Nearly two thirds of clinical trials conducted under the US Paediatric Exclusivity provision involve at least one site outside the US, while more than a third of them use at least one site in a developing/transition country, a new analysis suggests.

This globalisation trend raises scientific and ethical questions about the extrapolation of trial results, economic pressures to take part in research, informed consent, and the applicability of trials to local health needs, say the authors of the study published in the journal Pediatrics.

A team from Duke University Medical Center and Duke Clinical Research Institute in Durham, North Carolina looked at published studies including the main outcomes of trials conducted between 1998 and 2007 under the Pediatric Exclusivity Provision, which offers six months of patent exclusivity to companies assessing the safety and efficacy of drugs in children.

According to Duke University, the programme has led to more than 150 labelling changes for children’s medicines in the US and has generated an estimated US$14 billion in profits for the pharmaceutical industry.

Of the 174 trials included in the analysis, 9% did not report any information on the location or number of study sites used. Of those trials that did supply this information, 65% were conducted in one or more countries outside the US while 11% did not include any sites in the US.

A total of 54 countries were represented in the trial reports and 38% of the studies covered enrolled patients at one or more site in a developing/transition country, including over one third of infectious disease, cardiovascular disease and allergy/immunology trials.

Lead author Dr Sara Pasquali acknowledged the potential benefits of globalisation in paediatric research, such as reducing costs and time lines for drug development, fostering global clinical innovation and improving access to therapies worldwide.

But she also questioned whether trials conducted outside the US were always scientifically appropriate.

The original objective of the paediatric exclusivity programme “was to encourage research that enables the FDA [Food and Drug Administration] to label drugs for appropriate use in children in the US”, Pasquali noted.

“Whether it’s valid to extrapolate the results from trials conducted in other countries is not known. The efficacy of a medication may depend on genetic background and access to healthcare resources, among other factors, which may differ across countries.”

The study authors also raised concerns about whether paediatric research being conducted outside the US was sensitive to the health needs of the local population and whether the treatments assessed would be readily available to children in those countries once the trial had ended.

They were also worried about how children and families in developing countries might be induced to participate in trials. Taking part in a clinical study might be the only access a family had to medical care, while compensation for trial subjects could be significant, they observed. Moreover, ensuring adequate informed consent could be problematic in countries with widespread illiteracy.

Among a number of recommendations put forward by Pasquali et al for tightening up the conduct of paediatric trials conducted outside the US were:

  • Insisting that pharmaceutical companies describe how the proposed study  population for a paediatric trial matched the intended market for the drug under evaluation.
  • Requiring all studies conducted under the Pediatric Exclusivity Provision to be published and to include specific data about the setting and location of the trial.
  • Improving mechanisms of global regulatory oversight, with input from all stakeholders.