Culture - The influence of the pharmaceutical industry on medical research & practice

[Paracelsus]

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Memorandum by Richard Horton (PI 108)

THE PHARMACEUTICAL INDUSTRY AND MEDICAL JOURNALS
The Lancet is a weekly general medical journal that publishes clinically oriented research about common diseases. A substantial part of the research that we publish concerns drugs manufactured by the pharmaceutical industry. Most of these research studies—notably, the gold standard means of assessing the efficacy and safety of a product, the randomised clinical trial—are paid for by the makers of the drug. There are many safeguards in place to protect the integrity of this research endeavour, from ethics committees to good clinical practice guidelines to journal peer-review systems. The standards set by the pharmaceutical industry in the conduct of clinical trial research are second to none. However, the extent of the commercial sponsorship of medical research and its intrusion into the academic sphere is one of the gravest threats to the independent evaluation of new medicines—indeed to the notion of an independent science base. Without greater scrutiny of the interaction between private and public sectors, the health of our population will continue to be put at risk by biased, over-interpreted, and misreported research findings. At present, our population is part of a largely unregulated experiment involving poorly investigated new medicines that have been licensed on the basis of insufficient data.

In my own very narrow area of interest—medical publication—I would draw attention to 10 especially damaging practices that distort the evidence base of medicine today.

1.Manipulation of research findings: In August, 2004, The Lancet published an important and rigorously conducted trial called ACTION, which was designed to investigate the effectiveness of a drug—nifedipine—in patients with heart disease. The results were presented at the European Society of Cardiology in Munich. The authors considered that the drug had "no effect" according to its predetermined criteria for judging effectiveness. The sponsor was Bayer. In the copious marketing material distributed to over 10,000 doctors in Munich, Bayer stressed that ACTION was "proving safety and improving outcomes...adding even more for hypertensive patients." The marketing claimed "primary endpoints significant in hypertensive patients", a total distortion of the actual result. Doctors were seriously and deliberately misled. This is not an uncommon practice.

2.Bias in sponsored studies: Research has demonstrated clearly that sponsored studies are more likely to produce a positive result for a company than an independent study of their product. The inherent biases in design, conduct, analysis, and reporting of research all reveal this pervasive undermining of scientific excellence. Examples include calcium channel blockers for heart disease and trials of drugs for myeloma.

3.Undisclosed adverse data: Research sponsored by industry is sometimes published at an early stage when there is a positive result for a new drug. But longer term follow up may yield an unwanted negative result. This finding may not be reported even when it is known at the time of publication of the early report. JAMA suffered a particularly egregious example of this deception. In another recent case, a journal was forced to reject a negative article after objections from its marketing department—an outrageous incursion into scientific integrity.

4.Hiding negative data: The classic recent example concerned Paxil (GlaxoSmithKline). The hidden trials showed a pattern suggesting limited efficacy of the drug and risks of potentially fatal adverse effects. The available published evidence indicated a very different story. Under severe reputational threat, GSK was forced to reveal these hidden results—leading to a $2.5 million US legal settlement and an unequivocal FDA warning about the risks of the drug. In response, the International Committee of Medical Journal Editors has called for all trials to be disclosed and registered at an early stage in their development.

5.Supplement publishing: Journal supplements often represent little more than information-laundering operations for industry. A company will sponsor a promotional meeting, pay a pharma communications company to convert the lectures of paid experts into articles, and then seek to publish these papers as a non or lightly peer-reviewed supplement to an established journal. The company will pay the publisher a large sum to secure publication, thereby buying, not earning, the imprint of the journal on its marketing-driven symposium. In one email that The Lancet has seen about a supplement, the sponsor argued that the more the article was peer reviewed the less value the supplement would be to the company—showing clearly the marketing goals rather than the scientific endeavour that lies behind supplement publishing. Multiple research studies confirm the scientific weaknesses of such supplements.

6.Undisclosed conflicts of interest: The escalating problem of industry payments to scientists—stock options, consultancy fees, research grants, staff costs, entertainment, conference fees, hospitality—has been recognised for several years. The International Committee of Medical Journal Editors (which includes the editors of the New England Journal of Medicine, JAMA, and The Lancet), has tried to force such competing interests into the open through tough disclosure requirements. But the continuing privatisation of much of science (science in the service of wealth creation rather than health improvement) threatens to make independent research almost impossible to do.

7.Editorial kick-backs: The Lancet has been offered substantial sums of money in exchange for publishing certain research studies. In all cases, we have declined such offers and these papers have been rejected. The mechanism of this intended exchange is commonly through the explicit promise by the company of a large order of commercial reprints in return for publication of a research paper. The impression left is that if editors reject the paper or try to alter its message, there will be an often major loss of income to the journal.

8.Ghost-writing: It is standard operating procedure for pharmaceutical companies to seed the medical literature with ghostwritten editorials, reviews, and opinion pieces emphasising off-label indications of licensed drugs. These papers are commissioned to a specific marketing-driven brief and are written by non-specialists. A company friendly expert is then paid to have his or her name appear on the article, facilitating publication in a respected journal and thus enhancing the impact of the message.

9.Continuing medical education: Industry is now a major sponsor of medical "education". As a former editor of the NEJM, Marcia Angell, has argued in her powerful book, The Truth About the Drug Companies, this leap into education is driven more by a desire to lever messages concerning prescribing opportunities than it is about truly educating doctors about the prevention and treatment of disease. She estimates that about 60% of CME in the US is paid for by industry.

10.Failure to align commercial with public interests: Pharmaceutical companies clearly have a legal requirement to earn as much return as they can for shareholders. But their untrammelled power in shaping the research priorities of medicine means that national and international gaps in knowledge remain unfilled—eg, concerning the relative efficacy and safety of one product versus another (the damaging dominance of placebo-controlled trials), drugs for neglected diseases, health systems or health services research, and in returning a fair proportion of profit back to the public sector where many of the scientific ideas fuelling drug development have originated.

It is perfectly true to say that industry plays a vital part in developing new medicines to ameliorate suffering and to cure disease. Modern medicine needs a dynamic, innovative, and robust pharmaceutical industry. But it is also the case that the for-profit motive of the pharmaceutical sector clashes with the public-health values of NHS clinical care and independent scientific research. The compromised integrity of medicine's knowledge base should be a serious concern to politicians and public alike. It is surprising and disappointing that this danger does not seem a serious priority within medicine itself.

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Memorandum by Professor Andrew Herxheimer (P165)

PERSONAL STATEMENT
I have taught clinical pharmacology and therapeutics at London University from 1960 to 1991, most recently at Charing Cross and Westminster Medical School. I founded Drug and Therapeutics Bulletin, published by Consumers' Association, in 1962 and edited it until 1992. I chaired the International Society of Drug Bulletins from its foundation in 1986 till 1996, and the Health Working Group of Consumers International. I have many times been a consultant to the World Health Organization. I am interested in all aspects of providing independent, unbiased, clear and concise information about therapeutic interventions to professionals and the public, and have long experience of observing the pharmaceutical industry at work.

Since 1992 I have worked in the Cochrane Collaboration and am now Emeritus Fellow of the UK Cochrane Centre in Oxford.

If the Committee wishes, I would be willing to give oral evidence.

THIS MEMORANDUM FOCUSES ON THE FOLLOWING MAIN ISSUES, THE FIRST THREE OF WHICH CONTRIBUTE SUBSTANTIALLY TO A SYSTEMATIC OVER-ESTIMATION OF DRUG BENEFIT AND UNDERESTIMATION OF HARM
1. The influence of the industry on medical practice and on the regulation of medicines is pervasive, overwhelming and relentless. The problem of undue and unhelpful influence is, arguably, related much more to the extent and volume of industry influence, rather than to outright malpractice.

2. The industry takes little pro-active interest in adverse effects of drugs; only legal or commercial concerns move it to do more than the regulators require. The drug regulatory framework encourages this complacency by relying excessively on pre-marketing clinical trials in defining drug safety profiles.

3. The nature and extent of drug marketing is worrying, not least because of the intensity of promotion at and soon after a drug is launched—ie when relatively little is known about the performance of a drug in clinical practice. A conspicuous example of the negative impact of drug marketing relates to recommended drug dosage, which is often inappropriately uniform. It is not true that one size fits all, as marketing often demands; industry and the regulators need to take much more account of important differences among users.

4. What might be the most effective ways of containing undue industry influence in the future?

1. THE INDUSTRY'S INFLUENCE
The development of drug regulation in the UK that followed the thalidomide disaster has been described in detail by John Abraham (1995). From the beginning in 1962, when Lord Cohen's Committee reported on the testing and regulation of new drugs, the industry has greatly influenced what was to be done. Close collaboration between industry, ministers and civil servants on the principles and details of regulatory policies has continued, albeit with a marked shift towards international regulation since the 1990s.[15] During all this time the Ministry of Health and its successors, the DHSS and the DoH have been the sponsoring Department for the pharmaceutical industry, responsible for its welfare—while also of course being its biggest customer. The industry's exports were then and still remain important to the national economy, and might be threatened by strict regulation.

Government and industry have strived for and largely achieved a family atmosphere of cooperation and trust—hardly dimmed by some adversarial episodes—and reinforced by the blanket secrecy guaranteed by s 118 of the Medicines Act, 1968. Over the years many personal relationships have grown between regulatory officials and the staff of pharmaceutical companies, helped by a "revolving door" and frequent meetings to address regulatory matters. The argument has been that experience of working in the industry is highly desirable, if not essential, to understanding the practical implications of regulatory issues. Similarly comfortable contacts have existed between many of the members of the Committee on Safety of Medicines and industry, and this continues.

These close working relationships over decades have meant that industry views have been much more prominently represented—and to a notable extent internalised—in drug regulation than the interests of patients and consumers, or of clinicians.

The influence of the industry on medical practice is enormous, but largely intangible and unseen. It is mediated by its internationally and nationally dominant position in determining the agendas of therapeutic research and providing funding for it, by the huge volume of pharmaceutical promotion, direct and indirect (including its scientific publication policies and its selective support of continuing medical education), and intense public relations activity. Competition in the industry is based far more on innovative marketing methods and public relations than on the effectiveness and safety of its products.

The industry tries its considerable best to control information about its products and its work. It naturally wishes to guard all unfavourable information, claiming commercial and proprietorial rights, and ceaselessly pushes the positive aspects at all its target constituencies—prescribers, patients, consumers, health service managers, politicians. This is called "Providing information".

One seriously harmful result of these frenetic activities, which governments have ignored, is that drug treatments are uppermost in the minds of doctors and the public, and non-drug treatments (including non-intervention) are very often not adequately considered. There is much less money to promote these.

Recommendations

1.1 The sponsoring Department for the pharmaceutical industry should be the Department of Trade and Industry instead of the Department of Health. Similarly, responsibility for regulation of the pharmaceutical industry in Europe should rest primarily with the Directorate-General for Health and Consumer Protection, rather than the Commission's departments for Enterprise and Trade.

1.2 Policies should be developed for reducing the potential for conflicts of interest in medicines regulation, including complete transparency about the conflicts that may exist.

1.3 The NHS, which pays for the promotion of medicines as an important part of their cost, should thoroughly investigate the health impacts of promotion, including the benefits and harms of various forms of medicalisation of common problems, and of disease awareness campaigns aimed at the public. It would be logical to fund such research through a small levy on promotional spending by companies.

1.4 If self-regulation of pharmaceutical promotion by the industry is to continue, independently chosen representatives of the public interest should play a substantial if not dominant part in it.

2. ADVERSE EFFECTS OF DRUGS
All medicines have unwanted effects, which prescribers and users must understand and be able to manage. They need to know what may happen and what to do if it does. They have to use the drug in ways that minimise the chance of unwanted effects and their intensity.

The task of medicines regulation is to assure their "safety, quality and efficacy". This work is done mainly before products are licensed. The regulators have to satisfy themselves about these before approving a product, and for this purpose require detailed data from the company, including "safety data" from studies of pharmacology and toxicology in animals, studies in healthy volunteers and in patients. These studies are primarily intended to demonstrate the harmlessness ("safety") of the drug. Companies themselves undertake and commission the large amount of work needed to meet all the regulators' requirements. They do not usually investigate how various adverse effects are produced.

After a licence has been issued and the product marketed the Post-Licensing Division of the MHRA is in charge of continuing surveillance of safety; companies must report to the MHRA all adverse events they become aware of. This is the mainstay of what is called pharmacovigilance, but the scope of pharmacovigilance is, in practice, quite limited. Lack of transparency has proved an obstacle to assessing its quality and impact overall, though there are obvious grounds for concern (Medawar & Herxheimer, 2003). Companies rarely do more research on safety aspects unless they need to defend the product when a serious adverse effect is alleged or suspected, or to show that it is safer than a competing product. The design of studies performed in these circumstances is liable to be much influenced by legal and commercial considerations.

It is unusual for regulators to require (as opposed to request) companies to do further studies of adverse effects on a licensed product; they may not have the power to do so, nor can they check that such studies are adequately designed and performed. It is no-one's job to undertake or to fund such work. What little work is done tends to be done by interested independent researchers without specific funding.

Since the Inquiry focuses on the impact of the industry on the regulatory review of drug safety and efficacy, it may be necessary to discuss some aspects of pharmacovigilance in detail, and I have therefore tried to put these briefly into context in Appendix A.


Recommendations

2.1 Research on the natural history, mechanisms, prevention and clinical management of adverse drug reactions (ADRs) should be encouraged and publicly funded. It should be independent of industry and of drug regulatory agencies. Consideration might be given to organising the funding of such work through a modest levy on pharmaceutical sales.

2.2 Adverse drug reactions represent only one (the most visible) aspect of the ill-effects of drugs on health. The impact of drug use on communities, including the medicalisation of personal problems and the drawbacks of "disease awareness" promotion need also to be addressed.

3. DOSES
The doses to be recommended for new drugs are decided by the manufacturers, on the basis of their experimental dose-ranging studies in healthy volunteers and patients. These studies are submitted as part of the licensing application, but few are published. Many recommended drug doses are higher than is medically necessary, for two reasons (Herxheimer 1991; Cohen 2001).

The first is that manufacturers aim for a dose that will be effective in the great majority of people given it. A simple dosage scheme, one-size-fits-all, appeals to prescribers and so helps market penetration. Complicated dosage regimens tend to inconvenience doctors and to create practical difficulties for many patients. Also, doctors and patients will not wish to use the drug if it is ineffective in a substantial proportion of people. So drugs are typically introduced at a dose that will be effective in the highest proportion of the target population. But patients vary quite widely in their sensitivity to various drugs, and the standard "recommended" dose is too high for many, causing unwanted effects that range from transient unpleasantness and inconvenience to serious harm, while a lower dose would have been effective and much less likely to cause trouble.

The second reason for doses being higher than necessary or desirable is that manufacturers prefer doses rounded up to "convenient" numbers, especially those ending with the digits 1, 2, 5, and 0. The dose excess due to such digit preference may be as much as 70% of the correct dose and on average is probably 25% (Herxheimer 1991).

Drug regulators have traditionally paid little attention to dose and generally accept the doses proposed when drugs are first marketed. One reason for this may be that all the clinical trials that prove the drug's effectiveness have been performed at those doses: to require new trials at lower doses would cause long delays and high costs, which would be hard to justify. About one in six drugs have had dosage recommendations modified (generally downwards) at some time after licensing.

Recommendations

3.1 Companies should be required to submit evidence on the lowest effective dose for all drugs for any significant minority of users, and regulators should require that this dosage will be in the range of doses to be marketed.

3.2 Companies should be required to submit, and after licensing to publish, dose-effect data for all the intended beneficial effects, and the most important unwanted effects of the drug.

4. What might be the most effective ways of containing undue industry influence in the future?

Many factors complicate the Health Committee's task in assessing the impact of the pharmaceutical industry's influence, and addressing the problems it creates. The major factors include: the extent of acceptance and complicity among other stakeholders; the increasingly international character of the pharmaceutical industry; the introduction of supranational regulatory mechanisms and standards; and the traditional and pervasive secrecy in this field, in particular relating to drug risks and harms.

The options available for proposing reform seem limited, other than in relation to the last of these factors. Transparency seems all the more critical because of the rapidly waning influence of national authority in drug control. I believe there would be overwhelming support from all concerned about the adverse impacts of industry influence, for recommendations from the Committee that might lead to greater transparency in this field. Freedom of information—including freedom of expression and protection for whistle-blowers—is a prerequisite to the planning and implementation of reform. Without this it is unrealistic to suppose that pernicious influence can be contained. In the absence of transparency, it would seem much more likely to grow.

References

Abraham J. Science, politics and the pharmaceutical industry (esp. Chapter 2). London: UCL Press, 1995.

Cohen, Jay. Overdose: the case against the drug companies. New York: Tarcher/Putnam 2001.

Herxheimer A. How much drug in the tablet? Lancet 1991; 337: 346-8.

Medawar C, Herxheimer A.Risk of suicidality and dependence with Paroxetine: Comparing Yellow Card reports of suspected adverse drug reactions with reports from users. Int. J. Risk & Safety in Medicine 2003; 16: 3-17.