The European Medicines Agency (EMA) has announced the release of a new final guideline regarding the investigation of medicinal products intended to treat depression, providing a nuanced approach to treating depression in several subpopulations and bringing a two-year consultation process to a close.
The guideline covers all products intended to treat Major Depressive Disorder (MDD) on a consistent basis, with a particular emphasis on treating major depressive episodes. EMA notes that despite the availability of several treatments, "There is still a need for new medicinal products with better efficacy (e.g. faster onset of action, higher rates of response and remission) and improved safety profile in patients with MDD."
That doesn't mean much will be changing with the basic trials now used to approve the drugs, EMA explained. The gold standard will remain randomized, double-blind, placebo-controlled, parallel group studies that assess the drug's meaningful impact on MDD. Regulators said that the use of a placebo can be controversial, particularly during acute episodes, and trial sponsors must take precautions to balance risks to the patient with the impact on the study. This can be done by limiting the length of the trial to six weeks. Longer trials will have to be justified and include fail-safe provisions. Acceptable rating scales must be used during the course of these trials, EMA wrote.
In addition, EMA said it "has to be shown that initial response to treatment is maintained in at least one study following a randomized withdrawal design or an extension study for 6 months." Data suitable for supporting an approval decision would show that a short-term effect can be maintained during this time, regulators added.
What is changing, however, are the requirements for clinical trials designed to assess a treatment's effect on children, adolescents and the elderly, as well as patient populations that express only a partial response or general resistance to treatment. EMA said approximately 20% of MDD patients are considered non-responsive, even when fully compliant with the therapy. "Notwithstanding that no validated clinical criteria and thresholds to define TRD and partial response at present are available, generation of such data would be highly supported," EMA added, saying it defined treatment-resistant depression as failure to respond to at least two different antidepressant agents.
Despite the difficulties associated with identifying patients with TRD, EMA said its treatment could be a "separate but additional claim" on the drug's approved label. At least one additional short-term trial would be needed to support such a claim, though no additional maintenance studies would be required. Patients would likely be selected via a subgroup analysis of the main treatment group, EMA added.
Augmentation Therapy and Special Populations
EMA's guideline also covers the use of add-on therapies, something known as augmentation. Companies must substantiate claims of added effectiveness through their use in short- or long-term trials enrolled with patients that failed to fully respond to monotherapy (excluding those thought to have TRD). "It is of critical importance that the applicant can establish that the population recruited to the trial are true partial responders," EMA said.
Sponsors should also take care to monitor subpopulations for potentially adverse responses. These populations include the elderly, children and adolescents. EMA takes divergent views when it comes to determining whether data extrapolation is permissible in these populations. For example, extrapolation may be used in some instances under the ICH E7 guideline when dealing with elderly patients so long as some elderly patients are included in a trial to compare response rates. However, for newer products, specific trials may be required to test a drug's efficacy in an elderly population.
Extrapolation is not, however, considered appropriate for populations of adolescents or children, and specific studies are necessary to support approval, EMA said. Stratification of age groups is also necessary when conducting a trial that includes both young children and adolescents. Such trials should be at least eight weeks in length (or longer).
The guideline also addresses something outlined by FDA in a 2012 draft guidance: suicidal ideation, a side effect long associated with antidepressants. EMA said these thoughts and behaviors will need to be closely monitored using validated tools to ensure that they do not develop or worsen.
Other adverse events that should be monitored include serotonin syndrome, Qt prolongation, delirium, metabolic changes, haematological events, decreases in cognitive function, psychiatric adverse events, sexual dysfunction, cardiovascular adverse events, dependence and withdrawal symptoms, and other potential long-term safety issues.
The guideline goes into effect on 1 December 2013.
EMA: Guideline on clinical investigation of medicinal products in the treatment of depression