Presentation on theme: "NIMH Practical Trials: Implications for Practice and Policy"— Presentation transcript:
1 NIMH Practical Trials: Implications for Practice and Policy Matthew V. Rudorfer, M.D.Division of Services & Intervention ResearchNational Institute of Mental HealthJune 5, 2007
2 Translational Research Two Kinds ofTranslational ResearchBenchBedsidePracticePractical TrialsClinical Trials NetworksServices ResearchDissemination & ImplementationPathophysiologyDiagnostic testsBiomarkersNew treatments
3 Utility of Large Studies – “Practical Clinical Trials” Public health perspective on clinical issuesBig questions and community effectChronic diseases require long term lookLongitudinal follow-up and link intermediate change to long term outcomesLinkage of biological (biomarker, genetics – Perlis et al, STAR*D, Arch Gen Psychiatry June 2007) and clinical data; potential for targeted interventionsIdentification of subgroups (differential response -- “personalized treatment”)
4 Personalized Treatment Optimizing the Benefit:Risk Ratio
5 Practical Clinical Trials: NIMH Approach 1999 – 2006: Multiple large clinical trials launched under contract mechanism2006 – onward: With completion of practical trials, infrastructure for disorder-focused clinical trials networks formed from nucleus of high-performing sites + coordinating center
6 Clinical Trial Design Efficacy Effectiveness Patients Narrow dx; few comorbidities or concurrent medsFew exclusion criteriaPhaseII, IIIIII, IVN10s – 100s100s – 1,000sSettingsHealth careVariousMasked TreatmentYes (Protocol)No (Clinician / Algorithm)Masked RatersYesOutcomeMeasuresSymptomatic onlyFunctional, Cost/ Utilization as well‡Allowed if not depression-targeted, empirically tested therapy.*To establish efficacy versus placebo.
7 Methodology Designed for High Generalizability in Practical Trials Equipoise design, in some cases using patient preference, reflects practice, increasing generalizability of findingsReal-world patients enrolled (comorbidities OK)Use of cutting-edge technology, e.g. Web-based quality control of treatment, ratings entry via IVRAdvances in valid and reliable clinical ratings, e.g. QIDS-C or QIDS-SR instead of traditional Hamilton score; “all-cause discontinuation” as a measure of effectivenessOutcomes beyond symptomatic ratings, e.g. quality of life, functional measures
8 NIMH Contracts: Practical Clinical Trials STEP-BD (Bipolar Disorder)4,360 / 13 sitesStandard care and random pathwaysCATIE (Schizophrenia / Alzheimer’s Disease)1,914 / 57 sites1,493 in Schizophrenia; 421 in Alzheimer’s DiseaseRandomized comparisonSTAR*D (Refractory Depression)4,041 / 41 sitesSequential pathways
9 Less than 1/3 of symptomatic bipolar patients reach recovery and remain well over 2 years in STEP-BD Achieved recovery %(< 2 mood symptoms for at least 8 weeks)Relapse into depression %Relapse into mood elevation %Total relapse rate %Total that stayed recovered over 2 years(100%-48.5%) %Total who recovered and remained free of depressive and mood elevation recurrences over 2 years(51.5% out of 58.5% who achieved remission)30.1%N=1469 who entered symptomaticPerlis et al, STEP-BD, Am J Psychiatry 2006 Feb;163:
10 Anxiety comorbid conditions with higher risk of relapse in bipolar disorder in STEP-BD Overall relapse rate = 41.4%Overall Hazard Ratio (HR)= 1.764( 2=10.9, P=0.001)HR=1.55 for one disorderHR=2.17 for two or more disordersHR=2.07 for social anxiety disorderHR=2.45 for PTSDwithout anxietywith anxietyOtto et al., STEP-BD, Br J Psychiatry 2006 Jul;189:20-5.
11 Effectiveness of Adjunctive Antidepressant Treatment April 26, 2007Effectiveness of Adjunctive Antidepressant Treatmentfor Bipolar DepressionGary S. Sachs, M.D., Andrew A. Nierenberg, M.D., Joseph R. Calabrese, M.D., Lauren B. Marangell, M.D., Stephen R. Wisniewski, Ph.D., Laszlo Gyulai, M.D., Edward S. Friedman, M.D., Charles L. Bowden, M.D., Mark D. Fossey, M.D., Michael J. Ostacher, M.D., M.P.H., Terence A. Ketter, M.D., Jayendra Patel, M.D., Peter Hauser, M.D., Daniel Rapport, M.D., James M. Martinez, M.D., Michael H. Allen, M.D., David J. Miklowitz, Ph.D., Michael W. Otto, Ph.D., Ellen B. Dennehy, Ph.D., and Michael E. Thase, M.D.
12 Intensive psychosocial interventions for bipolar depression better than collaborative care, but over a third never reach recovery1-year recovery rate for intensive group, 105/163 [64.4%]; for CC, 67/130 [51.5%];log-rank 2(1) = 6.20, p = 0.013; hazard ratio (HR) = 1.47; 95% CI =Miklowitz et al., STEP-BD, Arch Gen Psychiatry, April 2007
14 Volume 353:1209-1223 September 22, 2005 Number 12 Effectiveness of Antipsychotic Drugs in Patients with Chronic SchizophreniaJeffrey A. Lieberman, M.D., T. Scott Stroup, M.D., M.P.H., et al. for the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators
15 CATIE: Primary Questions Addressed How do the atypical antipsychotic medications compare with an older, less expensive conventional antipsychotic?How do the atypical antipsychotics compare to one another?Are the atypical antipsychotics cost-effective?Stroup TS et al. Schizophr Bull. 2003;29:15-31.
16 Use of Atypical Antipsychotic Medications in U.S. TRx (000s)Source: IMS NPA Plus, Dec 05. Lieberman – Presentation to NIMH Advisory Council, Sept 2006
17 CATIE Schizophrenia Trial Design Phase 1*Phase 2Phase 3Double-blind, random treatment assignment.Participants who discontinue Phase 1 choose either the clozapine or the ziprasidone randomization pathwaysParticipants who discontinue Phase 2 choose one of the following open-label treatmentsARIPIPRAZOLECLOZAPINEFLUPHENAZINE DECANOATEPERPHENAZINERISPERIDONEOLANZAPINEZIPRASIDONEQUETIAPINE2 of the antipsychotics aboveOLANZAPINECLOZAPINE(open-label)ROLANZAPINE, QUETIAPINE or RISPERIDONEQUETIAPINE1500 participants with schizo-phreniaRRISPERIDONEZIPRASIDONEROLANZAPINE, QUETIAPINE or RISPERIDONEZIPRASIDONEPERPHENAZINENo one assigned to same drug as in Phase 1Responders stay on assigned medication for duration of 18-month treatment period* Phase 1A: participants with tardive dyskinesia do not get randomized to perphenazinePhase 1B: participants who fail perphenazine will be randomized to an atypical (olanzapine, quetiapine, or risperidone) before they are eligible for Phase 2Stroup et al 2003
18 PHASE 1: Time to Discontinuation for Any Reason 36%26%25%21 %18%▬▬▬ Risperidone (n=333)▬▬▬ Perphenazine (n=257)▬▬▬ Ziprasidone (n=183)▬▬▬ Quetiapine (n=329)▬▬▬ Olanzapine (n=330)
19 Problems with Movement During the Trial Percent (%)PerphenazineRisperidoneQuetiapineOlanzapineZiprasidoneProlactin: Change from BaselineExposure-adjusted Mean(ng/mL)PerphenazineRisperidoneQuetiapineOlanzapineZiprasidone
20 Body Weight: Change from Baseline Weight Gain >7%PerphenazineRisperidoneQuetiapineOlanzapineZiprasidoneFasting Glucose: Change from BaselineExposure-adjusted Mean(mg/dL)PerphenazineRisperidoneQuetiapineOlanzapineZiprasidoneFasting Triglycerides: Change from BaselineExposure-adjusted Mean(mg/dL)PerphenazineRisperidoneQuetiapineOlanzapineZiprasidone
21 Chronic Schizophrenia Who Did Not Respond to American Journal of Psychiatry 163: , April 2006Effectiveness of Clozapine Versus Olanzapine, Quetiapine, and Risperidone in Patients WithChronic Schizophrenia Who Did Not Respond toPrior Atypical Antipsychotic TreatmentJoseph P. McEvoy, M.D., Jeffrey A. Lieberman, M.D., T. Scott Stroup, M.D., M.P.H., Sonia M. Davis, Dr.P.H., Herbert Y. Meltzer, M.D., Robert A. Rosenheck, M.D., Marvin S. Swartz, M.D., Diana O. Perkins, M.D., M.P.H., Richard S.E. Keefe, Ph.D., Clarence E. Davis, Ph.D., Joanne Severe, M.S., John K. Hsiao, M.D. for the CATIE Investigators
22 Stroup TS et al. Schizophr Bull. 2003;29:15-31. CATIE Phase 2: Preference Pathways (for people who discontinue Phase 1)Clozapine—open-labelEfficacyPathwayRandomizedOlanzapine, Quetiapine, or Risperidone—drug not taken in Phase 1TolerabilityPathwayRandomizedZiprasidoneStroup TS et al. Schizophr Bull. 2003;29:15-31.
23 PHASE 2E: Time to Discontinuation for Any Reason 44%29%14%7%
24 PHASE 2T: Time to Discontinuation for Any Reason 36%33%23%16%
25 Negative Symptoms and Cognitive Function No differences between atypical antipsychotics and a conventional antipsychotic (perphenazine) on negative symptoms and cognitive functions
26 Older Medication May Be More Cost-Effective for December 1, 2006Older Medication May Be More Cost-Effective forSome Patients with SchizophreniaA new study analyzing the economic implications of CATIE concludes that the older (first generation) antipsychotic medication perphenazine was less expensive and no less effective than the newer (second generation) medications used in the trial during initial treatment, suggesting that older antipsychotics still have a role in treating schizophrenia. Total monthly health costs, a figure that includes both average medication costs and inpatient and outpatient costs, were up to 30 percent lower for those taking perphenazine than for those taking the second generation medications.-- NIMH Press Release Re: Rosenheck et al, Am J Psychiatry, December 2006
27 Study May Boost Use of Cheaper Antipsychotic Drug By Avery Johnson, The Wall Street Journal,December 1, 2006For the cost-effectiveness portion of the Catie study, a team of researchers led by Yale Medical School's Robert Rosenheck found that patients taking the generic antipsychotic paid $960 in average health costs per month, including the $50 price of the drug. The average monthly cost of treatment with Eli Lilly & Co.'s Zyprexa, for instance, was $1, the lowest of the branded drugs -- after accounting for the $545 per month cost of the antipsychotic, plus additional medications and hospital costs. Average health costs for patients on Johnson & Johnson's Risperdal were $1,533 a month, including $474 for the drug. Two other branded drugs were also analyzed
28 CATIE HIGHLIGHTSAll antipsychotic medications studied are effective but have substantial limitations reflected by high discontinuation ratesOlanzapine and Clozapine show the best efficacy but the worst side effectsPerphenazine was surprisingly comparable to atypicalsDifferences in types and severity of side effectsZiprasidone has least weight and metabolic side effects (Aripiprazole was released later)
29 “CATIE has opened the door to more choice in treatment options." -- Robert Rosenheck, M.D.Treatments for persons with schizophrenia must be individualized. Doctors and patients must carefully evaluate the tradeoffs between efficacy and side effects and past treatment history in choosing an appropriate medication.Lieberman – Presentation to NIMH Advisory Council, Sept 2006
30 Issues in Schizophrenia Treatment Research Still Needing Attention Need for strategies beyond clozapine or alternatives to clozapine for patients with refractory symptomsRational antipsychotic polypharmacy?What are optimal strategies for first-episode psychosis?How to enhance treatment adherence ?Lieberman – Presentation to NIMH Advisory Council, Sept 2006
31 355: October 12, Number 15Effectiveness of Atypical Antipsychotic Drugs in Patients with Alzheimer's DiseaseLon S. Schneider, M.D., Pierre N. Tariot, M.D., Karen S. Dagerman, M.S., Sonia M. Davis, Dr.P.H., John K. Hsiao, M.D., M. Saleem Ismail, M.D., Barry D. Lebowitz, Ph.D., Constantine G. Lyketsos, M.D., M.H.S., J. Michael Ryan, M.D., T. Scott Stroup, M.D., David L. Sultzer, M.D., Daniel Weintraub, M.D., Jeffrey A. Lieberman, M.D., for the CATIE-AD Study Group
32 Schneider et al, CATIE-AD, N Engl J Med, Oct 2006 "The antipsychotic medications may be effective against some symptoms in Alzheimer's patients compared to placebo, but their tendency to cause intolerable adverse side effects in this vulnerable population offsets their benefits."Lon Schneider, MDSchneider et al, CATIE-AD,N Engl J Med,Oct 2006
33 Psychotherapy in NIMH Effectiveness Trials – completed STEP-BD (Bipolar Depression)– 3 types of structured psychotherapy are effective adjuncts to pharmacotherapy(Miklowitz et al, Arch Gen Psychiatry, April 2007)STAR*D (Refractory Depression)– Only 26% of patients agreed to treatment with cognitive therapy (CT) as a second-line treatment after inadequate response to citalopram. Responses to CT, as monotherapy or augmenting citalopram, were equivalent to medication-only groups. Time to remission was slower with CT but with fewer side effects(Thase et al, & Wisniewski et al, Am J Psychiatry, May 2007)
34 Psychotherapy in NIMH Effectiveness Trials – in progress Research Evaluating the Value of Augmenting Medication with Psychotherapy (REVAMP / Chronic Major Depression)– Does CBASP or supportive psychotherapy add to pharmacotherapy in the treatment of chronic forms of major depression? (Kocsis et al)Coordinated Anxiety Learning and Management (CALM / Anxiety Disorders)– Does computer-based individualized CBT add to pharmacotherapy for anxiety disorders in primary care? (Roy-Byrne et al)
35 What Questions Should Be Pursued Next? Widely used treatments and treatment combinations that are untested?New molecules ready for wider testing?Patient attrition?Longer-term outcomes?Tailoring treatment to individuals?Enhancing cost efficiency?Practice procedures that are controlled by payor costs without regard to patient outcomes?Rush – Presentation to NIMH Advisory Council, Sept 2006
36 What’s Next at NIMHThree new clinical trials networks (Depression, Bipolar Disorder, Schizophrenia), building upon completed Practical Clinical TrialsPlatform fundingCentral data managementCollaboration with new partnersIdentify challenging public mental health questions suitable for study on NetworksContinue regular grant support of non-Network services and interventions research
37 For complete details of NIMH-supported Clinical Trials, please see