FDA Approves lurasidone For Treatment of Schizophrenic Adolescents
The recent (January 2017) US Food and Drug Administration (FDA) approval of a supplemental new drug application for lurasidone (Latuda, Sunovion Pharmaceuticals Inc.) for the treatment of schizophrenia in adolescents aged 13 to 17 years, adds to the existing list of approved medications for the use in that subpopulation. Yet, it reminds us that there is still an unmet medical need for identification of new medic
ines given their currently observed response rates, safety profiles and cost, and also indirectly illustrates difficulties in conducting studies in children and adolescents with schizophrenia.
Historically around 50 percent of medicines currently used in children have never been studied in this population (unlicensed and off-label medicines used either for the disease states or for the age group). First-generation antipsychotics are generally cheaper and still widely available for use in schizophrenic adolescents and although some are approved for use in adolescents (i.e. chlorpromazine, perphenazine or haloperidol), they are however often associated with significant adverse events related to neurological disorders (dystonias, dyskinesias, cognitive dysfunctions, etc.).
Protecting Children and Adolescents Through Clinical Research
Since the beginning of the 21st century, there has been a shifting paradigm from protecting children and adolescents from clinical research to protecting them through clinical research (through acknowledgement that general lack of information and appropriate pharmaceutical formulations may expose children to unwanted side-effects or underdosing without the expected efficacy). That, coupled with an evolving regulatory approach to the development of new medicines in that population (demonstrated by FDA defining products that require pediatric studies, outlining necessary studies, and issuing sponsors pediatric written requests), new medications – a second-generation of antipsychotics – have become available (i.e. risperidone, olanzapine, aripiprazole, quetiapine, paliperidone approved for use in schizophrenic children from 12 years of age). Those are generally preferred because they have fewer side effects than the first-generation antipsychotics and arguably better efficacy in some cases and symptoms. However their use might be still related to increased incidence of metabolic and cardiovascular disorders.
Pediatric Research for Treatment of Schizophrenia Poses Challenges
Lurasidone is the first novel antipsychotic medication approved by FDA in five years for use in schizophrenic adolescents. Understanding the development of new medications for adult patients with schizophrenia is challenging; pediatric research adds challenges that should be considered at all times.
The following reviews a few considerations for the design and conduct of clinical studies in adolescents with schizophrenia.
Considerations for the Design of Schizophrenia Clinical Research in Adolescents
Each clinical study designed and conducted for adolescent schizophrenics should be scientifically sound, ethically justified but also acknowledging potential local clinical differences in medical management of those patients. Appropriate attention needs to be paid to the correct statistical power of the study. It is acknowledged that pediatric and adolescent studies often might involve fewer subjects given difficulties in subject identification, consenting etc. However, an insufficient number of those recruited could result in the inaccurate assessment of differences between studied groups where no difference is detected, while true differences could exist.
Another consideration is that some countries and regions might be historically opposed to use of placebo in pediatric research, despite the fact that placebo is universally accepted and required for efficacy and safety evaluation. Appropriate justification of the placebo component of a study design is therefore an integral part of each study submission dossier to national and local regulatory bodies.
Similarly, carefully developed informed consent for parents and subjects allows for full and clear information to be provided to parents and caregivers as well as to subjects in language and length that will allow them to fully consider participation, and also will improve the ease of the consenting process.
Although in most regions adolescents with schizophrenia are diagnosed and treated by pediatric psychiatrists, some countries or regions might not recognize such subspecialty. However, it is mandatory that eligibility of subjects and diagnosis is established by individuals who have the minimally required experience in diagnosing and managing children and adolescents with schizophrenia. The reliability of the diagnosis should also be confirmed by use of standardized structured interviews, i.e. NIMH Diagnostic Interview Schedule for Children – Version IV (NIMH DISC-IV) [1] or semi structured interviews such as the Kiddie-SADS-Present and Lifetime Version (K-SADS-PL) [2]. Individuals involved in study conduct should also have appropriate experience in managing the subject’s expectations, and also in helping to manage fear and pain.
Contrary to many studies in the adult population, neuroscience clinical research in children and adolescents should consider that the response of children to drugs may differ for developmental, physiological and hormonal, including genetic, reasons. Therefore, data on growth and sexual maturation, as well as cognitive, emotional and behavioral development, should be collected. Utilization of simple extrapolation of dose from adult experience, based on body weight or body surface area, represents a potential safety hazard by causing adverse events through overdosing, inefficacy through underdosing and the use of inappropriate formulations or substandard medicines, and should be avoided. With that, establishing an independent Data Monitoring Committee (DMC) or Data Safety Monitoring Board (DSMB) is always recommended.
Resources
[1] Shaffer D, Fisher P, Lucas CP, Dulcan MK, Schwab-Stone ME. NIMH Diagnostic Interview Schedule for Children Version IV (NIMH DISC-IV): description, differences from previous versions, and reliability of some common diagnoses. J. Am. Acad. Child Adolesc. Psychiatry 39, 28–38 (2000)
[2] Kaufman J, Birmaher B, Brent D, Rao U, Ryan N. Kiddie-Sads-Present and Lifetime Version (K-SADS-PL). University of Pittsburgh, PA, USA (1996). www.wpic.pitt.edu/ksads
