Absence of proof is not proof of absence
(found by Per
Dalén, Sweden, who also delivered
me the quotation at the end of this article)
Aim of Therapy
To most patients, this is to be understood as a treatment of the condition to establish a complete restitution. History has proved less still to be an advantage, i.e. delaying progress of the disease and to ameliorate and shorten relapses. Some restitution (remyelinization) remains one option, and still there seems to be a scope in reaching a state where the disease is burned out. Could it be that these patients, while suddenly not seeking any further medical help, have been forgotten in the hectic of performing studies including newcomers?
Principal Problems with Therapeutic Studies
In order to study the therapeutic value of a drug (or even alternative therapies), it is necessary to be able to define the therapy, the disease and the parameter measured. Moreover, in a controlled study, all study arms must be shown to be comparable. Sounds easy? It is not, in particular in a slowly progressing, ill-defined condition like MS where already the latter two items gives rise to serious problems. Moreover, MS has a high placebo response rate with 65-70% of patients referring improvement from a completely ineffective treatment, a fact stimulating a wild amount of alternative "treatments" for MS. Also modern drugs profit from the natural tendency of the disease of producing less attacks throughout its course. But let us start with the beginning: how to derive a new therapy?
Ideally, a Working hypothesis would yield the basis for a new treatment. In fact, such a mechanism can be found in new drugs, e.g. Matrix-Metalloproteinase-Inhibitors [MMP-I] but it can be regarded an exception. Alternatively, a drug can be used according to one hypothesis, is found valuable and then its use is suddenly shown (or expected) to relate to another mechanism. Such can be found with interferon-beta [IFB], initially used under the presumption that a virus infection causes MS and only later shown to possess immunomodulatory properties, including an inhibition of MMP]. Possibly, the same will be found concerning tetracyclines, utilized under the similar assumption of a chlamydia infection but then also shown to be active inhibitors of some MMPs.
Most therapeutic drugs exist already, only they are used for another purpose (possibly in a different dosage). Their transferal to MS may again be due to theory or incidental observation. Finally, some drugs are refined to exert a more favorable balance between attempted and adverse effects (pharmacological terminology.: 'side effect' although this term also would include additional effects which are not strictly adverse). In all these cases, an experimental study should pave the way for the introduction of the new drug into clinical studies (term.: ‚preclinical pharmacology') before a definite introduction into clinical use can be dared. This is confirmed by the fact that a much larger supply of potential drugs are tested compared to the small minority which finally reaches clinical use.
New Drugs vs. Non-Patent-Protected Substances
Development of a new substance is expensive, drugs are very expensive (the firms live from it), while other substances are cheap. For that reason, whether you like it or not, you cannot expect any firm to invest in investigations concerning cheap (and possibly competing) substances. For the same reason, as far as these approaches are interesting, it can be demanded that hospital departments, apart from commercially sponsored research, also keeps the cheaper approaches in mind. This is the vacuum where the MS-organizations can be assumed to step in, leaving it to the industry to care for their own problems.
Please keep in mind, that if the use of fish oil and vitamin D3 in appropriate dosage (see environmental factors) should ever be broadly accepted by the physicians, it has lasted many decade for them to reach this recognition. That again could be used against their current preference for medical studies. Perhaps for that reason, these substances are not studied in the same way, and I can only recommend all MS-patients to stay away from the placebo-group in such studies, should they ever be performed.
The most frequently used animal model for MS is endogenously activated encephalomyelitis [EAE] which is precipitated in mice in response to injection of myelin basic protein [MBP]. This disease possesses important histogical and clinical similarities to MS, but it progresses much faster, enabling an evaluation of the impact of many approaches within some months. Also other autoimmune disease models are interesting for MS research, in particular those concerning neurological disease (e.g., Sjögren's disease and Guillain-Barre Syndrome).
Experimental studies naturally pose some problems: what works in mice (possibly with an extreme drug dosage) may not work in men, the disease is not white identical and the duration of therapy is in human measured in decades, making adverse effects more presumable than can be found in mice within less than a year. Moreover, the amount of experimental studies is quite unsurveyable. In 1999, some 1200 experimental studies are found annually in Medline which at least touches MS (add to them studies which are published elsewhere or not at all). Further restriction is therefore required for a comprehensive understanding - but restriction is associated with the risk of missing something important.
Parameters Studied in MS
The symptoms which causes the MS patient problems are generally impossible to measure. This does not turn the MS-patient into a hypochondrite but it makes studies of the disease exceptionally difficult. There is no simple laboratory investigation (to be improved in response to therapy), relapses are ill-defined and of extremely varying duration. Even the degree of invalidity (altering over several years) is unreliable in its registration. Many such scales have been developed but the standard (necessary for comparison of different studies) is Kurztke's Expanded Disability Severity Scale [EDSS]. Among different neurologists, the EDSS has been found to differ a whole degree, which is quite much for a ten-point scale and even more when the interesting area is to be found between 2 and 6. With an occupational interest in conclusing studies reasonably fast, a slowly progressing disease like MS may be further hampered. The study over several years can hardly be done on an individual basis.
With magnetic resonance imaging [MRI], a parameter was finally found which shows a reasonably fast response to therapy - but then the question is, in how far this is imaged in clinical symptoms. The patient will, of course, prefer having his symptoms cured, not the MRI if there should be a choice. Indeed, the biggest therapeutic impact of, e.g. IFB, is to found in T2- weighted images, whereas T1-weighted images are better related to the clinical condition.
The explanation probably relates to insights reflected in the hypothesis presented here: The disease process of MS is months ahead of clinical findings. This process may then be determined by T2-weighted MRI or by spectroscopy. In this way, these parameters are much more sensitive than other means of determining disease activity.
The amount of therapies which have been suggested for MS is immense and still, the disease remains. It is as if the jungle thickens rather than clarity rises for all the substances which are suggested to be of importance in the pathogenesis of the disease. Is it too easy or too difficult to test various ways in the fight against the disease?
The question of control dominates frequent statements and rare discussions about research methodology. Dr. Cooke brought it to a point with a frequently cited statement, that "studies with enthusiasm tend to have no control and studies with control tend to have no enthusiasm." Other have measured that the use of historical controls will often, and prospective controls seldom result in the demonstration of differences (recent publications in 2000 disagree with this conclusion). To this could be added the motivation for publishing the historical control, even accepting a certain bias of its authors, and methodological problems (including insufficient number of patients studied inclusion of patients not apt to profit from the therapy, wrong use and short duration) are apt to produce too many negative conclusions in prospective randomized controlled trials [RCT].
Some sort of control is necessary, there is hardly any resistance to this claim. The question is, which level of control it should be and which are the ethical consequences of enrolling patients into studies. This phenomenon is strongly counteracted by various bias hardly given any attention: an RCT is expensive and will hardly be paid for, if there is not a reasonable chance that it will show a positive outcome for the therapy tested. This impression has been created in experimental and in human Phase I-II studies. The stronger this bias is, the more problematic are the ethical aspects. Unfortunately, this problem is not understood identically on both sides of the Atlantic Ocean.
From an understanding that only RCTs can yield valuable conclusions, predominantly North American doctors consider it unethical not to use it for all questions possibly be made subject to such a study. Claiming that only an RCT can demonstrate the value of any, possibly expensive therapy, they enforce this study type onto an increasing amount of clinical decisions. Thereby, they often neglect the demand of the Declaration of Helsinki that "in any clinical study, patients of the control group should be given the best proven therapy." The vast number of placebo-controlled studies in areas, like the MS, where a proven therapy already exists, demonstrates how the so-called "ethics commission" at some places has been reduced to an unimportant formality. Strange that the ethics commission (demanded in the 2nd and later versions of the Helsinki Declaration) fails to deal with this crucial aspect of an RCT.
If a therapy is demonstrated to be effective in an RCT, it is to my comprehension of ethics strictly unethical to make another placebo-controlled RCT - and, fortunately, the Helsinki Declaration says the same (while this was doubted, the 5th amendment in October 2000 was very specific with this issue) - only the socalled "Note of Clarification" obviously contradicts the advantages once made. That, however, makes it even more difficult for a novel therapy to show its value in relation to the established therapy - which is anyhow what a text of the zero-hypothesis demands, the foundation of any RCT: you must not expect that a difference exists (would you join any control group if you were the patient?).
The question seemingly standing open for decision is, whether placebo-studies are necessary and are therefore ethical even in the presence of effective therapy (FDA's point of view), or whether unethical studies should be primarily forbidden and you then have to consider the rest (making rules out of the Helsinki-Declaration guidelines). This decision should, of course, not be made by doctors alone, representatives of the patients must also be present. Influenced is, I hope, the decision by the fact that other studies are not so bad as they are claimed, and that the dominance of RCTs had considerable adverse intellectual effects in not considering questions that could not be studies by means of such trials.
The RCT was developed for studies on animals and human volunteers where these ethical considerations are not valid. I have tried, largely in vain, to emphasize that this study type can only be utilized in clinical settings to a limited degree. Although the trend is up against my position, I do not believe that the RCT in the clinical setting can survive very long now. It is therefore time to consider alternatives, even if these do not appear so straightforward as could be experienced in the standardized mathematical labor of an RCT.
There are many MS-patients worldwide, but there is still hardly any valid description about the prognostic outcome with respect to sex and age at "entrance," duration and progression of symptoms. What sharpens the interest in this phenomenon is the fact that the mortality of MS was much higher only a few decades ago. In the network of an ongoing registration of progression (e.g. according to EDSS in spite of the mentioned reservations), selected therapy and including older materials, the impact of a range of therapies may be analyzable in this matrix. Of course, this is a kind of historical control but how, else, can you cope with a disease 15 years later?
Simultaneously, the search for more sensitive parameters of disease progression goes on. The little which has so far been found may reflect our methods, rather than actually prove that there is only little to be discovered.
Evidence-Based Medicine – a More Advanced Illusion?
It is difficult to argue against concepts in the highest fashion. Though slowly losing the relation to MS, I abuse this homepage to publish some remarks which are obviously in opposition to this highly laurelled concept and (also) therefore not likely to be published anywhere else.
Evidence-Based Medicine [EBM] is a man-made hierarchy, evaluating different kind of research in new sheep fur for the researching wolf. The basic recognition was that rather few RCTs exist as basis for various therapies (although thousands of RCTs are published annually), and that different levels would have to be included, though at lower levels of importance. In general practice, many researchers have difficulties to discriminate between EBM and RCT, thus seeing the first as a continued call for the last study model.
What these researcher completely ignore is, that there is a high degree of random in what has been studied (to be made subject to EBM) and what not. The latter is then regarded unimportant. Anyhow, it seems that modern doctors are not only afraid of logic, they are also incapable of utilizing it. Moreover, the use of wrong principles are bound to give negative conclusions and may well turn a valuable principle into undeserved disrepute (quotations on my publications in medical research).
weaknesses related to EBM have been repetitively pointed out, daily practice
seems to ignore such shortages while the adoration for RCT is unbroken. In
effect, research has lost both its clinical and philosophical background and
has not been so unintellectual for several decades, in spite of (or partly even
caused by) other technical advantages.
The Controlled Study and the Singular Case
There is a good basis in the available studies for utilizing interferon-beta [IFNB] for both relapsing-remittant and secondary progressive MS. Somewhat disturbingly, there are quite a number of other substances which seems to have some effect there. This is in accordance with the fact that, in spite of all fascinating models, a strict knowledge of the cause (or causes) of MS remains a hypothetical one. There may well be a number of causes for the disease. IFNB was originally introduced from the expectation that a virus was responsible and later it was recognized that also immunomodulatory mechanisms were found which were perhaps rather active than the anti-infective properties - which did not prevent the study of other, newer antiviral drugs in MS. The effect of compositions like copolymer-1 (glacimer-racemate) and intravenous immunoglobulins, which are basically undefined substances difficult to consider in connection with purified drugs, makes the impression than an unspecific irritation in a certain direction may ameliorate the condition, whereas other irritations seem to have the opposite effect (and often, as in vaccination programs, you do not know what will happen). And then there are patients who claim to have had an MS decades ago and seems to have a burned-out pathology, no therapy taken and no progress of relapses noticed. A desirable condition, if someone could find out how to gain this (but the current literature does not seem to be much interested in this form). In a serious contrast is the MS-patient, who does not seem to profit from what helped a study population. As expressed by in an article: „Determining the effect of different therapies on the course of the disease within large clinical studies appears easier than determining individual responsiveness. Therefore, standardised methods for evaluating individual patients receiving disease-modifying therapies and development of effective therapeutic algorithms are needed.“
The first step must be to define the non-responder. Therapeutic drug combinations are to be expected but currently (2001), this field remains completely open. Ideally, markers of the disease could enable a more rapid recognition of what might help, rather than to wait for the clinical and paraclinical deteriorations. Careful revision of the immense MS registers of many centres could define the expected course in a group of patients as a control to the one achieved by certain sensible therapies, but first this control must be defined. Emerging audit circles in quality control yields further immense materials, but some standardization is necessary to make them comparable. This is the way one could go if there was not the mental blockade of the RCT as only source of balanced recognitions according to most physicians. I hope that these will soon discover that it is both necessary (for ethical reasons) and advantageous to utilize other sources of study for their control group. Maybe, in some 10 years, the RCT will have been pushed back to where it came from: the experimental scene.
What permanently annoys me is the presentation of ethically marginal or obviously unethical (expensive) studies of a limited amount of patients while huge amounts of patients are not considered. In contrast to that is an Australian study  from which I include fractions of the abstract: “Evolving information technology has raised the possibility of new methods of data collection in MS research … a total of 2529 people completed the questionnaire … Common factors reported as beneficial were cannabis, cold baths, meditation and dietary factors. Common adverse factors reported were high stress, exposure to high temperatures and viral infections. There was an increasing report of high temperatures as being adverse with increasing respondent age ... The adverse report of high temperatures correlated significantly with the report of strong sunlight apparently making MS worse ... In Australia, high temperatures were more likely to be reported as adverse in warmer, lower latitude regions… People with MS may risk vitamin D deficiency because of sun avoidance due to heat-related fatigue or intolerance.
1 Simmons RD, Ponsonby AL, van der Mei IA, Sheridan P. What affects your MS? Responses to an anonymous, Internet-based epidemiological survey. Mult Scler 2004;10:202-11.
In general (not restricted to MS-studies): A Conflict to Come ...
Written February, 2000
Revised Juni 10, 2004
Knowledge is proud that he has learned so much;
Wisdom is humble that he knows no more.