Year Before Europe’s New Clinical Trials Regulation Take Effect, Pharma Companies Must Prepare For A Tough Compliance Challenge


Next year about this time, the European Union will implement a new clinical trial regulation (EU CTR) meant to help pharmaceutical companies by offering clear and consistent rules for conducting clinical trials. The new regulation, EU CTR 536/2014, adopted last year and scheduled to take effect in May 2016 is intended to simplify a previous set of requirements governing clinical trials.

But the new rules also are expected to spark considerable turmoil around the conducting of non-interventional trials (also known as observational studies). Many questions remain around vague regulatory language and the need for every EU country to review and alter existing national regulations. In fact, the new regulation created an entirely new category of trial that almost no one has tried to implement before.

The resulting confusion makes it increasingly difficult to satisfy the first order of regulatory compliance: knowing the rules with which you need to comply.   And, confusion costs money – sometimes a lot of it.

The new regulation repeals a Directive issued by the European Parliament in 2001 that established common rules for good clinical practice in drug development.  It set forth clear rules for interventional trials on everything from adverse event reporting and safety monitoring to the type of information to be submitted to regulatory bodies and ethics committee.  While the Directive did a good job of clarifying the rules for conducting clinical trials in Europe, it considerably muddied the waters for companies wishing to conduct non-interventional studies.

The definition of a non-interventional trial was clear enough.  The 2001 Directive said it was:

  • A study where the medicinal product is prescribed in the usual manner in accordance with the terms of the marketing authorization;
  • A trial in which patients are assigned to a particular therapeutic strategy that is not decided in advance by a trial protocol but falls within current practice and the prescription of the medicine is clearly separated from the decision to include the patient in the study; and,
  • A trial in which no additional diagnostic or monitoring procedures shall be applied to the patients and epidemiological methods shall be used for the analysis of collected data.

It was this last aspect of the 2001 definition that has led to some of the greatest confusion.   While the Directive offered a reasonable definition of a non-interventional study, it did not mandate how they should be conducted.  That was left up to each of the 28 European countries to define and codify.  Some countries, for example, saw a blood draw as reason for classifying research as a clinical trial while other nations did not.  What evolved was a jigsaw puzzle of differing legal requirements that could cause a single research study to be classified in multiple ways depending on where it was conducted.

The new regulation seeks to standardize the rules Europe-wide, as well as increase the scope of what is considered a clinical trial. Expanding the definition of a clinical trial, as it turns out, will have an enormous impact on companies wishing to conduct non-interventional studies.

As of May 2016, there will be three categories of research: clinical trials, non-interventional studies and a new third category called low-interventional clinical trials.  A low-interventional clinical trial is a non-interventional study by design but one that includes some form of additional diagnostic or monitoring procedures that carry minimal risk or impact on patients, such as a study-specific blood draw.

These low-interventional clinical trials will cost sponsors far more than the standard non-interventional study.   In addition, how a study is classified, directly and significantly impacts which regulations must be followed.  Consequently, getting a study classified correctly is essential for research sponsors, from both a financial and legal perspective.

As the deadline for implementation of the new regulation approaches, individual companies must stay current with the changing landscape, take measures to mitigate risk, and find partners for navigating the shifting seas of European regulation.   Over the next few years national laws across Europe will be under review to assure compliance with the EU regulation, and companies must stay abreast of these country-specific changes.

Meanwhile, the only certainty is that uncertainty is going to get worse.  The rules and regulations governing clinical trials have not been changed for a decade, but globally, the rules, regulations and guidelines governing non-interventional studies are changing about every six months. So what is the sponsor of a non-interventional study to do?

  • First, make sure your study is appropriately classified. Become as familiar as possible with the new requirements for non-interventional studies and low-interventional clinical trials so as not to confuse the two.
  • Incorrectly classifying a study as non-interventional that should be classed as interventional or low-interventional could jeopardize the data and endanger patients.   But doing the reverse, and out of an excess of caution misclassifying a non-interventional study as a clinical trial, could waste tens of millions of dollars.
  • Talk to payers about their requirements.
  • Be aware that the regulatory requirements for non-interventional studies are different in every country and are likely to change (again) throughout Europe in 2016.
  • Work closely with Regulatory Affairs staff and with trusted advisors.
  • Continue to lobby EU regulators for clear guidance on what makes a study a low intervention clinical trial versus a non-interventional study.

All this confusion is playing out at the very moment when real-world data from non-interventional studies has never been more important.   Such data obtained from patients in real life conditions is now essential for building the evidence required by regulators for payment and reimbursement decisions.

Companies that expect and prepare for a regulatory environment in flux will be more likely to marshal their resources, call in their experts and be aware of the specific, potential pitfalls to be avoided.   There are a lot of pitfalls ahead.