The offshoring of clinical research to emerging markets may now have reached saturation point, an industry executive suggested at last week’s Annual Spring Conference of the UK-based Institute of Clinical Research (ICR).

Regulatory agencies in the developed world are “beginning to say enough is enough”, commented Dr David Jeffreys, senior vice president in charge of global regulatory affairs for Eisai Europe, at the ICR meeting in Birmingham. The corollary, he believes, may be more trial networks that restore the attractiveness of established regions such as Europe and the US as locations for clinical research.

Jeffreys has viewed the offshoring trend from both sides of the regulatory fence, having served as director of the Medicines Control Agency’s Licensing Division, chief executive director of the Medical Devices Agency and acting chief executive director of the combined Medicines and Healthcare products Regulatory Agency in the UK prior to joining Eisai.

He cited a number of the familiar drivers for offshoring clinical trials, such as faster patient recruitment, access to treatment-naïve patients, improved cost/time ratios for clinical development, facilitation of global registration strategies and entry routes to emerging markets as the pharmaceutical sector shifts from a price to a volume paradigm.

But not all types of studies are readily exportable, Jeffreys noted. For example, there is a major offshoring trend for routine Phase I trials but few companies are likely to take this step with first-in-human studies. These and other, innovative Phase I trials such as microdosing tend to be conducted closer to home in specialist centres. Adaptive study designs are also more difficult to offshore, Jeffreys added.

The future could see more polarisation in this respect, with more innovative clinical trials returning to established markets while studies needing larger patient volumes head overseas, he suggested.

There are also signs of regulatory unease, Jeffreys pointed out, citing the recent strategy paper setting out the European Medicines Agency’s (EMEA) efforts to ensure that clinical trials conducted in ‘third countries’ to support drug approval applications in the European Economic Area meet the necessary ethical and Good Clinical Practice (GCP) standards.

The EMEA’s Committee for Medicinal Products for Human Use (CHMP) has also put out for consultation a reflection paper on The extrapolation of results from clinical studies conducted outside Europe to the EU population, which explores how ‘extrinsic’ factors, such as medical practice, disease definition and study population, may influence the applicability of third-country data to the EU setting.

Globalisation pains

As Jeffreys observed, this paper acknowledges that differences within the European population can sometimes be as marked as those between regions that fall into the widening embrace of global drug development.

Yet this globalisation “does not necessarily support the approval of unrestricted indications in an EU population”, the CHMP states. “On the contrary, a sponsor should take into consideration and discuss the possible influence of extrinsic factors on the interpretation of the results and ultimately the wording of the indications.”

The paper’s conclusion is to favour “an in-depth prospective analysis of potential ethnic factors when conducting a clinical trial in a certain region. Depending on the outcome of such analyses, it can be decided whether certain clinical trials conducted in a specific area of the world would be relevant to the EU setting or if there are reasons to perform additional clinical trials within the EU”.

Jeffreys’ take on the reflection paper is that the CHMP is “sending a warning” – the implication being that third-country data could lead to restrictions on labelling.

The corporate objective is a single global trial database for a single global approval filing in all commercially appropriate markets. At the same time, Jeffreys cautioned, companies need to hedge their bets by drawing up an early, comprehensive drug development plan that takes into account factors such as potential for regional sub-analyses of study data and for ‘destructive’ analyses, whereby an identified trend may not hold up if data from emerging markets are removed from the equation.

Scientifically, there are regional, national or ethnic differences in pharmacodynamic response, drug metabolism, genetic polymorphisms, pathophysiology of disease, diet and environment, not to mention associated influences like support structures, comparator therapies and reporting of adverse drug reactions (ADRs), Jeffreys recognised.

He also highlighted some of the other potential obstacles to offshoring clinical trials, both ethical and practical. These range from interpretative difficulties in areas such as patient acceptability scoring to start-up delays, infrastructural weaknesses, varying expectations of post-trial treatment or travel time/costs.

Elephant in the room

Paul Wathall, senior clinical trials manager for HCA International, was even sceptical. He pointed to concerns about companies ‘dumping’ trials that would be unacceptable in the developed world, exploiting poor and desperate patients to develop drugs that will be sold primarily in other markets.

But the real “elephant in the room” is just how applicable developing region data are to populations in the West, Wathall told the conference. He offered a number of case studies suggesting that the impact of globalisation on external validity – how much trial results can be generalised to other populations – “has largely been overlooked”.

In popular offshoring regions like Eastern Europe, for example, there are significant variations in baseline risks for key conditions such as coronary heart disease, Wathall pointed out. Other potential confounding factors include whether more extensive drug naivety in emerging markets could mask higher potential for ADRs in the West.

These distortions may lead to an overestimation of drug benefits or harm, Wathall warned. Offshoring should still be encouraged but there may be an argument for limiting the numbers of patients from other countries used in clinical trials. Meanwhile, he proposed, both regulators and peer journal reviewers should be paying closer attention to external validity.