Medical Studies on MS
and some general
remarks to medical research strategy
Absence of proof is
not proof of absence
William Cowper
(1731-1800)
(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.
Experimental MS-Studies
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.
Human Studies
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).
Although the
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 [1] 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.
See
meta-analysis of randomised studies in MS
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.
William
Cowper (1731-1800)