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Long-term Efficacy Data for Psychiatric Drugs Rationale for Long-Term Treatment

Long-term Efficacy Data for Psychiatric Drugs Rationale for Long-Term Treatment. Earl Giller, MD, PhD Pfizer Global Research & Development. Long-Term Efficacy for Psychiatric Drugs Psychopharmacology Drugs Advisory Committee October 25, 2005. Overview.

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Long-term Efficacy Data for Psychiatric Drugs Rationale for Long-Term Treatment

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  1. Long-term Efficacy Data for Psychiatric DrugsRationale for Long-Term Treatment Earl Giller, MD, PhDPfizer Global Research & Development Long-Term Efficacy for Psychiatric DrugsPsychopharmacology Drugs Advisory Committee October 25, 2005

  2. Overview • Treatment duration beyond the acute episode depends on multiple factors, including diagnosis, illness course/chronicity, severity, treatment resistance, concomitant therapy and patient preference • Guideline recommendations for duration of treatment beyond the acute episode vary from months (eg first episode of MDD) to several years (eg 1st episode of schizophrenia) to lifetime (for patients with severe recurrent episodes or chronic symptoms) • Clinically relevant stabilization times differ by disorder • Most patients discontinue or switch medications well before guideline recommended durations • Given this variability in the rationale for long-term treatment, long-term clinical trials will be different by disorder, indication and medication

  3. Acute, Continuation and Long-Term Treatment • Most psychiatric disorders require acute, continuation and long-term treatment • New medications are still urgently needed for acute treatment • Continuation (maintenance) treatment prevents immediate return of symptoms (relapse) • For many disorders, long-term treatment is also required for • Prevention of new episodes (recurrence) • Control of chronic symptoms not necessarily associated with an acute episode • The majority of patients require long-term treatment, however, so the terminology of maintenance treatment to prevent relapse for most psychiatric disorders is reasonable

  4. Different Courses of Illness by Disorder (DSM-IV) Supports Different Trials • Unipolar and Bipolar Disorder (episode = 4-6 months) • Relapse: return of symptoms within episode • Recurrence: return of symptoms after full remission (recovery) • Recovery duration: 2-6 months • Symptom worsening without full inter-episode recovery not well defined • Schizophrenia (episode length undefined) • Episodic with or without inter-episode residual symptoms • Full remission only after single episode • Anxiety Disorders (episode not considered) • No definition of relapse/recurrence • Most have a chronic, fluctuating course • Long-term efficacy study designs should differ because of disorder-specific courses of illness and treatment

  5. Episode (MDD) Multiphase Treatment Recovery (2-6 months) Remission Relapse Recurrence “Normalcy” Symptoms Response Syndrome Treatment Phases Acute Continuation Maintenance Kupfer DJ et al., 1991: J Clin Psychiatry 52:28 –34. Frank E et al., 1991: Arch Gen Psychiatry 48: 851-855

  6. Multiphase Treatment Approach More Complex in Bipolar Disorder Mania Hypomania Euthymia MinorDepression MajorDepression Preliminary Phase Preventive Phase Frank E et al. Biol Psychiatry. 2000;48:593-604

  7. Guidelines Durations of Long-Term Treatment 1 Practice Guideline APA 2000; 2APA practice guidelines for Panic Disorder, Am J Psychiatry 1998;155 (5, suppl):1-34; 3Foa et al. Expert Consensus Guideline series: treatment of PTSD J Clin Psychiatry 1999;60 (Suppl 16): 1-76; 4March et al. Expert Consensus Guideline series: treatment of OCD. J Clin Psychiatry 1997 58 (suppl 4): 1-72; 5APA 2004; 6Robinson et al. Schizophrenia Bulletin 2005; 7TIMA 2005; 8Sachs et al. J Clin Psychopharmacology 1996

  8. Guideline Durations of Treatment Rarely Obtained in Clinical Practice: Rx Data Discontinuation Curves Discontinuation from Treatment with 5 SSRIs Discontinuationsby Antipsychotic – Schizophrenia Discontinuationsby Antipsychotic –Bipolar Disorder 1.0 1.0 1.0 0.8 0.8 0.8 0.6 0.6 0.6 Proportion Remaining on Treatment 0.4 0.4 0.4 0.2 0.2 0.2 0.0 0.0 0.0 0 60 120 180 240 300 360 420 0 60 120 180 240 300 360 420 0 600 1,200 1,800 Days on Treatment Days on Treatment Days on Treatment Median = 4- 6.5 Months (Includes acute treatment) Median = 3 - 4.5 Months Median = 3- 4.5 Months Clinically relevant stabilization period about 2-3 months Patients remaining after 6 months are small minority Verispan Persistency & LOT Analysis, July 2005 (class of antidepressants); Verispan Persistency & LOT Analysis, July 2004 (class of antipsychotics)

  9. Guideline Durations of Treatment Rarely Obtained in Clinical Practice: CATIE Schizophrenia Study Discontinuation Curves 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 3 6 9 12 15 18 Proportion of Patients Without Event Time to Discontinuation for Any Cause (Mo) Source: Lieberman et al., N Engl J Med 2005; 353:1209-23

  10. Conclusions • Clinically relevant stabilization time is about 2-4 months because of discontinuation rates in clinical practice and trials • Regulatory requirements for long-term treatment data should be flexible because the type, extent and timing of long-term clinical studies differs by indication, type of medication and existing data for the medication and class • Expert consensus workgroups should be convened to develop guidelines for appropriate study designs for long-term efficacy data for each indication

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