Opening up data at the European Medicines AgencyBMJ 2011; 342 doi: https://doi.org/10.1136/bmj.d2686 (Published 10 May 2011) Cite this as: BMJ 2011;342:d2686
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Congratulations to Gotzsche and Jorgensen for their excellent
exposure of EMA shortcomings. EMA were criticized for their data access
and opaque decision making over 10-years ago, specifically regarding
orlistat (see http://www.bmj.com/content/322/7287/637.3.extract/reply).
It is a pity that Gotzsche and Jorgensen's report has not stimulated
EMA to move to a position of full public disclosure, but it is great to
see some progress being made.
Competing interests: No competing interests
It took us 3.5 years to get access to the clinical study reports and
trial protocols of the placebo-controlled clinical trials of two anti-
obesity drugs at the European Medicines Agency (EMA) (1), but our
breakthrough created an important precedent. Subsequently, it took only
3.5 months before we received similar documents for an antidepressant
drug, duloxetine. We had applied for access to eight antidepressant drugs,
but the EMA advised us to contact the relevant national drug agencies for
the other drugs, as these had not been approved centrally.
For one of the drugs, fluoxetine, the United Kingdom acts as
Reference Member State according to the Mutual Recognition Procedure in
the EU, and we therefore wrote to the UK Medicines and Healthcare products
Regulatory Agency (MHRA). The MHRA informed us on 25 May 2011 that it no
longer holds the requested reports:
"Under MHRA record management policy, all application files and data
for licences are held for 15 years. After this period, files are destroyed
unless there is a legal, regulatory, or business need to keep them, or
unless they are considered to be of lasting historic interest." (The MHRA
does hold some study reports on fluoxetine, however, submitted later "for
a variation to the Marketing Authorisation.")
The European Commission held a public hearing on scientific
information in Luxembourg on 30 May. I informed the attendants that the
MHRA destroys the clinical evidence about the benefits and harms of the
products it approves after 15 years, and I also informed a member of the
European Parliament about it. In both cases, the reaction was shock and
How can a drug regulator be allowed to destroy all the evidence? In
particular when it is the Reference Member State for that drug in the EU?
From where would we then get the evidence?
Court cases in the United States that have provided access to
internal company archives have revealed serious scientific misconduct in
placebo-controlled industry-sponsored trials of antidepressant drugs,
including those of fluoxetine. This misconduct includes recoding of
suicidal events on the antidepressant drug as "emotional lability,"
"hospital admission," "lack of effect," or "drop-out," and adding suicides
to the placebo group, although they had not occurred while the patients
were randomised to placebo (2,3).
The new openness at the EMA is unique. As far as I know, it has not
been possible to get access to unredacted clinical study reports and
protocols at any other drug agency allowing independent evaluation of the
adverse events at the patient level. Drug companies do not grant
researchers access either. The action of the MHRA may therefore mean that
it is impossible for independent researchers to correct the seriously
flawed publication record on fluoxetine, which, ironically, is the only
drug approved for use in childhood depression, despite the fact that we
already know that SSRIs as a drug class increase the risk of suicide in
children and adolescents (2,3).
As citizens in the EU, we should not accept this state of affairs. I
will therefore send this letter to the Department of Health in the UK and
to the EMA, requesting a response as to how we can obtain the data the
MHRA has destroyed. The UK government should introduce legislation that
will prevent the MHRA in future from destroying the evidence in its
possession. Applications for marketing authorisation should, in the first
place, be submitted electronically, e.g. as searchable pdf-files, and if
this is not the case for older drugs, it is fairly easy to scan the
documents. Lack of space is therefore no excuse for destroying the
1. G?tzsche PC, J?rgensen AW. Opening up data at the European
Medicines Agency. BMJ 2011;342:d2686.
2. Healy D. Did regulators fail over selective serotonin reuptake
inhibitors? BMJ 2006;333:92-5.
3. Healy D. Let them eat Prozac. New York: New York University Press,
Competing interests: No competing interests
The comprehensive account in the BMJ by Peter Gotzsche and Anders
Jorgensen  on their efforts to obtain clinical trial data from the
European Medicines Agency (EMA) highlights the problems researchers still
face in the evaluation of healthcare interventions. In its response to the
BMJ article, EMA refers to the steps it has undertaken to improve
transparency, including the long-awaited launch of the EU Clinical Trials
Register (EU-CTR). EMA also states that "further developments of this
system are planned in the future" . These are urgently required as, due
to its restricted functionality, the current version of EU-CTR is of
limited use to researchers.
The major goal of clinical trial registration and results
registration (which is not yet available in EU-CTR) is to enable the
unbiased assessment of an intervention. However, the simple disclosure of
clinical trial data in registries does not solve the problem, as treatment
decisions based on the extraction and evaluation of individual data sets
or individual trials from registries will inevitably run a high risk of
bias. Therefore, in order to be effective in improving healthcare, the
primary target group of results registration should be researchers
providing systematic reviews of the available evidence and not individual
clinicians or patients trying to find their way through a jungle of study
data. Consequently, certain technical preconditions need to be fulfilled:
in order to use registry data in systematic reviews, the trials and data
sets must be adequately searchable and processable.
The current search functions of EU-CTR are limited, as neither a
proper keyword search nor a search for synonyms seems to have been
implemented. The search results therefore depend heavily on how the
registered trials have been named, while the retrieved study pool is
highly likely to be incomplete. In addition, a downloading function is not
yet available, so the search results cannot be exported for further
EMA has announced that the functionality of the registry will be
improved . However, in view of the previous delays, explained amongst
other things by "difficulties encountered in data migration and testing of
the software,"  it remains to be seen how and when this will be
Thus Europe is still lagging behind, in contrast to the United
States, where the trial registration and results database
ClinicalTrials.gov has been in operation for several years and is becoming
an increasingly important source of evidence for systematic reviewers.
Hopefully the current discussions on increasing transparency in clinical
research in Europe will accelerate the development of EU-CTR so that
researchers will finally have appropriate access to a more complete data
1. Gotzsche PC, Jorgensen AW. Opening up data at the European
Medicines Agency. BMJ. 2011; 342: d2686.
2. Pott A. Rapid response to "Opening up data at the European
Medicines Agency by Gotzsche PC and Jorgensen AW, BMJ
2011;342:doi:10.1136/bmj.d2686". 2011 [cited 26 May 2011]; Available
3. European Medicines Agency. EU Clinical Trials Register -
Frequently Asked Questions. 2011 [cited 26 May 2011]; Available from:
Competing interests: Non-financial competing interests: We require full access to clinical trial data for the production of unbiased reports and support mandatory trial registration and results disclosure.
The Journal wisely dare to report that the European Medicines Agency
(EMEA) seems more interested by protecting the secrecies of the Big Pharma
than by protecting the health of the European people.(1,2)
Since too long the European Medicines Agency (EMEA) has deliberately
breached the Freedom of Information with cynicism. Prescrire, the famous
independent drug bulletin, after a first refusal and a long delay
following a second request, finally obtained from the EMEA the scientific
analysis of rimonabant. The EMEA sent a document ... where only 2 pages
out of 68 could be read, as you can see.(3)
Moreover, the European Parliament just produced a damning report on
the EMA budget management and handling of conflicts of interest. (4) 626
of the 700 MEPs voted to postpone the closure of the EMA's 2009 accounts
until an audit of the Agency is produced. The EMA has been given until the
end of June 2011 to produce the information requested.
1 Gotzsche PC, Jorgensen AW. Opening up data at the European
Medicines Agency.BMJ. 2011;342:d2686.
2 Barbui C, Baschirotto C, Cipriani A. EMA must improve the quality
of its clinical trial reports. BMJ. 2011;342:d2291
Competing interests: No competing interests
Letter to the editor
We are writing in response to the Analysis
'Opening up data at the European Medicines
Agency', which was published by Peter C
Gotzsche and Anders W Jorgensen on the website
of the British Medical Journal on 11 May 2011,
and Mr Andreas Pott's letter published on 13 May 2011.
According to this letter, the authors allegedly
failed to acknowledge steps taken by the
European Medicines Agency towards increasing
its transparency over recent years.
Formindep is an independent, self-funded association of health
professionals and citizens advocating for a
medical information and education transparent
and freed from any other interest than the
patients'. Our own experience of EMA
transparency policy implementation does concur
with Mr Gotzsche and Mr Jorgensen's findings.
Transparency is governed in European institutions, including EMA, by
Whereas this regulation has been in force for a decade, its main
requirements are still
ignored by the Agency.
Mr Pott in his letter announces that 'reactive disclosure of documents
will be complemented
by an extended proactive publication of these
documents over the next years'.
In plain terms, the EMA plans to roll out
sometime in the indefinite future the public
register of documents that should have been
implemented as early as 2001, as laid in article
11 of the said regulation.
Abiding by the law, a fortiori with such delay, cannot be construed as
EMA experts' involvement and 'public' declarations of interests
remain undisclosed, although they are key to the mission of the Agency to
provide independent scientific opinion. The European Parliament
resolution adopted on 10 May reads: '(the EP)
Finds it unacceptable that the Agency does not
apply the relevant rules effectively, resulting
in the fact that there is no guarantee that the evaluation of human
medicines is performed by independent experts'.
Should they wish to exercise their right of access to check these
declarations, citizens from all over Europe are invited to come to the EMA
premises in London and consult the original paper declarations onsite. Contrary to national counterparts such as the French AFSSAPS, the EMA has indeed constantly refused to
publish these documents online.
Two years ago, Formindep requested the disclosure of two internal
audit reports from the EMA. The first one focused on the evaluation of
human medicines, the second on access to documents. But EMA is not even
transparent about transparency itself, and refused the access. Formindep
as well had to lodge a complaint before the European Ombudsman, that is
Only under the pressure of the European Ombudsman - who concluded in
several decisions that EMA repeated refusals to disclose public documents
indeed constituted acts of 'maladministration'- did the
EMA start to evolve, very recently.
A.Chailleu: Member of the Management Board, Formindep
P.Foucras: President, Formindep
Competing interests: A.Chailleu: Member of the Management Board, Formindep
The article by Gotzsche and Jorgensen (BMJ 2011;342:d2686) describes a laborious and cumbersome intervention, indeed between them, the EMA and the European ombudsman. It lasted from mid-2007, when request for obtaining detailed clinical trial data was first lodged, until 1st February 2011 when such request was finally fulfilled. During this time period many things have happened, among others the removal of rimonabant containing medicinal products from the EEA market, initiated November 2008. The article meticoulously sets out the many communication steps undertaken by the authors and the EMA, both being stubbornly repetitive, and involving the European ombudsman - and the reading is totally frustrating. During this time period the overall judgment of anti-obesity drugs became more and more negative - for various reasons and resulting in ever fewer medicines being available to support obesity treatments. Such judgment can be found already in the nineties, when the EMEA with its CPMP worked very hard on removing anti-obesity drugs from the European markets (so-called Article 12 procedures). During this time period the policies towards transparency and access to documents was greatly improved, lodging requests like the one described today would be settled within very short time frame. Whereas EMEA in its earlier days interpreted the need for openness and transparency as an obligation for early provision of unimpaired access to readable and structured information, culminating in benefit-risk assessment and SmPC/PIL (the EPAR), thus informing health care professionals and patients alike, constantly revising its contents according to the state of scientific art: all toward and untoward information must (and continues to) be provided by the applicant/marketing authorisation holder and be included by EMA in the EPAR. I was responsible for the development and implementation of such EPARS as Head of Human Unit at the EMEA in those days, and the EMEA was hailed for such incredible openness unheard of before by other Agencies in Europe. Soon after discussion was initiated searching for improvement opportunities (BMJ 1998;317:898), and EPARS have been recognised needy of improvement. Access to documents in the meantime has been widened to include trial protocols and reports (BMJ 2010;341:c7039). During this time (very recently) the correct desire to be able to know about all clinical trials has been fulfilled.
I express pity with the authors, as they went through procedures at the wrong time, although they even may have helped to achieve improvement. At the same time it is now my term to be inquisitive: where are the clinical trial protocols and reports requested and received? It would be of much greater value and benefit to the reader to read and compare those reports to the EPAR (which for rimonabant containing medicinal products has become very brief after its removal from the market). What do we learn from these reports vs EPARs, where did EPARs fail (to inform), where did CHMP fail with their opinions on marketing authorisation? The relevance of the article for public health professionals and patients is barely visible when "the robustness of the results by adjusting for the many missing data on weight loss and to study selective publication ..." remains unexplored and does not benefit others as deemed necessary by the authors. What is the additional knowledge gained, on top of the since long well-known clinical facts that anti-obesity drugs are of limited efficacy, may exhibit severe adverse events, and should be taken for limited time periods only in support of overall therapeutic regimes (if recommended at all)?
By the way, I have requested today from the marketing authorisation holder the 8 phase 3 studies addressed by the authors in 2007, and I will inform BMJ about the outcome of this request. Data, protocols and reports are available and have been available from a variety of sources. FoI in the USA has been around for quite some time, and its usefulness in the sense claimed by the authors will be up for discussion again.
Rolf Bass 13 May 2011
Dr. med., apl. Professor for Pharmacology and Toxicology (Charit?), Visiting Professor for Pharmaceutical Medicine (Basel), FFPM (Hon), retired from BfArM (Bonn)
Boelckestrasse 80 12101 Berlin, Germany
Competing interests: No competing interests
Dear Dr Godlee
We are writing in response to the Analysis 'Opening up data at the
European Medicines Agency', which was published by Peter C Gotzsche and
Anders W Jorgensen on the website of the British Medical Journal on 11 May
The authors make what appears to be a compelling call for more
transparency by the regulatory authorities. However, they do so by
ignoring the steps taken by the European Medicines Agency since it was
established in 1995 and the latest actions and policy adopted over the
last few years.
The European Medicines Agency has taken important steps towards
increasing its transparency over recent years. Mr Gotzsche and Mr
Jorgensen themselves have acknowledged that the Agency's new access to
documents policy which became effective in November 2010 has pushed
transparency further forward than in most other drug regulatory
authorities. The current policy grants wider access than ever before to
documents originated, received or held by the Agency. This includes
clinical trials reports submitted to the Agency as part of a marketing
authorisation application. The extended access to documents and reactive
disclosure of documents will be complemented by an extended proactive
publication of these documents over the next years.
The recent launch of the EU Clinical Trials Register has been
welcomed by patients' and healthcare providers' organisations as a major
step towards transparency of medical research that will allow patients and
doctors to find information about clinical trials taking place in Europe.
Further developments of this system are planned in the future, including
publication of summaries of clinical trial results.
In addition to its new rules on access to documents and the launch of
the EU Clinical Trials Registry the Agency has launched a number of major
initiatives to increase transparency of its operations over recent years,
including public consultation on a policy on access to safety data
contained in EudraVigilance and a new transparency policy setting out the
Agency's vision of its level of openness towards its stakeholders. These
policies will strengthen the Agency's approach to proactive and reactive
dissemination of information on the quality, safety and efficacy of
(signature on file)
Acting Executive Director
Competing interests: No competing interests