Treating Stress in Patients in Europe

June 1, 2009

Applied Clinical Trials

Volume 0, Issue 0

EMEA releases new guideline for studies in PTSD, as new figures depict a lagging EU.

New perspectives are opening up for pharmacological treatment of post-traumatic stress disorder (PTSD), according to the European Medicines Agency (EMEA). So far, drug treatment options for this severe and prevalent pathology have been limited.

Peter O'Donnell

Serotoninergic agents, tricyclic antidepressants, mood stabilizers, adrenergic inhibiting agents, antipsychotics, and benzodiazepines have all been proposed for controlling symptoms, but to date only sertraline and paroxetine have been authorized for treatment. But the prospects are now "potentially promising," says EMEA, presenting a new guideline on the planning of studies in this area.

As the agency points out, numerous biological dysregulations are being identified among PTSD patients, covering the opioid, glutaminergic, noradrenergic, and serotoninergic neurotransmitter systems, resulting in neuro-endocrinological disturbances and physiological symptoms. Neuroimaging studies in PTSD show alterations in brain function in the medial prefrontal cortex, hippocampus, thalamus, amygdala, anterior cingulated gyrus, temporal cortex, and visual association cortex.

However, advances in understanding the disorder "also raise the question of how to deal with the complexity," the agency observes. The clinical response to a medicinal product could depend on its pharmacological properties, on the time to treatment after exposure to the trauma, on the type of trauma, and on predominant symptoms. Further challenges include the high prevalence of co-morbid depression, substance abuse, and anxiety disorders and the diagnostic criteria to be used. Hence the guideline.

In designing studies, says the agency, patients should be diagnosed by an experienced psychiatrist according to an acknowledged classification system, and confirmed by a structured interview. The use of a severity rating scale alone is insufficient and is not equivalent to a diagnosis. But the severity of the disorder should be assessed, and a minimum severity for inclusion should be defined and justified.

Further parameters, such as duration of the disorder, whether onset was immediate or delayed, presence/absence of childhood trauma-neglect-abuse, and the type of precipitating event (i.e., combat, abuse, natural disaster, whether physical injury was involved, and whether the event had an acute or a chronic nature) should be ascertained and specified in the inclusion criteria. Patients with a current or recent history of major depression should be excluded from the study, as should patients with recent or concurrent psychiatric co-morbidities or patients receiving specific psychotherapy.

Efficacy assessment

In assessing efficacy, the primary endpoint should be based on an established severity scale that captures the core symptoms and has known and acceptable psychometric properties.

The scale needs to be validated in advance in the target population. Improvement of symptomatology should be documented as a difference between baseline and post-treatment score, and also expressed as the proportion of responders and/or remitters. Criteria for response and remission should be outlined and justified in the protocol. Results should be discussed in terms of both clinical and statistical significance, and improvement should be demonstrated on all core symptom clusters. Global assessment or other scales addressing issues such as social functioning may be used as secondary efficacy endpoints in confirmatory studies.

In the strategy for clinical trials, exploratory trials can make use of pharmacodynamic tests to support the working mechanism of the test product, by demonstrating effects on dysregulated neurotransmitter systems in brain areas that are hypothesized to be involved.

The usual pharmacokinetic studies should be performed, and in dose-response studies, plasma levels may be studied. Controlled, parallel, fixed-dose studies, using at least three dosages are needed to establish the effective dose range as well as the optimal dose, based on efficacy and tolerability. The agency recommends the addition of a placebo as well as an active comparator to these studies.

In therapeutic confirmatory studies, parallel, double blind, randomized placebo controlled studies are necessary to establish acute efficacy. The duration of these studies should be derived from pilot studies indicating the time necessary for achieving a stable effect. Comparison with a standard product already registered for the treatment of PTSD as a third study arm is recommended to make it possible to put the size of the effect into context in relation to standard treatment. The dose and the comparator should be justified.

When estimating the effect on PTSD, it is necessary to control for the effect of treatment on depressive symptoms in the statistical analysis. The effect should be robust when residual depression symptoms are controlled for.

Since PTSD is a chronic condition, long-term efficacy and safety should be demonstrated. A possible design for demonstrating maintenance of effect over longer durations is a randomized withdrawal study. The duration of the long-term studies should be justified. Efficacy in long-term controlled studies is usually expressed as the proportion of patients worsening (relapsing) and/or time to this event. Both efficacy criteria are of interest and should be presented. Worsening and relapse have to be defined in the protocol and should reflect clinical relevant increase of symptoms, scored on a validated rating scale at one or more visits.

Multinational trials

Meanwhile, the European Forum for Good Clinical Practice is turning its attention to the equally thorny question of whether it is possible to achieve a single clinical trials authorization (CTA) in multinational clinical trials. It has chosen the rather pessimistic title of "Dream or Option?" for the workshop it is organizing in Brussels in July. It is, however, promising to offer views on the current situation in the European Union from the viewpoints of regulatory authorities and of commercial and academic sponsors, with a focus on how the authorities interact in a pan-European, investigator-driven trial.

Current projected solutions include a form of voluntary harmonization, and versions of the current centralized or mutual recognition procedures that apply to marketing authorizations in Europe. The difficulties are evident as soon as discussion turns to how far European research ethics committee procedures—notoriously divergent in Europe—could be harmonized, or the review process and accreditation of research ethics committees in Europe could be coordinated.

Pessimism is likely to turn to gloom, however, as the workshop includes titles such as "Can We Agree on a Common Priority List of Deficiencies in the Current CTA System?"

Europe slipping behind

While Europe continues to labor over the creation of a credible system for regulating clinical trials, it is falling ever further behind in the international innovation stakes, according to a study released in early summer by the European chambers of commerce.

As disappointing 2009 growth forecasts confirm the scale of the global recession, the EU continues to lose ground on its global competitors, says the latest edition of Eurochambres' annual "Time-distance study." This study—which compares the distance between the main global economies in terms of years—confirms that the 27-member EU still lags well behind the United States, while the gap with so-called BRIC countries (ie., Brazil, Russia, India, and China) remains significant, but is narrowing dramatically.

The EU27 is lagging behind the United States for all key economic indicators (GDP per capita, productivity, investment in R&D) by an average of 24 years. This means that the current performance of the EU for these indicators was reached by the United States in the 1980s. Investment in R&D is the worst indicator, with the current level of European investment in research and development having been attained by the United States 30 years ago, says the study.

If the growth rates presented today are confirmed in the long term, the EU will only catch up with the current level of U.S. GDP per capita in 2047, it warns. Arnaldo Abruzzini, Secretary General of Eurochambres, said: "These figures tell us that if the EU is to maintain and enhance its global competitiveness, it must put in place not only a short-term strategy to exit the recession, but also long-term structural reforms. Time is not on our side...we cannot afford to delay any longer much needed investment in R&D and skills. Policy makers must provide businesses with the right framework conditions to drive Europe's recovery and future growth."

The same theme was picked up recently by the president of the European Federation of Pharmaceutical Industries and Associations (EFPIA), Arthur Higgins, who is also the boss of Bayer Healthcare. On the eve of the EFPIA's annual conference, he warned that Europe's neglect of innovative industries was obliging companies to move their operations "to where the markets are"—which was, he said, increasingly in the BRIC and other emerging economies.

He lamented the European tendency in this time of recession to provide support only for industries that were already weakened (EU governments have been bailing out their ailing automotive manufacturers), instead of backing strong industries with a sustainable future—notably the pharmaceutical sector.

Peter O'Donnell is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium.