Gajski Medical Science Serving Corporate Interests

Lidija Gajski, Medical Science Serving Corporate Interests, page 1

Medical Science Serving Corporate Interests Evidence-based medicine and the randomized clinical trial by Lidija Gajski This lecture was held at the 17th World Congress on Medical Law (WCML), in Beijing, China, October 2008 The transformation of the concept of medicine as a predominantly humanistic and empirical discipline towards viewing it as an exact scientific one began in the 19th century. In the last two decades, this tendency has maximally accelerated. As a consequence, today's medicine is considered practically a natural science. The appearance of the concept of “Evidence-Based Medicine“ (EBM)1 can be viewed as a symptom of this process. Since its emergence in the 1990's, this new approach has gained quick acceptance and approval from the medical establishment, and has overtaken global medical thinking and practice. Modern medicine is now based on the EBM approach. Scientific evidence, i.e. the result of a scientific research is at the center of the EBM. The original idea includes critical judgement and clinical experience, as well as individualized adjustment to each patient. However, today, EBM is presented and applied in a restricted form. This means that scientific results are directly translated into patient treatment by means of clinical practice guidelines. EBM is most often associated with the randomized controlled clinical trial (RCCT), the type of scientific research which has been widely accepted in the last twenty years as the standard methodology for acquiring medical knowledge. At present, clinical trial is considered the best and most reliable product of medical science. It proves or disproves the hypothetical benefit or harm of the tested intervention by comparing outcomes in two similar groups of patients, one of which receives the experimental intervention and the other receiving inactive substance or the standard treatment (placebo). The tested intervention is most often a new pharmaceutical substance, but may be some other therapy, e.g. a surgical procedure. If a new drug has proven better or equal to the control drug, the experiment results are directly applied in clinical practice, inasmuch as the conditions for the approval of the substance and its clinical use have been met. All the medicines used in clinical practice today have received approval in this way. It is the case in the field of therapy of chronic diseases as well, including cardiovascular diseases, which comprise the major health problem of the developed world, and the field in which most of the medicines are used. Since evidence produced by clinical study is the main basis of the present-day health politics and clinical practice, it is legitimate to question the reliability of this type of scientific research. Contrary to the widely accepted view that considers randomized trial as a “gold standard“ of modern medicine, it reflects narrow-minded thinking inappropriate for medicine. Clinical study lacks the ability to assess therapeutical intervention in its globality and complexity. The indicators of illness are reduced to objective, measurable, pathophysiologic parameters. The trial ignores the complex nature of disease and does not evaluate its other determinants and aspects. Neither does it take into account the social, cultural, economic, and personal aspects, i.e. how the patients themselves evaluate the quality of life and treatment. Clinical studies are performed in a controlled environment and it is often hard to apply their results in real life and 1

Sackett DL, Straus SE, Richardson WS, et al. Evidence-based medicine: how to practice and teach EBM. 2nd ed. New York: Churchill Livingstone; 2000.

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clinical practice. Moreover, if we leave these considerations aside, and accept today's dominant biological concept of a disease and clinical trial as a product of pure, exact science, even in this frame it is still a product of debatable quality. RCCT is a methodologically imperfect, biased, and in a clinical sense, often irrelevant scientific product. Methodology and design of the clinical trial In spite of the efforts to improve the methodology and design, clinical study is still far from a methodologically valid scientific product. One of the most common errors occurs in the selection of participants. The population sample is not representative of the population to whom the medicine will be prescribed. Women are underrepresented in cardiovascular drug testing, although this medication is used by both sexes.2 Studies with antirheumatics experiment on the young or middle-aged populations in spite of the fact that the medication is taken mostly by older people.3 Weaknesses have been identified in the process of equalizing the compared groups, in the procedure of assuring therapy assignment neutrality, and in measuring the outcomes (randomization, blinding, allocation concealment).4 In some trials the substance with which the drug was compared was incorrectly administered and underdosed, leading to false conclusions of better drug effectiveness.5 Participants in the experiment often take many different drugs. Consequently, there are no more “clean“ groups, which reduces the reliability of the results.6 A fraction of the participants withdraw from the study for various reasons. If this number is significant and if these patients are not included in the statistical analysis (“intention to treat“ principle), this can change the results in favor of the tested substance. Loss to follow up was the major methodological weakness of the studies with drugs for osteoporosis and depression.7 Experiments with preventive medicines which should be taken for two or three decades, lasted only several years, and those with symptomatic drugs, only a few months. This period of time is too short to assess the efficacy and especially too short to assess the harm of the medication. It has been demonstrated that the effects of the treatments vary over time, and the length of the study may change the results.8 Some trials, particularly those which experiment with rare or malignant diseases, have too few participants for reliable conclusions. The choice of the outcomes which will be observed and measured is one of the most important elements of the study design. Surprisingly, trials do not necessarily evaluate clinically relevant outcomes, such as mortality, i.e. extension of life and other clinical events like heart attack, stroke, blindness, renal failure and bone fracture. Since the regulatory agencies do not always require clinical outcomes in order to register the drug, the studies use 2

Jochmann N, Stangl K, Garbe E, et al. Female specific aspects in the pharmacotherapy of chronic cardiovascular diseases. Eur Heart J. 2005;26:1585-95. 3 Rochon PA. The evaluation of clinical trials: inclusion and representation. CMAJ. 1998;159:1373-4. 4 Hewitt C, Hahn S, Torgerson DJ, et al. Adequacy and reporting of allocation concealment: review of recent trials published in four general medical journals. BMJ. 2005;330:1057-8 5 Johansen HK, Gøtzsche PC. Problems in the design and reporting of trials of antifungal agents encountered during meta-analysis. JAMA. 1999;282:1752-9. 6 Lithell H, Hansson L, Skoog I, et al. The study on cognition and prognosis in the elderly (SCOPE): principal results of a randomised double-blind intervention trial. J Hypertens. 2003;21:875-86; Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:7-22. 7 Cranney A, Guyatt G, Griffith L, et al. IX: Summary of meta-analyses of therapies for postmenopausal osteoporosis. Endocr Rev. 2002;23:570-8; Kirsch I, Moore TJ, Scoboria A, et al. The Emperor´s new drugs: an analysis of antidepressant medication data submitted to the U.S. Food and Drug Administration. Prevention & Treatment. 2002;5:Article 23. Available at: http://journals.apa.org/prevention/volume5/pre0050023a.html. Accessed 14 February 2006. 8 Jüni P, Rutjes AWS, Dieppe PA. Are selective COX 2 inhibitors superior to traditional non steroidal antiinflammatory drugs? BMJ. 2002;324:1287-8.

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surrogate end-points, such as blood pressure, cholesterol concentration, blood glucose, proteins in the urine and bone density.9 Research into new drugs for diabetes – tablets as well as insulin, is almost completely limited to surrogate end-point – reduction of the blood glucose concentration. In trials with antineoplastics, tumor response (the decrease in tumor mass) is usually used as the outcome, which is in fact a surrogate end-point. Many studies evaluate intermediate outcomes, e.g. heart hypertrophy and arterial wall thickness, or technology-based outcomes, such as surgical interventions or hospitalization. The reason for choosing the surrogate end-points lies in the fact that the assessment of clinical outcomes requires long-term follow-up of a great number of patients. This significantly increases costs and, more importantly, the effect of a drug in such settings is much more difficult to prove. For most medicines prescribed to asymptomatic individuals today, impact on the life span cannot be demonstrated, whereas the effect on the undesired clinical events is minimal. In order to show the efficacy of the drug, surrogates are resorted to, with the claim that they are predictors and causal factors of real illness and death. However, this is only partially true. For example, hypolipemics lower cholesterol 30-40%, while the impact on cardiovascular incidents in low-risk population is minimal; decrease in tumor mass often brings no increase in survival rate. The outcomes, such as hospitalization and surgical interventions are particularly problematic since they depend on local possibilities and traditions in health care. Besides using surrogate end-points, the designers of the studies have additional ways of manipulating the outcome. Since clinical events are relatively rare, especially in low-risk populations, and because separately, they do not reach the level of statistical significance, the studies regularly cluster them into a combined outcome. The problem with combined outcome is that it can be formulated in a way that is desired, rather than objective findings are demonstrated. A particular difficulty in assessing the clinical study's methodological validity is the fact that it is judged on the basis of the report, i.e. an article published in a medical journal. When the description of participant characteristics, methods and trial protocol is incomplete, which is sometimes the case, it is impossible to make valid conclusions about its methodological quality.10 The manner in which the study is carried out, independent of the concerns of methodology and design, is also lacking in rigor. Manipulation of procedures and data, i.e. “corrections“, falsifications, and post-hoc changes in design (the shortening of the trial duration, adding and excluding outcomes), all examples of what is known today as “scientific misconduct“, is considered a serious problem in contemporary medical research.11 The flaws in the methodology and design of therapeutic trial described in this chapter are only part of the long list of well-defined errors and biases typical of randomized trial. However, the subject does not end here. Questionable results are followed by problematic interpretation. Interpretation of the clinical study One of the most important elements in the interpretation of a study is the way in which the findings are presented. Before that, each report in the medical journal begins with an introduction. It is often misleading. The clinical significance and the prevalence of the medical condition for which the drug is used is often exaggerated. 9

Temple R. Are surrogate markers adequate to assess cardiovascular disease drugs? JAMA. 1999;282:790-5. Chan A-W, Hrobjartsson A, Haahr MT, et al. Empirical evidence for selective reporting of outcomes in randomized trials. JAMA. 2004;291:2457-65. 11 Petrovečki M, Scheetz MD. Croatian Medical Journal introduces culture, control, and the study of research integrity. Croat Med J. 2001;42:7-13. 10

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Presentation of the findings of the study is aimed not at giving an objective insight into the therapeutic potential of the substance, but at emphasizing its good sides and minimizing its bad sides. Outcomes reflecting effectiveness are shown incompletely and the presentation of adverse effects is even more incomplete.12 Experiments with cardiovascular drugs focus on their positive effect on morbidity (disease); whereas the mortality rate, i.e. survival, which is often unchanged, is usually less clear. Some papers do not show numerical data, but graphic presentations. This makes it difficult to see the real effect of the treatment. Furthermore, only the most impressive parts of the graphs and curves are shown. Subgroups of patients are inadequately analyzed and presented (e.g. only the group with the best results is shown). The most important factor that determines false perception of the value of drugs is the way in which the therapeutic effect is presented. Trial results can be displayed in different ways. The one most often presented is the relative risk reduction (RRR) of the unwanted event. RRR is the percentage of the reduction of the event in the experimental group compared to the reduction of the event in the control group. T. Lang took the example of the hypolipemic drug gemfibrozil, which in the Helsinki study reduced the rate of heart attack 34% compared to the placebo.13 RRR is presented as a main finding of the trial, and it is often the sole result included in the summary of the study. Much less attention is given to the absolute risk reduction (ARR), which would offer better insight into the effectiveness of a drug. ARR contains information on the prevalence (significance) of a particular clinical problem. In the above-mentioned study, the rate of heart attack with gemfibrozil fell from 4.1% in the control group to 2.7% in the treated group. This shows an absolute risk reduction of 1.4% – much less impressive than the RRR 34%. An even better indicator, also rarely presented and discussed, woud be the number of examinees needed to be treated in order to prevent one event (number needed to treat, NNT). In this particular case, 71 treated people are needed to prevent one heart attack. ARR and NNT refer to the whole duration of the trial and the authors do not stress this enough. RRR, ARR and NNT in the Helsinki study have been reached after a period of five years. This means that the ARR per year is less than 0.3%. NNT is 355 people per year to prevent one heart attack. The Helsinki study example is in no way unusual. Similar numbers are found in many trials in which drugs that lower cholesterol, blood pressure and glucose, or medication, such as aspirin are claimed to be effective in groups of people without cardiovascular disease. The effectiveness of the medication in high-risk populations or in populations of sick people is somewhat better. In the articles that report about studies, the presentation of results is followed by a discussion, a conclusion and a summary. Instead of a well-balanced and critical analysis of the findings and an objective synthesis, very often the discussion more or less subtly offers an artificially embellished picture of the tested drug. By not only carefully choosing the data which will and which will not be discussed, but by carefully choosing the vocabulary, the authors of the study offer the consumer misleading information. Positive sides of the medication are overemphasized and statistically unreliable findings are presented when they are in favor of a drug. The adverse effects, minimal effectiveness of the drug and the weaknesses of the study are all marginalized and justifications are proposed. In an effort to interpret findings which are sometimes hard to logically explain, new, sometimes confused constructions and simplifications of the complex pathophysiological processes are made. In addition, there are extrapolations which are not justifiable. 12

Chan A-W, Hrobjartsson A, Haahr MT, et al. Empirical evidence for selective reporting of outcomes in randomized trials. JAMA. 2004;291:2457-65. 13 Lang T. Twenty statistical errors even YOU can find in biomedical research articles. Croat Med J. 2004;45:361-70.

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From the beginning to the end of the discussion, the tendency is to generalize by increasing the size of the population and the number of outcomes in the experiment. The borderline between secondary prevention (treatment of sick people) and primary prevention (treatment of healthy people) is blurred. Some cardiovascular drugs and drugs for treating osteoporosis are effective in preventing heart attack or bone fracture in patients who already have heart disease or who have broken a bone, but they have no effect on healthy people. If the discussion repeatedly promotes the thesis that the drug prevents cardiovascular incidents or prevents fractures, the average reader will not realize that clarification should be given as to whether we are referring to healthy or to sick people. In practice the consequences of this “oversight“ are enormous. Substitution of clinical significance with statistical significance is one of the very important manipulations in the interpretation of study results. “Statistical significance“ means that the results obtained experimentally can be generalized to the whole population with the specified characteristics. Statistical significance has little to do with clinical relevance.14 Nevertheless, “the effect of the drug was statistically significant“ is a typical sentence in the discussions and summaries of scientific reports. Readers interpret this as meaning that the substance is effective and should be used. By hiding behind the expression “statistical significance“, the authors of clinical trials avoid commenting on and analyzing the real, the practical meaning, of their findings.15And when they do discuss them, interpretation of the benefits is arbitrary and biased. They pronounce valuable and worthy substances whose effects are demonstrated using surrogate end-points, or substances which prevent a few heart attacks or strokes out of a thousand patients a year. Because of the need to shorten and simplify, further alteration of results occurs due to the process of formulating the study's conclusion and summary. The claims found in the conclusion and summary are often neither substantiated, nor precise and objective.16 The marginal, partial, and dubious results of the study are reduced to one sentence claiming the effectiveness of the tested drug. Since most of the physicians and other consumers of medical literature read only summaries, which in many cases are the only part available on the internet, it is clear that incomplete and distorted presentations of trial results send erroneous messages. Furthermore, these conclusions are propagated by the system of education and are quoted and incorporated into subsequent scientific works. Medical opinions, including therapeutic choices, are not made on the basis of a single trial, but on the basis of systematic review of all the accessible pieces of research on the same subject (where the same therapeutic substance has been tested). The major problems here are the lack of elaborated methodology of systematic reviews on the one hand, and on the other hand, the fact that the studies with negative results are published less often than those with positive findings.17 If trials in which a new drug is shown to be less effective than the drug with which it is compared are not published, the bias occurs in the direction of magnifying the supposed therapeutic effect. Bias in applied medical research After the discussion about the main deficiencies in the methodology and interpretation of the clinical trial, that honored representative of medical science, doubts appear about its 14

Lang T. Twenty statistical errors even YOU can find in biomedical research articles. Croat Med J. 2004;45:361-70. 15 Chan KBJ, Man-Son-Hing J, Molnar FJ, et al. How well is the clinical importance of study results reported? An assessment of randomized controlled trials. CMAJ. 2001;165:1197-202. 16 Gøtzsche PC. Methodology and overt and hidden bias in reports of 196 double-blind trials of nonsteroidal antiinflammatory drugs in rheumatoid arthritis. Control Clin Trials. 1989;10:31-56. 17 Easterbrook PJ, Berlin JA, Gopalan R, et al. Publication bias in clinical research. Lancet. 1991;337:867-72.

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quality and credibility. Unfortunately, other forms of medical research, such as epidemiologic (observational) studies, which describe illnesses, and pharmacoeconomic analyses, which count the cost-effectiveness of treatment, suffer from even bigger flaws. As a result, we get false or at best unreliable information about disease and its treatment. In this way, pharmaceutical substances with unknown side-effects, almost non-existent effectiveness and high prices, are turned into very useful and cost-effective.18 The questions are: is this intentional and who is responsible for the low quality of medical science? The answers are pretty clear. The pharmaceutical industry finances about 70% of the clinical trials published in major journals.19 The biomedical research takeover by drug manufacturers has been going on for the last 25 years. In 1980, the pharmaceutical industry in the USA sponsored 32% of biomedical research. The remainder was financed by academic institutions. By 2000, pharmaceutical participation grew to 62%, most of it in applied research, while fundamental research was mainly left in the public domain.20 Similar trends are present in the rest of the world. Clearly, it is the sponsor of the scientific project who conceptualizes and monitors its performance and presents its findings. Academic scientists are only technicians who receive partial access to data, hired solely to give legitimacy to the scientific product.21 In such circumstances, the industry is misusing its position. Studies which prove this have analyzed the relationship between outcomes of the studies and their sponsorship. Meta-analyses (syntheses) of the numerous studies on this issue were unambiguous and highly convincing. Studies financed by the pharmaceutical companies are four to five times more likely to produce results in favor of the sponsor, compared to studies financed by other sources. In other words, when the research is paid for by the drug manufacturer, the likelihood that the substance will turn out better than the comparator is several times bigger than when it is paid for with public money. The authors of these meta-analyses concluded that private financing leads to systematic bias in medical research.22 The bias is produced by means of manipulation with the methodology, design, performance and interpretation of the study. Subject of applied medical science The penetration of private enterprise into the field of applied medical science has further contributed to its degradation. The quality of science lies not solely in its methodological validity, but in the subjects studied and in the questions asked. With this in mind, it is evident that contemporary medical science is going in the wrong direction. What does modern medical science deal with, and with what does it not deal? First of all, it is not interested enough in what causes disease. This is particularly true in the case of chronic diseases which escape the biological frame. It is very easy to show that for many years there has been no significant step forward in pharmacotherapy. The study of non-pharmacological prevention and cure is neglected compared to the study of drug interventions. There is no 18

Healy D. The dilemmas posed by new and fashionable treatments. Adv Psychiatr Treat. 2001;7:322-7. Bodenheimer T. Uneasy alliance: clinical investigators and the pharmaceutical industry. N Engl J Med. 2000;342:1539-44. 20 Bekelman JE, Li Y, Gross CP. Scope and impact of financial conflict of interest in biomedical research: a systematic review. JAMA. 2003;289:454-65. 21 Bekelman JE, Li Y, Gross CP. Scope and impact of financial conflict of interest in biomedical research: a systematic review. JAMA. 2003;289:454-65. 22 Bekelman JE, Li Y, Gross CP. Scope and impact of financial conflict of interest in biomedical research: a systematic review. JAMA. 2003;289:454-65; Lexchin J, Bero LA, Djulbegovic B, et al. Pharmaceutical industry sponsorship and research outcome and quality: systematic review. BMJ. 2003;326:1167-70; AlsNielsen B, Chen W, Gluud C, et al. Association of funding and conclusions in randomized drug trials. JAMA. 2003;290:921-8. 19

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research in the field of herbs and natural healing. The diseases that kill millions of people in the Third World have been systematically neglected. The reason why all these topics are ignored is the fact that they do not bring direct and rapid financial profit. Medical industry, the main “owner“ of medical science, explores commercially interesting areas. These are the ones directly or indirectly associated with drugs or other technological products. These are tested even when they are of marginal public health interest. Clinical trials deal with expensive preventive drugs intended for lifelong use by a large population. This research always begins with the same question, sticks to a standard design and tests similar substances. It experiments with the variations of already known drugs in such a way that the new representatives of the class, new formulations, combinations and doses are “found“, or it discovers other characteristics of an old substance that will ensure that it will continue to be prescribed.23 To a large extent, it can be described as a comparison of similar drugs. The sponsor's aim is to prove that his product is superior to the competing substance and thus to impose it as the better therapeutic choice. Medications compete for lowering cholesterol, lowering blood pressure, for having less side-effects or better 24-hour profiles. The differences are never too trivial for a study to be conducted. Companies are satisfied even with neutral results. Moreover, they intentionally plan research knowing that differences between the new and the established drug will not be demonstrated. The purpose of such “metoo“ projects is to show that the sponsor has an equivalent product, in other words, the aim is to seize a part of the market. Today's cardiovascular drug market is inundated with a great number of similar substances from only few classes. And the non-inferiority study, which is the name of the above-mentioned type of trial, has become the dominant type of clinical research and a synonym for the best that the contemporary medical science has. The actual conclusion of such studies could be summarized in the following sentence: “It is estimated that the new drug is not worse than the poorly effective predecessor.“ Modern drug science is characterised by a lack of creative ideas. It is no wonder that in spite of the immense overproduction (authors of one meta-analysis have identified 1731 trials with hypocholesterolemics that deal more or less with the same subject)24 and engagement of vast human resources (studies today include more than a thousand researchers),25 therapeutic progress has not been achieved. Industrial domination leads medical science astray, leading it down a blind alley without solutions, without answers to the important questions of disease and health. The main purpose of the majority of clinical trials is to prove the benefit of drugs, i.e. the necessity to use them. The other types of research which are indirectly associated with drugs support this idea. Fundamental studies propose concepts of pathophysiology which can be used to prove treatment needs. For example, the model based on the cholesterol metabolism disorder and inflammation dominates the way we define pathophysiology of atherosclerosis, although it is full of weak points and is only one of many models. Cholesterol is one of the most studied topics in medicine (hypocholesterolemics are the best selling drugs), although it is only one of 200 or so risk factors in developing heart disease. The pathophysiological model of heart failure has lately undergone a redefinition in which antihypertensives of the ACE inhibitor class fit in perfectly. The perception of diabetes has steered away from emphasis on the dysregulation of glucose and insulin towards the concept of a global 23

Angell M. The truth about the drug companies: how they deceive us and what to do about it. New York: Random House; 2004. 24 Walsh JME, Pignone M. Drug treatment of hyperlipidemia in women. JAMA. 2004;291:2243-52. 25 Sever PS, Dahlöf B, Poulter NL, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the AngloScandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet. 2003;361:1149-58.

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metabolic disorder. This enables hypocholesterolemics, antihypertensives and aspirin to become first line treatment in addition to hypoglycemic drugs. For hundreds of years, scientists were not able to find a consistent pathophysiologic substratum that would reliably distinguish sane from mentally ill people. Recently, they have succeeded – science has reduced the pathophysiology of depression to a lack of serotonin in the brain. Then antidepressants of the SSRI class are offered to correct the deficiency. Moreover, a hundred year old belief that the brain cells cannot regenerate, has recently been denounced. Neuroscience has proved that antidepressants can restore this ability. Important support for the application of clinical trials' findings is provided by pharmacoeconomic studies, since besides proving the effectiveness of drugs, their cost-effectiveness has to be demonstrated as well. By means of awkward methodology which hides the true cost of treatment, pharmacoeconomic analyses supposedly demonstrate that through long-term use of expensive substances (of trivial effectiveness), great economic benefits are achieved for the health system. The observational studies find the benefit of lowering blood glucose, cholesterol and pressure at very low levels of these parameters. The epidemiologic studies show a large prevalence of those diseases which are commercially attractive, such as cardiovascular, osteoporosis and depression. They also demonstrate low levels of awareness and knowledge of these problems, inadequate diagnosing, as well as under-treatment, all of which raise the awareness of these conditions. Aim and tendencies of contemporary medical science The aim of the above-mentioned types of research is, to a large extent, to increase the use of medication. This is reached by means of “smaller“ goals which sometimes overlap. At the same time, these goals reflect the main characteristics and tendencies of modern medical science. One tendency is the increase in indications, i.e. finding new conditions for which pharmacotherapy can be introduced. This is achieved through interventions in the trial design. Special populations and special outcomes are created in which the effect of the substance is demonstrated. When they appeared twenty years ago, ACE inhibitors, the most popular class of drugs today, were licenced only for lowering blood pressure. Subsequently they were approved for heart failure, then for heart attack and angina pectoris, and finally for kidney and eye disease. In ten years statins have gradually evolved from being considered as cholesterol lowering drugs, particularly for patients with heart conditions, into medication useful in cardiovascular disease in general. The indication has widened further to healthy people with high cardiovascular risk, until, finally, the statins were labelled general antiatherosclerotic drugs, regardless of the blood cholesterol level. Antidepressants (SSRI class), formerly given for severe forms of depression, now have twelve indications which also include milder anxiety disorders. Erythropoietin, indicated only recently for the severe anemia of patients on hemodialysis, now extends to other types of anemia, as well as to different conditions involving organ lesions, regardless of the presence of anemia, thanks to the clinical trial and other research that have “proved“ its beneficial traits. Extending definitions of diseases and creating new clinical entities are further important aims of current medical science. The phenomenon is present in areas where the new pharmacologic substances exist and coincides with their appearance. Definitions of symptomatic illnesses, such as asthma and depression, have widened by lowering diagnostic criteria with respect to the intensity and the duration of symptoms. Clinical trials have simply been designed to show that drugs are effective in these situations as well. The same has been demonstrated in a number of physiological and borderline conditions, as well as in temporary disorders, such as menopause, “premenstrual syndrome“, erectile dysfunction, or the so called “social anxiety disorder“ (better known as shyness). These conditions are then pronounced

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illnesses.26 The main “problem“ the pharmaceutical industry encounters is the fact that there is a limited number of people who are really sick and require the medication. The best way to increase the number is to extend the definition of the disease, encroaching on the domain of health. Osteoporosis is considered by some experts the classical example of the “invented“ disease or at least a heavily exaggerated problem. Considered as one of the leading health problems of the modern world today, osteoporosis has been unknown to mankind until recently. It is about losing bone mass, a physiological phenomenon associated with aging. Osteoporosis has no symptoms, except for bone fracture associated with it, which appears relatively rarely. The effect of drugs on preventing it is minimal. The definition of the disease, which is currently in use, was created only in 1994. It is the measure of the deviation from the average bone density of a young adult woman. Such a controversial construction, in which the bones of the elderly and of menopausal women are compared to those of a 25-year-old woman, has led to a situation where a vast number of healthy women has been diagnosed with osteoporosis.27 The definition of a new disease was created by means of bone density, which is the predisposing (or risk) factor for the real clinical entity (bone fracture). The same type of model already existed in cardiovascular medicine. The concept of cardiovascular risk factors was created when epidemiologic studies found that high blood pressure, lipids, and sugar predispose a person to cardiovascular disease, mainly heart attack and stroke. Clinical trials then showed that taking drugs can reduce the risk of such unwanted events. In this way, asymptomatic conditions were turned into illnesses. Hypertension (high blood pressure), hyperlipidemia (high blood fat), and hyperglycemia (diabetes), are the most common diseases today. Except for the cases of very high blood pressure and of high sugar present, there are no symptoms. These are not illnesses in the traditional sense; they are not clinical entities, but laboratory and technical parameters. The concept itself stands on a very shaky ground. The validity and credibility of the claim of risk factors is questionable (particularly for glucose and cholesterol). The causal connection is not reliably proved and the degree of risk is small. The hypothesis that risk factor reduction leads to reduction of morbidity and mortality is highly problematic. This is in accord with the modest effect of drugs. Antidiabetics decrease neither cardiovascular, nor total mortality, the effects of antihypertensives are limited, and those of hypolipemics are marginal and restricted to groups of high-risk individuals. This concept represents a simplification of the etiology and pathophysiology of cardiovascular disease and it is not likely to lead to the solution of this major health problem. It suits only drug manufacturers. To propose a substance that changes the level of metabolic or physiological parameters is the beginning of great business success. This is why the pharmaceutical industry is engaged in the “creation“ of new cardiovascular risk factors for which it already possesses substances. After-meal blood glucose (PPG), early morning blood pressure, high levels of uric acid, high levels of proteins in the urine, C-reactive protein (CRP), depression, anemia, pathoanatomic parameters (narrowing of heart arteries, arterial wall thickening, left heart ventricle hypertrophy) and genetic markers, are on the way to being declared, with the help of the scientific evidence, new cardiovascular risk factors. Traditional medicine dealt with illnesses that had a clinical picture. That picture included personal discomfort and/or a visible disorder. The definition of the disease was simple. Today, when diseases are diagnosed by means of laboratory and other technical parameters, the question – what is the borderline level at which the disease is pronounced? – arises. This 26

Moynihan R, Heath I, Henry D, et al. Selling sickness: the pharmaceutical industry and disease mongering. BMJ. 2002;324:886-91. 27 Moynihan R, Heath I, Henry D, et al. Selling sickness: the pharmaceutical industry and disease mongering. BMJ. 2002;324:886-91.

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value is deduced from findings of the studies which have shown that at a particular level of blood pressure, cholesterol, glucose or total cardiovascular risk, it is more beneficial to introduce the intervention, than not, i.e. that the treatment brings more benefit than nontreatment. This level of the parameter is pronounced pathological. It is clear that the boundaries of the disease estimated in this way, i.e. obtained from the problematic studies and the arbitrary consensus of the clinicians afterwards, are highly questionable. The new approach in cardiovascular medicine hightens the dilemma of the already problematic definition of the boundary between normal and abnormal (pathology). “Normal“ is a category which is defined statistically. In the population distribution of the parameter, within the 95th percentile is considered normal. Pathology is outside of this percentile. However, scientific studies have shown that some populations with statistically normal levels of blood pressure and cholesterol nevertheless die more often from cardiovascular disease. Consequently, it is not the normal, but the healthy level of the risk factor that is striven after.28 So the “target value“ of the parameter (located eccentrically low on the Gauss curve) has been introduced. It is the level of blood pressure, cholesterol or glucose towards which one should strive during the therapeutic process. It is the point where it is estimated probable, based on scientific data and determined consensually, that future complications grow to unacceptable levels. This definition method is as vague and non-transparent as is the definition method of borderline diagnostic parameter levels. The way in which statistical limits of pathological conditions and parameter target values are determined, leads to serious dangers – borderline and target values can very easily be lowered. It is sufficient that studies “prove“ that parameter levels which are lower than previously thought, are beneficial. And this is exactly what is happening. The process is facilitated by the parallel adoption of two “assisting“ concepts. One concept deals with the linear relationship and the other with the lack of a threshold for intervention. The classic curve from the textbooks about hypertension, which shows a correlation between blood pressure and mortality, and is deduced from observational studies, has the shape of the letter “J“. It explains that, to a certain extent, mortality falls with the lowering of blood pressure. As blood pressure is decreased, the curve stagnates and then starts to rise. According to new studies of hypertension and their interpretation, the “J“-curve no longer exists. It now has a linear shape, it is a straight line. The same thing happened with cholesterol. Because current thinking considers these parameters as continuous variables, i.e. that there is no threshold at which the frequency of complications abruptly rises, it follows that there is no parameter value under which further lowering would be worthless. Therefore, the goal of therapy becomes to lower blood pressure, cholesterol and glucose as much as possible. A minimum level does not exist. In spite of being in conflict with clinical experience as well as with common sense, this “scientifically“ founded, dubious stance, gets incorporated into clinical practice guidelines. Year after year, clinical studies have been experimenting with lower and lower levels of cholesterol, blood pressure and glycemia, creating preconditions for the lowering of target values. And these values really have been continuously sliding down. Only fifteen years ago, the upper limit of the total cholesterol norm in medical textbooks was 6.5 mmol/L, and for LDL-cholesterol 4.1 mmol/L.29 As a result of several meetings of the lipid committees in the USA and Europe, total cholesterol target value has been lowered to less than 5 mmol/L and LDL to < 3 mmol/L; for high-risk individuals to < 4.5 mmol/L and < 2.5 mmol/L,

28 29

Murray S, James MA. What is hypertension? Lancet. 1999;354:593-4. Vrhovac B, et al. Internal medicine. Zagreb: Naprijed; 1991 (in Croatian)

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respectively.30 Newer guidelines have even stricter demands. Some of them require a target of only 3.5 of total, and 1.8 mmol/L of LDL-cholesterol for heart patients, diabetics, and healthy high-risk individuals. Others suggest that for these groups pharmacotherapy should be introduced regardless of the cholesterol level. 31 Medical textbooks from the nineties proposed that blood pressure of 160/95 mm Hg or more should be considered hypertension.32 Using the same model as in the case of cholesterol, today hypertension is defined as a condition with 140/90 blood pressure. At the same time, this is considered an indication for the use of antihypertensives. When the patient is diabetic, has suffered heart attack or stroke, an intervention is already introduced at 125-130/70-80 mm Hg. The optimal blood pressure level in general is less than 120/80 mm Hg.33 In a similar manner, albeit to a lesser degree, targets for glycemia in diabetic patients have been reduced as well. It is not difficult to conceive the motive for the systematic lowering of target and borderline values for the biological parameters. To indicate a target means to insist on using therapy until the target is reached and permanently maintained. To set it lower means to start pharmacotherapy earlier, to use higher doses of drugs and to add substances. This is exactly what is happening in today's clinical practice – patients are taking more and more medication. The outcome of the above-described scenario is that with each new edition of guidelines, more and more people become candidates for treatment. The population who qualifies for pharmacotherapy increases. In the eighties, data showed that 10-25% of the population was hypertensive.34 Today's estimation is that in six big European countries, 44% of the population has blood pressure higher than 140/90 mm Hg.35 With the introduction of the “prehypertension“ concept a few years ago, the health status of 50 million Americans has been redefined overnight. The implementation of the 2001 guidelines for hypercholesterolemia increased the count of Americans eligible for treatment from 15 to 36 million. With the 2004 guidelines, the number rose to 50 million.36 With the application of the new European guidelines for the prevention of cardiovascular diseases, 76% of the adult

30

Third Joint Task Force of European and other Societies on Cardiovascular Disease Prevention in Clinical Practice. European guidelines on cardiovascular disease prevention in clinical practice. Eur J Cardiovasc Prevent Rehab. 2003;10:S1-78; Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285:2486-97. 31 Mitka M. Guidelines: new lows for LDL target levels. JAMA. 2004;292:911-3; European Society of Hypertension – European Society of Cardiology, Guidelines Committee. Guidelines for the management of arterial hypertension. J Hypertens. 2003;21:1011–53; Williams B, Poulter NR, Brown HJ, et al. British Hypertension Society guidelines for hypertension management 2004 (BHS-IV): summary. BMJ. 2004;328:634-40. 32 Vrhovac B, et al. Internal medicine. Zagreb: Naprijed; 1991 (in Croatian) 33 European Society of Hypertension – European Society of Cardiology, Guidelines Committee. Guidelines for the management of arterial hypertension. J Hypertens. 2003;21:1011–53; Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. The JNC 7 Report. JAMA. 2003;289:2560-72. 34 Pajak A, Kuulasmaa K, Tuomilehto J, et al., for the WHO MONICA Project. Geographical variation in the major risk factors of coronary heart disease in men and women aged 35-64 years. World Health Stat Q. 1988;41:115-40. 35 Wolf-Maier K, Cooper RS, Banegas JR, et al. Hypertension prevalence and blood pressure levels in 6 European countries, Canada and the United States. JAMA. 2003;289:2363-9. 36 Mitka M. Guidelines: new lows for LDL target levels. JAMA. 2004;292:911-3.

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Norwegian population falls into the category of increased risk.37 In Great Britain, 87% of men and 56% of women over 65 have a coronary heart disease risk which, according to British guidelines, makes them candidates for at least one preventive pharmacological intervention.38 The fact is that not all these people use medication, but the number of those who do increases day after day. For example, 6-9% of the USA population regularly take aspirin, unnecessarily, completely out of control, and with a significant risk of complications.39 Traditional medicine dealt with the sick by trying to eliminate or at least alleviate suffering. More recently, medicine has turned towards those who have previously suffered such events as heart attack or stroke, or who have asthma or depression, but currently do not experience any difficulties. In these cases, the goal of pharmacotherapy is to prevent new incidents, exacerbation, or aggravation of the disease (secondary prevention). Most recently, medication is being introduced more and more to healthy people. The explanation is that the individuals with predisposing factors have an increased risk of an unwanted event (primary prevention). Early studies with hypocholesterolemics, antihypertensives, and aspirin experimented mainly with ill people. Gradually, healthy individuals with “high risk“ of disease were introduced in testing and it was demonstrated that they also benefit from treatment. The effectiveness of medication has been decreasing since the early studies, both in terms of absolute risk reduction and with respect to the severity of outcomes. But this could neither be easily deduced by noting the relative reduction in risk, which has stayed the same, nor from the combined outcomes. By demonstrating the “evidence“ of effectiveness, one by one, different classes of drugs were indicated for use in primary prevention. The drugs owe their wider use today to prevention, i.e. to the increased interest in preventive medicine. The potential market in this area is unlimited and treatment is lifelong. Physicians have been put into a situation where they can routinely prescribe medication to people without symptoms. Once the drug has been introduced, nothing limits its continuous use. Clinicians are unaware of how unclear the definitions of many chronic diseases are, and to what extent the borderline between health and disease is blurred. It is possible to “sell“ them a substance for the prevention of diabetes or osteoporosis. It is an absurd construction, in fact a double prevention, considering that diabetes is the risk factor for cardiovascular disease and osteoporosis is the predisposing factor for bone fracture. Similarly absurd are recently introduced new entities of “prehypertension“ and “prediabetes“ which are defined as conditions which have an increased risk of developing hypertension and diabetes. There is nothing wrong with the preventive approach to disease, on the contrary. The problem is that the concept of modern preventive medicine comes from the pharmaceutical industry. It assumes that medication will be used, usually expensive substances, over a long period of time. Such an approach to dealing with healthy people who have a small chance of getting ill is not cost-effective. It is useless and unreasonable – exactly the opposite of the idea of true prevention. Drug makers and their assistants have reduced disease prevention to a model of medication. The projects for prevention of cardiovascular diseases mainly focus on hypocholesterolemics and antihypertensives. The prevention of bone fractures concentrates on bisphosphonates and hormone replacement therapy, and prevention of suicide on antidepressants. The drug industry has claimed prevention for itself, distorted it and adjusted 37

Getz L, Kirkengen AL, Hetlevik I, et al. Ethical dilemmas arising from implementation of the European Guidelines on cardiovascular disease prevention in clinical practice. A descriptive epidemiological study. Scand J Prim Health Care. 2004;22:202-8. 38 Marshall T. Coronary heart disease prevention: insights from modelling incremental cost effectiveness. BMJ. 2003;327:1264-7. 39 Sanmuganathan PS, Ghahramani P, Jackson PR, et al. Aspirin for primary prevention of coronary heart disease: safety and absolute benifit related to coronary risk derived from meta-analysis of randomised trials. Heart. 2001;85:265-71.

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it to its own interests. By applying supposed preventive approaches in situations where such approaches were not previously used, it is changing the medical paradigm itself. For thousands of years, medicine was treating the sick. Now the orientation to treating healthy people is becoming dominant. We are confronted with a process which has far-reaching cultural implications and important social and economic consequences. Limited resources, originally intended for health care interventions that really helped and were directed to the people in need, are being diverted into so-called preventive activities which are of questionable relevance for the individual and are potentially and indirectly harmful for society. Primary and secondary pharmacological prevention of cardiovascular and other disease is a concept which has not at all been systematically evaluated. It is practised without having defined effectiveness and efficacy criteria. The clinical trial is its only foundation. Its legitimacy comes exclusively from a scientific construct of problematic value coming from the pharmaceutical industry. Scientific product as a product of marketing In the beginning, with the new rigorous methodology, the clinical trial represented an advanced and more solid base for therapeutical decision making compared with the experience and suppositions on which it had been previously founded. Indeed, some evidence collected in this way differred from previous beliefs. However, today, clinical study no longer meets scientific criteria. The mission of science is to search for the truth; in medicine it is the truth about treating and preventing disease. The clinical trial, with its false presentation of drug effectiveness, is a delusion. The manipulation of facts and the creation of falsely embellished pictures of products do not reflect qualities of a scientific approach. These are marketing characteristics. This leads us to the devastating realisation that the clinical trial, a synonym of quality in the medical research of the second half of the 20th century, is in fact the product of marketing. Its aim is not to establish the truth about a certain pharmacological substance; its goal is to sell it. Today, clinical studies are planned in marketing departments of pharmaceutical companies and in public relations agencies. Here it is decided what should be investigated and with which methods, and how it should be interpreted and presented, in order for the product to have the best possible market success. There are no scientists and physicians who are creative in this medical research; they are just performers. The real authors are the marketing experts whose job is to design science in the way that best serves corporate interests. In treatment of ill people, there is hardly a need for a clinical trial. If a drug is effective, pathologic conditions and symptoms disappear. The result is obvious to both the doctor and the patient. Clinical trial emerged and fully established itself in the field of prevention, which deals with healthy people, or those without symptoms. Here, the effect of drugs cannot be assessed on the basis of clinical judgement and common-sense conclusions. The outcomes targeted by the therapy are in the far future, the sample is small, and the doctor is forced to rely on evidence provided by scientific testing. It is exactly in this domain that manipulation is possible, and this is where a clear road of opportunity has opened for marketing. This is where clinical trial finds its place. Randomized controlled clinical trial (RCCT), a quasi-scientific product, only mimics science. The perception created that it is a top scientific product which brought about the “revolution“ in clinical medicine is just an illusion motivated by commercial interests. But the delusions do not end here. In addition to painting an embellished picture of the pharmacological substance, the therapeutic trial has a further marketing function – creating artificial demands for drugs. Prevention is the field where there is generally no need for pharmaceutical products, at least not the expensive ones which are offered today. Clinical study, with risk factors and target values that are deduced from its conclusions, creates an

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imaginary need to take drugs. By proving the efficacy of the substances in temporary, borderline, and physiological conditions, boundaries of disease are enlarged and new “pathologic“ entities which “require“ pharmacotherapy are made. The process is backed up by other types of medical research with hidden promotional characteristics. Epidemiologic studies magnify health problems. By presenting them to the public on round tables, they raise the awareness of these conditions, thus creating an artificial demand for drugs. One such study, which is being conducted on a regular basis in Europe, examines the prevalence of cardiovascular risk factors and prescribed medication for patients who have been discharged from hospitals due to heart disease.40 Behind the mask of science, lies on the one hand marketing research for the pharmaceutical companies. On the other hand, through citing this “research“ in symposia and literature, the pressure is put on clinicians to introduce the expensive antihypertensives and hypolipemics. Studies of the therapeutic attitudes of physicians, and their knowledge of clinical guidelines and drug indications, have a similar significance and goal. “Science“ of this kind is particularly popular in small countries. They readily join such “projects“ which successfully further physicians' professional careers and influence. The introduction of the private sector into applied science results in the imposition of industrial priorities and the use of science for the purpose of profit making. Scientific research in the field of pharmacotherapy has become an instrument for drugs' promotion. This leads to a dangerous overlapping of science and marketing. Although it should not be so, the pharmaceutical industry has turned drugs into merchandise, the same as any other product on the market. What is even more unhealthy is that scientific research itself is acquiring the characteristics of merchandise. Even its written form begins to resemble a commodity. Result of the scientific work, its report, has always been a serious and well-balanced article published in scientific journals. There is no need to have attractive “packaging“, to advertise it, or to deliver it to the consumers. Yet, this is what happens with clinical studies these days. Corporate designers and public relations people put considerable effort into the outward appearance of the study and into promoting it, in order to draw attention to it. The names of the trials, acronyms, carry striking messages (CURE, LIFE, HOPE, ADVANCE, PROGRESS, PROSPER). Stopping the trial suddenly and prematurely because of the “clearly beneficial effect“ of the tested substance, is one of the marketing tricks comparable to those in advertising of any other kind. The size of the trial is constantly increasing and already reaches 20 000 participants, in the most recent studies even 50 000 participants. Sponsoring companies use the huge numbers as supposed proof of the quality and reputation of the study and of the drug (the truth is exactly the opposite – the effect of the substance on a healthy population is so trivial that it can only be demonstrated on a very big sample). Contrary to publication standards, the authors of one of the most famous studies of hypocholesterolemics took the liberty of dividing the discussion into three parts which, in fact, would fit perfectly into an advertisement. At the end of the report, the tested drug was offered to no less than the Chinese market.41 Until a few years ago, practising doctors did not have much contact with medical science. Today, they encounter drug trials at every turn. Pharmaceutical representatives bring them to their offices (companies invest large amounts of money in reprints and distribution), and they are the main topics of the continuing medical education (symposia, congresses). These days the drugs are less and less offered to doctors. They are being offered clinical studies. This is what they really “buy“. In the same way, trials are “bought“ by the health administration and 40

EUROASPIRE II Study Group. Lifestyle and risk factor management and use of drug therapies in coronary patients from 15 countries. Eur Heart J. 2001;22:554-72. 41 Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:7-22.

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by insurance companies when decisions need to be made about drugs that are covered by the health insurance policies. Clinical studies are more and more geared to lay people. Since in the most of the world the public advertising of drugs is not allowed, therapeutic studies are promoted. Today, one can read about them in popular magazines, and hear about them on radio or TV. Just like any other “ordinary“ product, they have their own web-sites. When a new study is revealed, it is followed by marketing campaigns and attracts wide-spread media attention. The statin studies were announced in advance and made the front pages of the most popular weekly magazines. Pharmaceutical companies have always produced medicinal substances. Recently, they have been producing scientific research as well. Although a typical large-scale trial costs tens of millions of euros, we are witnessing a true explosion in the number of clinical studies. Drug manufacturers invest more and more money in this sort of research because they are aware that it is extraordinarily influential and helps make huge profits. We are dealing here with an exclusive and a very “sophisticated“ product. Its exclusivity is established thanks to the legitimacy and the significance that science has in today's world. Since it is virtually identified with the truth, scientific argument is a strong and unquestionable argument for corporate goals. Taking over science is the most productive, cost-effective way of making money, and the most profitable initiative that private business has conceived. Literature Als-Nielsen B, Chen W, Gluud C, et al. Association of funding and conclusions in randomized drug trials. JAMA. 2003;290:921-8. Angell M. The truth about the drug companies: how they deceive us and what to do about it. New York: Random House; 2004. Bekelman JE, Li Y, Gross CP. Scope and impact of financial conflict of interest in biomedical research: a systematic review. JAMA. 2003;289:454-65. Bodenheimer T. Uneasy alliance: clinical investigators and the pharmaceutical industry. N Engl J Med. 2000;342:1539-44. Chan A-W, Hrobjartsson A, Haahr MT, et al. Empirical evidence for selective reporting of outcomes in randomized trials. JAMA. 2004;291:2457-65. Chan KBJ, Man-Son-Hing J, Molnar FJ, et al. How well is the clinical importance of study results reported? An assessment of randomized controlled trials. CMAJ. 2001;165:1197-202. Cranney A, Guyatt G, Griffith L, et al. IX: Summary of meta-analyses of therapies for postmenopausal osteoporosis. Endocr Rev. 2002;23:570-8. Easterbrook PJ, Berlin JA, Gopalan R, et al. Publication bias in clinical research. Lancet. 1991;337:867-72. EUROASPIRE II Study Group. Lifestyle and risk factor management and use of drug therapies in coronary patients from 15 countries. Eur Heart J. 2001;22:554-72. European Society of Hypertension – European Society of Cardiology, Guidelines Committee. Guidelines for the management of arterial hypertension. J Hypertens. 2003;21:1011–53. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285:2486-97. Getz L, Kirkengen AL, Hetlevik I, et al. Ethical dilemmas arising from implementation of the European Guidelines on cardiovascular disease prevention in clinical practice. A descriptive epidemiological study. Scand J Prim Health Care. 2004;22:202-8. Gøtzsche PC. Methodology and overt and hidden bias in reports of 196 double-blind trials of nonsteroidal antiinflammatory drugs in rheumatoid arthritis. Control Clin Trials. 1989;10:31-56. Healy D. The dilemmas posed by new and fashionable treatments. Adv Psychiatr Treat. 2001;7:322-7. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebo-controlled

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