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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 of Mental HealthPrague Psychiatric Centre & Charles University, Prague
Czech Medical Academy
“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
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
InvestigatorsSubject selection Inclusion criteria
Sample sizeRandomization
Intervention
Fees, costs and expenses
Parallel group design
Parallel group design
Parallel group design
Parallel group design
Outcome measure
Van Helmont JA. Oriatrike. London: Lodowick-Loyd, 1662, p.526
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.
Conventional, Classical neuroleptics, 1st Generation Antipsychotics
History of antipsychotic treatment
Source: Lieberman J, et al., APA Annual Meeting, May 2001
1900 '40
ReserpineHaloperidol
Fluphenasine
Trifluoperazine
Thioridazine
Perphenazine
MolindoneLoxapineClozapine
Risperidone
Olanzapine
Quetiapine
Ziprasidone
Aripiprazole
Iloperidon
2000'50 '60 '70 '80 '90
Atypical antipsychotics, 2nd Generation
Jean DelayPierre Deniker
Chlorpromazine
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
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.
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.
Incentives
1. High placebo responses and failure of active treatments to demonstrate significant efficacy vs. placebo1,2
2. High rates of subject discontinuation3
3. Questionable generalization of results to real-world patients4
Clinical Research with a Focus on Psychiatry/Neurosciences
Methodological pitfalls:
1Papakostas GI and Fava M, Eur Neuropsychopharmacol 2009
2Khan A et al, CNS Neurosci Ther 20103Kemmler G et al, Arch Gen Psychiatry
2005 4Hofer 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
Signal fades away.
Antidepressant vs Placeboresponse rate
Source: Papakostas and Fava, 2009
53.8
37.3
95% CI
146 mns 182 CT N=36 385
Verum Placebo
1980-1989 1990-1999 2000-2007
Res
pons
e ra
te
N=36 385262 verum-placebo pair comparisons
Publication year and response rate
antidepressants
Source: Papakostas and Fava, 2009
Factors influencing signal detectionResponse to placebo in CNS studies
Kinon et al. Curr Opin Psychiatry. 2011 Mar;24(2):107-13
Kemp AS et al. Schizophr Bull 2010; 36:504–509
Placebo response in acute clinical studies of schizophrenia
PA
NS
S t
otal
sco
rech
ange
fro
m b
asel
ine
(pla
cebo
) Placebo response correlates with the time when the study was conducted
rispe
ridon
e
olan
zapi
ne
quet
iapi
ne
zipr
asid
one
arip
ipra
zole
asen
apin
e
bife
prun
ox
palip
erid
one
sone
pipr
azol
e
aseb
apin
e
lura
sido
ne
1993
1996
1997
2001
2002
~2000-1
2000-32004-52004-6
2004-6
~2007-8
Khan A et al., CNS Neurosci Ther 2010
Publication year
Pla
ceb
o-v
eru
m d
iffe
ren
ce in
HA
MD
130 DB RCT betwen 1981-2008N=35122Verum N=23157Placebo N=11965
Factors influencing signal detectionResponse to placebo in CNS studies
Publication year
130 DB RCT between 1981-2008N= 35 122Verum N=23157Placebo N=11965
19801985
19952000
20052010
19901980
19851995
20002005
20101990
HA
MD
10
40
30
20
0
10
40
30
20
0
HA
MD
AD group HAMD0
AD group HAMDdecrease
PL group HAMD0
PL group HAMDdecrease
Factors influencing signal detectionResponse to placebo in CNS studies
Khan A. et al., CNS Neurosci Ther
2010
Publication year
130 DB RCT between 1981-2008N= 35 122Verum N=23157Placebo N=11965
19801985
19952000
20052010
19901980
19851995
20002005
20101990
HA
MD
10
40
30
20
0
10
40
30
20
0
HA
MD
AD group HAMD0
AD group HAMDdecrease
PL group HAMD0
PL group HAMDdecrease
Factors influencing signal detectionResponse to placebo in CNS studies
Khan A. et al., CNS Neurosci Ther
2010
NS
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
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.
IVR HAM-A (V2)
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54
Total Score
Num
ber
OBS HAM-A (V2)
0
10
20
30
40
50
60
70
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54
Total Score
Num
ber
Source: Feltner et al, NCDEU, 2001
HAM-A total score HAM-A total score
Doctor’s rating Interactive voice system (IVRS)
The graph on the left indicates that inclusion criterion was HAM-A total score „at least 20“
Num
ber
of p
atie
nts
Num
ber
of p
atie
nts
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 factorswhich impair signal detection
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.
Gustavsson A, et al. Cost of disorders of the brain in Europe 2010.
Eur Neuropsychopharmacol 2011
ECNP/EBC Report 2011 [Methodology]
• Direct successor of a benchmark study of the Cost of Disorders of the Brain in Europe published in 2005
• 27 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
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.
Brain research is underfunded
Charity funding
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
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 andreimbursement
Public / private R&Dand regulatory Clinical delivery
Regulatoryapproval
Marketentry
Patientuse
Monitoring and knowledge back loop into R&D
Knowledgefeedback
Accelerated Access to Treatment
Accelerated Access to Treatment
Number of clinical trials applied for in EU
2007 2008 2009 20103600
3800
4000
4200
4400
4600
4800
5000
5200
№ trials
№ trials
EU CTD concept paper 25/2011
Morgan S et al. Health Policy 100 (2011) 4–17
The cost of a new drug developmentMillion $
9x!
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
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
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
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)
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
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
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
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!
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
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
Clinical Research with a Focus on Psychiatry/Neurosciences
Feam Spring Conference, Dublin, 28th – 29th May 2013
Cyril Höschl www.hoschl.cz
National Institute of Mental HealthPrague Psychiatric Centre & Charles University, Prague
Czech Medical Academy
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