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Clinical Research with a Focus on Psychiatry/Neurosciences Feam Spring Conference, Dublin, 28th – 29th May 2013 Cyril Höschl www.hoschl.cz National Institute.

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Presentation on theme: "Clinical Research with a Focus on Psychiatry/Neurosciences Feam Spring Conference, Dublin, 28th – 29th May 2013 Cyril Höschl www.hoschl.cz National Institute."— Presentation transcript:

1 Clinical Research with a Focus on Psychiatry/Neurosciences Feam Spring Conference, Dublin, 28th – 29th May 2013 Cyril Höschl National Institute of Mental Health Prague Psychiatric Centre & Charles University, Prague Czech Medical Academy

2 “Let us take out of the Hospitals, out of the Camps, or from elsewhere, 200, or 500 poor People, that have Fevers, Pleurisies, etc. Let us divide them in Halfes, let us cast lots, that one half of them may fall to my share and the other to yours; I will cure them without bloodletting and sensible evacuation; but do you do as ye know. We shall see how many funerals both of us shall have: But let the reward of the contention or wager, be 300 Florens, deposited on both sides…” Jean Baptiste van Helmont, 1626 History of clinical trials Van Helmont JA. Oriatrike. London: Lodowick-Loyd, 1662, p.526

3 History of clinical trials “Let us take out of the Hospitals, out of the Camps, or from elsewhere, 200, or 500 poor People, that have Fevers, Pleurisies, etc. Let us divide them in Halfes, let us cast lots, that one half of them may fall to my share and the other to yours; I will cure them without bloodletting and sensible evacuation; but do you do as ye know. We shall see how many funerals both of us shall have: But let the reward of the contention or wager, be 300 Florens, deposited on both sides…” Jean Baptiste van Helmont, 1626 Investigators Subject selection Inclusion criteria Sample size Randomization Intervention Fees, costs and expenses Parallel group design Outcome measure Van Helmont JA. Oriatrike. London: Lodowick-Loyd, 1662, p.526

4 James Lind (1747): The first placebo (?) controlled trial: „A Treatise of the Scurvy“ 12 sailors on the ship HMS Salisbury  6 groups: cider, vitriol, vinegar, sea water, 2+1 citrus & mixture. Outcome: scurvy. 12 sailors on the ship HMS Salisbury  6 groups: cider, vitriol, vinegar, sea water, 2+1 citrus & mixture. Outcome: scurvy.

5 Conventional, Classical neuroleptics, 1 st Generation Antipsychotics History of antipsychotic treatment Source: Lieberman J, et al., APA Annual Meeting, May '40 Reserpine Haloperidol Fluphenasine Trifluoperazine Thioridazine Perphenazine Molindone Loxapine Clozapine Risperidone Olanzapine Quetiapine Ziprasidone Aripiprazole Iloperidon 2000'50'60'70'80'90 Atypical antipsychotics, 2 nd Generation Jean Delay Pierre Deniker Chlorpromazine

6 Major contributions in the last decades 1.Mega-trials (CATIE, CUtLASS, SOHO, EUFEST, Tiihonen) 2.Major focus on glutamatergic system (mGlu) 3.Meta-analyses (Leucht) 4.Updated therapeutical guidelines including non-pharmacological interventions 5.Destigmatisation Clinical Antipsychotic Trials of Intervention Effectiveness Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Schizophrenia Outpatient Health Outcomes European First Episode Schizophrenia Trial

7  Clinical research is in crisis, particularly in CNS There are two main reasons for that unfortune trend: 1.Methodological pitfalls 2.Ethical and bureaucratic restraints Clinical Research with a Focus on Psychiatry/Neurosciences The main points of the presentation: The two reasons are interrelated. As a result, patients’ access to treatment worsens, pharma industry closes CNS branches, pipelines are drying up and in contrast to tremendous progress in basic research in neuroscience the innovative research in pharmacology is slowing down.

8  Clinical research is in crisis, particularly in CNS There are two main reasons for that unfortune trend: 1.Methodological pitfalls 2.Ethical and bureaucratic restraints Clinical Research with a Focus on Psychiatry/Neurosciences The main points of the presentation: The two reasons are interrelated. As a result, patients’ access to treatment worsens, pharma industry closes CNS branches, pipelines are drying up and in contrast to tremendous progress in basic research in neuroscience the innovative research in pharmacology is slowing down.

9 Incentives 1.High placebo responses and failure of active treatments to demonstrate significant efficacy vs. placebo 1,2 2.High rates of subject discontinuation 3 3.Questionable generalization of results to real-world patients 4 Clinical Research with a Focus on Psychiatry/Neurosciences Methodological pitfalls: 1 Papakostas GI and Fava M, Eur Neuropsychopharmacol Khan A et al, CNS Neurosci Ther Kemmler G et al, Arch Gen Psychiatry Hofer A et al, J Clin Pharmacol 2000 Professional guinea-pigging Layman rating  Human rights Exclusion of real world conditions: Alcohol&drug abuse Comorbidity Suicidal thoughts Other treatments Severity of illness Exclusion of real world conditions: Alcohol&drug abuse Comorbidity Suicidal thoughts Other treatments Severity of illness Signal fades away.

10 Antidepressant vs Placebo response rate Source: Papakostas and Fava, % CI 146 mns 182 CT N=36 385

11 VerumPlacebo Response rate N= verum-placebo pair comparisons Publication year and response rate antidepressants Source: Papakostas and Fava, 2009

12 Factors influencing signal detection Response to placebo in CNS studies Kinon et al. Curr Opin Psychiatry Mar;24(2): Kemp AS et al. Schizophr Bull 2010; 36:504–509 Placebo response in acute clinical studies of schizophrenia PANSS total score change from baseline (placebo) Placebo response correlates with the time when the study was conducted risperidone olanzapine quetiapine ziprasidone aripiprazole asenapine bifeprunox paliperidone sonepiprazole asebapine lurasidone ~ ~2007-8

13 Khan A et al., CNS Neurosci Ther 2010 Publication year Placebo-verum difference in HAMD 130 DB RCT betwen N=35122 Verum N=23157 Placebo N= DB RCT betwen N=35122 Verum N=23157 Placebo N=11965 Factors influencing signal detection Response to placebo in CNS studies

14 Publication year 130 DB RCT between N= Verum N=23157 Placebo N= HAMD HAMD AD group HAMD 0 AD group HAMD decrease PL group HAMD 0 PL group HAMD decrease Factors influencing signal detection Response to placebo in CNS studies Khan A. et al., CNS Neurosci Ther 2010 

15 Publication year 130 DB RCT between N= Verum N=23157 Placebo N= HAMD HAMD AD group HAMD 0 AD group HAMD decrease PL group HAMD 0 PL group HAMD decrease Factors influencing signal detection Response to placebo in CNS studies Khan A. et al., CNS Neurosci Ther 2010 NS

16 Multiple overlapping factors which impair signal detection   Design of a study   Type of facility (level, qualification of raters, blinding)   Patients’ characteristic (severity, suicides, comorbidity, co- medication)   Factors related to rating: accuracy, honesty Kahn et al., 2010; Papakostas and Fava, 2009; Höschl 2009

17 Obvious manipulation of screening assessment: An example of preventable bias? HAM-A was used as a screening for inclusion and as an outcome measure in the relapse prevention study. Source: Feltner et al, NCDEU, 2001 HAM-A total score Doctor’s ratingInteractive voice system (IVRS) The graph on the left indicates that inclusion criterion was HAM-A total score „at least 20“ Number of patients

18   Design of a study   Type of facility (level, qualification of raters, blinding)   Patients’ characteristic (severity, suicides, comorbidity, co- medication)   Factors related to rating: accuracy, honesty   Outcome measure (type of a scale, e.g., HAMD 17 vs 21)   Type of a disorder (pain vs diabetes)   Medication and dosage (more frequent contact)   Sample size, randomization (regression to average)   Placebo response (non-pharmacological variables, culture)   Length of a study (the longer the lower signal)   Probability of placebo (the higher the stronger signal)   Qualification of raters (doctors vs volunteers) Kahn et al., 2010; Papakostas and Fava, 2009; Höschl 2009 Multiple overlapping factors which impair signal detection

19  Clinical research is in crisis, particularly in CNS There are two main reasons for that unfortune trend: 1.Methodological pitfalls 2.Ethical and bureaucratic restraints Clinical Research with a Focus on Psychiatry/Neurosciences The main points of the presentation: The two reasons are interrelated. As a result, patients’ access to treatment worsens, pharma industry closes CNS branches, pipelines are drying up and in contrast to tremendous progress in basic research in neuroscience the innovative research in pharmacology is slowing down.

20 Gustavsson A, et al. Cost of disorders of the brain in Europe Eur Neuropsychopharmacol 2011

21 ECNP/EBC Report 2011 [ Methodology ] Direct successor of a benchmark study of the Cost of Disorders of the Brain in Europe published in European + 3 allied countries [Norway, Iceland, Switzerland] Collaboration between almost a hundred prominent epidemiologists and many expert health economists Based on the best currently available data in Europe, and the best currently available estimates as identified via a systematic review of the soundest studies published Cost model inputs: Statistics from Eurostat, estimates of the prevalence and cost per person, local currencies converted to Euro and adjusted to purchasing power parity (PPP), Data were extrapolated to countries where no data could be found

22 ECNP/EBC Report 2011 [ Results ] €798 billion => €1550 per capita 60% direct costs (37% direct healthcare costs and 23% direct non- medical costs); 40% indirect costs associated with patients‘ production losses Over 160 million people affected – more than 36% of the total region‘s population 26% of DALY – more than from any other group of medical disorders; more than in any other part of the world No evidence for any improvement since previous pan-European study conducted in 2005 The burden of disorder of the brain will likely increase further because of the aging European population.

23 Brain research is underfunded Charity funding

24 Brain research is underfunded The total funding of brain research p.a. is only 1% of the annual cost of brain diseases The burden and cost of brain diseases are twice those of cancer Brain research receives, per unit of cost or disability: 50% of the total funding of cancer research 25% of the public funding of cancer research 10% of the charity funding of cancer research Not a high enough priority for politicians, media or the general public

25 Bottlenecks Hurdles in the current process prevent fast and fair access to novel treatments in CNS Complexity of brain-blood-barrier and multi-symptomatic conditions complicate R&D Low funding in CNS compared to other therapeutic area limits breakthrough Lack of public clinical research hinders biomedical progress The drug development paradigm is often not robust enough to provide sufficient safety and efficacy profile Communication between stakeholders is not optimal Despite variation in GDP, drug pricing is consistent across Europe Health authorities hold back high- price treatments in some countries Role of effectiveness studies not clear but essential to assess relative therapeutic value Pricing and reimbursement schemes are not considered flexible enough to allow retrospective price increases Payers continue to focus on cost- containment measures Disease awareness is limited and the share of voice for CNS is low Uptake depends on a variety of factors, incl. attitude of providers, nature of innovation, budgeting, etc. Providers are under pressure of cost-containment measures Widespread implementation of guidelines often time consuming Lack of standardized patient registries affects disease knowledge Clinical learning from trial and in-life settings are insufficiently fed-back Pricing and reimbursement Public / private R&D and regulatory Clinical delivery Regulatory approval Market entry Patient use Monitoring and knowledge back loop into R&D Knowledge feedback Accelerated Access to Treatment

26 Number of clinical trials applied for in EU EU CTD concept paper 25/2011

27 Morgan S et al. Health Policy 100 (2011) 4–17 The cost of a new drug development Million $  9x!

28 THE EU CLINICAL TRIALS DIRECTIVE (CTD) 2001/20/EC CTD implemented in 2004 –to harmonise authorisation procedures for trials on medicinal products –to improve collection of reliable patient data –to increase protection of health and safety of participants and ensure ethical soundness of trials In 2004, FEAM welcomed potential benefits for multi-national collaboration but predicted problems to academic research in case of inflexible application

29 PROBLEMS AFTER IMPLEMENTATION Continuing inconsistencies in regulatory standards and uncertainties in practice Increased administrative burden and costs both for academia and industry EU becomes less attractive location - deterrent effect on new clinical research No good evidence to show improved patient protection or ethical soundness

30 CONCERNS ABOUT NEGATIVE IMPACT OF CTD “UK research trials are on verge of extinction” Letter signed by >100 leading medical academics The Times, January 2009

31 NEGATIVE IMPACT - FACTS (1) Reduction of planned number of participants in EU trial applications (DG Sanco statistics) –2007: 535,000 –2009: 358,000 Reduction of proportion of world’s pharmaceutical CT in UK (BMJ 2009) –2000: 6% –2009: 2% EU trials (ICREL statistics) –More costly –More difficult to plan, start and conduct To analyze the impact of CTD, a consortium created by the European Forum for Good Clinical Practice (EFGCP) and comprised of the European Clinical Research Infrastructure Network (ECRIN), the European Organization for Research and Treatment of Cancer (EORTC), Ethics Committee of the Medical University of Vienna, and Hospital Clinic I de Barcelona, established the Impact on Clinical Research of European Legislation (ICREL)

32 NEGATIVE IMPACT - FACTS (2) Particular problems in multi-national, non- commercial trials in cancer, paediatrics, transplantation (PLoS Medicine 2009) Striking decrease in number of drug development companies formed in Europe (EuropaBio 2010) Drying pipelines

33 ADOPTING A RISK-BASED APPROACH (1) Current central CTD weakness: regulation is not proportionate to expected risks Need to develop regulatory flexibility to: –Handle different types of current and future trials –Focus on benefit-risk, not safety alone Consider implications for: –Ethics –Safety reviews –Monitoring –Insurance –Quality assurance By courtesy H.Blum

34 FEAM - CONCLUSIONS AND MAIN MESSAGES - Clinical research is vital for Europe - administrative burden can be lessened CTD must be urgently reformed - key issues: –Clarifying –Simplifying –Streamlining roles and procedures Discussion of options for regulatory reform and building supportive infra-structure must include all research interests - patients, academia, industry, other funders

35 Needs and challenges in CNS clinical research More valid animal models Predictive clinical biomarkers Definition of outcomes Collaboration, networking New regulatory frameworks (FEAM initiative on Clinical Trials Directive) New genetic tools to shed light on the ‘dark matter’ of psychiatric genetics The application of novel basic cellular and molecular techniques to drug target discovery and drug development Not only torture of healthy animals Prediction of therapeutic outcome needed  symptoms? Functioning? QOL? Academia, industry, patients  bureaucracy,  hurdles + GxE interaction! + information technology!

36 Summary of FEAM recommendations Better understanding of psychosocial and biological factors and their interactions Capitalising on scientific advances and collaboration for more effective recognition and classification of mental disorders, further development of diagnostics and treatment methods Sharing best practice to attain consistently high standards of psychiatry throughout EU Success depends also on improved data collection, commitment to research and innovation priorities, and enhanced infrastructure

37 Requires coherent strategy and active networks across research, innovation and health services including partnerships from academia, industry, patient groups, funders and policy-makers Biomedical community has continuing responsibility to communicate about disorders, their determinants, prevention, and management FEAM academies can play vital role in analysing issues and encouraging scientific community to bring about change Clinical Research with a Focus on Psychiatry/Neurosciences

38 Feam Spring Conference, Dublin, 28th – 29th May 2013 Cyril Höschl National Institute of Mental Health Prague Psychiatric Centre & Charles University, Prague Czech Medical Academy


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