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International lifesciences lawyers Nicola Dagg and Paul Brown from Lovells explain the need-to-know law on marketing drugs and treatments in Europe.

International lifesciences lawyers explain the need-to-know law on marketing drugs in Europe

Q: Why has the innovative pharmaceutical industry adopted a joint position on the disclosure of clinical trial data?

GavelA: In June 2004, the New York Attorney General, Eliot Spitzer, filed a lawsuit against GlaxoSmithKline (GSK) alleging that the company had committed fraud by: (a) withholding negative trial information, and (b) misrepresenting prescribing data relating to the use of its antidepressant, paroxetine (Paxil; Seroxat in the UK) in children.

For media commentators, this lawsuit begged answers to two questions: do antidepressants increase suicidal tendencies in children? Do drug firms only publicise study and trial results that cast their products in a good light?

However, these questions were never looked at in court because, in August 2004, a settlement was reached whereby GSK agreed to post on its website the results of all clinical trials involving its drugs. This settlement led to increased scrutiny of the way the rest of the pharmaceutical industry deals with clinical trial data, and prompted calls for greater transparency.

To this end, the innovative pharma industry, represented by the European Federation of Pharmaceutical Industries and Associations (EFPIA), the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA), the Japanese Pharmaceutical Manufacturers Association (JPMA) and the Pharmaceutical Research and Manufacturers of America (PhRMA), discussed the adoption of a policy on the disclosure of clinical trial information.

On January 6, 2005, the four bodies stated their agreement to differentiate between a clinical trials registry and a clinical trial results database.

Q: What is a clinical trials registry?

A: All clinical trials, except exploratory trials (see below), should be listed in a publicly-available registry within 21 days of the start of patient enrolment, subject to national requirements.

Submissions to the registry will include a trial description in lay terminology, information on the trial type, status and purpose, the condition or disease that the trial is intended to address, eligibility criteria and the location of the trial, as well as contact information.

One of the purposes of the clinical trials registry is to enable patients and doctors to access such information in order to make an informed decision about enrolment in trials. Each trial will be assigned a unique, identifying code number to ensure the transparency of the trial from its start to the publication of the results. All sponsors of clinical trials are requested to commit to keeping the registries accurate and up to date.

The reason that a trial is registered at its start, as opposed to the sponsor simply agreeing to publish the results of all trials, is to ensure that negative data arising from trials cannot be buried, or not published. Therefore, enrolment data will be available for all clinical trials planned or commenced, other than exploratory trials.

Q: How do you define an "exploratory" trial?

A: There is a phrase used in the agreement, all clinical trials, other than exploratory trials, which is intended to have the same meaning as hypothesis - testing clinical trials or confirmatory clinical trials, as defined in the ICH Harmonised Tripartite Guideline E9.

The difference between confirmatory clinical trials and exploratory trials is that exploratory trials only serve to set the direction of, or generate hypotheses for, possible future studies, whereas confirmatory trials test hypotheses using statistically valid plans and provide firm evidence of safety and/or efficacy to support product claims.

It is possible that we will see more exploratory trials being run by pharma companies in order to finely tune the hypothesis for full clinical trials, increasing the chances of a trial being considered a success, while in the meantime avoiding any general disclosure obligations.

The danger is that pharmaceutical firms will become more risk averse, and as a result, potentially lifesaving treatments with less than perfect safety records from exploratory trials may never get to the full clinical trial stage, never mind to market.

Q: What is a clinical trial results database? 

A: The clinical trials results database will contain information on completed clinical trials. The theory is that the results of all clinical trials (other than exploratory trials of course) conducted on drugs that are approved for marketing and commercially available should be publicly disclosed, regardless of the trial's success.

However, results from exploratory trials should be published if they are deemed to have significant medical importance, or if they could have an impact on the labelling of a marketed product. All results should include the unique identifier used to register the trial at its commencement.

There may be trials which are not exploratory trials and where the product is never marketed due to the trial being considered a 'failure'. In this case, there is no obligation to publish the trial data, but study sponsors are encouraged to post the results (if possible), if the information has significant medical importance.

The pharma associations' joint position states that generally, results should be posted within the first year of a product being approved and marketed in any country. For post-marketing trials, the results should be published within one year of trial completion.

However, there is a 'get-out', in that these timings do not have to be complied with if posting such results would either compromise publication in peer reviewed medical journals, or contravene national laws or regulations.

The purpose of permitting trial results to remain unpublished until up to one year after marketing (which may be several years after trial completion) is not made clear, but may serve to give the companies enough time to prepare the summaries that are actually published. It will also benefit companies that discover further potential uses for their products during the clinical trial, in that they will have a time window in which to seek patent protection, before revealing their data.

It is also possible that the companies would not want any scrutiny of their results prior to marketing authorisations being issued by regulatory agencies - if results were published on the immediate
completion of trials, it would be possible for competitors to make representations to the regulatory agencies and delay entry to the market for the new products.

It is worth noting that for both the clinical trial results database and registry, registration on any one of a number of internet-based registries amounts to compliance with the joint position.

It seems likely that most of the large innovative pharmaceutical companies will set up clinical trial registries and results databases that will be accessed through their own website. However, smaller innovative companies, or generics companies, may be able to effectively hide clinical trial results by posting them to less well known registries, thus keeping them out of the public gaze. Yet, it is difficult to know at this point if this is likely to happen in reality.

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Date for compliance 

Any trials that start on, or after, July 1, 2005, should be included in the clinical trials registry, and data from ongoing clinical trials that are covered by the joint position should be included in a clinical trials registry by September 13, 2005.

The proposals on the clinical trial results database only apply to clinical trials that are completed after the date of the publication of the joint position statement, which was January 6, 2005.

Q: Will the data reporting obligations bring new risks?

A: On first glance, the new commitment to transparency, combined with the potential effects of the Freedom of Information Act 2000 in the UK (which was fully implemented in January 2005), seems to severely erode the confidentiality that pharmaceutical companies have, up until now, used to protect their data.

However, some people believe that this is a positive change, as the publication of the data will lead to increased scrutiny, and ultimately safety, of pharmaceutical products. Yet, several questions arise.

It is unclear exactly which data the pharmaceutical companies propose to publish in the registries. When discussing the settlement of the GSK action, New York Attorney General, Eliot Spitzer, acknowledged that posting clinical trial results on-line was not a panacea, and said that there would not be a perfect understanding of testing and clinical variables. To the lay person, the clinical trial results will be largely unintelligible, but the theory is that their publication will allow academics and doctors to make enquiries on new pharmaceuticals, when previously they may not have had access to the data.

GSK reported in its original analysis of its trials for Seroxat that there was an increased level of, what the company termed, emotional liability among children given the drug - it was only when a reviewer at the FDA questioned this that it became clear that children and teenagers given Seroxat were more likely, specifically, to have suicidal thoughts than those given a placebo. So, it may still be open for pharmaceutical companies to phrase reports in opaque language.

Product liability 

If all data from all clinical trials in relation to marketed products is made available to the public, there may be more incentive for patients to pursue product liability actions against pharmaceutical firms.
Currently, trial data is available on discovery in litigation in common law jurisdictions, but is often not available at all in civil law jurisdictions. When the data is published, it will be possible to read the reports and look for evidence of knowledge of side effects, or other detrimental characteristics. It could then be argued that further investigation should have been carried out into those effects or characteristics, so helping to build a case against the producers of the product.

Marketed products

As explained previously, there is only compulsion for companies to publish the trial results for marketed products. If the results of an investigational trial bear significant medical importance, sponsors are encouraged to publish the results. However, if there is the possibility that those results will affect sales of other products in that company's range, it seems unlikely that negative data will be published. This may present dilemmas for pharmaceutical companies, but only in the same way that such data would cause similar problems now.

There may also be a question over data from a clinical trial for a product that was marketed previously, but has since been withdrawn - for example, Thalidomide. Would this data need to be published within one year of the trial, or within one year of any relaunch?

Positive spirit

The good publicity that the innovative pharmaceutical industry received for the publication of the joint position paper was very welcome, and now it is for the industry to build on this to restore the public's faith in it.

In order to do this, the spirit, and not just the word, of the joint position will have to be complied with. It seems at this stage that this is the intention of all the main players, but it remains to be seen if this is still the case when negative trial results emerge for otherwise promising products.

The Authors
Nicola Dagg is a partner and Paul Brown is an associate solicitor in Lovells' international life sciences practice (www.lovells.com)

2nd September 2008

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