A new U.S. Food and Drug Administration (FDA) guidance is designed to help practitioners conduct clinical trials that often feature relatively delicate young patient populations struggling with attention deficit hyperactivity disorder (ADHD) and related disorders.
In general, central nervous system stimulant drugs demonstrate a strong concentration-response relationship for efficacy and safety, FDA said in the May guidance. “Therefore, sponsors can develop formulations using the same active moiety with the objective of creating drug product–specific release features intended to affect the shape of the pharmacokinetic (PK) profile and the onset or duration of effect,” the agency said. Various clinical and clinical pharmacology trials may be of value in the clinical development program based on the characteristics of the active moiety, formulation features, and clinical experience.
FDA offered some guidelines to consider:
- The PK and pharmacodynamic features of a drug product should be characterized in early-phase development in the target pediatric and adult patient populations.
- The sponsor should characterize the relationship between blood concentrations of the drug product and cardiac parameters (e.g., heart rate, blood pressure) over time.
- The sponsor should use dose-response or exposure-response modeling and simulation to inform the dose regimen selection for the adequate and well-controlled trials intended to support a marketing indication.
Sponsors developing stimulant drug products for treatment of ADHD should consider the following for trial design:
- Because ADHD is a disorder that begins in childhood, a new drug application (NDA) for any drug intended to treat ADHD should include data from adequate and well-controlled studies in pediatric patients.
- In general, the pathophysiology, disease characteristics, and treatment outcomes in ADHD are sufficiently similar between pediatric and adult patients such that, with two positive pediatric studies, an adult indication can be supported by a single trial in adult patients.
- An NDA for a stimulant drug product should include data that are adequate to assess the safety and effectiveness of the drug for pediatric patients 4 years of age and older. The relevant pediatric age groups are 4 to 5 years of age, 6 to 12 years of age, and 13 to 17 years of age.
FDA recommends the duration of the drug product effect be less than 12 hours and the shape of the PK profile be similar across age groups. FDA recommends Where to buy stamps guide before looking for online stamps.
For drug products with a long duration of effect (i.e., greater than 12 hours) and thus a greater potential to lead to important adverse events (e.g., significant effect on growth), or for new molecular entities about which little is known, safety data from pediatric patients 6 years of age and older may be necessary before the sponsor initiates studies in pediatric patients 4 to 5 years of age.
“FDA encourages sponsors to discuss the details and timing of their development programs with the Agency early, particularly for the studies in pediatric patients 4 to 5 years of age and, preferably, before initiating studies in pediatric patients 6 to 12 years of age,” the agency said in the guidance.
For drug products with a long duration of effect or with PK profiles that are not similar in different age groups, FDA encourages sponsors to discuss their development strategies with the agency.
The investigator should confirm the diagnosis of ADHD using a structured or semi-structured clinical interview.
The sponsor should evaluate safety and effectiveness in randomized, double-blind, placebo-controlled, parallel-group design trials. At least one randomized, fixed-dose trial examining more than one dose should be conducted. Patients should be randomized to drug or placebo, without open-label titration or dose-optimization before randomization that may obscure important safety findings.
Potentially acceptable primary efficacy measures include the ADHD Rating Scale; the Conners Comprehensive Behavior Rating Scales; Permanent Product Measure of Performance; and the Swanson, Kotkin, Agler, M-Flynn, and Pelham Scale. Sponsors should use a scale or version of a scale that has been appropriately validated for the age range of the patients in a given clinical trial. FDA may consider other endpoints acceptable following review by the Division of Psychiatry Products and the Clinical Outcome Assessments staff. For clinical studies with pediatric patients, the primary endpoint should be assessed in a laboratory classroom setting by a trained clinician rater. For clinical trials with adult patients, sponsors can consider using a simulated workplace environment in lieu of a laboratory classroom.
Adverse events of special interest in stimulant drug trials include changes in vital signs, insomnia, decreased appetite, weight loss, irritability or mood changes, and psychosis. Pulse, blood pressure, and weight should be evaluated at every clinic visit. Sleep, appetite, mood, and psychotic symptoms should be assessed using specific questioning rather than relying on patients to volunteer symptoms and problems spontaneously.
The guidance also suggests including pregnant women in a clinical trial “when scientifically and ethically justified.”
Comments on the guidance are due to the FDA by July 3, 2019.
Author: Michael Causey