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EMA accused of putting pharma profits before patients - access to all trials' data
 
 
  pharmatimes World News | May 11, 2011
 
Kevin Grogan
 
Regulators are "protecting drug company profits rather than the lives and welfare of patients by withholding unpublished trial data", according to researchers in articles published by the BMJ.
 
They call for full access to full trial reports, both published and unpublished, "to allow the true benefits and harms of treatments to be independently assessed by the scientific community." Peter Gotzsche and Dr Anders Jorgensen from the Nordic Cochrane Centre in Denmark write that despite the existence of hundreds of thousands of clinical trials, "doctors are unable to choose the best treatments because research results are being reported selectively".
 
They claim that selective reporting can have "disastrous consequences". For example, they say Merck & Co's now-withdrawn painkiller Vioxx (rofecoxib) has "probably caused about 100,000 unnecessary heart attacks in the USA alone, while anti-arrhythmic drugs have probably caused the premature death of about 50,000 Americans each year in the 1980s".
 
Three-year 'struggle' to get unpublished data
 
The authors go on to describe what they call a three-year struggle to access unpublished trial reports for two anti-obesity drugs, Sanofi-Aventis now-withdrawn Acomplia (rimonabant) and Roche's Xenical (orlistat), submitted by the manufacturers to the European Medicines Agency.
 
This information "was important for patients because anti-obesity pills are controversial," they say, and "people have died from cardiac and pulmonary complications or have experienced psychiatric disturbances, including suicidal events, and most of the drugs have been de-registered for safety reasons".
 
However, Prof Gotzsche and Dr Jorgensen claim the EMA refused access, arguing that this would undermine "commercial interests and that there was no overriding public interest in disclosure". They also cited the "administrative burden involved and the worthlessness of the data after they had edited them".
 
The authors appealed to the European ombudsman, who criticised the EMA's refusal to grant access. But only after the ombudsman accused the agency of maladministration did the regulator agree to widen public access to documents.
 
'Fundamentally wrong'
 
"There is something fundamentally wrong with our priorities in healthcare if commercial success depends on withholding data that are important for rational decision making by doctors and patients," say Prof Gotzsche and Dr Jorgensen. They call on other drug regulatory agencies to follow suit and suggest that access should be prompt and that documents should be provided in a useful format to allow for independent scrutiny.
 
"Drug agencies should get rid of the huge paper mountains and require electronic submissions from the drug companies, including the raw data, which should also be made publicly available," they conclude.
 
In an accompanying editorial, researcher Andrew Vickers of the Memorial Sloan-Kettering Cancer Center, New York says "the system is broken and needs fixing". He describes a new initiative by the Wellcome Trust to tackle the problem by developing principles for funders with regard to data sharing, and suggests that the medical research community "get used to it."
 
He argues that once medical researchers start publishing their data, and depositing it in data archives, "they will discover not only that it is painless, but that it affords huge advantages to medical science, and to patients present and future."
 
The BMJ added that it believes "systematic efforts are needed to assess this largely unexamined threat to the integrity of evidence-based medicine".
 
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(Published 4 May 2011)
BMJ
 
Editorial
 
Making raw data more widely available
 
Andrew J Vickers associate attending research methodologist Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
 
New initiative by the Wellcome Trust sets out some guiding principles Medical investigators routinely refuse to share data from medical studies, seeming to regard such data as private property rather than a public resource for the benefit of medical science and future generations of patients. One survey found that 75% of pharmaceutical researchers were opposed in principle to making raw data available.1 Two studies have found that only a minority of researchers (10% and 25%) share data when publishing in journals with explicit policies that raw data must be made available.2 3 Even in genomics research, where the principle that microarray data should be deposited in a publicly accessible database is widely accepted, many published studies do not have an associated data set publicly available.4 5
 
The benefits of sharing raw data from medical studies have been widely discussed.6 7 8 9 Data sharing ensures reproducibility, allows testing of secondary hypotheses, facilitates development of new statistical methods, provides a resource for teaching, aids design of new studies, simplifies data acquisition for meta-analysis, and helps prevent fraud and selective reporting. Reasons that investigators give for why they cannot or should not share their data can be shown to be trivial. Researchers have claimed that data sharing would affect patient confidentiality, even though, anonymisation of data is generally straightforward and can follow established guidelines.10 Alternatively, data requests have been refused on the grounds that compiling a data set would be too much work, although this has to be done anyway for the published statistical analysis. Another common worry is that data might be analysed using invalid methods, which is a fair point, but surely a judgment for the scientific community as a whole.
 
The system is broken and needs fixing: investigators ought to share data, but they do not, and they ignore explicit policies aimed at increasing the availability of data. One obvious solution would be for journals to beef up enforcement-for example, by demanding a data set or a link to a data repository at the time of paper submission in the same way that a conflict of interest statement is required before a manuscript can be sent for peer review. Another alternative is to hit researchers where it hurts: their funding.
 
The Wellcome Trust has devised its own initiative to tackle the problem by developing principles for funders with regard to data sharing.11 At a meeting in May 2010, about 17 funders committed to work together to increase the availability of data generated by the research they fund, signing up to a statement of purpose.12 The statement includes overall aspirations, such as data sets for published papers being archived and made available to other researchers in a clear and transparent manner; general principles-that data sharing should be equitable, efficient, and ethical; and specific recommendations for developing knowledge and good practice, such as data management standards. The leadership of the Wellcome Trust should be applauded, even though there are currently no plans for enforcement, such as cutting the funding for researchers who refuse to share data. But it seems likely that open access to raw data will go the same way as open access to published papers. It started as a simple idea-that the results of research funded by the US government should be available to the American people-then became voluntary policy, which was toothless and failed, and was therefore transformed into a mandatory requirement. When researchers submit a new grant to the National Institutes of Health, or write a progress report for an existing grant, they have to provide the PubMed Central ID numbers for any papers based on federally supported research. It would not be a surprise if, in a decade's time, funders finally get tired of paying for data that researchers keep to themselves. If the purpose of a grant is to improve public health, and if public health will benefit most from making grant related data more widely available, we should fully expect funders to demand that grantees share data: whoever pays the piper calls the tune. In the meantime, a modest recommendation to the medical research community: get used to it. Once medical researchers start publishing their data, and depositing it in data archives, they will discover not only that it is painless, but that it affords huge advantages to medical science, and to patients present and future.
 
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BMJ 2011 (Published 10 May 2011)
 
· Analysis
 
Opening up data at the European Medicines Agency
 
Peter C Gotzsche professor, Anders W Jorgensen PhD student Nordic Cochrane Centre, Rigshospitalet and University of Copenhagen, Dept 3343, Blegdamsvej 9, DK-2100 Copenhagen o, Denmark
 
Widespread selective reporting of research results means we don't know the true benefits and harms of prescribed drugs. Peter Gotzsche and Anders Jorgensen describe their efforts to get access to unpublished trial reports from the European Medicines Agency
 
Doctors cannot choose the best treatments for their patients despite the existence of hundreds of thousands of randomised trials. The main reason is that research results are being reported selectively. Comparisons of published drug trials with unpublished data available at drug regulatory agencies have shown that the benefits of drugs have been much over-rated1 2 3 and the harms under-rated.4 Comparisons of trial protocols with published papers have also shown widespread selective reporting of favourable results.5 6
 
Selective reporting can have disastrous consequences. Rofecoxib (Vioxx) has probably caused about 100 000 unnecessary heart attacks in the United States alone,7 and class 1 antiarrhythmic drugs probably caused the premature death of about 50 000 Americans each year in the 1980s.8 An early trial found nine deaths among patients taking the antiarrhythmic drug and only one among those taking placebo, but it was never published because the company abandoned the drug for commercial reasons.9
 
Allowing researchers access to unpublished trial reports submitted to drug regulatory agencies is important for public health. Such reports are very detailed and provide more reliable data than published papers,1 2 3 4 but it has been virtually impossible to get access to them. We eventually succeeded in getting access to reports held by the European Medicines Agency (EMA) after three years of trying. Our case has set an important precedent, and we summarise here the process and the arguments.
 
Our application for access
 
On 29 June 2007 we applied for access to the clinical study reports and corresponding protocols for 15 placebo controlled trials of two anti-obesity drugs, rimonabant and orlistat. The manufacturers had submitted the reports to the EMA to obtain marketing approval in the European Union. We explained that we wanted to explore the robustness of the results by adjusting for the many missing data on weight loss and to study selective publication by comparing protocols and unpublished results with those in published reports.
 
The information was important for patients because anti-obesity pills are controversial. The effect on weight loss in the published trials is small,10 and the harms are substantial. People have died from cardiac and pulmonary complications11 or have experienced psychiatric disturbances, including suicidal events,12 and most of the drugs have been deregistered for safety reasons. A basic principle in the European Union is to allow its citizens the widest possible access to the documents its agencies possess (box 1).13 But there are exemptions, and the EMA refuses access if disclosure would threaten commercial interests unless there is an over-riding public interest.14 We argued in our first letter to the EMA that secrecy was not in the best interests of the patients because biased reporting of drug trials is common.2 5 Furthermore, we hadn't found any information that could compromise commercial interests in 44 trial protocols of industry initiated trials we had reviewed previously.5 Box 1: Basic principles on citizens' access to EU documents13
 
· "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." Without any comment on our arguments, the EMA replied that the documents could not be released because it would undermine commercial interests. We appealed to the EMA's executive director, Thomas Lšnngren, and asked him to explain why the EMA considered that the commercial interests of the drug industry should over-ride the welfare of patients. We argued that the EMA's attitude increased the risk of patients dying because their doctors prescribed drugs for them without knowing what the true benefits and harms were. He sent us a similar letter to the EMA's first letter, ignoring our request for clarification, and told us we could lodge a complaint with the European ombudsman, which we did. Over the following three years the EMA put forward several arguments to avoid disclosing the documents: protection of commercial interests, no over-riding public interest, the administrative burden involved, or the worthlessness of the data to us after the EMA had redacted them (box 2). It also did not respond to the ombudsman's letters before his rather generous deadlines had run out.
 
Box 2: The path to the data
 
The delays on our part amounted to 130 days (11% of the time); we awaited replies for 1028 days.
 
· 29 Jun 2007: We asked the EMA to provide access to the clinical study reports and their corresponding protocols on rimonabant and sibutramine
 
· 20 Aug 2007: The EMA replied that the documents could not be released because they came under the exception of commercial interests
 
· 24 Aug 2007: We explained that the EMA's lack of transparency violated basic principles in the EU treaty and that it leads to suboptimal treatment of patients
 
· 17 Sept 2007: With no comment on our arguments, the EMA referred again to commercial interests and noted we could institute court proceedings against the EMA or complain to the European ombudsman
 
· 8 Oct 2007: We appealed to the ombudsman, noting that the published literature on drugs is flawed and arguing that protocols and study reports did not disclose anything that could undermine commercial interests
 
· 30 Jan 2008: The EMA replied to two letters from the ombudsman, referred to protection of commercial interests and mentioned that it could not identify any over-riding public interest that could justify disclosure of the requested documents
 
· 26 Feb 2008: We told the ombudsman that the EMA had failed to explain why commercial interests would be undermined
 
· 28 Apr 2008: The EMA replied to the ombudsman that it needed to protect the data against unfair commercial use; that evaluating the balance between benefits and risks of medicines is the EMA's job; and that redaction of personal data would cause disproportionate effort
 
· 17 Jun 2008: In our reply to the ombudsman, we argued against this and noted that if commercial success depends on withholding data that are important for rational decision making by doctors and patients, there is something fundamentally wrong with our priorities in healthcare
 
· 22 Jan 2009: The ombudsman proposes a friendly solution to the EMA and asks it to grant us access to the documents or provide a convincing explanation why such access cannot be granted
 
· 26 Feb 2009: The EMA restates the commercial interests; claims that we have not given evidence of an over-riding public interest; and refers to the workload involved in redacting the documents
 
· 10 Mar 2009: The ombudsman again proposes a friendly solution to the EMA and asks it to clarify its reasoning
 
· 7 Apr 2009: The EMA repeats its previous arguments.
 
· 19 May 2009: We again counter the EMA's arguments: the EMA has provided no evidence that the documents are commercially sensitive; many patients had been harmed by selective publication of trial data on COX 2 inhibitors; and redacting the documents should be quick and easy
 
· 31 Aug 2009: We tell the ombudsman that we have received trial data from the Danish Medical Agency on a third anti-obesity drug, sibutramine
 
· 6 Oct 2009: The ombudsman goes to the EMA to inspect the documents we had requested
 
· 19 May 2010: The ombudsman issues a draft recommendation that the EMA should grant us access to the documents or provide a convincing explanation as to why not
 
· 7 Jun 2010: In a press release the ombudsman accuses the EMA of maladministration because of its refusal to grant access
 
· 31 Aug 2010: The EMA informs the ombudsman that it will provide access
 
· 1 Feb 2011: We receive the data
 
Protection of commercial interests
 
Protection of commercial interests was the EMA's over-riding argument. It would undermine the protection of commercial interests to allow us access, it said, as the documents represented the full details of the clinical development programme and the most substantial part of the applicant's investment. Competitors could use them as a basis for developing the same or a similar drug and gather valuable information on the long term clinical development strategy of the company to their own economic advantage.
 
We explained that the clinical study reports and protocols are based on well known principles that can be applied to any drug trial; that the clinical study reports describe the clinical effects of drugs; and that nothing in the EMA's guidelines for preparation of such reports indicates that any information included in them can be considered a trade secret. The trial protocols are always sent to the clinical investigators, and it is unlikely that companies would have left in any information that could be of commercial value (such as a description of the drug synthesis). We also noted that the clinical study reports and trial protocols represent the last phase of drug development, which has been preceded by many years of preclinical development. Other companies could hardly use them as a basis for developing similar drugs. In fact, unpublished trial data are generally less positive than published ones,1 2 3 4 5 6 and competitors would therefore be less likely to start drug development if they had access to the unpublished results. Other companies are more likely to be interested in in vitro, animal, and early human studies, and drug companies have no problems with publishing such studies because the results may attract investors.
 
The European ombudsman, P Nikiforos Diamandouros, considered that commercial interests might be at stake but noted 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. He inspected the relevant reports and protocols at the EMA and concluded that the documents did not contain commercially confidential information. He therefore criticised the EMA's refusal to grant us access.
 
Over-riding public interest in disclosure
 
Even if commercial interests were undermined by disclosure, access would still have to be granted if there was an over-riding public interest. The EMA argued that it could not identify any over-riding public interest and remarked that the evaluation of safety and efficacy of drugs is its responsibility-the EMA constantly monitors drugs and updates its assessment reports and requires changes in product information as appropriate.
 
We considered this insufficient. Monitoring adverse effects reported by doctors to drug agencies would not have revealed that rofecoxib causes heart attacks. Few such events are reported, and heart attacks are common in people with arthritis. Postmarketing passive surveillance systems can therefore usually not detect whether a drug leads to more heart attacks than expected; randomised trials are needed for this.
 
We provided more evidence of the detrimental effects of selective publication but to no avail. The EMA continued to claim that we had not documented the existence of an over-riding public interest. We noted that we could not prove this in this specific case because we were denied access to the data, but we drew attention to the fact that the total number of patients in the main clinical studies of orlistat differed according to the source of the information: published reports, the EMA's website, and the website of the US Food and Drug Administration.
 
The ombudsman indicated that we had established an over-riding public interest, but he did not take a definitive stance on whether an over-riding public interest existed because this question needed answering only if disclosure undermined commercial interests. He asked the EMA to justify its position that there wasn't an over-riding public interest, but the EMA avoided replying by saying that we had not given evidence of the existence of such an interest. We believe that we had. Furthermore, the EMA's 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.
 
Administrative burden
 
According to the EMA, the redaction of (unspecified) "personal data" would cause the EMA a disproportionate effort that would divert attention from its core business, as it would mean redacting 300 000-400 000 pages. This was surprising. The Danish Drug Agency had not seen the workload as a problem when it granted us access to the reports for the anti-obesity drug sibutramine, which was locally approved in Denmark. The 56 study reports we received comprised 14 309 pages in total, and we requested only 15 study reports from the EMA (the pivotal studies described in the European Public Assessment Reports (EPARs) on rimonabant and orlistat). The ombudsman declared that the EMA had overestimated the administrative burden involved.
 
Worthlessness of data after redaction
 
The EMA argued that, "as a result of the redaction exercise, the documents will be deprived of all the relevant information and the remaining parts of them will be worthless for the interest of the complainant."
 
From what we know of clinical trial reports and protocols it struck us as odd that they would contain so much personal data that the documents became worthless. The ombudsman noted that the requested documents do not identify patients by name but by their identification and test centre numbers, and he concluded that the only personal data are those identifying the study authors and principal investigators and to redact this information would be quick and easy.
 
The EMA also remarked that a possible future release of the assessment reports of the EMA's Committee for Medicinal Products for Human Use and the (co)rapporteur assessment reports "could satisfy the request of the complainants." These reports were not available and they would have been worthless to us because they are merely summaries used for regulatory decisions.
 
Maladministration
 
The EMA was completely resistant to our arguments and those from the ombudsman. However, after the ombudsman accused the EMA of maladministration in a press release on 7 June 2010,15 three years after our request, the EMA reversed its stance. The EMA 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 but that it would consider the need to redact part of the documents.
 
The EMA's last letter was unclear: "The Agency will do its utmost to implement its decision as quickly as possible, in any case within the next 3 months at the latest. The Agency will keep the European Ombudsman promptly informed of the exact implementation date."
 
It was not clear whether the three months was the deadline for sending the reports to us, for implementing its new policy, or both. We received the data we requested from the EMA on 1 February 2011, which in some cases included individual patient data in anonymised format, identified by individual and test centre numbers.
 
Concluding remarks
 
According to the EMA's responses to the ombudsman, the EMA put protecting the profits of the drug companies ahead of protecting the lives and welfare of patients. Moreover the EMA's position is inconsistent because it resisted requests to give access to trial data on adult patients while providing access to data on paediatric trials, in accordance with EU legislation.16 The Declaration of Helsinki gives authors the duty to make publicly available the results of their research on humans.17 The declaration also says that, "Medical research involving human subjects must . . . be based on a thorough knowledge of the scientific literature." If the knowledge base is incomplete, patients may suffer and cannot give fully informed consent9 and research resources are wasted. The EMA should be promoting access to full information that will aid rational decision making, not impede it.
 
Our case sets an important precedent. On 30 November 2010 the EMA declared it would widen public access to documents, including trial reports and protocols.18 We recommend that the FDA and other drug regulatory agencies should follow suit. Access should be prompt-for example, within three months of the regulator's decision-and documents should be provided in a useful format. Drug agencies should get rid of the huge paper mountains and require electronic submissions from the drug companies, including the raw data, which should also be made publicly available.
 
 
 
 
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