Opening up data at the European Medicines Agency

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
disbelief.

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
evidence.

References

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,
2004.

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

3 http://www.prescrire.org/editoriaux/EDI33693.pdf

4 http://www.europarl.europa.eu/sides/getDoc.do?pubRef=-
//EP//NONSGML+EPORT+A7-2011-0153+0+DOC+PDF+V0//EN&language=EN

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

rolf_bass@web.de