Deadly Medicines and Organised Crime

by Peter Gotzsche

  Conflicts of interest at drug agencies

  There are pervasive financial conflicts of interest in drug regulation,1,2 and regulators may go back and forth between the industry and drug agencies, the ‘revolving door’ phenomenon. FDA commissioner Lester Crawford left the agency after the Vioxx scandal (see Chapter 13).3 Crawford approved Vioxx, a Merck drug, and after resigning he became senior council for Merck’s PR firm, Policy Directions Inc.4 Crawford later received a fine of $90 000 for falsely reporting he had sold stock in companies regulated by the FDA while he still owned the shares.5 These companies included Pepsico, which sells soft drinks and junk food that make people obese, and at the same time, Crawford was head of FDA’s obesity working group.6

  Eyebrows were also raised in Denmark when the drug regulator who helped Nycomed get approval for a slimming pill, Letigen (which means ‘light again’), went directly to a senior post in the company that was going to market the drug. Letigen was a bad drug. It contained ephedrine, and was later taken off the market because of its cardiovascular harms.

  Members of advisory committees at drug agencies also contribute to the corruption of scientific integrity. Some of them work for both sides and extort the drug companies by commanding unusually high consulting fees from them, which are difficult to decline if the companies want to have their drugs approved.2 Obviously, people who are paid by the industry to be its voice at committee meetings cannot possibly be advocates also for their patients, which means that their role as ‘independent experts’ doesn’t exist.

  Drug agencies don’t live up to laws about impartiality in public administration, although this would seem easy to do. In Denmark, for example, an expert isn’t allowed to give advice on matters where the expert has a conflict of interest that could influence the advice, if it’s possible to get qualified advice from an expert without conflicts. Some years ago, there was uproar in the press when the Danish drug agency had employed psychiatrist Bente Glenthøj in its registration committee, which not only gives advice but make decisions about approval of new drugs.7 She had many conflicts of interest in relation to drug companies, but couldn’t see this was a problem. That’s how virtually everyone in the world evaluates their financial conflict of interest: no problem.

  The drug agency defended itself by saying it wasn’t possible to get the expertise it needed unless it accepted conflicted people. That argument was impossible to swallow. In 2011, there were 1201 registered psychiatrists in Denmark, and only 92 of these (8%) had permission to work for a drug company. The drug agency wanted us to believe that none of the remaining 1109 psychiatrists were qualified. Nonetheless, the Ministry of Health granted her an exemption from the law provided she didn’t participate in cases where doubt could be raised about her impartiality. Now wait a minute. If she couldn’t deal with cases where she was an expert, in psychiatry, there was no argument for retaining her at the agency. But of course nothing was done. The fake fix was in place.

  The Danish case is typical. What drug agencies do all over the world is not to avoid using conflicted experts but to ask them to declare their conflicts of interest. Excuse me for the comparison, but I think it’s relevant: what would your confidence in the police force be if police detectives routinely invited criminals to participate in their work, after the criminals had declared that their conflict of interest was that they hoped the case would never be resolved (because some of their friends had committed the crime)?

  Scientists at drug agencies are not only up against a powerful industry, they are also often up against their own superiors and their advisory committees who may have less than ideal motives for their decisions. The bosses often look the other way because they depend on licensing fees and political goodwill, and because questions about harms lead to trouble. A culture develops where many decisions are made that ordinary citizens would not have agreed with if they had been represented in the drug advisory committees.

  This is called regulatory capture. The regulators come to work so closely with the industry it regulates that it’s inevitable that friendships develop and that they acquire a greater understanding for the industry’s problems and positions than those of the patients who are anonymous. The industry is no longer effectively regulated and agencies indulge in protracted and amicable negotiations with the industry instead of acting when there is a public health danger.1,3 This explains why the culture within the FDA has been described as one of intimidation and fear and as overly industry-friendly.1,2,8,9,10,11,12 The general public is viewed as a hysterical and irrational mob who should be protected from any suggestion of product hazards.8 However, it’s curious that citizens participate in town planning in a democratic fashion, whereas they are not supposed to know anything about what goes on in drug agencies.

  In 2006, the Institute of Medicine wrote a critical report and suggested radical changes,13 but the response from the FDA was inadequate and demonstrated an almost total lack of understanding of the magnitude of the changes required to create a culture of safety.14 When FDA scientists find signs of serious harms, they are often overruled and intimidated by their superiors – even to the point of being prevented from presenting their findings of lethal harms of drugs at advisory meetings – or are assigned to another job.1,8,9,10,15 It doesn’t even stop there. As described in Chapter 3, the FDA has accepted safety data it knew were fraudulent,12 and – on many occasions – data that clearly showed the drug was not safe.16

  If we look at what happens after approval, it doesn’t exactly warrant blind trust in drug agencies either. They are much too slow to react to reports of lethal harms of drugs, if they react at all.1,9,12,15,17,18,19 One reason is that, most unfortunately, drug regulation doesn’t build on a precautionary principle but on a permissive principle where the benefit of doubt is consistently awarded to the drug industry and not the patients. For example, FDA approved Vioxx because it lacked ‘complete certainty’ that the drug increased cardiovascular risk,9 although this was expected based on the drug’s mode of action (see Chapter 13). Another reason is about saving face. Warnings about a drug, or its withdrawal from the market, suggest that the agency failed when it approved it.20

  It is really scaring that a survey showed that 70% of FDA scientists are not confident that products approved by the FDA are safe.9,21 And that 66% lack confidence in the FDA’s safety monitoring of marketed drugs.22 The citizens have a similar view. In a public poll, 76% worried that the FDA didn’t communicate safety issues effectively.23

  These concerns are supported by facts. No less than 51% of drugs have label changes because of major safety issues discovered after marketing; 20% of drugs get new black box warnings; and more than 1 in 20 are withdrawn from the market.24,25,26

  It’s actually much worse than this. Post-marketing studies are few and generally of poor quality, and spontaneous reports of harms are a hugely inadequate method to detect even serious harms. There can therefore be no doubt that many of our drugs are dangerous, but the problem is we don’t know which ones. Associate Director David Graham, who has spent 40 years working for the FDA’s Office of Drug Safety, has illustrated the regulatory impotence with excruciating sharpness:9

  ‘The way FDA approaches safety is to virtually disregard it. FDA believes there is no risk that cannot be managed in the post-marketing setting … The case of antidepressants and suicidality is a perfect example. How does the FDA handle this? With labelling changes. FDA knows that labelling changes don’t change physician behavior. Yet they act as if they are doing a great public good when they change the warning … Rather than ensuring with 95 percent certainty that a drug is safe, what FDA says is: We can’t be 95 percent certain this drug will kill you, therefore we will assume it doesn’t – and they let it on the market … if we wanted drugs that are safe, we could have it tomorrow. It is easy to design those studies. But FDA is not interested in that.’

  People behind desks make decisions that won’t work in real life and they know it. I shall say more about this in Ch
apter 21.

  Corruption at drug agencies

  It must be very tempting for drug companies to bribe officials at drug agencies, as an enormous amount of money is at stake. The approval of a new drug can be the difference between life and death for a company and a recent case illustrates these issues. I don’t suggest any wrongdoing, I just give the information. In 2012, Danish Lundbeck and its Japanese partner Takeda submitted vortioxetine, an SSRI, for regulatory approval in the United States.27 This doesn’t appear too exciting, as we already have lots of antidepressants, but it could be important for Lundbeck, as its blockbuster, escitalopram, will soon run out of patent. A spokesman said the company would receive a $43 million milestone payment from Takeda if the FDA accepted the drug.

  We don’t know much about corruption at drug agencies, but some of what I describe in this book is difficult to explain unless money is involved in one way or another, which could be a future reward in terms of a well-paid job in the industry or insider trading of drug company stocks (see below). Here is an example.28 In 2006, the FDA introduced new labelling regulations, but after the 5-year period of comments had expired, the agency quietly added a new section that would make it virtually impossible for patients to file liability claims against the companies when the patients had been harmed by their drugs.

  The FDA said that any label it had approved, ‘whether it be in the old or new format, pre-empts … decisions of a court of law for purposes of product liability litigation’. This immunity would apply even if a company failed to warn prescribers or patients adequately about a known risk, unless a patient could prove that the company intentionally committed fraud. This is what was so outrageous. Not only must there be fraud, but it should be intentional. How can a patient know what goes on in a company executive’s brain? I have often wondered myself. And how can a patient prove it was fraud?

  The data may be in the company’s archives, but that doesn’t prove it was fraud not to analyse them and tell the world about them. Understandably, several politicians objected vigorously to this provision, as well as to the fact that there was no opportunity to debate it before the regulations were made final. For years, the industry had tried to obtain legislation that immunised them against litigation but Congress had consistently rejected the idea, and suddenly, out of the blue, there it was, produced by the very agency that is supposed to have the American people’s interests as their first duty. How can this be explained – all done discreetly, in essence secretly, after the comments period had expired – if there wasn’t corruption?

  In 2009, nine FDA scientists wrote to President Obama about widespread corruption in the FDA at the highest levels, including several commissioners.4,29 The scientists were frustrated and outraged and gave many examples of the corruption, which they described as systemic and violating the law. They noted that there was an atmosphere at FDA in which the honest employee fears the dishonest employee, and that senior officials had suppressed or altered scientific or technological findings and conclusions, had abused their power and authority, and had engaged in illegal retaliation against those who spoke out.

  In 2012, it was revealed that FDA management had installed spyware on the computers of five scientists who had alerted the FDA to safety problems to no avail and therefore had informed the politicians.30 This came to light because thousands of confidential documents from the scientists’ computers were posted on a public website, apparently by mistake, by a private document-handling contractor that worked for the FDA. The posting of the documents was discovered inadvertently by one of the scientists the FDA had fired who did Google searches to check for negative publicity that might hinder chances of finding work.

  There were other revelations in 2012. A former FDA scientist, Ronald Kavanagh, spoke out about crimes and gangster methods at the agency:31

  While I was at FDA, drug reviewers were clearly told not to question drug companies and that our job was to approve drugs … If we asked questions that could delay or prevent a drug’s approval – which of course was our job as drug reviewers – management would reprimand us, reassign us, hold secret meetings about us, and worse. Obviously in such an environment, people will self-censor … Human studies are usually too short and the number of subjects in them too small to adequately characterize the most dangerous risks. That’s why even a single case has to be taken seriously … I frequently found companies submitting certain data to one place and other data to another place and safety information elsewhere so it could not all be pulled together and then coming in for a meeting to obtain an agreement and proposing that the safety issue is negligible … if reviewers say things that companies don’t like, they will complain about the reviewer or they will call upper management and have the reviewer removed or overruled. On one occasion, the company even told me they were going to call upper management to get a clear requirement for approval that they did not want to fulfill eliminated, which I then saw happen. On another occasion a company clearly stated in a meeting that they had ‘paid for an approval’ … Sometimes we were literally instructed to only read a 100–150 page summary and to accept drug company claims without examining the actual data, which on multiple occasions I found directly contradicted the summary document. Other times I was ordered not to review certain sections of the submission, but invariably that’s where the safety issues would be … FDA’s response to most expected risks is to deny them and wait until there is irrefutable evidence postmarketing, and then simply add a watered down warning in the labeling … When you do raise potential safety issues, the refrain that I heard repeatedly from upper management was‚‘where are the dead bodies in the street?’ Which I took to mean that we only do something if the press is making an issue of it … Later, I found that the FDA had internal documents that had the same conclusion [as] my analysis but they had been withheld from the advisory committee … After FDA management learned I had gone to Congress about certain issues, I found my office had been entered and my computer physically tampered with. I saw strange cursor movements on my computer when I was just sitting at my desk reading that I suspected was evidence of spying … The threats, however, can be much worse than prison. One manager threatened my children – who had just turned 4 and 7 years old – and in one large staff meeting, I was referred to as a ‘saboteur.’ Based on other things that happened and were said, I was afraid that I could be killed for talking to Congress and criminal investigators … I found evidence of insider trading of drug company stocks reflecting knowledge that likely only FDA management would have known. I believe I also have documentation of falsification of documents, fraud, perjury, and widespread racketeering, including witnesses tampering and witness retaliation … In fact, thanks in part to the Prescription Drug User Fee Act [in which drug companies pay for expedited reviews], thalidomide could not be stopped today.

  About 50 years ago, Henry Welch, chief of FDA’s antibiotics division, collected more than a quarter of a million dollars in private fees from companies while he was certifying the efficacy and safety of their antibiotics.32 Welch also edited a journal and shared papers in print with drug companies saying he would make changes they suggested in return for reprint orders and steering advertising revenues his way.33 There have been other cases of named FDA officials being bribed in return for approval of drugs, which have involved delivery of confidential information from competitors’ files at the FDA and prison terms, both for FDA officers and company staff.34

  When I worked in the industry, a colleague told me that his previous company had paid a clinical pharmacologist what corresponded to about 1 year’s salary for browsing a registration application before it was submitted to the drug agency. A pretty handsome payment for a few days of work, and the doctor wasn’t likely to reveal the arrangement when she later sat on the other side of the table in the drug agency and contributed to evaluating the same application.

  Duilio Poggiolini, general manager of the pharmaceutical department of the Italian Ministry of Health, was arrested
in 1993 due to a series of charges related to forgery and bribery favouring the entry of useless drugs.35 The scandal involved the minister of health who arranged for drug companies to pay bribes in order to get their drugs approved and sold at ‘suitable’ prices.36 The corruption network also involved academics who received shares of the bribes in return for expert advice in favour of the drugs, some of which were dangerous and sold at exorbitant prices. It has been estimated that just by taking five of the useless drugs off the market, Italy could have saved $3 billion back in 1993. Poggiolini went to jail while the minister had parliamentary immunity. In 2012, Poggiolini was fined €5 million, a small amount considering that the authorities had initially charged Poggiolini with having accumulated $180 million over 30 years.37 Crime certainly pays in healthcare.

  In 2008, the vice president of the Italian Drug Agency, Pasqualino Rossi, one of Italy’s most senior representatives at the EMA, was arrested.38 Six drug company lobbyists were also arrested, and the case concerned alleged falsification of clinical data in return for cash, revealed by wire tapping and covert cameras. The prosecutor said the corruption had resulted in concealment of life-threatening harms of the drugs. It was a soap opera right from the beginning. The drug agency issued a statement that none of its employees were under investigation, but when the Italian press named the senior officials arrested, the statement was removed and a new one was being prepared. Just like when the drug industry has been caught – it denies everything, even in the face of indisputable evidence.

  Internal documents from Pfizer show that UK psychiatrist Stuart Montgomery deliberately avoided to inform the drug regulator for which he worked that he also worked for Pfizer at the same time. He advised Pfizer about how the regulator had reasoned in relation to its application for sertraline (Zoloft) and what the company should do in order to get the drug approved.39