techniques are both accurate and available as early as possible.

Applied research

The traditional kind of research on MS has focused on the causes and cures of the disease, and indeed this kind of research is still the most important in terms of size and funding. However, this research generally does not tackle all the everyday problems that people with MS have of living with the condition. To put it another way, whilst waiting for a cure, people with Multiple Sclerosis have had to live for years with many difficult and annoying problems, and indeed may have to wait many more years before MS and its problems are banished. Thus an area of ‘applied research’ has arisen where the focus is on researching the best ways in which people with MS can live with or manage their current and future symptoms, and their consequences. This research might include:

• clinical trial research on drugs and other means of managing everyday symptoms;
• the most appropriate forms of equipment that people may need, to live as comfortably as possible;
• the most effective ways in which physiotherapy, occupational therapy and speech therapy can help people with MS;
• the most appropriate ways in which issues of employment, housing and insurance can be dealt with;
• the psychological and social consequences of MS, especially in relation to concerns about the quality of life, and
• issues about counselling and support for the family consequences of the condition.

In practice, this broad area of ‘applied research’ is one of the most significant of current research areas, and is one which – on reflection – many people with MS find extremely valuable and relevant. Although everyone wishes to find a cure for MS, a realistic view is that this will take some time, and meanwhile research on how people with MS can make the best of their everyday lives is very important.

Clinical trials

Much of the hugely expensive development work on new (drug) therapies is undertaken by pharmaceutical companies. The commercial return on their investment in these costs, including clinical trials, has to come from patenting and protecting the rights to the therapy involved. Potential medicines that may be freely available, or are not patentable, offer very little incentive for such companies to invest in them, unless they can in some way lay claim to a variant of the medicine concerned or a particular way of administering it. In such cases, other funding agencies, such as the Medical Research Council (MRC), step in to support formal trials on drugs or other substances that are considered promising therapies for MS.

What is a clinical trial?
A clinical trial is actually a formal scientific means of testing the safety or the effectiveness of a drug or other treatment, either against another drug or treatment, or against what is called a ‘placebo’, i.e. an inactive substance that cannot be distinguished from the ‘real’ or active drug by people who are taking part in a trial nor the doctors who are administering it. This way the drug can be tested for efficacy compared to the other drug or substance.
In a clinical trial of a potential therapy for Multiple Sclerosis, usually one group of patients (the experimental group) receives the active drug or the drug being tested, and another group (the control group) receives the drug against which it is to be compared, or the placebo, the inactive substance.
The two groups of patients should be as similar as possible at the outset of the trial, so that the drug alone will make the dif ference between the groups. Various characteristics of the two groups of people will be measured before, during and after the trial – typically these will include measures of disability, the number of MS ‘attacks’ or ‘relapses’ people have had, and other things such as blood cell counts or hormone levels. It is always hoped, of course, that the trial will show that the group who has received the active drug will do better. Thus, for the active drug to be shown to be ef fective, the trial must finally result in a statistically significant difference between the characteristics of the two groups. However, many trials are relatively inconclusive and, because MS is a complicated condition, statistically significant differences will be observed for some characteristics but not others, or indeed only for certain types of participant.

Blinded and randomised clinical trials
‘Blinded’ in this sense means that you do not know which drug – active or inactive – you are taking, and thus you will not be able to exert any psychological impact on the results, or be tempted to take supplements if you know that you are in the control rather than the experimental group. People are also usually ‘randomized’, meaning that they are allocated to either the experimental or control groups randomly, i.e. they cannot choose which group they join. If people are allowed to choose which group they go into, biases may arise in the trial, as certain people, for example with milder or more serious forms of Multiple Sclerosis, may elect to join one of the groups and not the other. ‘Double-blinded’ means that the researchers also do not know which people receive which substance. The placebo and the active substance must therefore look and taste identical, so they are often provided in coded containers to each person. Only at the end of the trial is the code broken to reveal who received which compound, when the trial is ‘unblinded’. This minimizes the possibility of researchers influencing the outcome, for instance by paying more attention, or giving additional and dif ferential care, to people in the treatment group during the trial.

The placebo effect
The ‘placebo ef fect’, i.e. feeling better as a result of taking any
‘medication’ that people believe may have a beneficial effect whatever its real and unique (physiological) effects, has been shown to operate even when coloured water is drunk. Therefore there is a danger that any real effects of a drug being tested could be mixed up with this ‘placebo effect’, which is why comparing treatments in identical ways is so important. Indeed, the problem caused by the placebo ef fect is one reason why rigorous clinical trials must be performed before a new drug or other therapy can be scientifically accepted.

Clinical trial phases
Before a drug can be licensed for normal clinical use, there are three essential sets of information that have to be researched: its safety (a Phase 1 trial), its appropriate dose levels and the medical conditions or symptoms for which it is best suited (a Phase II trial), and its effectiveness (a Phase III trial).

• A Phase I clinical trial is a test of safety, or toxicity, and is aimed primarily at determining whether the substance has any adverse effects on humans. Of course, before the drug is given to humans, toxicity will also have been tested in animals, cell cultures or computer simulation tests.
• A Phase II clinical trial is usually only undertaken on a small scale and determines whether a larger scale trial is worth undertaking. Phase II trials also help to clarify which groups of people and, for example, which types of MS are most likely to benefit, and how that benefit might be measured. However, Phase II trials may not test for effectiveness, which often requires large numbers of subjects.
• So a Phase III trial is necessary to prove the effectiveness of a drug to enable it to be licensed for clinical practice. Phase III trials are usually very large, very expensive and very lengthy, but show to a high degree of statistical certainty how effective a substance is in treating the chosen people and conditions.
• Sometimes Phase IV trials are undertaken. These are conducted after the drug has been licensed, and thus may be described as the
‘post-marketing phase’ of trials. In such trials, longer term side effects may be assessed; the drug may be tested in different types of MS; or its use may be tested in other conditions – perhaps not associated with MS.

Of course it is important to say that, even when a drug has been tested in all three Phases (I,II and III) and is licensed for clinical use, it may still not become widely available owing to its cost, practical problems in administering it, or its generally unacceptable side effects.

Which drugs are tested in clinical trials?
As we have implied, in order for a drug to be licensed for clinical use, it has to go through the complicated process of clinical trials, and such a process is very expensive. Increasingly, international pharmaceutical companies sponsor the majority of such trials, with additional support from national Multiple Sclerosis Societies, and government-funded Medical Research Councils. Whilst pharmaceutical companies necessarily use scientific methods to evaluate the drugs that they themselves have developed, the choices as to which are subjected to the most expensive Phase III trials, or indeed the initial choices as to which drugs are developed, must – in their terms – be subject to a commercial judgement on their part. This would involve making a judgement about the size of the market for such a drug, and its likely profitability, as well as, of course, making a judgement about its likely efficacy.
It would be reassuring to believe that only a scientific basis was used to decide which drugs were subject to Phase III trials, but generally there are far more drugs that could be subject to such trials than the funding available, and it is clear that commercial as well as scientific factors must intrude in the selection process. Such a process, at least from a commercial point of view, is likely to relegate drugs with a potentially low profitability, or which cannot be patented. The history of therapeutic possibilities in Multiple Sclerosis is littered with the hopes of people often for non- patentable substances in relation to the disease – such as evening primrose oil, hyperbaric oxygen and, most recently, cannabis. It is very unlikely that pharmaceutical companies would be involved in testing such substances unless they can patent a variant of the substance concerned, and thus usually – as in the case of all three substances mentioned – medical charities and/or the government-funded Medical Research Councils themselves would need to fund such trials. Such funding may occur in response to the continuous and widely expressed concerns of people with MS, although decisions for this kind of funding are not normally justified on this basis.
Finally, it is worth saying that, although some major potential therapeutic advances will remain untested because of the particular focus of the pharmaceutical companies, this is unlikely because of the significant number of checks and balances made by the Multiple Sclerosis Society and the Medical Research Council.

Participating in a clinical trial
First of all it is important to say that, if you participate in a clinical trial (especially a Phase III trial) for MS, it will generally not be guaranteed that you will receive the new drug – but you will indeed have a chance to take it, probably on the basis of being randomized to the ‘treatment group’. You will probably have a 50–50 chance of receiving the new drug or being randomized into the ‘control’ group, who will use either a placebo or another comparison drug.
However, there are several reasons why it is still worth your while joining a clinical trial, even if you are not given the new drug by being randomized to a comparison group:

• To be frank, it is likely that you will receive more careful clinical assessment and support, than you otherwise would do, if you participate in a clinical trial, whether you receive the new drug or not. This is because all those participating have to be meticulously and regularly monitored.
• You will almost certainly gain from the placebo effect, whatever you are taking in the trial.
• You would have the altruistic satisfaction of participating in a trial that would benefit others, even if you do not have the new drug yourself.
• Often trial procedures allow standard tried and tested therapies to continue to be used if, for example, you have an attack or exacerbation during the trial.
• More frequently now, trials compare one drug with another, not just with a placebo substance. In these trials you would receive an active drug, whichever group you were in. Indeed the comparison drug will already have been shown to effective in managing some aspects of MS, and often the new drug is one in which only a marginal additional assistance for MS is hoped for – but not yet known.

Depending on the type of clinical trial concerned, people are used from many different sources, but the largest sources of all are people with MS already under the care of neurologists, or those who are attending hospital clinics. In Britain the major means of recruitment is usually directly through your neurologist. When they are notified of a particular trial, they will investigate their own lists of people with MS to see whether any are suitable for the trial. You would then be contacted and asked if you would be prepared to participate. Of course, you can make your neurologist aware of your interest in clinical trials at one of your assessment meetings or by letter. Increasingly, in the United States, trials are more widely advertised through specialist centres and publications, and people can apply directly to participate, but in Britain this more open process of recruitment is still in its infancy.

Eligibility
One of the things about clinical trials is that they all have what are called eligibility criteria. These are often very specific, and relate to the particular types of people and the particular types of MS that they feel would most benefit from the new drug. These criteria could mean that your type of MS is not considered to be the type that could gain most from the new drug. There is also another consideration here. In order to be able to test for the effectiveness of a drug over a reasonable period of time, people whose Multiple Sclerosis is currently changing relatively rapidly, or who are having attacks, or in whom progression is more measurable (for example in relation to changes in the ability to walk) may well be chosen, in preference to people whose MS is worse overall but is relatively stable. Thus it is often frustrating for people with long-standing MS to be excluded from some trials, on the grounds that they cannot walk, or that their MS is too advanced. However, more recently, for such people who wish to participate in clinical trials, some of the newer interferon family of drugs, and indeed others, are now being tested on people with longer term and progressive MS. Do not to get too disheartened if you are not eligible for one clinical trial, because there may be others you can join in due course.

Payment for drugs
You should not be asked to pay for any drugs you receive in clinical trials in which you participate. As a matter of principle, either pharmaceutical companies or other funding bodies of trials pay for these drugs. Indeed your travelling expenses will usually be reimbursed if, for example, you need to attend for assessment at a hospital more frequently for the trial than you would otherwise have done.
There is one issue of payment, however, that sometimes arises, and that is at the conclusion of a trial, when a new drug may be found to be ef fective, and participants wish to continue taking it. Usually trial funding bodies will not pay for any continuing administration of the drug beyond the end of trial, and you would have to negotiate any such administration through your usual doctor. In many cases this may be difficult, not only because new drugs may be very expensive but also because they may not yet be licensed for clinical use outside a trial.

Patient consent
It is a requirement for participation in all properly conducted trials that you – as a potential participant – give your ‘informed consent’. You will have received a form and almost certainly have had a discussion with your doctor, and this form states the nature, benefits and risks of the trial, and asks you formally to give your consent to participation in the trial. You are also agreeing to follow the procedures that the trial requires. The form should be written in clear and plain English, and usually Ethics Committees, who give necessary ethical approval for such trials, try and make sure that such forms are not written in medical or legal jargon. If there is anything, anything at all, that is not clear in the document, then it is essential that you ask for clarification before agreeing to participate.

Some recent trials on beta-interferon
The results of some recent clinical trials have shown that the beta- interferons may slow down the course of the disease over a 3–4-year period. We must remember that the criteria for ‘relapsing-remitting MS’ in trials are drawn very tightly and many people have types of MS that were not covered by previous trial findings. New trials are underway to test whether these other people might benefit as well. However, because it is more difficult to test the effects of such drugs in people with more complicated relapsing-remitting, or progressive types of MS, the findings are taking some time, although initial results are promising. The difficulty is turning out to be not just the effectiveness of interferons in these cases but their cost effectiveness. Although it has been shown that interferons may slow down the disease in some people, the number in which this occurs is not large, and the costs of the drugs are very expensive. A number of clinicians and also, importantly, other bodies regulating the extent to which the drugs can be used on the NHS for such types of MS were reluctant to see it made available for all categories. Now there is agreement with the pharmaceutical industry to share expenses of the treatment.

Previous trials on steroids
One trial on steroid therapy has indicated that the steroids reduced the risk of developing clinically definite MS by half over a 2-year period. There have been serious criticisms of some aspects of the trial, and further trials are needed on this issue. However, further trials to test whether this was an abnormal result or not are very difficult to organize. It is almost impossible to identify and ensure that enough people participate in such a trial with very early, and especially the first, symptoms of Multiple Sclerosis, i.e. within a month or so of those symptoms appearing
– and also to ensure that they have an MRI scan within this phase. Because the beta-interferons and other drugs have shown more overall promise in MS, there is now some reluctance to conduct large-scale and expensive trials on steroids.