> Message from:
>
> Wim J. van der Steen and Vincent K.Y. Ho
> Faculty of Biology
> De Boelelaan 1087
> 1081 HV Amsterdam
> the Netherlands
> E-mail: <[log in to unmask]> and <[log in to unmask]>
>
> Dear colleagues,
>
> We are sending this request to students and professionals in areas, pure
> and applied, of the life sciences (biology, medicine, psychiatry). Also
> included are areas that may help to uncover strengths or flaws in the life
> sciences, for example philosophy and sociology of science, psychology,
> technology assessment, ethics.
>
> The request is to submit to us an essay of at most 1000 words in response
> to the text below (written by WJS). Your essay may amount to a commentary,
> but you may also choose to express your own view about any particular theme
> in the text, while disregarding the text itself. For example, you may
> choose to focus on benefits or dangers of medication.
>         The text is technical since it comprises many themes in a succint
> way. In contrast, we would like you to use a more popular style.
>
> Some essays will be included in a primer we are writing this year, which
> aims to offer guidelines beyond fashionable ones, both for writing and for
> interpreting texts in the life sciences. In the primer, we will argue that
> knowledge accumulation currently produces chaos best revealed by showing
> that disciplines covering similar themes are out of touch with eachother,
> that philosophy made practical should have remedial functions (see W.J. van
> der Steen, "A Practical Philosophy for the Life Sciences", SUNY Press
> 1993), and that ethical concerns should intrinsically contribute to science
> in progress (see W.J. van der Steen, "Facts, Values and Methodology; A New
> Approach to Ethics", Rodopi 1995).
>         Essay not included in the primer will become part of course
> materials for students.
>
> The text will also develop into a longer, more popular version to be
> published as a seperate article. In case your essay helps shape this
> article, we will mention this in the acknowledgements.
>
> If you wish, you may remain anonymous in the primer and the course
> materials. But we should be able to mention your position (e.g., graduate
> student, professor, science reporter), the discipline(s) you are working in
> and/or are acquainted with, and your country. Please let us know by email
> to Vincent K.Y. Ho <[log in to unmask]> if you are willing to cooperate.
> Our schedule calls for receiving essays before the end of March.
>
> Please forward our message to persons known to you who might be interested,
> or to members of internet-lists.
>
> Format for response:
>
> I will contribute an essay.
> I wish to remain anonymous/I do not wish to remain anonymous
>
> Name:
> Position:
> Discipline (expertise):
> Country:
>
> BIASED PROMOTION OF DRUGS: THE CASE OF NSAIDS
>
> WIM J. VAN DER STEEN
>
> Cultural factors affect medical science. Few researchers would quarrel with
> this. The point has been made in a general way by sociologists of science.
> But few sociologists would take their cues from primary sources of medical
> research. Conversely, medical researchers in their writings seldom consider
> how culture affects their work. I aim to close this gap by a case study
> revealing profound negative effects of cultural factors in medical research
> and practice in the wake of it. My subject is a class of drugs, non-steroid
> anti-inflammatory drugs, NSAIDs, which are used on a massive scale although
> they have serious side-effects. Overuse of these drugs is caused by several
> forms of bias that are seldom investigated in medicine. Regulation has been
> biased in favour of the pharmaceutical industry to the detriment of
> patients. Further, researchers funded by a pharmaceutical industry
> manufacturing a drug, tend to produce biased reports in favour of the drug.
> Medical research is also biased by its focus on drug therapies. Diet
> therapies may be equally effective and without serious side-effects.
> Further, inappropriate prescriptions are common. Some forms of bias are
> unavoidable. Thus, the methodology chosen for controlled studies depends on
> ethical decisions. All the forms of bias deserve more scrutiny. It is
> anyhow desirable that we reduce the use of NSAIDs.
>
> EFFECTS OF NSAIDS
> Many studies indicate that NSAIDs may palliate symptoms in inflammatory
> diseases such as rheumatoid arthritis. But the drugs have dangerous
> side-effects also. A recent study notes that 10-40% of elderly people in
> the populations studied use NSAIDs, while the drugs frequently have
> gastrointestinal side-effects. NSAIDs increase the risk of peptic ulcer
> complications by 3-5-fold, and in several different populations it has been
> estimated that 15-35% of all peptic ulcer complications are due to NSAIDs.
> In the United States alone, there are an estimated 41,000 hospitalisations
> and 3,300 deaths each year among the elderly that are associated with
> NSAIDs (Griffin, 1998). In another study the drugs are even estimated to
> cause 20,000 deaths in the US each year (Wolfe, 1996). Any cursory
> inspection  of the literature will uncover many articles with a similar
> message.
>         The alleged benefits of NSAIDs are not unchallenged. One source
> describes recent data regarding the prognosis of rheumatoid arthritis with
> the use of the current drug treatments as "gloomy" (Odeh, 1997), and
> according to another source, most standard medical approaches to treatment
> have had little or no impact on the course of rheumatoid disease (Schiff,
> 1997). Further, we should not simply take positive data in the literature
> for granted. Controlled trials concerning drugs in rheumatoid arthritis are
> often problematic due to pitfalls to do with outcome measures, patient
> populations, characteristics of the study design, and economic evaluation
> (Ortiz, Tugwell and Yocum, 1997). Impressions concerning the long-term
> natural history and results of therapy are strongly influenced by the types
> of measures and study designs used to assess patient status and outcomes
> (Pincus, 1995). Randomised controlled trials are often a poor measure of
> long-term outcomes (Pincus and Stein, 1997; Simon, 1995).
>
> A BROAD PERSPECTIVE
> How should we explain the massive use of NSAIDs? The most obvious answer
> would be that controlled trials indicate that NSAIDs alleviate symptoms of
> inflammation, at least in the short term, that they admittedly have
> dangerous side-effects, but that the overall balance of evidence warrants
> continued usage. This answer is unsatisfactory. It presupposes that the
> research is unbiased and that it affects practice in an unbiased way. I
> would assume that the wide-spread use of NSAIDs does not sit well with the
> observed side-effects, and that it points to undesirable forms of bias. Let
> me review some potential sources of bias.
>         Abraham offers a detailed survey spanning decades of NSAID
> regulation in the US and the UK (Abraham, 1995). The survey demonstrates
> that research by the pharmaceutical industry on benefits and side-effects
> of NSAIDs has been biased in favour of its own products. That should not
> surprise us. Surprising is incontrovertible evidence that authorities
> responsible for regulation have on a grand scale acted in violation of
> their own guidelines, so as to favour the industry, to the detriment of
> patients. Many dangerous NSAIDs now on the market should never have been
> approved for sale.
>         Bias in favour of the industry may also exist in medical research
> itself. The chances that researchers observe positive effects of NSAIDS are
> way above average if they are paid by the industry manufacturing the drugs
> (Goetsche 1989).
>         Medical practice also appears to be biased in favour of NSAIDs,
> since unnecessary prescriptions are very common (Coste, Hanotin and
> Leutenegger, 1995; Tamblyn, Berkson, Dauphinee et al., 1997). Further, in
> spite of the side-effects noted, the use of NSAIDs is fostered by their
> being available as over-the-counter drugs.
>         These kinds of bias could be avoided in principle, but other forms
> of bias are unavoidable. Consider the problem of false positives
> (statistical type I errors) and false negatives (statistical type II
> errors). Of course we should aim at tests ensuring that the probabilities
> of errors of either kind are low. The trouble is that a decrease in one
> type of error logically entails an increase in the other type of error
> (with a given sample size and effect size). Thus, the methodological set-up
> of our research depends on ethical considerations concerning the
> acceptability of particular errors which are part of our culture (Cranor,
> 1992). This can be generalised. Ideal experiments cannot satisfy all
> methodological requirements at the same time. We have to prioritise
> requirements, and that cannot be done without ethical considerations (Van
> der Steen, 1995).
>         As I noted, some medical researchers have argued that the
> methodological set-up of experiments affects conclusions about the value of
> NSAIDs. We should add to this that the choice of a methodology is
> determined in part by ethical issues which are seldom made explicit in
> medical research. They should be brought out into the open. We are not
> dealing here with bias in a pejorative sense, because we have to opt for
> some methodology, but we should be aware of normative presuppositions.
>         Considering tests of drug effects, patients and the industry have
> different interests with respect to different types of error. In the
> interest of patients, we would like to minimize type I errors of falsely
> attributing positive effects to drugs. But the industry would rather
> benefit from low levels of type II errors of falsely attributing no effects
> to drugs. In most research, significance testing is done without power
> analysis. This allows for type I errors at the standard 5% level, while
> type II errors remain unkown. If tests of a drug are repeated over and over
> again, a common practice nowadays, we will sooner or later get a
> significant result due to a type I error. To the extent that drugs are
> marketed on the basis of this, the type I error level is inflated while the
> type II error level is decreased, and we get a bias in favour of the
> industry, to the detriment of patients. Patients and the industry also have
> different interests in the study of adverse side-effects. The trouble is
> here that methodologically proper tests are hardly feasible since the set
> of potential side-effects is open-ended, and guidelines for the time-scale
> of experiments are arbitrary. In the interest of patients, we should aim at
> comprehensive short-term and long-term studies, but this would not be
> palatable for the industry. In practice, comprehensive long-term studies
> are rare, which again favours the industry. Next, controlled experiments
> are problematic if drugs are compared with a placebo without side-effects.
> The chances are that this will generate false positives when patients
> conclude from experienced side-effects that they are receiving the drug
> rather than the placebo. This kind of phenomenon has on a grand scale
> resulted in inappropriate drug treatments in psychiatry (Jacobs, 1995).
>         Medical research may also be biased in that the choice of subjects
> to be investigated is one-sided. Concerning therapies for rheumatoid
> arthritis, research reveals a pronounced bias in favour of drugs. As I am
> writing this (August 1999), Medline lists 11,017 articles on drug therapy,
> 126 articles on diet therapy. This fits in with a pervasive
> negligence of ecology in medical research and medical practice (Chivian,
> McCally, Hu and Haines, 1993; Garrett, 1994; Van der Steen, 1998a). Diet
> therapy, for that matter, does seem to have positive effects.
>         Particular diets, or components of diet, most notably particular
> unsaturated fatty acids, reduce disease activity in rheumatoid arthritis
> (Ariza-Ariza, Mestanza-Peralta and Cardiel, 1998; De Luca, Rothman and
> Zurier, 1995; James and Cleland, 1997; Rothman, De Luca and Zurier, 1995).
> It is indeed conceivable that poor diet is among the factors which
> predispose toward the disease (Kowsari, Finnie, Carter et al., 1983;
> Morgan, Hine, Vaughn and Brown, 1993). We should add to this that modern
> techniques of food processing cause the destruction of natural components
> of diets, not least unsaturated fatty acids including essential ones. This
> fosters degenerative and systemic diseases, and it may well contribute to
> aetiology in rheumatoid arthritis (Erasmus, 1995).
>         The emphasis in medical research on pathology is now overwhelmingly
> on genetics and molecular biology. In part, this may be explained by the
> history of medicine, which developed biological approaches prior to the
> emergence of ecology. Further, this emphasis fits in with current
> reductionistic paradigms. These paradigms foster a self-perpetuating bias.
> Considering genetics, I have elsewhere explained how this works, by an
> analysis of research on schizophrenia (Van der Steen, 1998b). Twin studies
> have shown that concordance for schizophrenia is much higher in identical
> than in non-identical twins. Researchers have concluded from this that
> genes are implicated in etiology. The following counterexample shows how
> problematic this is. Suppose, a number of twin pairs are on a trip in a
> coastal plain. A flood wrecks the trip. Tall individuals survive, and short
> individuals drown since they cannot keep their heads above the water.
> Identical twins will obviously show a higher concordance than non-identical
> twins. If we follow the logic of schizophrenia research, we should conclude
> that genetic factors rather than the flood were causally responsible for
> the drowning. Something is obviously wrong with the logic of common
> research.
>         Researchers do admit that the environment modifies the effects of
> genetic factors. But they commonly conceptualise the environment as the
> psychosocial environment. Ecological factors are simply disregarded. This
> happens in psychiatry and in many areas of medicine.
>
> CONCLUSIONS
> NSAIDs are reported to alleviate symptoms in inflammatory diseases. This
> may be true, but we should beware of exaggerating positive effects, and we
> should realise that short-term benefits may not be extrapolatable. The
> pervasive use of these drugs is indeed problematic in view of serious
> side-effects. If we wish to assess NSAIDs, we should not be content with an
> appraisal of existing controlled trials. Such an appraisal would not
> uncover all sources of bias.
>         Research mostly conducted outside medicine itself has revealed many
> sources of cultural bias. Drug regulation is biased in favour of the
> pharmaceutical industry. Likewise for medical research funded by the
> industry. Further, the emphasis in research is overmuch on drug therapy,
> while less dangerous treatments such as diet therapy may be equally
> effective.
>         It is desirable that medical journals pay more attention to these
> forms of bias. More research is needed on alternative treatments,
> especially diet therapy. The highest priority should go to trials that aim
> to compare drug therapies with diet therapies. We might save thousands of
> lives if we replace drug therapies by diet therapies.
>
> REFERENCES
> Abraham, J. (1995) Science, Politics and the Pharmaceutical Industry:
> Controversy and Bias in Drug Regulation. London: UCL Press.
> Ariza-Ariza, R., Mestanza-Peralta, M., Cardiel, M.H. (1998) 'Omega-3 fatty
> acids in rheumatoid arthritis: an overview', Seminars in Arthritis and
> Rheumatism  27: 366-370.
> Chivian, E., McCally, M., Hu, H., Haines, A. (1993) Critical Condition:
> Human Health and the Environment. Cambridge, Mass.: MIT Press.
> Coste, J., Hanotin, C. and Leutenegger, E. (1995) '[Prescription of
> non-steroidal anti-inflammatory agents and risk of iatrogenic adverse
> effects: a survey of 1072 French general practitioners] [French]',
> Therapie, 50: 265-270.
> Cranor, C.F. (1992) Regulating Toxic Substances: A Philosophy of Science
> and the Law. New York: Oxford.
> DeLuca, P., Rothman, D., Zurier, R.B. (1995) 'Marine and botanical lipids
> as immunomodulatory and therapeutic agents in the treatment of rheumatoid
> arthritis', Rheumatic Diseases in the Clinics of North America, 21: 759-777.
> Erasmus, U. (1995) Fats That Heal, Fats That Kill. Burnaby: Alive Books
> (third ed.).
> Garrett, L. (1994) The Coming Plague: Newly Emerging Diseases in a World
> Out of Balance. New York: Farrar, Straus, and Giroux.
> Goetsche, P.C. (1989) 'Methodology and overt  and hidden bias in reports in
> 196 double-blind trials of nosteroid anti-inflammatory drugs in rheumatoid
> arthritis', Controlled Clinical Trials, 10: 31-56.
> Griffin, M.R. (1998) 'Epidemiology of nonsteroidal anti-inflammatory
> drug-associated gastrointestinal injury', American Journal of Medicine,
> 104: 23S-29S, 41S-42S.
> Jacobs, D.H. (1995) 'Psychiatric drugging: Forty years of pseudo-science,
> self-interest, and indifference to harm', Journal of Mind and Behavior, 16:
> 421-470.
> James, M.J. and Cleland, L.G. (1997) 'Dietary n-3 fatty acids and therapy for
> rheumatoid arthritis', Seminars in Arthritis and Rheumatism, 27:85-97.
> Kowsari, B., Finnie, S.K., Carter, R.L. et al. 'Assessment of the diet of
> patients with rheumatoid arthritis and osteoarthritis', Journal of the
> American Dietetic Association, 82: 657-659.
> Morgan, S.L., Hine, R.J., Vaughn, W.H., Brown, A. (1993) 'Dietary intake
> and circulating vitamin levels of rheumatoid arthritis patients treated
> with methotrexate', Arthritis Care Research, 6: 4-10.
> Odeh, M. (1997) 'New insights into the pathogenesis and treatment of
> rheumatoid arthritis', Immunopathology, 83: 103-116.
> Ortiz, Z., Tugwell, P. and Yocum, D.(1997) 'The design of clinical trials
> aimed at assessing the DC-ART properties of new molecules in rheumatoid
> arthritis', Clinical and Experimental Rheumatology, 15: S39-S44.
> Pincus T. (1995) 'Assessment of long-term outcomes of rheumatoid arthritis.
> How choices of measures and study designs may lead to apparently different
> conclusions',  Rheumat. Diseases in the Clinics of North America, 21:
> 619-654.
> Pincus, T., and Stein, C.M. (1997) 'Why randomized controlled clinical
> trials do not depict accurately long-term outcomes in rheumatoid arthritis:
> some explanations and suggestions for future studies', Clinical and
> Experimental Rheumatology, 15: S27-38.
> Rothman, D., DeLuca, P. and Zurier, R.B. (1995) 'Botanical lipids: effects
> on inflammation, immune responses, and rheumatoid arthritis', Seminars in
> Arthritis  and Rheumatism, 25: 87-96.
> Schiff, M. (1997) 'Emerging treatments for rheumatoid arthritis', American
> Journal of  Medecine, 102: 11S-15S.
> Simon, L.S. (1995) 'Actions and toxicity of nonsteroidal anti-inflammatory
> drugs', Current Opinion in Rheumatology, 7:159-166.
> Tamblyn, R., Berkson L., Dauphinee, W.D. et al. (1997) 'Unnecessary
> prescribing of NSAIDs and the management of NSAID-related gastropathy in
> medical practice', Annals of Internal Medecine, 127: 429-438.
> Van der Steen, W.J. (1995) Facts, Values, and Methodology: A New Approach
> to Ethics. Amsterdam and Atlanta: Rodopi.
> Van der Steen, W.J. (1998a) 'Forging links between philosophy, ethics, and
> the life sciences: A tale of disciplines and trenches', History and
> Philosophy of the Life Sciences 20: 233-248.
> W.J. van der Steen (1998b) 'Bias in behavior genetics: An ecological
> perspective', Acta Biotheoretica 46: 369-377.
> Wolfe, M.M. (1996) 'NSAIDs and the gastrointestinal mucosa', Hospital
> Practice, 31: 37-44, 47-48.