Thinking of Phase IV Trials? The EU May See Things Differently!

With the shadow cast by Mediator across Europe now receding to a focus on the French law courts, the European Union (EU) said in late November that its pharmacovigilance arrangements offer "one of the most advanced and comprehensive systems in the world". Certainly the EU's legislative framework has been significantly boosted over the last year (and, not least, to prevent any recurrence of the persistent regulatory failures to respond to negative signals that the Mediator episode became emblematic of). The framework is still being strengthened, and the latest development is a new consultation on when post-marketing studies should be mandatory. The more leisurely concept of Phase IV efficacy studies looks as if it may be swept aside by the EU's thinking.

Any new information received or new pharmacovigilance signals detected may have an impact on the assessment of a product's benefit-risk balance, says the EU. The recently adopted rules allow national authorities to request the marketing authorization holder to conduct post-authorization efficacy studies (PAESs), complementing efficacy data that are available at the time of the initial authorization. The result, it says, is "a more global and systematic approach to post-authorization efficacy studies".

PAESs may be required where concerns are identified about some aspects of the efficacy of a medicine, and can be resolved only after the product has been marketed. They may also be imposed when the understanding of the disease or the clinical methodology indicate that previous efficacy evaluations might have to be revised significantly. What the EU now has to decide is whether additions are needed to the existing framework to specify more explicitly how and when regulatory authorities would be entitled to exercise their new powers. It is reflecting on whether it should create a new piece of secondary legislation to provide clarity about what companies need to do, and to ensure that the rules national authorities impose are fair and clear.

The obligation to conduct a post-authorization efficacy study would be imposed on the basis of well-reasoned scientific concerns on issues that could affect the maintenance of the marketing authorization, the EU points out. The study is meant to provide the authorities and the marketing authorization holder with information that would complement initial evidence, or contribute to a decision on whether the marketing authorization should be maintained as granted, varied or even withdrawn on the basis of the new data resulting from the study.

Part of the EU's reasoning is that the value of the criteria used in the standard approach to establishing efficacy, through randomized controlled clinical trials, has, "in the past decade, been subject to some debate." This is a delicate allusion to the contamination of efficacy assessments by the search for measures of relative effectiveness – driven by the harsher environment of health technology assessment, with its eye on value for money, rather than the more disinterested investigations in the name of science.

This "increased focus on real-market access" of new medicines, which means that new products not only have to satisfy the regulatory requirements of quality, safety and efficacy, but also have to obtain positive reimbursement decisions from national healthcare systems, "has often been complicated by the inconsistent use of terminology", admits the EU. In addition, the methodologies  that are used to generate data on real-world practice - observational studies and pragmatic controlled trials - have limitations, in that, says the EU, they "sacrifice internal validity to achieve generalizability", with an impact on data quality and completeness.

Anyone with a view on the subject is invited to comment before mid-February next year. Take a look

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