The Report on Clinical Trials agreed yesterday in the ENVI Committee would bring more transparency than before, but less than was originally proposed by the Rapporteur, Glenis Wilmott.

She had proposed the publication of a Clinical Study Report within one year of the completion or termination of a trial. The compromise agreed a two stage approach – the submission of an extended summary for every trial within one year of completion or termination and, for trials submitted with an application for a Medicines Authorisation, the publication of a Clinical Study Report within 30 days of the decision on the authorisation. This will not bring disclosure of all clinical trials, or timely disclosure of results in many cases, as I explained in my previous post, but it would be better than what we have now.

You can read the definition of the required summary here. It may have limited value in terms of science or prescribing. I would welcome comments on this point – or any other.

Access to the summary would also be subject to an exception for “protecting commercial confidentiality”. Unfortunately, an amendment seems to have slipped through from Anna Rosbach (DK, European Conservatives and Reformists Group) to extend this phrase to say “ protecting commercially confidential information, in particular through taking into account the authorization status of the product”. This would muddy the waters and reduce transparency.

However, another amendment would greatly improve access to Clinical Study Reports (after a decision on authorisation). It states in part “ in general the data included in clinical trial study reports should not be considered commercially confidential once a marketing authorisation has been granted or the decision-making process on an application for marketing authorisation has been completed”. This is very good, but support was not unanimous. Industry will no doubt fight very hard to try to keep it from the final text of the regulation, to be agreed between Commission, Council and Parliament.

If this amendment is in the final text, as I hope it will be, the two companies taking legal action against disclosure by the European Medicines Agency may be wasting their time, whatever the outcome of their cases.

Another amendment also takes the side of the EMA in this context in stating “The definition of what is considered as commercial confidential shall be in accordance with EMA guidelines and shall not be allowed to override the interest of public health research.” That precise wording will not make its way into the final text of the regulation but I hope the sentiment will. This amendment actually has very wide support in that it was proposed by the Industry Committee of the Parliament.

On other points, there was near universal agreement on the issue of ethics committees. There was majority support for complicated amendments dealing with definitions of clinical trials, and around such concepts as “low intervention”, “non-intervention” and “low risk” in relation to clinical studies and trials. The implications of these amendments will need careful study, and more knowledge than I have.

The next stages will include negotiations between Commission, Council and Parliament for a final text, and a vote in Plenary in the Parliament – possibly in October. It’s not over yet. END

The proposal for the revision of the Clinical Trials Directive will be discussed tomorrow (29th May) in the Envi Committee of the European Parliament. On transparency and disclosure of trial results I am not hearing good news.

The rapporteur, Glenis Wilmott, made a good proposal in her report – for the publication of a Clinical Study Report within one year of the completion or termination of a clinical trial.

It seems this proposal has not enough support from other MEPS, particularly from the biggest group in the Parliament, the EPP, for which Philippe Juvin is the “shadow” rapporteur. Therefore a compromise is likely tomorrow.

If I understand correctly, and I may not, the compromise would require the publication of an extended summary of every trial and, for trials intended to be used to obtain a marketing authorisation, the publication of a Clinical Study Report within 30 days of the decision on the authorisation.

This “solution” is clearly not as good as Glenis Wilmott’s original proposal, and would have a number of bad effects.

It would delay the publication of Clinical Study Reports until after a decision on an authorisation.

It would also allow companies to conceal the full results of many trials, on the grounds that they were not intended to be used for a marketing authorisation. Suppose there are two medicines authorised for a particular condition and a trial was conducted to find out which was more effective – a good thing to know and in the interest of patients. This trial would not be intended to be used for a marketing authorisation and therefore there would be no requirement to publish a Clinical Study Report.

In another scenario, a company could postpone indefinitely the results of a trial it did not want to make public by claiming that it was intended to be used (some day) for a marketing authorisation.

It seems too that Clinical Study Reports would not have to be published for “academic” studies since these are often not intended to be used for a marketing authorisation. Some academic interests had expressed concern about having to publish a Clinical Study Report; this is a pity since academics above all should favour open science and open medicine. Moreover, there is often little difference in practice between many “commercial” trials and “academic” trials.

I may have got this wrong, and indeed I hope I have. If the compromise is along the lines that I fear the European Parliament will miss the chance to support a reform that is strongly in the interests of good science, good medicine and patients. END

The European Voice has just published my opinion piece on the legal actions taken against the European Medicines Agency.
It’s behind a paywall but you can read it here.

Like AbbVie, described in my last post, a second American company, InterMune, has taken legal action to prevent or restrict the European Medicines Agency from disclosing certain clinical trial data after a medicine is approved for marketing.

On 4th March a federal appeals court upheld the conviction of the former chief executive of InterMune, W. Scott Harkonen, relating to the dissemination of false and misleading statements about the results of a clinical trial of the medicine Actimmune. (Mr Harkonen may launch further appeals.)

According to an earlier statement from the FBI:
“Evidence at trial further showed that Harkonen caused InterMune to issue a false and misleading press release publicly announcing the results of a clinical trial of Actimmune for the treatment of IPF on Aug. 28, 2002. Although the clinical trial had failed, InterMune’s press release falsely stated that the results of the clinical trial established that Actimmune helped IPF patients live longer. The headline of the press release read, “InterMune Announces Phase III Data Demonstrating Survival Benefit of Actimmune in IPF,” with the subheading “Reduces Mortality by 70% in Patients with Mild to Moderate Disease.”

In 2006, the company itself had reached a Deferred Prosecution Agreement with the Department of Justice and agreed to paid fines and penalties of $36 million. One clause in the agreement states that it “does not provide any protection to any former employee of InterMune”. Mr Harkonen had left the company in 2003.

Actimmune was promoted as treatment for idiopathic pulmonary fibrosis (IPF), a rare but fatal disease. Treatment cost around $50,000 per annum, generating revenue of over $100 million, mostly for treatment of IPF. (Doctors may prescribe but companies may not promote medicines for uses for which they have not received an authorisation. )

In so far as the offending press release had a basis it seems to have come from the selective use of the data from a clinical trial labelled GIPF-001 – a practice sometimes known as data mining or data dredging. From the beginning, there were some sceptical voices about the company’s claims and in January 2004 an article in the New England Journal of Medicine concluded that Actimmune “did not affect progression-free survival, pulmonary function, or the quality of life”.

Another case for timely and full disclosure.

On the indictment of Mr Harkonen, Intermune issued a press release, of which this is an extract:
“Since 2004, InterMune has been a transformed company with a new management team, a rigorous compliance program and a promising pipeline focused on serious pulmonary and hepatic diseases.”

Still, it’s a pity that the earlier experiences of InterMune and AbbVie/Abbott have not convinced them of the merits of more transparency on the part of the European Medicines Agency… END

Two American pharmaceutical companies, AbbVie and Intermune, have taken legal action to prevent or restrict the European Medicines Agency from disclosing certain clinical trial data after a medicine is approved for marketing.

In my opinion, both companies have been involved in activities that seem to prove the need for more transparency and not less.

AbbVie is a new company founded to carry on the work of most of the former medicines division of Abbott Laboratories. This was not a third party takeover, but a split of one company into two separate entities. AbbVie is basically the old medicines division of Abbott and therefore inherited the Corporate Integrity Agreement signed between Abbott and the US Government last October.

In October 2012, Abbott was required to pay $1.5 billion in criminal fines and civil settlements for promoting a medicine, Depakote, to treat dementia and schizophrenia. The medicine was not authorised for these indications.

According to the US Dept of Justice:
“Abbott has pleaded guilty to misbranding Depakote by promoting the drug to control agitation and aggression in elderly dementia patients and to treat schizophrenia when neither of these uses was FDA approved. In an agreed statement of facts filed in the criminal action, Abbott admits that from 1998 through 2006, the company maintained a specialized sales force trained to market Depakote in nursing homes for the control of agitation and aggression in elderly dementia patients, despite the absence of credible scientific evidence that Depakote was safe and effective for that use. In addition, from 2001 through 2006, the company marketed Depakote in combination with atypical antipsychotic drugs to treat schizophrenia, even after its clinical trials failed to demonstrate that adding Depakote was any more effective than an atypical antipsychotic alone for that use”.

According to the Agreed Statementof Facts, Abbott delayed for years in disclosing the full results of clinical trials showing that Depakote was no more effective than a placebo, and aggressively promoted Depakote through its sales force, special “educational” material, speakers fees, and selective use of study results.

For schizophrenia, Abbott submitted to the FDA in January 2002 the results of a trial described as “negative” by the company itself. (This was a trial of Depakote combined with another medicine.) Patients showed some improvement up to 21 days, but not up to 28 days – the primary “endpoint” of the study. However, Abbott used the 21 day results, the “secondary endpoints to promote Depakote to health care providers as a treatment for schizophrenia” at least up to 2006. The promotion was expensive and intensive and is described in the Agreed Statement.

Abbott carried out a second study on Depakote and had concluded by January 2005 that the results were negative. However, they continued for a very long time to use the first study in their promotion and did not disclose, even to their own reps, the results of the second study. In August 2006 they published a synopsis of the second study, which spoke of the Depakote combination as being “well tolerated”. It did not mention that patients treated with Depakote were more than twice as likely to suffer from “somnolence” than those treated with the alternative.

If the company had made a full and timely disclosure of their clinical trial results in this case they could not have continued to misbrand this medicine for as long as they did.

I will say something, also interesting, about the other company, InterMune, in a later post. END

Euractiv has a piece on the clinical trials proposal that has attracted a number of comments – including one from me.

It would be great if more people joined in – on any side of the question.

Here is the link

EurActiv a publié aujourd’hui une version française de mon article au sujet de la proposition de règlement de la Commission révisant la directive relative aux essais cliniques qui sera discuté cette semaine au sein de la Commission Environnement, santé publique et sécurité alimentaire.

Vous trouverez l’article ici.

Well, it’s been a long time since my last post but I have not been neglecting the subject of science and medicine. I have been following the progress of the European Commission’s proposed regulation to revise the Clinical Trials Directive, and have just published an article on the subject in Euractiv, which you can find here.

The European Parliament was to begin to debate the proposal on 24th April in the Committee on the Environment, Public Health and Food Safety, with the Committee vote scheduled for 29th May.

The Rapporteur, Glenis Wilmott, a British Labour MEP and part of the S&D Group, has prepared a Draft Report proposing some 74 amendments – not a lot for such a complex and important dossier. Other MEPS have proposed 657 amendments, which is a lot, making a total of 731.

You can find the proposal here, and all the amendments here – if you have the time to go through them. Being retired, I did have the time.

I focused on those amendments that will determine whether, how and when the results of clinical trial may be disclosed, and whether there will be more or less transparency about clinical trials in the future. My conclusions are too long for a blog but my good friends in Euractiv kindly agreed to publish my article on the subject.

In brief, I think the Commission’s proposal does aim for more transparency but probably would not achieve very much in that regard. The Rapporteur’s amendments would greatly increase transparency, by requiring in effect the publication of a Clinical Study Report within a year of the conclusion of each trial. Amendments from a few other MEPs would go even further but most of the amendments from other MEPs, especially those from the PPE and ALDE groups in the Parliament would actually reduce transparency, either in terms of substance or in terms of timing. You can read more about this in the article.

MEPs from across the political spectrum clearly felt that the Commission’s proposal did not give enough attention to ethics. Applications for clinical trias must be assessed by a “reporting” member state and, separately and in a more limited way, by each member state in which the trial will be conducted (the “Part II Assessment”). Many MEPs have proposed mandatory consultation with an ethics committee in the Part II assessment. I think the Commission might argue that member states are free to do this anyway, but I have not gone into this issue in any detail. Nor have I analysed the amendments regarding the reporting of adverse and unexpected events in clinical trials; this obviously is a vital issue and one that is the subject of many amendments. There are also some complex amendments regarding the definition of “low intervention” or as some would have it “low risk”- trials that could require a lower level of scrutiny in the application process.

When the Committee debates the proposal they will probably work from a set of consolidated amendments rather than go through every amendment from 1 to 731. The debate in Plenary is scheduled for the 10th June, but that will not the end of the story. The Parliament is a “co-legislator” and the final text of the regulaton will have to be agreed between the Parliament, 27 national governments (the Council) and the Commission – all the targets of many lobbyists.END

At a recent lunch in the European Parliament I met a hero of mine, Dr Ben Goldacre, author of Bad Pharma, a great book on science and medicine in the pharmaceutical industry. It is a worthy follow-up to his earlier best seller Bad Science, also a favorite of mine.
“Bad Pharma” is not anti-industry but rather an argument that the industry must do better. It is a carefully argued and evidence based analysis of how science is conducted and used by the pharmaceutical industry. It sets out the problems that inhibit good science, including publication bias, lack of transparency, methods of marketing, and undue influence. It does describe some instances of outright deceit but even without those examples the case for urgent reform is compelling.
It should be compulsory reading for everybody working on the proposal to update the Clinical Trials Directive.
Responding quickly to the publication of extracts from the book, the Association of the British Pharmaceutical Industry stated that “it contests some of the assertions made in the article” and “that the examples he refers to are long documented and historical, and the companies concerned have long addressed these issues”. This last claim was flatly and effectively rejected by Ben Goldacre in his Guardian column here.
(Now, people who have done something bad in the past will naturally claim that they won’t do it again, but are assurances enough in these cases?)
The rest of the APBI response was mostly a set of standard statements of the importance of the industry, a point that had never been denied, but one sentence was absurd:
“The pharmaceutical industry seeks full transparency and discloses all data in-line with international standards such as the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) Code of Practice”
In other words, they will disclose what they want according to standards and rules they make up for themselves.
EFPIA, the EU level equivalent of the ABPI tends to make similar positive and soothing statements in favour of this or that good thing. In response to my question at a seminar sometime ago about access to clinical data the EFPIA Director General Richard Bergstrom said simply that EFPIA was in favour of transparency and access to data. Well, yes they are, but only on their own terms.
Voluntary or pro-active transparency is rare. Most clinical data that is released has come about by law or by recommendations of the European Ombudsman, and against the will of their industry.

I have been looking at the proposed regulation for the revision of the Clinical Trials Directive.

To help my own understanding I prepared a “simplified” summary of most of the provisions of the proposal, which I am happy to share here.

I welcome comments, especially from anyone who feels I’ve got it wrong on any point – this is complicated stuff.

You can find a copy of the full proposal in pdf format here.

Other formats and languages are available on this link.