Deadly Medicines and Organised Crime

by Peter Gotzsche

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  11

  Public access to data at drug agencies

  If companies wanted to publish negative studies they could, but companies don’t like to publish negative studies. It’s amusing so many people are making pronouncements about the data – scientists and physicians – without seeing the data.

  Russel Katz, director of the neuropharmacology division at the FDA1

  If commercial success depends on withholding data that are important to prescribe drugs rationally and safely, there is something fundamentally wrong with our priorities in healthcare. It is of vital importance for public health that doctors and the public can get access to all data generated from all trials in patients and healthy human volunteers and not just a biased sample, as is currently the case.

  A good starting point for total access is the data the drug companies have submitted to drug agencies. Chief statistician Hans Melander and his co-workers at the Swedish drug agency have such access and they showed in 2003 that published trial reports of SSRIs were seriously flawed, compared to the study reports submitted in registration applications.2 In all 42 trials submitted to the agency but one, the companies had performed both an intention-to-treat analysis and a per-protocol analysis (where dropped-out patients are not accounted for). In only two of the publications, however, were both analyses presented, whereas in the remainder, only the more favourable per-protocol analysis was presented. This created a large misconception about how effective the drugs are (Figure 11.1).3 Moreover, separate trials were sometimes published as if they were the same trial, cross-references to multiple publications of the same trial were missing, and sometimes there were no author names in common in multiple publications of the same trial.

  Figure 11.1 Difference in percent responders between an SSRI and placebo as stated in study reports at the Swedish Drug Agency and as stated in publications of the same trials. Points above the line indicate an overestimation of the effect in publications

  A 2008 study, also of antidepressants, confirmed that the published data are seriously flawed, compared to data submitted to the FDA.4 The effect in the published trials was 32% larger than in all trials in FDA’s possession, and more than double as large as in unpublished trials. Furthermore, there was spin on the results. Six trials that were deemed questionable by the FDA were positive when published, and when 8 of 24 negative trials were published, 5 were positive. Another study, of 164 trials included in 33 new drug applications, also found that what was published didn’t reflect what was submitted to the FDA.5

  Drug regulators have used absurd arguments to deny researchers access to unpublished trials and data; they have gone so far as regarding suicides occurring while taking a drug that was supposed to prevent suicide a trade secret.6

  The drug industry’s arguments have been equally absurd and exploitative of patients. The proposal to register all trials, so that we would know also about the unpublished ones, was rejected in 2000 by drug industry representatives claiming that the very existence of trials was a trade secret!7 Drummond Rennie, deputy editor of JAMA, wondered why the FDA had been completely absent from the debate over trial registration and why it didn’t correct journal results that directly conflicted with what the FDA knew to be true facts, with the excuse that they have no mandate to inform the public. Wrong. The FDA is supposed to do exactly that: to guard the health of the public.

  Iain Chalmers, the founder of the Cochrane Collaboration, considers underreporting of research an equally serious form of scientific misconduct as fabrication of data.8 I agree. In fact, the consequences for patients are much more devastating, as it is so common. On average, only about half of all studies ever get published,9 but it can be far worse. A review of dyspepsia caused by five old NSAIDs found 15 published placebo-controlled trials and 11 unpublished trials on the FDA’s website.10 Only one trial was both published and submitted by the companies to the FDA, but the authors of the published paper were completely different from the investigators listed in the FDA report.

  Don’t you wonder why any type of scientific misconduct flourishes in healthcare, all over the place? If researchers in a single study decided to delete half of their results because they didn’t give the result they had hoped for and published the rest, we would call it scientific misconduct. But when whole studies go missing, we accept it as a normal part of life, although it is deeply unethical towards our patients.7,11 Selective reporting of results is scientific misconduct,12 which the Danish Association of the Pharmaceutical Industry has acknowledged.13 But our institutions have generally fail
ed us. Not a single organisation has used its powers, stood up and announced that this must stop, apart from one: the UK Faculty of Pharmaceutical Medicine, a small organisation with about 1400 members.11

  Our breakthrough at the EMA in 2010

  In 2007, PhD student Anders Jørgensen and I decided that the secrecy at drug agencies was so unbearable that we would do everything we could to get access to unpublished studies at the EMA. If we failed, which we expected, we would publish our experiences, particularly the arguments from the regulator, to expose to the world how deeply unethical the secrecy was, and we would then continue our fight from there, till we succeeded.14

  We chose anti-obesity drugs as our test case because they are so dangerous that most of them have been taken off the market after having caused horrific harms. We asked the EMA for access to the clinical study reports and corresponding trial protocols for rimonabant and orlistat, submitted to the agency.

  We outlined the plans for our research and explained that it was essential that the submitted documents became available for independent researchers because of the likely widespread future use of these drugs, the relatively small effect on overweight in published reports and the serious safety concerns that had been raised. In fact, rimonabant was withdrawn from the European market in the middle of the process when independent studies found that adverse effects, including severe depression and increased risk of suicide, were more serious and common than shown by the manufacturer, Sanofi-Aventis, in their clinical studies.15

  We argued that secrecy isn’t in the best interest of the patients because biased reporting of drug trials is common and also noted that we hadn’t found any information that could compromise commercial interests in 44 trial protocols of industry-initiated trials we had reviewed previously. Although the EMA’s primary aim is to protect the public, the EMA replied – without any comment on our arguments – that the documents could not be released because it would undermine commercial interests.

  We appealed to the EMA’s executive director, Thomas Lönngren, and asked him to explain why the agency considered that the commercial interests of the drug industry should override the welfare of patients. We argued – with convincing real-life examples – that a likely consequence of EMA’s position was that patients would die unnecessarily and would be treated with inferior and potentially harmful drugs because their doctors didn’t know what their true benefits and harms were.

  Lönngren sent us a similar, cut-and-paste type of letter to the first one, ignoring our request for clarification, and told us we could lodge a complaint with the European ombudsman, P Nikiforos Diamandouros, which we did.14

  It took 3 years before our case was settled. We described it in the BMJ14 and posted the 27 documents that circulated between the ombudsman, the EMA and us and a comprehensive report of the case on our website (www.cochrane.dk/research/EMA).

  To avoid disclosing the documents, the EMA put forward four main arguments: protection of commercial interests, no overriding public interest, the administrative burden involved, and the worthlessness of the data to us after the EMA had redacted them.14 I’m sure Lönngren felt the armour he had built up was impenetrable, but he had not calculated with the ombudsman, who rejected all his arguments. He stated that commercial interests might be at stake but that the risk of an interest being undermined must be reasonably foreseeable and not purely hypothetical. He could not see that access would specifically and actually undermine commercial interests. After having inspected the relevant reports and protocols at the EMA in London, he concluded that the documents didn’t contain commercially confidential information.14

  The ombudsman indicated that we had established an overriding public interest but noted that this question needed answering only if disclosure undermined commercial interests. He asked the EMA to justify its position that there wasn’t an overriding public interest, but Lönngren avoided replying by saying that we had not given evidence of the existence of such an interest. We surely had and, in addition, the argument was irrelevant. A suspect asked for his alibi on the day of the crime doesn’t get off the hook by asking for someone else’s alibi.14

  About the administrative burden and the uselessness of the documents after the EMA had redacted them, the ombudsman noted that the requested documents didn’t identify patients by name but by their identification and test centre numbers, and he concluded that the only personal data were those identifying the study authors and principal investigators and to redact this information would be quick and easy (when we received the documents, nothing was redacted).

  Since the EMA continued to be completely resistant to our arguments and those from the ombudsman – in the most shameless and arrogant fashion – he played his final card, 3 years after our request: he accused the EMA of maladministration in a press release. This had the effect that the agency reversed its stance completely. It now gave the impression that it had favoured disclosure all the time, agreed with the ombudsman’s reasoning, and noted that the same principles would be applied for future requests for access. This is how drug companies operate. They fight forcefully against openness, but when there is no escape, they pretend they have been in favour of it all the time. They usually go one step further, as they give the impression that it was their own idea to begin with.

  Obviously, it isn’t possible to protect the profits of the drug companies and the lives and welfare of the patients at the same time. One has to choose, and our case illustrates beyond a shadow of doubt that the EMA sided with the drug industry and put profits over patients. Moreover, its position wasn’t even consistent, which we also pointed out in our letters. It denied access to trial data on adult patients while providing access to data on paediatric trials (which it had to do because of EU legislation).

  I felt it was an aggravating fact, which we also pointed out in our letters, that the EMA had helped the drug industry to get away with violating the Declaration of Helsinki, which states that researchers have a duty to make publicly available the results of their research on humans.16 We also noted that by violating these universal human rights, the EMA was complicit in the exploitation of patients for commercial gains, as the patients are used as a means to an end and treated suboptimally as well, which are both unacceptable.

  Furthermore, we drew attention to the declaration’s statement ‘Medical research involving human subjects must … be based on a thorough knowledge of the scientific literature’ and argued that if the knowledge base is incomplete, patients may suffer and cannot give fully informed consent.17 Thus, by being secretive, the EMA also acquiesced to unethical research in future. Worst of all, it didn’t bother the EMA that it contributed to the unfortunate situation that doctors and patients were unable to select those treatments that provide the best balance between benefits, harms and cost, as they were denied access to the evidence. It didn’t bother either that tens of thousands of unnecessary deaths could have been avoided each year, if the public had had access to the unpublished information.17,18,19,20,21,22,23,24

  Our case was a major breakthrough for public health. In November 2010, the EMA declared it would widen public access to documents, including trial reports and protocols.25 But it shouldn’t have been so difficult to get there, given the fundamental principles on which the European Union is based:26

  Any citizen of the Union, and any natural or legal person residing or having its registered office in a Member State, has a right of access to documents of the institutions, subject to the principles, conditions and limits defined in this Regulation.

  Openness enables citizens to participate more closely in the decision-making process and guarantees that the administration enjoys greater legitimacy and is more effective and more accountable to the citizen in a democratic system. Openness contributes to strengthening the principles of democracy and respect for fundamental rights as laid down in Article 6 of the EU Treaty and in the Charter of Fundamental Rights of the European Union.

  Lönngren made sure my PhD student
was unable to do the work we had planned. After his efforts at protecting the industry’s commercial interests, he quit the EMA, also in a shameless fashion. Although Lönngren had been told by the EMA that he should not provide product-related advice to drug companies or take managerial, executive or consultative positions in the industry for a period of 2 years, he became director of a new company, Pharma Executive Consulting Ltd, in November 2010 while still employed by the EMA!27

  A year later, the EMA held a workshop at its headquarters that made history.28 Its new head, Guido Rasi, started by announcing that ‘We are not here to decide if we will publish clinical-trial data, only how.’ The industry representatives were stunned. Their usual arguments for secrecy were torn into pieces during the discussions, and the head of the UK drug regulator, Kent Woods, looked like a thing from the past when he tried to argue that there wasn’t really a need for the EMA’s new openness and transparency. I have never before seen the mighty drug industry lose a public battle so completely as during this afternoon. There is a video in two parts on the EMA’s website that takes up 3.5 hours in total, but it is really worth seeing.28

  There had been another case before ours. Liam Grant, father of a boy who committed suicide while on the acne drug isotretinoin (Roaccutane from Roche), had tried to find out which harms the company had informed the authorities about before marketing approval. The EMA granted access to the reported harms in 2010. In 2002, Danish journalists had also tried to get access to reported adverse events on Roaccutane, the so-called Periodic Safety Update Reports (PSUR), from the Danish medical agency. The agency was willing to give access, but Roche blocked this by arguing it would create a substantial risk for considerable losses for Roche. Roche even threatened to sue the Danish state if disclosure harmed the company’s commercial interests!29,30 Sue a state because fewer patients will take a drug after they found out it might kill them? How absurd can healthcare get? This is how gangsters operate: ‘If you do anything that will harm our sales of heroin, we’ll come after you.’ The comparison is appropriate, as Roche built its fortune on massive profits from illegal sales of heroin and morphine (see Chapter 3). The fact that Roche regards the harms reported by patients or their relatives as the company’s private property demonstrates such an outrageous disrespect for patients and human lives, particularly in this case where the drug had been associated with severe depression and suicide, that I’m speechless.