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Disease And Compound Specific Approaches To The Development Of Psychotherapeutic Agents. Robert A. Leadbetter, MD Group Director, Neurosciences Medicines Development Center. Drug Development in Psychiatric Diseases. Issues:
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Disease And Compound Specific Approaches To The Development Of Psychotherapeutic Agents Robert A. Leadbetter, MDGroup Director, Neurosciences Medicines Development Center
Drug Development in Psychiatric Diseases • Issues: • Will a delay in filing to obtain long-term efficacy data be in the patient’s best interest? • How should long-term trials be designed to best examine chronic psychiatric illnesses? • Current practice: • NDAs are submitted based on acute efficacy data • Longer-term data is provided after NDA approval as new information to be included in product label • Position: • When and how long-term efficacy data are provided should be determined on a case-by-case basis
Development of Psychotherapeutic Agents • Obtaining long-term data should account for differences In Disease Target And Compound Characteristics • Not All Psychiatric Disease States Require Long Term Treatment • Conversely, Some Treatments Can Target Only Long Term Intervention • Psychotherapeutic Drugs Differ in PK/PD Characteristics • These differences in treatment goals and product characteristics should influence when and how long-term data should be obtained • Study designs to generate longer-term efficacy data must differ based on disease state being studied “One size does not fit all”
Not All Psychiatric Disease States Require Long Term Treatment • Acutely symptomatic patients may require psychopharmacologic intervention that would not be continued long-term • Acute bipolar depression with antidepressants • Short-term use of hypnotics for insomnia • Psychiatric disorders that generally do not require long-term treatment • Delirium • Brief reactive psychosis • Adjustment disorders
Some Clinical Uses Target Primarily Long Term Intervention • Prevention (or delay) of future events • Lamotrigine for bipolar (acute efficacy has not been confirmed) • Anticonvulsants for seizure disorders • Beta-blockers for migraine • Chronic persistent or deteriorating symptoms – i.e. likelihood of spontaneous remission very low • Adult ADHD • Adjunctive Rx for cognitive impairment in schizophrenia
Innate Differences in PK/PD Characteristics Necessitate Individualized Approaches • Pharmacodynamics • Benzodiazepines are associated with tolerance but other anxiolytics such as SSRIs are not • Future novel therapies may require different approaches to establishing long-term efficacy • Pharmacokinetics • Long ½ life agents may need different study designs
Study Designs to Generate Longer-term Efficacy Data May Vary Per Disease Being Studied • Study design to generate longer-term efficacy data should be determined based on disease target and compound being studied • Randomized (PBO) withdrawal may not be appropriate • Study design should take into account known consequences of treatment interruption to the patient • In some diseases, the risk to the patient may outweigh the knowledge gained given symptoms will recur eventually if treatment is withheld, e.g. schizophrenia • There are limitations to the data obtained for the trial design proposed, e.g. generalizability
Requiring Longer-term Efficacy Data At Time NDA Filing will Delay Availability of New Treatments to Patients • It is usually necessary to obtain fundamental information prior to institution of long-term efficacy studies • Some evidence of acute efficacy • Dose response relationship • Longer term open-label safety data • Data sufficient for IRB approval • The additional information gained with inclusion of longer-term efficacy data at NDA file must be weighed against the delay incurred in making new medications available to patients
Summary • Differences in psychiatric disorders, treatment objectives, and compound characteristics necessitate an individualized approach for long-term efficacy requirements • Providing longer-term efficacy at time of NDA filing will incur a delay in the submission of the NDA • This time lost meeting this requirement needs to be weighed against the benefit of making new medications more quickly available to patients
Requirement for Long-term Efficacy Data Needs To Consider Disease State And Compound Characteristics • Differences in the treatment objectives for the target disease state • Acute intervention • Preventative therapy • Chronic persistent/deteriorating symptoms • Differences in the drug profile • Pharmacokinetic characteristics • Mechanism of action “One size does not fit all”