IQWiG calls for mandatory registration and publication of all clinical trial results

Institute for Quality and Efficiency in Health CareNov 25 2009

Today the Institute for Quality and Efficiency in Health Care (IQWiG) is calling for registration and publication of the results of all clinical trials to be made obligatory. The German Federal Government must push for a mandatory regulation to be implemented at EU level; in the USA this obligation has been in force since 2008. This has been brought to a head by the publication of the final report on three antidepressants which was greatly hindered by Pfizer. For a long time, the manufacturer refused to make information on trials available to IQWiG. Only when put under public pressure did Pfizer finally disclose the data.

"By concealing available study data, the manufacturer is depriving patients and doctors of the opportunity to make an informed decision on different therapy options," explains Peter T. Sawicki, Director of IQWiG. Furthermore, it hinders the work of institutions such as IQWiG. IQWiG's aim is to draw reliable conclusions concerning the benefit and harm of drugs. These provide the Federal Joint Committee (G-BA) with a scientific basis for its decisions on reimbursement of drugs.

The fact that study results are only partially published has been known by the term "publication bias" for over 20 years. In this respect, it has been shown that particularly "negative studies", in which, for example, the company's drug did not produce the hoped-for result or even proved to have no effect, are published only years later or not at all. This means that patients and doctors receive an overoptimistic picture of the effects based solely on published reports.

This trend is still one of the most important and dangerous sources of error in medicine. "Deception through concealment is no trivial offence," says Sawicki. "In extreme cases, patients may even receive useless or harmful treatments if information is incomplete."

For example, in the treatment of depression other researchers have already shown that the effect of several agents has always been overestimated in the published literature - up to 70% (on average about 30%). In the case of some agents, it is even doubtful whether a benefit is detectable at all, if all trials are considered.

It is particularly dangerous that doctors and researchers are often totally unaware that unpublished trials exist. In order to solve this problem, IQWiG concluded a basic agreement on the transfer of such data with the German Association of Research-based Pharmaceutical Companies (VFA) as early as 2005. Furthermore, in January 2005 the international associations of the pharmaceutical industry announced a voluntary commitment to disclose information on clinical trials.

However, these announcements from the pharmaceutical industry cannot be relied upon. In recent years, companies have repeatedly refused to provide the Institute with study documents required for the benefit assessment of drugs. Frequently, clinical trial registries, which have been set up in recent years, do not contain these data either.

The aim of the project just completed was to assess the benefit of the three agents, reboxetine, mirtazapine and bupropion XL in the treatment and prevention of depression. The complete data on reboxetine now available to us show that approximately 5100 patients were treated in the 17 trials included in the benefit assessment. Sufficiently transparent published data were available for only 1600 of those patients. Thus, the results of approximately 2/3 of the patients are missing in the publicly available literature. The published results suggest a benefit, but this cannot be proven when all the data are considered.

IQWiG's experience has shown that the existing countermeasures, which are primarily based on voluntary solutions in Germany and Europe, are inadequate. It is not known when and how statutory regulations aimed at solving the problem will actually take effect. IQWiG is therefore calling for an EU-wide legal obligation, bound by tight deadlines, to publish the results of clinical trials.

"In the USA this obligation has been clearly implemented by law since 2008," explains Sawicki. "We need a comparable, definite and transparent implementation for Europe as soon as possible." In this context, it is essential that such an obligation must also apply retrospectively to drugs already approved. Moreover, statutory regulations are necessary so that all data are provided on request to institutions such as IQWiG or the G-BA.

By concealing data, manufacturers are also breaking agreements that were made with study participants, who put themselves at risk by taking part in experiments both voluntarily and altruistically. Through their participation and the publication of the results, they also want to help others who are ill. This is a prerequisite of their consent to participate in drug trials. Sawicki concludes, "Keeping the results of a trial secret is cheating the participating patients and questions the legitimacy of their consent to participate in trials.