The United States is more open about its scandals than other countries, but the little we know confirms US experiences. When a scientist at the German drug agency called for deregistration of a dangerous antibiotic, which had been taken off the market in most other countries, his career came to a stop. The director of the agency, Karl Überla, whom he later described as corrupt, moved him into a post where he was supposed to take care of ‘research that didn’t exist’.40 The antibiotic was marketed by the German firm Hoechst, and Überla, who had previously lobbied for the US tobacco industry, accepted favours from Hoechst.
The multitude of regulatory decisions provide many opportunities for buying off regulators. In some Asian countries, drug registration can be secured for small amounts of money.8
In Chapter 17, I shall describe how the antidepressant Prozac was approved in Sweden through bribery.
The unbearable lightness of politicians
The drug industry also does what it can to corrupt politicians. In the United States, the drug industry contributes generously to election campaigns and there is more than one lobbyist for each member of Congress, which makes it the strongest lobby in Washington.41,42 The drug industry also contributes handsomely to political campaigns, and most of the money go to the Republicans.41 Between 1998 and 2006, the industry spent $1.2 billion on lobbying and political contributions,43 and in 1994, the Republicans attempted to eliminate the FDA altogether and let the drug industry regulate itself!33
Lobbying is also strong in Brussels, which until 201044 had resulted in extreme secrecy in European drug regulation.45,46 The lobbying has been so successful that FDA executives now see the industry, and not the American people, as their clients1,2,15 and even negotiate with industry about performance goals.22 Politicians have consistently pushed the FDA in this direction, e.g. in the 1990s, President Clinton urged FDA leaders to trust industry as ‘partners, not adversaries’.15
In 2002, the nomination of a new FDA commissioner, Alastair Wood, was withdrawn in the last minute, and a senator said that Wood put too much emphasis on drug safety.2,47 Fair enough. It surely must be a mortal sin to be interested in drug safety when offered the highest position in America’s drug regulatory agency. Wood was replaced by Mark McClellan who echoed the outrageously false claim from industry that the high drug prices are a consequence of the high development costs (see Chapter 20),2,48 and he also argued against price controls.2,49 The title of an article in the Boston Globe didn’t leave any doubt about what had happened: ‘Drug industry costs doctor top FDA post’.47 The industry had demonstrated its omnipotence again.
As this example illustrates, political interference with FDA matters contributes to what has been described as the moral decline of the work in the agency. In Europe, politicians in the Danish Parliament and in the EU Parliament have vividly explained to me how they are constantly being haunted by representatives from big pharma. The industry pushes the politicians through lobbying, donations and sometimes outright bribery – which I have also been informed about – into introducing new laws that sacrifice public health for profits. Taxpayers don’t write the tax laws, but in considerable measure drug companies write the drug regulations.8
In the United States, the politicians have demanded shorter turnaround times, which have resulted in more superficial evaluations of the safety of drugs, also for marketed drugs, as those working with drug safety have become more and more understaffed. The focus is on getting drugs approved quickly, thereby boosting the national economy through exports.15,25 These influences have caused a marked deterioration in drug regulation. Only 1.6% of drugs approved in 1993–96 were later withdrawn from the market because of serious harms, which increased to 5.3% of drugs approved in 1997–2000.25,26 Furthermore, drugs approved just before the official deadline – which the politicians had pushed the FDA into accepting although it is way too short for a careful assessment of most drugs – were double as likely to be withdrawn from the market than drugs that, despite the intentions, didn’t make it in time and were approved after the deadline.50,51
Adverse drug event reporting to the FDA shows the same decline in safety of drugs. From 1998 through 2005, reported serious adverse drug events increased 2.6-fold and fatal adverse drug events increased 2.7-fold, and reported serious events increased 4 times faster than the total number of outpatient prescriptions.52 There was a disproportionate contribution of pain medications and drugs that modify the immune system, but there was also a substantial increase for other drugs.
Other data confirm the untoward consequences of the FDA’s increasing focus on speed rather than on safety.15 In 1988, only 4% of new drugs introduced into the world market were approved first by the FDA; 10 years later, it was 66%. By the end of the 1990s, the FDA was approving more than 80% of the industry’s applications for new products, compared with 60% at the beginning of the decade. The FDA, once the world’s unrivalled safety leader, was the last to withdraw several new drugs in the late 1990s that were banned by health authorities in Europe.
In Canada, it’s similarly bad.53 The probability of a new active substance approved between 1995 and 2010 acquiring a serious safety issue after approval was 24%, and for accelerated priority reviews of drugs that were not even major therapeutic advances, the rate was 36%.
This demise of the FDA started in 1992 with the Prescription Drug User Fee Act, after which the companies paid the FDA for its services.54 For the first 10 years, Congress prohibited the FDA from applying user fees to evaluate drug safety after approval.55 The FDA demoralised the Office of Drug Safety by pulling scientists from it, shortened review times, approved drugs based solely on their effect on a surrogate outcome (see what the problem with this is below), and broadened its interpretation of potentially life-saving drugs, which were approved under expedited programmes.14,54 These medicines now included drugs for common chronic conditions, although it is hard to believe that any of the drugs could be life-saving. Further, several of them were later withdrawn for safety reasons, such as troglitazone (Rezulin) for diabetes, dexfenfluramine (Redux), for obesity and rofecoxib (Vioxx) for pain. This looks scandalous to me. I have never heard of slimming pills or pain pills that were life-saving, but I have heard of many that were deadly and I shall say more about these drugs later.
Understandably, the morale of FDA scientists is low, which is very sad. Few jobs are more important than being a scientist at a drug agency. Their responsibility is huge, as a misjudgement can sometimes result in thousands of deaths among rather healthy citizens. They should therefore be exceptionally well paid and effectively protected from any improper influence from their bosses, the politicians, and the drug industry and its patient pressure groups, and they should be allowed the time they need to review the applications carefully and to ask uncomfortable questions. All of this is so far from reality that it seems almost a joke to suggest it, but in 2007 four previous FDA commissioners agreed that the agency should be funded through the Treasury rather than industry payments.54 Nothing changed, however. Governments argue they cannot find the money, but it’s wrong. The user fee system leads to approval of far too many highly expensive drugs that have nothing to offer, which carry a much larger burden on the public purse than if drug agencies were allowed to do a more thorough job without having to please the industry. Furthermore, the money could be provided by a minute tax on prescriptions; as little as 0.5% would suffice.
Politicians interfere directly with FDA decision making although this is equally unacceptable as if politicians interfered with a judge’s verdict. A poll showed that 61% of FDA scientists were aware of such political interference.21 An example was mentioned in a 2009 FDA report that said that four congressmen and the FDA’s former commissioner, Andrew von Eschenbach, had unduly influenced the process that led to approval of a malfunctioning patch for injured knees. It occurred despite the fact that the agency’s scientific advisers repeatedly and unanimously over many years had deemed the device unsafe because it often failed, forcing
the patients to get another operation.56 The FDA report talked about extreme, unusual and persistent pressure, which started shortly after the congressmen had received campaign contributions by the manufacturer, but as always, the accused said they weren’t influenced by the money. An FDA manager said that Eschenbach not only demanded an expedited process but also a favourable outcome. Less than a year after the device was approved, the FDA stated it would revisit its decision.
Patient safety is particularly poor for medical devices. Cardiovascular devices are far more risky than a knee patch and therefore subjected to the most stringent type of assessment. Even so, the requirements are minimal although they should be higher for cardiovascular devices than for drugs, as devices are implanted and cannot be removed as a drug can.57 A review of 78 applications for cardiovascular devices that received premarket FDA approval showed that only 27% of studies were randomised, 65% of the applications were based on just one study, and in 31%, the control group was retrospective, which is an extremely poor study design that almost always puts the new intervention in a good light.57 Adding insult to injury, the US Supreme Court has decided that patients harmed by an FDA-approved device cannot sue the company!
Transcatheter aortic valve implantation (TAVI) offered hope to patients too old or too ill for conventional aortic valve replacement operations, and since its introduction, 40 000 implantations have been done.58 However, it is very costly, and its effect was thrown into doubt by a follow-up study authorised by the FDA, in which more patients died when given TAVI instead of standard therapy. This trial remains unpublished, and when independent researchers asked for access, they were rebuffed by the FDA and the study sponsor.
This complete lack of respect for the patients – some of whom died because they were treated with an inferior device – is unbelievable. Unfortunately, there is little hope that the politicians will help us create a better system. After the British House of Commons Health Committee had examined the drug industry in detail in 2004–2005,17 the members of Parliament felt that the drug agency wasn’t competent to undertake its duties as a guardian of public health, but the government declined a public hearing and also a recommendation that a drug should not be launched until full clinical trial data were put on a public register.59 The excuse for not demanding access to the trial data – that this would require a change in EU regulations – was a red herring. We can decide not to buy or reimburse new drugs until the clinical data have been made available. That would save us a lot of money. What is available in the published literature in the years immediately following approval of new molecular entities is a heavily biased selection of all the results that are available at drug agencies.60
Also in the EU, industry lobbying leads to curious proposals that are not in the patients’ interest. In 2007, the European Commission published a tragicomic document called Strategy to Better Protect Public Health.61 The Commission proposed to delete the clause that marketing authorisation for a drug shall be refused if its therapeutic efficacy is insufficiently substantiated by the applicant! How it might better protect public health to allow ineffective drugs onto the market is hard to explain. Health Action International (HAI) Europe, a large consumer organisation, protested against this and many other harmful proposals, e.g. to bring new medicines to the market faster to provide faster return on investments, which would be obtained by making conditional authorisations the norm rather than awarding them only in exceptional circumstances, when there is an urgent therapeutic need.62 The EU document is horrific, as it goes on and on, undermining patient safety. For example, the proposal that the companies should be entrusted with the task of gathering and analysing data, issuing warnings and informing of their products’ adverse effects after marketing approval is a recipe for public health disasters. The Commission’s proposals provided for the industry’s intervention at every level of decision making, putting them in the position of both judge and defendant. HAI noted that the companies’ pharmacovigilance systems cannot under any circumstances become a substitute for national public pharmacovigilance systems, which unequivocally serve the public interest.
The Commission also proposed that for post-authorisation studies, it should be up to the firms to: ‘consider whether the results of the study impact on the product labelling’ or ‘might influence the risk-benefit balance of the medicinal product’. It’s unbelievable that politicians can be so far away from reality and cool facts. My whole book is about patients being harmed tremendously because we allow the industry to be its own judges. HAI Europe strongly condemned the Commission’s proposals and called on it to refocus its efforts and defend the public interest, in accordance with its remit to protect European citizens that follows from Article 125 of the Treaty establishing the European Community. It’s so depressing that a consumer group needs to say the obvious. It cannot be repeated too often that – even without such foolish initiatives – in the United States and Europe, drugs are the third leading cause of death after heart disease and cancer (see Chapter 21).
Another example of how damaging ignorant and ideologically driven politicians can be for public health is related to the Danish system for handling alleged cases of scientific misconduct. We had one of the oldest and best systems in the world. However, in 2005, the Danish Minister of Science, Helge Sander, who knew nothing about science but introduced professional football in Denmark, decided that the misconduct committee from now on could only handle alleged cases of misconduct for private researchers and companies if these people accepted an investigation, whereas publicly employed researchers could still be investigated whether they liked it or not.63 There was a storm of protests from all corners of society, even from Novo Nordisk whose spokesperson said that whether research was private or public, it should be done properly. The minister’s comment? Research in the Danish drug industry should not be controlled by civil servants. All hell broke loose after this stupid remark. The minister’s next comment? No comment.
Novo Nordisk was right, but the Danish Association of the Pharmaceutical Industry used the opportunity for a most shameless response. They said they were tired of doctors who accused its members in the press for skewing their research results.64 (These ‘doctors’ were more or less one person: me!) The Association stated that it was completely wrong that its members skewed its results and added that publication of its research was the responsibility of the doctors. The Association was willing to let its members be subjected to investigations provided that the committee would agree to investigate possible scientific misconduct for those doctors who criticised trials that named companies had performed. I have rarely seen anything so shameless and appalling. Companies routinely manipulate the data they publish, so every time a doctor criticised this, whether in the press or in a letter to the editor of the journal where the research was published, the doctor should be referred to the committee for scientific dishonesty for investigation. This is like in the Soviet Union where people criticising those at power were subjected to psychiatric examinations and sometimes incarcerated for life, if they weren’t just murdered right away.
It’s detrimental to public health that the politicians have allowed direct-to-consumer advertising in the United States. When drugs switch from prescription status to over-the-counter status, the information about their harms and contraindications may disappear.65 Such a lack of balanced information is harmful for our citizens who are already overdosed, also in countries that don’t allow this additional assault on the good health most of us have, after all.
It is nauseating to see US TV commercials, which are delivered in a soft female tone like when stewardesses on an airplane express their hope that you will choose their airline again, or in a deep masculine voice aimed at instilling confidence. These commercials invariably end with something like, ‘Ask your doctor whether Lyrica is right for you.’ They can also end with, ‘You might have a disease you don’t know about.’ I agree, I surely have cancer, as cancer can be demonstrated in all of us who are above 50
, if only we are investigated thoroughly enough.66,67 But I prefer not to know, as I don’t have a ‘disease’ and treatment of these pseudocancers isn’t harmless.
Celebrity advertising is extensively used in the United States, e.g. in TV news and talk shows where the industry sponsorship isn’t revealed so that the testimony appears genuine.41 In Denmark, we don’t have this, but in 2004, we nevertheless experienced a curious case of celebrity advertising, imported directly from the highest circles in the United States.68 Merck was unhappy that its drug against osteoporosis, alendronate (Fosamax), hadn’t achieved maximum reimbursement, and it dragged the Danish government into court. It also arranged a meeting between our Minister of Health and the former US Secretary of State, Madeleine Albright, under the pretence that they should discuss the Danish healthcare and reimbursement system. Two days before the meeting, she asked whether she could also bring the director of Merck Denmark, which was accepted. However, during the meeting, which our minister couldn’t attend, Albright mentioned the drug she took against osteoporosis. She didn’t win many friends on this stunt, which is not how we behave in Denmark, and the embarrassment we felt was exposed in a newspaper: ‘Drug giant uses American pressure in Danish drug case.’68
Occasionally, we do see a little progress. Until recently, the European Medicines Agency was part of the Directorate General for Enterprise and Industry in the EU,46 but it has now been moved into the Directorate General for Health & Consumers. And in 2007, new legislation gave the FDA more power to react.69 However, we also see developments for the worse. In 2012, the US Senate proposed a further expansion of expedited review, with a new category for ‘breakthrough drugs’.70
Deadly Medicines and Organised Crime Page 21
