The European Medicines Agency (EMA) is out with a new guideline on conducting clinical trials for products intended to treat schizophrenia which it says addresses a number of specific issues, including study design, use in sub-populations and use of add-on and combination therapies.
Schizophrenia is a highly varied psychiatric disease that EMA notes is characterized by a "heterogeneous course and symptom profile." Approximately 1% of the population is affected over the course of their lifetimes, with many patients only assuming symptoms in their later teenage years or early 30s. Symptoms commonly include delusions, hallucinations, rambled speech and catatonic behaviors, EMA explained.
The guideline, entitled Guideline on clinical investigation of medicinal products, including depot preparations in the treatment of schizophrenia, focuses on the development of clinical trials to show an anti-schizophrenia product's safety and efficacy.
EMA notes the use of a placebo control group in a highly controlled setting is encouraged since, "Assay sensitivity cannot be guaranteed even in well designed and conducted trials if a placebo arm is not included." Relapsing patients should immediately receive treatment, notes EMA, and trial escape criteria should be well-defined.
"Confirmatory trials should be double-blind, randomized, parallel group trials," explained EMA. Crossover designs are not suitable, it added. Studies should also justify the use of their comparator product, which should be of the same class or have a similar pharmacological profile. First-in-class products should be compared to the existing "gold standard" product.
The product's effectiveness versus a broad range of symptoms should be assessed with the use of total score instruments such as the Positive and Negative Symptom Scale (PANSS) or the Brief Psychiatric Rating Scale (BPRS), EMA said, but cannot be extrapolated to other psychoses without specific testing to establish the drug's effect on the underlying cause of the disease. The use of scales is particularly important because cognitive impairment in schizophrenia patients may be the result of the disease, or may be the result of other illnesses, medications, depression or physical problems.
The use of biomarkers is allowed by EMA, but regulators said that will not be permitted to replace clinical testing.
Some medications may be permitted to be used along with the test treatment, "To the extent that they do not compromise detecting signals of safety and efficacy of the drug candidate." The rationalization for this determination should be provided, said EMA.
However, other products that "augment the test treatment" should not be used concomitantly, EMA explained. Psychotherapy, psycho-education, support and counseling may be offered so long as they are defined in the protocol and documented. If such treatments are used, they should be done only as a specific strategy in support of a therapy being used in conjunction with another.
Regulators said a 30% reduction in clinical symptoms as measured by the PANSS score will, "Generally [be] considered to be clinical relevant and can be accepted as a definition of responder." That definition may be subject to change if the trial includes more chronically ill patients, EMA said, though it did not clarify if it would be more accepting or what its general paradigm might be in such a case.
Sponsors should also be aware of specific adverse events, including extrapyramidal symptoms (EPC), withdrawal, dependence, psychiatric adverse events, decline in cognitive functioning, increased risk of suicide, cardiovascular adverse events, neuroleptic malignant syndrome, metabolic risk factors and hematological adverse events.
The guideline comes into effect on 1 April 2013.