Tardy Europe Finally Signs Up on Data Transparency

February 1, 2005

Applied Clinical Trials

Industry?s proposal for a shared database has merit, but is it ?too little too late??

Industry's proposal for a shared database has merit, but is it "too little too late"?


The rest of the world caught up with Europe in January, when an agreement was finally reached on an international joint position statement on disclosure about clinical trials. At least that's what Europe is saying.

The European Federation of Pharmaceutical Industries and Associations (EFPIA) claims that it was ready to come out with a commitment on public access to trial data way back in 2004. But it deferred its own publication, it says, so that a common announcement could be made, in concert with other major drug industry associations around the globe.

In the end, when the 6 January "Joint Position on the Disclosure of Clinical Trial Information via Clinical Trial Registries and Databases"1 was released by EFPIA, the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA), the Japanese Pharmaceutical Manufactures Association, and the Pharmaceutical Research and Manufacturers of America, it appeared to be more of a damp squib than a firework display of public accountability.

The public image had deteriorated significantly for clinical research, in the wake of the late-2004 controversies over the safety of many major products--notably the COX-2 inhibitors. So the commitments in the joint statement were not greeted with universal acclaim. "Too little, too late," was typical of some of the reactions to the declaration.

The unfortunate timing should not detract from the intrinsic merit of the new arrangements. They amount to an important engagement to increase the transparency of clinical trials sponsored by companies in membership of the signatory associations--which represent the vast majority of the world's innovative drug firms.

New or ongoing trials
Under the new arrangement, details of clinical trials initiated on or after 1 July 2005 will be submitted for listing in a free, publicly accessible clinical trial registry within 21 days of the initiation of patient enrollment. Any one of a number of Internet-based registries may be used--such as the clinical trial registry maintained by the U.S.'s National Institutes of Health at www.clinicaltrials.gov.

The entry in the registry about each trial will include a brief title and trial description in lay terminology; phase; type (e.g., interventional); and status and purpose of the trial--whether it is for treatment, diagnosis or prevention. It will indicate the intervention type (e.g., drug or vaccine); the condition or disease; the key eligibility criteria, including gender and age; the location of the trial; and contact information.

Each trial listed in the registry will be given a unique identifier, which will permit registry users to track the trial through multiple databases, including clinical trial results databases, to ensure transparency.

The declaration also indicates that industry "is also prepared to explore the concept" of a secure, nonpublic third party electronic repository for subsequent disclosure to medical journals. In fact, Europe has already set up the EudraCT database of interventional clinical trials initiated in the European Union since 1 May 2004. This is accessible to European regulatory authorities from the time of trial initiation. Some data fields will subsequently be made publicly accessible once the product is approved.

There are some qualifications to the commitments. They cover only "hypothesis-testing" or "confirmatory" clinical trials using statistically valid plans for data analysis, and aim at providing firm evidence of safety and/or efficacy to support product claims. They do not apply to "exploratory" trials aimed at setting direction or generating hypotheses for possible future studies.

Further, they apply only where there are no alternative national requirements. And the disclosure must maintain protections for individual privacy, intellectual property and contract rights, as well as conform to the regulations in relevant countries.

Completed trials
For completed clinical trials, the commitments go even further. From the beginning of 2005 onward, the results of all clinical trials (other than exploratory trials) conducted on an approved, commercially available drug should appear by 13 September 2005 on a free, publicly accessible, clinical trial results database, regardless of outcome.

And where trial results from exploratory trials could have significant medical importance and may have an impact on a marketed product's labeling, they should also be publicly disclosed. Similarly, where trial results for an investigational product that has failed in development have significant medical importance, study sponsors are also encouraged to post the results.

If trial results are published in a peer-reviewed medical journal, the database should include a citation to or link to the journal article and/or a summary of the results. This will be in a standard, non-promotional format covering trial design and methodology, results of the primary and secondary outcome measures, and safety results. If trials results are not published in a journal, the summary results should be posted on the database.

The results should include the unique identifier used to register the trial at inception, and should be posted within one year after either the drug is available or postmarketing trials are completed.

Now companies are being invited to subscribe to the joint position. Then it will be up to them to establish a process of verification for both the clinical trial registry and the clinical trial database, and to make public how they will adhere to these standards. And all trial sponsors are encouraged to commit to keeping registries accurate and up to date.

Regulatory concerns
Meanwhile, the European Medicines Agency has decided to accelerate its review of COX-2 inhibitors, after Vioxx raised cardiovascular concerns.

In December, the agency reviewed summaries of two clinical trials relating to celecoxib and found that while they were not consistent or conclusive, the data indicated that an increased risk of serious cardiovascular events seen in one trial--the Adenoma Prevention with Celecoxib trial--"may be related to the dose and duration of treatment."

The similar Prevention of Spontaneous Adenoma Polyps trial did not show any evidence of an increased risk of serious cardiovascular events, overall or in subgroups. The reason for the different results "is not apparent," the agency remarked, and will continue analysis.

Based on the preliminary assessment, the agency will not be recommending any immediate regulatory action to restrict the use of celecoxib and other COX-2 inhibitors, but it undertook to review on an expedited basis the full clinical trial data and further information on other COX-2 inhibitors in January 2005. The companies concerned were requested to submit all-new data and analyses in early January for review by the Committee on Medicinal Products for Human Use.

Meanwhile, the agency has limited its advice to encouraging prescribers to carefully follow the latest version of the summary of product characteristics for COX-2 inhibitors, especially regarding the warnings and precautions in patients with a history of cardiovascular disease. And it has reminded patients that they should be aware that all COX-2 medicines available in Europe already contain warnings regarding heart problems.

There is a lot riding on the outcome of these continuing reviews of COX-2 medicines. The credibility of the products are at stake. So are the regulatory processes themselves, in Europe and around the world. And the joint declaration from the industry on public access to registries and databases will not be enough to satisfy widespread concerns.

Reference1. http://www.efpia.org/4_pos/sci_regu/Clinicaltrials2005.pdf