THE POLITICS OF HEALTH
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Physicians and the Pharmaceutical Industry Is a Gift Ever Just a Gift?
Wazana, A.
JAMA 2000;283:373-380.The results of this study indicate that pharmaceutical companies significantly influence physicians' professional behavior through gifts, free meals, sponsored travels, teachings and symposia.
Every year the pharmaceutical industry spends over 12 billion dollars to push drugs, and invests an estimated $8,000 to $13,000 on each U.S. physician. While 85% of medical students judge as unethical for politicians to accept gifts, only 46% of them believe it is improper to accept a gift of similar value themselves from a pharmaceutical company. The interaction between physicians and the drug-industry could have crucial consequences if it can be demonstrated that such relationship results in changes in prescribing practices toward drugs that are more expensive or that are associated with negative health outcomes.
This study evaluated the impact that the pharmaceutical industry has on physicians' prescribing practices through analysis of 29 peer-reviewed relevant articles. In the studies, physicians were surveyed on the extent and the effects of industry contact through a postal questionnaire. Most articles emphasized that the self-report design was likely underestimating the real frequency of physician-industry interactions and their consequences. Contact with industry started during medical school and continued at a frequency of about 4 times per months. Most doctors believed that the information presented by industry representatives was accurate, and that acceptance of gifts did not affect their prescribing practices. Conversely, the researchers found that contact with pharmaceutical representatives significantly affected physicians prescribing practices and resulted in increase of non-rational prescribing, preference and rapid increase in prescribing of new drugs, reduced prescribing of generic drugs, and increased prescribing costs. Furthermore, acceptance of funding to attend a drug company-sponsored symposium was associated with changes in prescribing practices and with addition of the sponsored drugs to the hospital formulary. Changes in hospital prescribing practice were still present two years after two groups of physicians attended the symposium, thus indicating that exposing physicians to drug-industry promotions can have a long-standing effect on prescribing practices at the institutional level. The study also found an association between resident exposure during lunch rounds to speakers paid by pharmaceutical companies and learning of inaccurate information about the sponsor's and competitor's drug. A significant association was also found between participation of attending residents to teaching rounds led by a physician pharmaceutical representative and rational and non-rational treatment decisions. These findings indicate that physician-industry interaction has a mainly negative impact on physician knowledge of the appropriateness and the effectiveness of specific drugs, on physicians attitude towards drug representatives and their products with preferential prescribing of sponsored drug and rapid prescriptions of new drugs, and on physician behavior resulting in inaccurate prescribing, increased prescribing, prescribing of new, more expensive drugs with no benefits over cheaper generic drugs, and requests of adding sponsored drugs to the hospital formulary with no obvious advantages over pre-existing ones. These associations were significant and were strong in most studies. In all interactions a dose-response was observed.
The scandal of poor medical research
Altman, DG.
BMJ 1994;308:283-284 (29 January).This article questions the integrity of the medical research community responsible for the production and publication of scientific articles in which statistical analysis are often used wrongly, studies are poorly designed, results are misinterpreted and selectively reported, and unjustified conclusions are drawn. The author emphasizes that all of the above phenomena are frequently found in the medical literature and are due to physicians' pressure to publish in order to advance in their career. The consequences of the poor quality of research can be devastating since patient treatment is often based on trial results which can be statistically manipulated to prove the safety and effectiveness of a specific treatment. Referring to Bailar's comments, the article reports that, " there may be greater danger to the public welfare from statistical dishonesty than from almost any other form of dishonesty."
Interactions Between Physicians and the Health Care Technology Industry.
Tenery, RM.
JAMA, Vol. 283 No. 3, January 19, 2000.This article emphasizes that among the incentives provided by drug companies to influence physicians prescribing practices are: paid vacations, free airline miles that are awarded based on the number of prescriptions written, and all-expenses-paid continuing medical education (CME) seminars thought by speakers chosen by the pharmaceutical company.
Physicians' behavior and their interactions with drug companies
A controlled study of physicians who requested additions to a hospital drug formulary.
Chren MM, Landefeld CS.
JAMA 1994 Mar 2;271(9):684-9.The results of this study show that interactions with representatives of pharmaceutical companies strongly affect physicians' requests to add new drugs to a hospital formulary. The study evaluated the extent of physician-industry interaction in 40 doctors from a University hospital who made such request, and 80 randomly selected physicians who had not made the request. Physicians who requested the addition of a new drug to the hospital formulary were 5 times more likely to have received money from drug companies to attend meetings, giving speeches and performing research; in addition they were 13 times more likely to have met with drug company representatives, and 19 times more likely to have accepted money from those companies, compared to physicians who did not request a formulary addition. Furthermore, requested additions were 5 times more likely to be for drugs produced from the same companies whose sales representatives met with the physicians, than to be for drugs of other companies. These findings indicate that drug companies' representatives are highly successful in altering physicians' prescribing habits.
Reasons for not seeing drug representatives.
Griffith D.
BMJ 1999;319:69-70 ( 10 July ).This article highlights that contacts between doctors and drug companies' sales representatives are associated with changes in physicians' prescribing patterns and inappropriate and wasteful use of medications. Sales representatives are seen as the most valuable source of information for drugs that are newly released on the market, when little post-marketing information is available on the safety of the drug and few data are available comparing the efficacy and costs-benefits of new treatments with those of pre-existing ones. Several studies have shown that contacts with drug sales representatives result in changes of doctors' prescribing habits, and in inappropriate use of medications. These studies have also shown that the more doctors rely on information from drug company representatives, the less rationale their prescribing is. According to the author's own conclusions, there are indeed strong reasons for not seeing representatives.
Industry reimbursement for entering patients into clinical trials: legal and ethical issues.
Shimm DS, Spece RG Jr.
Ann Intern Med 1991 Jul 15;115(2):148-51.This study highlights that researchers who test the efficacy and safety of new drugs are usually offered a per-patient reimbursement by the drug manufacturer that exceeds the per-patient cost that they sustain. This extra money goes into funds that can be used by the investigator for traveling, purchasing of supplies and equipments, and funding of other research. The authors of the article highlight that this situation, besides being usually unknown to the patients enrolled in the trials, has the potential of creating conflicts of interests, and could be avoided by re-directing the extra funding to the medical school rather than to the individual investigator.
Is Academic Medicine for Sale? Editorial.
Angell, M.
N Engl J Med -- May 18, 2000 -- Vol. 342, No. 20.This letter wrote by Marcia Angell, the former editor of the New England Journal of Medicine, highlights how pervasive are the financial ties between pharmaceutical companies and the medical and research community. The letter explains that the authors of an article on anti-depressants that appeared on the same issue of the journal, exhibited such extensive affiliation with the drug industry that it would have taken too much space to disclose it in full in the journal and detailed information was therefore made available on the journal' website. Also presented is the difficulty of finding a research psychiatrist without financial ties to drug companies (the journal policy requires for editorialists to have no important financial relationships with drug manufacturers) to write the accompanying editorial to the article on antidepressants. The author of the letter emphasizes that this problem is not restricted to psychiatry, but on the contrary, is rather ubiquitous, affecting particularly those branches of medicine requiring use of expensive drugs and devices.
Sponsored drug trials show more-favourable outcomes.
Wahlbeck K, et al.
BMJ 1999;318:464 ( 13 February ).This article highlights that trials that are supported by pharmaceutical companies are significantly more likely to report favorable outcomes associated with use of the sponsored drug, compared to non-sponsored trials. The study evaluated whether drug company participation had an impact on the outcome of 29 randomized studies where the efficacy and tolerability of the anti-psychotic drug clozapine was compared with that of other antipsychotic drugs. According to the results of drug-sponsored trials, disease relapses occurred significantly less often in the group receiving clozapine, but this finding was not confirmed in non-sponsored trials. Similarly, benefits derived from clozapine treatment were significantly greater in sponsored versus non-sponsored trials. In addition, sponsored trials reported lower rates of dropout in patients receiving clozapine, but this effect was not observed in non-sponsored trials. The authors express concern about the differences in outcomes observed in trials supported by pharmaceutical companies, compared to those who did not receive any support. They also worry about the fact that licensing authorities make decisions based on drug-sponsored trials and not on research performed by independent investigators.
Competing interests and controversy about third generation oral Contraceptives.
Vandenbroucke, JP et al.
BMJ 2000;320:381 ( 5 February ).This article reports on the efforts made by the drug industry to disprove the results of several studies indicating that users of third generation contraceptives have a significantly increased risk of deep venous thrombosis compared to users of second generation pills. Four industry-funded studies evaluated the risk of this complication in users of third generation contraceptives, and their overall results indicated no increased risk. On the other hand, the results of nine non-sponsored studies indicated an overall 2.4-fold increased risk. As this article describes, the drug manufacturers affirmed that with almost total certainty the results of the non-sponsored articles were biased. They sponsored special symposia, paid supplements and exerted strong marketing pressure to convince physicians to disregards these findings as wrong. In addition, they exerted strong legal pressure on governments. The World Health Organization's scientific committee re-evaluated the studies and further confirmed that the risk of deep venous thrombosis is increased in users of third versus second generation pills. The authors conclude that in view of the pervasiveness of conflict of interests caused by industry funding, readers should be aware whose words they are reading.
Medical societies accused of being beholden to the drugs industry.
Gottlieb S.
BMJ 1999;319:1321 ( 20 November ).This article reports on a study published in the Western Journal of Medicine (owned by the British Medical Journal Publishing Group) alleging that medical organizations are increasingly becoming dependent on the drug industry for their income, and this situation can pose a threat to their objectivity. The study evaluated the profits of the clinical journals of several leading medical organizations, including the Journal of the American Medical Association, the New England Journal of Medicine, the Journal of the American College of Cardiology, Annals of Internal Medicine, Clinical Infectious Diseases, and others. Drug advertisement contributed from $715,000 to $18 million of revenue, a sum that, according to the authors, could place the organization in a position of dependency. The study findings also revealed that over 10% of the income of 5 medical organizations came from drug advertisements published in a single journal, while 4 organizations profited as much or more from drug advertisement as from members. The risk that economic ties with the drug industry will compromise the objectivity of the information promulgated in medical journals is high. A study published in the New England Journal of Medicine revealed that almost every investigator who supported the safety of calcium channel blockers had undisclosed financial ties with the drug manufacturers. And the problem is widespread. As an article published in the Los Angeles Times on 21 October 1999 reveals, of 36 review articles on drug treatments published in the New England Journal of Medicine in 1997, eight were written by investigators who had undisclosed financial ties with the manufacturers of the drugs presented in their articles. In addition, the newspaper discovered that the sole author of a 1998 review of treatments for breast cancer admitted to have been paid as a consultant by several manufacturers of drugs presented in his review only after the publication of his article.
Conflict of interest in the debate over calcium-channel antagonists.
Stelfox HT, et al.
N Engl J Med 1998 Jan 8;338(2):101-6.This study investigated the relationship between the pharmaceutical industry and the authors of 70 articles published in medical journals between March 1995 and September 1996 on calcium channel blockers. In 1995 a controversy arose on the safety of calcium channel blockers (CCBs). Some physicians and researchers were supportive of this class of drugs, some were neutral, and others were critical. The results of this study show that 96% of researchers and doctors who defended CCBs had financial ties with the drugs' manufacturers, as compared to 60% and 37% of those who were neutral and critical towards the drugs. Only 2 of the 70 articles revealed the authors' potential conflict of interest. Furthermore, 100% of supportive authors had financial relationships with the pharmaceutical industry, regardless of the product, compared to 67% and 43% of those who wrote neutral or critical articles. These data indicate that financial interest might have an important impact on the content of scientific articles.
Looking a gift horse in the mouth: corporate gifts supporting life sciences research.
Campbell EG, Louis KS, Blumenthal D.
JAMA 1998 Apr 1;279(13):995-9.In this study, 167 researchers from the top 50s research university in the U.S. were surveyed through a mailed questionnaire to determine the extent of academic-industry interaction in terms of physicians' gift receiving. Overall, 43% of researchers reported having received a gift from the industry in the 3 years before the survey. Gifts included biomaterials, research equipment, discretionary funds, trips to meetings and funds for students. Two thirds of the recipients reported that the gift was important or very important to their research. Over half of the recipients reported that the donors expected returns and placed restrictions over their work, including review of articles before publication and patent rights, that could pose a problem for the researcher and the institution.
Frequency and costs of diagnostic imaging in office practice--a comparison of self-referring and radiologist-referring physicians.
Hillman BJ, Joseph CA, Mabry MR, Sunshine JH, Kennedy SD, Noether M.
N Engl J Med 1990 Dec 6;323(23):1604-8.The results of this study indicate that physicians who perform imaging examinations in their own offices (self-referring) require significantly more imaging tests and charge significantly more for them, compared to those who refer their patients for testing to radiologists. The study was conducted on 6419 physicians and 65,517 outpatient visits for acute upper respiratory tract infections, low back pain, difficulty in urinating, and pregnancy. Every test evaluated in the study was required 4-4.5 times more frequently by the self-referring physician who used imaging equipments in their offices, compared to those who referred patients to outside radiologists. In addition, the self-referring physicians charged significantly more that the radiologists for the same tests. The authors estimated that, as a result of increased use of diagnostic equipments and higher charges, imaging costs of each visit are 4.4 to 7.5 times higher for patients visited by self-referring versus radiologist-referring physicians.
Physicians' utilization and charges for outpatient diagnostic imaging in a Medicare population.
Hillman BJ, et al.
JAMA 1992 Oct 21;268(15):2050-4.The results of this study show that physicians who utilize diagnostic imaging equipments in their own offices require significantly more tests and charge significantly more for them, compared to those who refer their patients to radiologists. In the study, evaluation of use of imaging tests for 10 common medical conditions revealed that physicians of all medical specialties who used equipment in their offices were 1.6 to 6.2 times more likely to require a test, compared to those who referred their patients to radiologists. Charges of self-referring physicians were significantly higher than those of radiologists.
Increased costs and rates of use in the California workers' compensation system as a result of self-referral by physicians.
Swedlow A, Johnson G, Smithline N, Milstein A.
N Engl J Med 1992 Nov 19;327(21):1502-6.The results of this study show that physicians who refer patients for tests and treatments to facilities that they co-own, require significantly more tests and charge more for them, compared to those who refer patients to independent facilities. Of note, the study showed that 38% of all MRI requested by self-referring physicians were medically inappropriate, and so were 28% of those requested by physicians who referred their patients to independent facilities.
Violations of the international code of marketing of breast milk substitutes: prevalence in four countries.
Taylor, A.
BMJ 1998;316:1117-1122 ( 11 April ).This study documented the extent of violation of the World Health Organization's code regulating the marketing of milk substitutes worldwide. Marketing efforts of milk substitutes' manufacturers have altered the perception of breast-feeding in women, and distribution of free samples of milk formulas and of advertisement material has resulted in a significant number of women opting for using commercial preparations rather than breast-feeding. This practice, however, is associated with significant harm, in that babies who have been bottle-fed have significantly higher rates of childhood diseases, impaired cognitive development, and higher risk of cardiovascular diseases in adulthood. The most devastating consequences of bottle-feeding occur in the developing countries, where neonates and infants are particularly at risk of infectious diseases. As reported in an editorial published in the same issue of the BMJ (BMJ 1998;316:1103-1104), the World Health Organization estimated that 1.5 million deaths could be prevented every year if women would breast-feed rather than bottle-feed their babies. To ensure protection of breast feeding the WHO developed a regulative code that prohibits the distribution of free samples of milk formulas to women or health facilities (except for professional research). In addition the code forbids the provision of incentives to health care workers, which has been shown to result in an increased likelihood of recipients promoting a particular product and showing lack of support toward breast-feeding. Several agencies have reported widespread violations of the code, but the companies have consistently rejected any allegation as unreliable and distorted by activists. This study monitored compliance to the WHO code by conducting a systematic, random survey of women and health care professionals in one city in each of Bangladesh, Poland, South Africa, and Thailand. Women were asked if they had been given free samples of milk substitutes, bottles and teats, while they were pregnant or in the 6 months after delivery. In addition, three health care workers in each facility were interviewed to assess whether the facility had received free samples of milk substitutes or gifts from companies manufacturing or distributing such products. The results of the survey showed that overall, 10% of all women (range 0-26%) and 25% of all health care facilities (range 8-50%) interviewed had been given free samples of milk, bottle, or teats for research purpose. Thirty percent of health facilities had received violating information and 11% of health care professionals had received gifts. These findings, which are likely underestimating the real dimension of the problem in the majority of countries, indicate that violation of the WHO code by manufacturers of breast milk substitutes is a frequent event. The consequences of these violations in terms of increased mortality and loss of health are staggering.
UNLICENSED AND OFF-LABEL DRUGS
Unlicensed and off label drug use in paediatric wards: prospective study.
Turner S, et al.
BMJ 1998;316:343-345 (31 January).The results of this study, conducted in a regional hospital in the U.K., show that 36% of hospitalized children receive drugs that are either not licensed for use in children, or that are off-label, i.e., given outside the conditions of the product license that regulates drug indications, age, dose, or route of administration.
Survey of unlicensed and off label drug use in paediatric wards in European countries.
Conroy S, et al.
BMJ 2000;320:79-82 ( 8 January ).The results of this study conducted in 5 European countries show that approximately half of the drugs administered to children aged 4 days to 16 years admitted to the hospital, are either unlicensed or off-label (given outside the terms of the product license). Overall, two thirds of hospitalized children receive at least one unlicensed or off label drug.
Unlicensed and off label drug use in neonates.
Conroy S, McIntyre J, Choonara I.
Arch Dis Child Fetal Neonatal Ed 1999 Mar;80(2):F142-4.The results of this study show that 90% of neonates in the intensive care units are prescribed an unlicensed or off-label drug. The extremely high prevalence of use of drugs that have not been tested on children or that are used for unapproved indications, and in doses, formulations, or route of administrations that do not meet the conditions of the product license is of extreme concern and the authors call for urgent action to halt the situation.
Adverse drug reactions in a paediatric intensive care unit.
Gill AM, Leach HJ, Hughes J, Barker C, Nunn AJ, Choonara I.
Acta Paediatr 1995 Apr;84(4):438-41.The results of this study indicate that 7% of children in pediatric intensive care units experience at least one adverse drug reaction (ADR). The study evaluated the rate of ADRs in 899 patients. Sixty-three children experienced 76 ADRs, which were of moderate severity in 19 cases, and severe in 8. A third of ADRs occurred for off-label drugs. Nurses and pharmacists reported most of the adverse events (63). Unfortunately, the prospective design of the study is likely underestimating the real extent of the problem.
Adverse drug reactions to unlicensed and off-label drugs on paediatric wards: a prospective study.
Turner S, et al.
Acta Paediatr 1999 Sep;88(9):965-8.The results of this study indicate that 11% of hospitalized children experience adverse drug reactions (ADRs). The study, conducted on 1046 children, shows that approximately 50% of them received one or more unlicensed or off-label drug. Unlicensed and off-label drugs were associated with higher rates of ADRs (6% of prescriptions), compared to licensed drugs (3.9% of prescriptions).
Off-label drug prescribing on a state university obstetric service.
Rayburn WF, Turnbull GL.
J Reprod Med 1995 Mar;40(3):186-8 .The results of this study show that pregnant women are often prescribed drugs in an off-label manner, i.e. for indications other than those approved in the product license. The study, conducted on 731 pregnant women, showed that 22.6% of them received a minimum of one off-label drug (average 1.7). In no occasion the chart of the patient contained records indicating that the woman was informed on the off-label use of the prescribed drug.
PUBLICATION BIAS AND QUALITY OF TRIALS
How important is publication bias? A synthesis of available data.
Dickersin K.
AIDS Educ Prev, 9(1 Suppl):15-21 1997 Feb.This article shows that the evidence of the effectiveness of a treatment is susceptible to significant bias due to the tendency on the part of investigators to publish studies based on the direction and the strength of the research results. Studies showing a negative or null effect of a treatment are significantly less likely to be reported than those that show a positive effect of treatment. Negative findings, however, are as important as positive ones in educating the public and the remaining scientific community on the effects of a treatment. The author emphasizes that failure to report research findings represents scientific misconduct.
The existence of publication bias and risk factors for its occurrence.
Dickersin K.
JAMA, 263(10):1385-9 1990 Mar 9.This article emphasizes how publication bias (the tendency on the part of investigators to publish the results of their study according to the direction or strength of the study findings) may affect the appropriateness of treatment decisions based on published literature. Meta-analyses, for example, evaluate the results of a number of similar studies to better determine the effect of a treatment. However, if the studies with negative or null results are not published, the resultant meta-analysis can be biased, and so can be treatment decisions based on their results.
Publication bias: evidence of delayed publication in a cohort study of clinical research projects.
Stern JM, Simes RJ.
BMJ, 315(7109):640-5 1997 Sep 13.The results of this study show that researchers are significantly more likely to report the results of studies showing a positive rather than a negative effect derived from treatment. Clinical trials with positive results are 3 times as likely to be published than trials with negative results. Furthermore, the publication of studies with negative results is significantly delayed, compared to that of studies with positive results. The average time of publication of studies with positive findings is 4.8 years, compared to 8 years for studies with negative findings. These results have important implications for the type of information that is available to the public and the research community.
Publication bias: the problem that won't go away.
Dickersin K, Min YI.
Ann N Y Acad Sci 1993 Dec 31;703:135-46; discussion 146-8.The results of this study show that randomized trials showing statistically significant treatment effects were 9 times as likely to be published than those with non-significant results.
NIH clinical trials and publication bias.
Dickersin K, Min YI.
Online J Curr Clin Trials 1993 Apr 28;Doc No 50.The results of this study show that clinical trials funded by the National Institute of Health showing significant results are 12 times more likely to be reported, compared to those showing non-significant results. The main reasons given by investigators for not reporting a trial were: results were "not interesting" and "did not have enough time".
Publication bias: the case for an international registry of clinical trials.
Simes RJ.
J Clin Oncol, 4(10):1529-41 1986 Oct.This study clearly illustrates some of the consequences of publication bias. Based on the analysis of published trials, combination chemotherapy was associated with a survival advantage over single agent chemotherapy in patients with advanced ovarian cancer. However, when unpublished registered trials were included in the analysis, the survival advantage disappeared. In patients with multiple myeloma, analysis of published trials showed that combination therapy was significantly superior to single agent chemotherapy plus prednisone. However, when all registered trials were included in the analysis, the magnitude of the benefits of combination therapy decreased substantially. This data emphasizes how important is that all information, including that with negative or null results, be readily made available.
Bias against negative studies in newspaper reports of medical research.
Koren G; Klein N.
JAMA, 266(13):1824-6 1991 Oct 2.This article emphasizes how newspapers report more frequently studies showing a positive effect of treatment than those that indicate negative or no effect.
A cohort study of summary reports of controlled trials.
Chalmers I, et al.
JAMA, 263(10):1401-5 1990 Mar 9.
This article emphasizes that a significant number of published clinical trials fail to report detailed information on the methods used to analyze and interpret the trial, thus making it impossible for other researchers to assess the validity of the results presented.
Analyzing the same data in two ways: a demonstration model to illustrate the reporting and misreporting of clinical trials.
Baar J, Tannock I.
J Clin Oncol, 7(7):969-78 1989 Jul.This article demonstrates the consequences of the application of different statistical methods to the interpretation of clinical trials. The authors designed an hypothetical clinical trial to evaluate the effectiveness of chemotherapy in patients with advanced cancer, and analyzed data from this imaginary trial with two different methods, one of low and the other of high quality. Each method of analysis led to opposite results. The type of errors that were inserted in the low-quality analysis were of the same type of those found in articles published in the Journal of Clinical Oncology and other leading cancer journals. These data emphasize the importance of fully disclosing the methodology used to analyze clinical trials, so that other investigators may determine the validity of the study results.
Design and interpretation of clinical trials that evaluate agents that may offer protection from the toxic effects of cancer chemotherapy.
Phillips KA, Tannock IF.
J Clin Oncol, 16(9):3179-90 1998 Sep.Randomized clinical trials have shown that some drugs can minimize the toxic effects of chemotherapy. This study investigated the methodology used in these trials. In several of them, the authors found evidence of errors in the selection of patients used as control in the study: control patients were exposed to higher doses of chemotherapy or were exposed to chemotherapy for prolonged periods of time, compared to patients receiving chemotherapy with the putative protective agent. The results of these trials, when re-interpreted, failed to show any advantage derived from use of protective agents, since the same effects were obtained by avoiding prolonged exposure to chemotherapy or by using standard doses of chemotherapy.
Systematic reviews and meta-analyses on treatment of asthma: critical evaluation
Jadad AR, et al.
BMJ 2000;320:537-540 ( 26 February ).The results of this study show that 92% (35 of 38) of reviews and meta-analyses that are published in peer-reviewed journals on asthma management have serious or extensive flaws. On the other hand, 7 of 12 reviews published by the Cochrane Collaboration, a recently emerged large international group that seems to publish systematic reviews and meta-analysis of better quality, were more rigorous and better reported than those published on peer-reviewed journals. All six reviews associated with industry and published on peer- reviewed journals were seriously flawed.
Empirical assessment of effect of publication bias on meta-analyses.
Sutton AJ, Duval SJ, Tweedie RL, Abrams KR, Jones DR.
BMJ 2000;320:1574-1577 ( 10 June ).The results of this study show that approximately 50% of meta-analyses from the Cochrane Database of Systematic Reviews contain publication bias, and these biases affect the studies' conclusions in about 10% of cases. In the study, of 48 meta-analyses analyzed, 26 (54%) were missing studies, and in 4 cases this bias altered the study' conclusions (3 positive significant results became non-significant, and one non-significant result became significantly negative). These data indicate that publication bias -the selective inclusion in studies of trials with strong positive results against those with negative results or with non-significant results- is a problem that is frequently encountered in meta-analysis, and that affects the validity of the research' conclusion in approximately 10% of cases. Of note, this study evaluated the presence of selection bias in meta-analyses of the Cochrane Library, whose quality has been demonstrated to be significantly superior to that of meta-analyses published in peer-reviewed journals (Jadad, AR et al. BMJ 2000;320:537-540 -26 February). It will be interesting to know the extent of publication biases found in meta-analysis from peer-reviewed journals and their supplements, and their impact on the studies' conclusions.
Methodology and overt and hidden bias in reports of 196 double-blind trials of nonsteroidal antiinflammatory drugs in rheumatoid arthritis.
Gotzsche PC.
Control Clin Trials 1989 Mar;10(1):31-56.This study evaluated the methodology used in196 double-blind trials testing the effects of different non-steroidal anti-inflammatory drugs (NSAIDs) in the treatment of rheumatoid arthritis. Only 93 trials (47%) reported statistically significant results. Of these, 73 favored only the new drug, and 8 only the control drug. The author of this article proposes different possible methodological and statistical bias as explanation of the large number of trials favoring the new drug. In 76% of the articles the authors' conclusions were doubtful or invalid. Eighty-one trials contained bias favoring the new drug, and only one trial contained bias favoring the control drug. The author questions the reliability of any meta-analysis conducted on these trials.
Statistical problems in the reporting of clinical trials. A survey of three medical journals.
Pocock SJ, Hughes MD, Lee RJ.
N Engl J Med 1987 Aug 13;317(7):426-32.In this article, 45 comparative studies extracted from the British Medical Journal, the Lancet, or the New England Journal of Medicine were evaluated to determine the accuracy of their data interpretation. Overall it was shown that results reported in the studies contained bias toward an exaggeration of treatment differences, and toward exaggerated emphasis of results of dubious significance.
Why review articles on the health effects of passive smoking reach different conclusions.
Barnes DE, Bero LA.
JAMA 1998 May 20;279(19):1566-70.The results of this article show that the conclusions of review articles written to elucidate the role of passive smoking on health are strongly influenced by whether the authors are affiliated or not with tobacco companies. The study evaluated 106 such reviews, and found that in 39 of them (37%) passive smoking was reported as not being associated with deleterious effects on health. Three-quarters of the articles concluding that passive smoking was not harmful were written by tobacco industry affiliates. Being affiliated with tobacco companies was associated with a 88-fold increased chance of the reviewers concluding that passive smoking is not harmful for the health. Only 23% of authors disclosed the sources of funding for research. These findings highlight that the conclusions of review articles can be strongly influenced by the affiliations of their authors, and raise the issue of whether those with potential conflict of interest should be writing such reviews at all.
Evaluating the quality of articles published in journal supplements compared with the quality of those published in the parent journal.
Rochon PA, Gurwitz JH, Cheung CM, Hayes JA, Chalmers TC.
JAMA 1994 Jul 13;272(2):108-13.The results of this study show that the quality scores of randomized controlled trials published in medical journals ranges from 4.2% to 87.5%, with an average score of 37.2%. Quality scores are significantly lower in articles published in supplement journals (33.6%) than in parent journals (38.5%). The authors point to the fact that during the review process, the same standards should be applied for papers submitted to supplement journals and parent journals. These findings also indicate that the overall quality of the studies published in medical journals is rather low.
High-dose chemotherapy for high-risk primary breast cancer
An on-site review of the Bezwoda study.
Weiss RB, et al.
Lancet 2000, 355: 999 - 1003.This article reports on the results of an on-site review of the clinical records of patients who participated in two studies, lead by a South African researcher, indicating that high-dose chemotherapy with stem cell rescue prolongs life in women with breast cancer. The validity of this technique has been debated for a long time. While uncontrolled trials showed increased survival rates in women treated with high-dose chemotherapy, every randomized trial failed to confirm these preliminary results, with the exception of two studies by Bezwoda and colleagues, demonstrating a clear survival benefit. Bezwoda's trial showed that 5 years after treatment, 25% of women who had received high-dose chemotherapy and bone marrow transplantation had relapsed, compared to 66% of those who had received conventional chemotherapy treatment. When U.S. investigators visited South Africa to review these results, they found several inconsistencies between the records and the published data, and uncovered the death of at least extra seven women, in addition to the reported eight. No records of signed informed consent or approval for the investigational therapy were found. The investigators discounted the results of the study due to non-compliance to standard research procedures, and Bezwoda admitted scientific misconduct.
PHYSICIANS INTERVENE TOO MUCH?
Doctors' strike in Israel may be good for health. News.
Judy Siegel-Itzkovich.
BMJ 2000;320:1561 ( 10 June ).This article reports on the sharp decline in mortality rates that occurred in Israel after physicians went on a strike to protest against the imposition of a new wage contract by the treasury. Elective surgical procedures, outpatient clinics and the Clalit HMO were hit by the strike, resulting in the cancellation of hundreds of thousands of visits and tens of thousands of surgeries. As assessed through figures provided by Jewish burial societies, rates of death significantly declined since the strike, and in May 2000 a famous Jerusalem burial society that covers 55% of all deaths in the Jerusalem area reported a 40% decrease in deaths, compared to May 1999. The manager of another burial society that covers most of the remaining Jerusalem area declared that the decline in death rates is connected to the strike, and that a similar reduction was also observed in 1983, when doctors went on a strike for four and a half months. Another city that was spared by the strike did not report any decline in death rates, making the connection between the strike and the reduction in mortality even stronger. These findings suggest that surgical procedures and drug treatments probably carry higher risks than what is commonly believed, as shown by the sharp reduction in death rates associated with the decline in number of non life-threatening surgeries and outpatient visits.
Primary Care Outcomes in Patients Treated by Nurse Practitioners or Physicians
A Randomized Trial.
Mundinger MO, et al.
JAMA 2000;283:59-68.The results of this study show that the quality of care offered by nurse practitioners is equivalent to that offered by physicians. The study evaluated the health outcome and the satisfaction in level of care in 1316 patients randomly assigned for care to a nurse practitioner or a physician. After a 6-month follow-up, no significant differences in the overall health status of the two groups were found. Patients with hypertension followed by nurse practitioners had significantly reduced diastolic blood pressure, compared to those followed by physicians. Satisfaction with quality of care was similar between the two groups.
DRUG COMPANIES FAIL TO COMPLY WITH FDA REQUIREMENTS
On Thursday, April 13, 2000, the consumer group Public Citizen wrote a letter to the FDA stating that drug companies are not complying with FDA's requirements of performing post-marketing studies. Normally, after a drug is released on the market, manufacturers are required to perform additional studies to monitor the efficacy of the drug and the potential occurrence of side effects that might have gone undetected during pre-licensure trials. But of the 88 such studies required by the FDA in the early 1990s, only 13% were completed, while none of the 107 studies that should have monitored the safety and efficacy of the drugs released between January 1995 and December 1999 were terminated. It is not uncommon for new adverse drug reactions to be discovered only after the drugs have hit the market, resulting in change of labeling or withdrawal of the drug, as it recently occurred with the diabetic drug Rezulin and the anti heartburn drug Propulsid, pulled from the market after over 140 deaths have been reported in users of the drugs. Dr. Sidney Wolfe, director of the Public Citizen's Health Research Group, reports that failure to perform post-marketing studies may result in lack of detection of adverse effects, and proposes that large fines be imposed to drug manufacturers that fail to comply with FDA's requirements.
Pharmaceutical advertisements in leading medical journals: experts' assessments.
Wilkes MS, Doblin BH, Shapiro MF.
Ann Intern Med 1992 Jun 1;116(11):912-9.
The results of this study show that the majority of drug advertisements that are printed in medical journals do not fulfill current FDA standards of quality. In the study, two physicians and a clinical pharmacist with pertinent expertise were asked to evaluate the overall quality of 109 individual full-page advertisements extracted from 10 medical journals. The reviewers felt that 40% of the ads did not report a balanced view of the benefits and complications of the treatment promoted. In approximately one-third of cases, the headlines were judged to be misleading in terms of efficacy of the product. In 30% of cases, reviewers disagreed with the manufacturers claims that the advertised product was the "drug of choice". Reviewers also affirmed that 44% of ads would lead to inappropriate prescribing if the physician would rely on the information they presented, and in 57% of cases they felt the advertisement had no or little educational value. Overall, reviewers estimated that 28% of ads were inappropriate for publishing, and 34% necessitated major changes before being considered for publication. This study shows that FDA standards of quality that regulate the publication of drug advertisements go often unmet, with potential risks to consumer's safety.
Doctors feel pressured by direct to consumer advertising.
Spurgeon, D.
BMJ 1999;319:1321 ( 20 November ).This article reports on the results of a survey conducted on 199 primary care U.S. physicians and presented at the annual meeting of the American Association of Pharmaceutical Scientists, revealing that doctors often give in to patients desire to receive a certain medication even if the drug they require is not the doctor' first choice.
The survey showed that every week, an average of 5 patients required a prescription for a specific drug to their physician. Patients' source of information came primarily from TV advertisements, followed by print advertisements, TV news stories and print news stories. Over 50% of doctors believed that the drug information reported by the manufacturers was only partially accurate, and 42% felt it was mostly accurate. In 30 to 36% of cases, doctors agreed to prescribe the drug, even though it did not represent their first choice. These data indicate that doctors often give in to patients request of drug prescriptions, even if the drugs are not the best choice for the patient. They also reveal another indirect way by which drug companies influence physicians prescribing practices.
During a congressional hearing held on February 2, 2000, in Washington, a very different picture on the safety of gene therapy trials emerged. While preliminary results of research trials usually highlight the potential benefits of newly developed gene therapy techniques, the risks associated with these experimental techniques are often downplayed. However, there is enough evidence demonstrating that these risks are substantial. After the death of the teenager Jesse Gelsinger from a systemic immune reaction to the adenovirus used as vector in a gene therapy trial, the National Institute of Health wrote a letter in October requiring all researchers involved in adenovirus-related experiments to report any adverse reaction associated with the vector. As a result, 652 reports of severe adverse events were submitted to the NIH. These adverse reactions occurred over a 7-year period and involved approximately 370 trials with adenovirus vectors. They raised to 752 the total toll of gene-therapy related complications, since the NIH already knew of 100 reactions occurring in 1999 alone. Furthermore, when the NIH, a month after its first letter, required immediate compliance to the new reporting rules, an additional 40 reports of adverse events for 1999 alone were notified. The omission of reporting of 692 severe adverse reactions occurring in trials using adenovirus-vectors to deliver specific genes raises important considerations on the integrity of the investigators involved in the trials, and on the NIH supervision system. In addition it highlights how precious information is withhold from patients enrolled in the trials, making them believe that the procedure carries minimal risks and great hopes. Jesse Gelsinger and his father, for example, were not told about previous cases of liver toxicity that occurred in an early phase of the trial, nor that two monkeys had died in previous experiments. The boy was not very sick when he was enrolled in the trial, but he nevertheless chose to participate because the treatment seemed to carry no particular risks.
On March 2, 2000 the FDA halted an experimental gene therapy trial that was testing the efficacy of a factor called Vascular Endothelial Growth Factor-2 (VEGF-2), produced by Vascular Genetics, in reversing the blockage of clogged arteries in patients with coronary artery disease. The order of suspension arrived after one of the leading investigators of the trial who is also a founder of Vascular Genetics, failed to report the death of 6 patients enrolled in the study.
On March 7, 2000, the FDA indefinitely halted all gene therapy trials conducted at the University of Pennsylvania's Institute for Human Gene Therapy, in Philadelphia, after it discovered several violations of the policies that regulate the use of investigational drugs in humans. This move came after the death, in January, of the 18-year old Jesse Gelsinger 4 days after he received an infusion containing the adenovirus-vector utilized in the gene-therapy protocol, and the subsequent discovery of several irregularities in the conduct of the researchers involved in the trial. Among the allegations presented by FDA officials that led to the indefinite suspension of the trials were: failure to immediately report the occurrence of adverse reactions, failure to submit results of animal tests indicating a significant risk for humans, and failure to update the informed consent forms to the standards required by the FDA after the death of Jesse Gelsinger.
On March 10, 2000, two gene therapy trials conducted on children with neuroblastoma, a type of malignant cancer derived from cells of the nervous system, were halted at the St. Jude Children's Research Hospital because the cell lines used in the protocol were not tested according to FDA's requirements.
On March 24, 2000, an article published in the Science magazine by Dr. Theodore Friedmann, director of the Program In Human Gene Therapy at the University of California in San Diego emphasized that patients who participate to human gene therapy trials are not fully informed of the potential risks of the experimental treatment and that too often investigators involved in the selection of patients have economic interests invested in the results of the studies. The author called for implementation of the policies that regulate gene therapy studies in humans and for the exclusion of researchers with potential conflict of interests from the direction of the trials.
On May 4, 2000, the FDA sent a warning letter to clinical investigator Dr. Jeffrey Isner, for failure to report the death of a patient enrolled in one of his gene therapy trials, occurring in June 1998. In addition, Dr. Isner was charged of having enrolled in the trial a patient who had been diagnosed with lung cancer, in spite of protocol requirements of exclusion of cancer patients. The cancer mass of the patient doubled in size in the 3 months after gene therapy, and this event was first reported in his medical records as a "severe" adverse reaction, and later downplayed as a "mild" adverse reaction. This is the fifth gene therapy trial conducted by Dr. Isner that was suspended during a 4 month-period. Dr. Isner is the cofounder of Vascular Genetics, Durham, North Carolina, and the company co-sponsored the trial together with the St. Elisabeth's Medical Center of Boston.
