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, PhDPfizer Global Research & Development

Earl Giller, MD, PhDPfizer Global Research & Development

Long-Term Efficacy for Psychiatric DrugsPsychopharmacology Drugs Advisory Committee

October 25, 2005

Long-Term Efficacy for Psychiatric DrugsPsychopharmacology Drugs Advisory Committee

October 25, 2005

2

OverviewOverview

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

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 TreatmentAcute, 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

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 TrialsDifferent 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

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 TreatmentEpisode (MDD) Multiphase Treatment

“Normalcy”“Normalcy”

SymptomsSymptoms

SyndromeSyndrome

Treatment PhasesTreatment Phases AcuteAcute ContinuationContinuation MaintenanceMaintenance

ResponseResponse

RemissionRemission RelapseRelapse

Recovery (2-6 months)Recovery (2-6 months)

RecurrenceRecurrence

Kupfer DJ et al., 1991: J Clin Psychiatry 52:28 –34.Frank E et al., 1991: Arch Gen Psychiatry 48: 851-855Kupfer DJ et al., 1991: J Clin Psychiatry 52:28 –34.Frank E et al., 1991: Arch Gen Psychiatry 48: 851-855

ManiaMania

HypomaniaHypomania

EuthymiaEuthymia

MinorDepression

MinorDepression

MajorDepression

MajorDepression

Preliminary PhasePreliminary Phase Preventive PhasePreventive Phase

Multiphase Treatment Approach More Complex in Bipolar DisorderMultiphase Treatment Approach More Complex in Bipolar Disorder

Frank E et al. Biol Psychiatry. 2000;48:593-604Frank E et al. Biol Psychiatry. 2000;48:593-604

7

Guidelines Durations of Long-Term Treatment

Guidelines Durations of Long-Term Treatment

IndicationIndication Recommended Length of TreatmentRecommended Length of Treatment

MDDMDDContinuation: 4-5 Months After RemissionContinuation: 4-5 Months After Remission11

Maintenance: Depending on risk, severityMaintenance: Depending on risk, severity

Panic DisorderPanic Disorder 6-9 months for response and response consolidation;6-9 months for response and response consolidation;and 3 months for stable symptom resolutionand 3 months for stable symptom resolution22

PTSDPTSD Acute: 6-12 months after response;Acute: 6-12 months after response;Chronic: 12-24 months after responseChronic: 12-24 months after response33

OCDOCD 12 months12 months44

SchizophreniaSchizophreniaChronic Maintenance treatmentChronic Maintenance treatment5,65,6

Stabilization: at least 6 months Stable: >1 episodeStabilization: at least 6 months Stable: >1 episode

Bipolar DisorderBipolar Disorder Chronic Maintenance treatmentChronic Maintenance treatment7,87,8

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

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

0.0

0.2

0.4

0.6

0.8

1.0

0 60 120 180 240 300 360 420

0.0

0.2

0.4

0.6

0.8

1.0

0 60 120 180 240 300 360 420

Guideline Durations of Treatment Rarely Obtained in Clinical Practice: Rx Data Discontinuation CurvesGuideline Durations of Treatment Rarely Obtained in Clinical Practice: Rx Data Discontinuation Curves

0.0

0.2

0.4

0.6

0.8

1.0

0 600 1,200 1,800

Discontinuation from Discontinuation from Treatment with 5 SSRIsTreatment with 5 SSRIs

Discontinuation from Discontinuation from Treatment with 5 SSRIsTreatment with 5 SSRIs

DiscontinuationsDiscontinuationsby Antipsychotic – by Antipsychotic –

SchizophreniaSchizophrenia

DiscontinuationsDiscontinuationsby Antipsychotic – by Antipsychotic –

SchizophreniaSchizophrenia

DiscontinuationsDiscontinuationsby Antipsychotic –by Antipsychotic –Bipolar DisorderBipolar Disorder

DiscontinuationsDiscontinuationsby Antipsychotic –by Antipsychotic –Bipolar DisorderBipolar Disorder

Prop

ortio

n R

emai

ning

on

Trea

tmen

tPr

opor

tion

Rem

aini

ng o

n Tr

eatm

ent

Days on TreatmentDays on Treatment Days on TreatmentDays on Treatment Days on TreatmentDays on Treatment

Median = 4- 6.5 Months (Includes acute treatment)

Median = 4- 6.5 Months (Includes acute treatment)

Median = 3- 4.5 MonthsMedian = 3- 4.5 Months Median = 3 - 4.5 MonthsMedian = 3 - 4.5 Months

Verispan Persistency & LOT Analysis, July 2005 (class of antidepressants); Verispan Persistency & LOT Analysis, July 2004 (class of antipsychotics)

Clinically relevant stabilization period about 2-3 monthsPatients remaining after 6 months are small minorityClinically relevant stabilization period about 2-3 monthsPatients remaining after 6 months are small minority

9Source: Lieberman et al., N Engl J Med 2005; 353:1209-23Source: Lieberman et al., N Engl J Med 2005; 353:1209-23

Guideline Durations of Treatment Rarely Obtained in Clinical Practice: CATIE Schizophrenia Study Discontinuation CurvesGuideline Durations of Treatment Rarely Obtained in Clinical Practice: CATIE Schizophrenia Study Discontinuation Curves

Pro

po

rtio

n o

f P

atie

nts

Wit

ho

ut

Eve

nt

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 3 6 9 12 15 18

Time to Discontinuation for Any Cause (Mo)

10

ConclusionsConclusions

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

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