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Clinical Research with a Focus on Psychiatry/Neurosciences

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

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Clinical Research with a Focus on Psychiatry/Neurosciences

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  1. Clinical Research with a Focus on Psychiatry/Neurosciences Cyril Höschl www.hoschl.cz National Institute ofMentalHealth Prague Psychiatric Centre &Charles University, Prague Czech MedicalAcademy Feam Spring Conference, Dublin, 28th – 29th May 2013

  2. 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 funeralsboth 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 Van Helmont JA. Oriatrike. London: Lodowick-Loyd, 1662, p.526

  3. History of clinical trials Inclusioncriteria Subject selection Investigators “Let us take out of the Hospitals, out of the Camps, or from elsewhere, 200, or 500poor 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 funeralsboth 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 Sample size Randomization Parallel group design Parallel group design Intervention Outcomemeasure Fees, costs and expenses Van Helmont JA. Oriatrike. London: Lodowick-Loyd, 1662, p.526

  4. James Lind (1747): Thefirst placebo (?) controlled trial: „A TreatiseoftheScurvy“ 12 sailors on theship HMS Salisbury 6 groups: cider, vitriol, vinegar, seawater, 2+1 citrus &mixture. Outcome:scurvy.

  5. Jean DelayPierre Deniker History of antipsychotictreatment 1900 '40 '50 '60 '70 '80 '90 2000 Risperidone Olanzapine Quetiapine Molindone Reserpine Ziprasidone Aripiprazole Iloperidon Loxapine Clozapine Haloperidol Fluphenasine Trifluoperazine Thioridazine Perphenazine Chlorpromazine Atypicalantipsychotics, 2ndGeneration Conventional, Classical neuroleptics, 1stGenerationAntipsychotics Source: Lieberman J, et al., APA Annual Meeting, May 2001

  6. SchizophreniaOutpatientHealthOutcomes Clinical Antipsychotic Trials of Intervention Effectiveness Major contributions in the last decades European First Episode Schizophrenia Trial Cost Utility of the LatestAntipsychoticDrugs in Schizophrenia • Mega-trials (CATIE, CUtLASS, SOHO, EUFEST, Tiihonen) • Major focus on glutamatergic system (mGlu) • Meta-analyses(Leucht) • Updatedtherapeuticalguidelinesincluding non-pharmacologicalinterventions • Destigmatisation

  7. Clinical Research with a Focus on Psychiatry/Neurosciences The main points of thepresentation: • Clinicalresearchis in crisis, particularly in CNS • There are twomainreasonsforthatunfortune trend: • Methodologicalpitfalls • Ethical and bureaucraticrestraints 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 with a Focus on Psychiatry/Neurosciences The main points of thepresentation: • Clinicalresearchis in crisis, particularly in CNS • There are twomainreasonsforthatunfortune trend: • Methodologicalpitfalls • Ethical and bureaucraticrestraints 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. Clinical Research with a Focus on Psychiatry/Neurosciences Methodological pitfalls: High placebo responses and failure of active treatments to demonstrate significant efficacy vs. placebo1,2 High rates of subject discontinuation3 Questionable generalization of results to real-world patients4 Exclusion of realworldconditions: • Alcohol&drug abuse • Comorbidity • Suicidalthoughts • Othertreatments • Severity of illness Humanrights Layman rating Signal fades away. Professional guinea-pigging Incentives 1Papakostas GI and Fava M, EurNeuropsychopharmacol 2009 2KhanA et al,CNS NeurosciTher 2010 3Kemmler G et al,Arch Gen Psychiatry2005 4Hofer A et al, J ClinPharmacol2000

  10. Antidepressantvs Placeboresponse rate 53.8 146 mns 182 CT N=36 385 37.3 95% CI Source: Papakostas and Fava, 2009

  11. Publicationyear and response rate antidepressants Response rate 1980-1989 1990-1999 2000-2007 Verum Placebo N=36 385 262 verum-placebo pair comparisons Source: Papakostas and Fava, 2009

  12. FactorsinfluencingsignaldetectionResponse to placeboin CNS studies Placebo response in acuteclinicalstudiesofschizophrenia Placebo response correlateswiththetimewhenthe study wasconducted PANSS totalscore changefrombaseline (placebo) 2001 2002 1997 1993 1996 ~2007-8 2004-6 ~2000-1 2004-6 2004-5 2000-3 asenapine asebapine quetiapine risperidone olanzapine bifeprunox ziprasidone lurasidone aripiprazole paliperidone sonepiprazole Kemp ASet al. SchizophrBull 2010; 36:504–509 Kinon et al. Curr Opin Psychiatry. 2011 Mar;24(2):107-13

  13. Khan A et al., CNS NeurosciTher 2010 FactorsinfluencingsignaldetectionResponse to placeboin CNS studies 130 DB RCT betwen 1981-2008 N=35122 VerumN=23157 Placebo N=11965 Placebo-verumdifference in HAMD Publicationyear

  14. Khan A. et al., CNS NeurosciTher 2010 FactorsinfluencingsignaldetectionResponse to placeboin CNS studies 130 DB RCT between1981-2008 N= 35 122 VerumN=23157 Placebo N=11965 PL group HAMD0 AD group HAMD0 PL groupHAMDdecrease AD groupHAMDdecrease HAMD HAMD  40 10 20 30 0 0 10 20 40 30 2010 1990 1995 2000 1980 1985 2005 Publicationyear 2010 1990 1995 2000 1980 1985 2005

  15. Khan A. et al., CNS NeurosciTher 2010 FactorsinfluencingsignaldetectionResponse to placeboin CNS studies 130 DB RCT between1981-2008 N= 35 122 VerumN=23157 Placebo N=11965 PL group HAMD0 AD group HAMD0 PL groupHAMDdecrease AD groupHAMDdecrease HAMD HAMD NS 40 10 20 30 0 0 10 20 40 30 2010 1990 1995 2000 1980 1985 2005 Publicationyear 2010 1990 1995 2000 1980 1985 2005

  16. Multiple overlapping factorswhich 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. HAM-A was used as a screening for inclusion and as anoutcome measure in the relapse prevention study. Obvious manipulation of screening assessment: An example of preventable bias? Doctor’s rating Interactivevoicesystem (IVRS) Numberofpatients Numberofpatients HAM-A totalscore HAM-A totalscore The graph on the left indicates that inclusion criterion was HAM-A total score „at least 20“  Source: Feltner et al, NCDEU, 2001

  18. Multiple overlapping factorswhich 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 • Outcome measure (type of a scale, e.g., HAMD 17 vs21) • Type of a disorder (pain vs diabetes) • Medication and dosage (more frequent contact) • Sample size, randomization (regression to average) • Placebo response (non-pharmacologicalvariables, culture) • Lengthof a study(thelongerthelowersignal) • Probabilityofplacebo(thehigherthestrongersignal) • Qualificationofraters(doctorsvsvolunteers) Kahn et al., 2010; Papakostas and Fava, 2009; Höschl 2009

  19. Clinical Research with a Focus on Psychiatry/Neurosciences The main points of thepresentation: • Clinicalresearchis in crisis, particularly in CNS • There are twomainreasonsforthatunfortune trend: • Methodologicalpitfalls • Ethical and bureaucraticrestraints 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. Costofdisordersofthe brain in Europe 2010. Eur Neuropsychopharmacol 2011

  21. ECNP/EBC Report 2011[Methodology] • Direct successorof a benchmark study oftheCostofDisordersofthe Brain in Europepublished in 2005 • 27 European + 3 alliedcountries[Norway, Iceland, Switzerland] • Collaborationbetweenalmost a hundred prominent epidemiologists and many expert healtheconomists • Based on thebestcurrentlyavailable data in Europe, and thebestcurrentlyavailableestimates as identified via a systematicreviewofthesoundeststudiespublished • Cost model inputs: StatisticsfromEurostat, estimatesoftheprevalence and cost per person, localcurrenciesconverted to Euro and adjusted to purchasingpower parity (PPP), • Data wereextrapolated to countrieswhere no data couldbefound

  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. Hurdles in the current process prevent fast and fair access to novel treatments in CNS • Bottlenecks • Regulatory • approval • Market • entry • Patient • use • Public / private R&D • and regulatory • Pricing and • reimbursement • Clinical delivery • Knowledge • feedback Accelerated Access to Treatment • Monitoring and knowledge back loop into R&D • 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 retrospectiveprice 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

  26. Numberofclinicaltrialsappliedfor in EU EU CTD conceptpaper 25/2011

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

  28. THE EU CLINICAL TRIALSDIRECTIVE (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 bothfor 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) Dryingpipelines

  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 courtesyH.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 clinicalresearch Not onlytorture of healthyanimals • 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 Prediction of therapeuticoutcomeneeded symptoms? Functioning? QOL? Academia, industry, patients bureaucracy, hurdles + GxEinteraction! + information technology!

  36. Summary of FEAMrecommendations • Better understanding of psychosocial and biological factors and their interactions • Capitalising on scientific advances and collaboration for more effective recognition and classification of mentaldisorders, further development of diagnostics and treatment methods • Sharing best practice to attain consistently high standards of psychiatry throughout EU • Success depends also on improved datacollection,commitment to research and innovation priorities, andenhanced infrastructure

  37. Clinical Research with a Focus on Psychiatry/Neurosciences • Requires coherent strategy and active networks across research, innovation and healthservicesincluding 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

  38. Clinical Research with a Focus on Psychiatry/Neurosciences Cyril Höschl www.hoschl.cz National Institute ofMentalHealth Prague Psychiatric Centre &Charles University, Prague Czech MedicalAcademy Feam Spring Conference, Dublin, 28th – 29th May 2013

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