Transcript Neurobiologie schizofrenie

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
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
Van Helmont JA. Oriatrike.
London: Lodowick-Loyd, 1662, p.526
History of clinical trials
Investigators
Subject selection
Inclusion criteria
“Let us take out of the Hospitals, out of the Camps, or from
elsewhere, 200, or 500 poor People, that have Fevers,
Sample size etc. Let us divide them in Halfes, let us cast lots,
Pleurisies,
Randomization
that one half of them may fall to my share and the other to
yours; I will cure them without bloodletting and sensible
Parallel group
evacuation;
but do you do as ye know. We shall see how
design
many funerals both of us shall have: But letIntervention
the reward of the
contention or wager, be 300 Florens, deposited on both
sides…”
Outcome
measure
Fees, costs and
Jeanexpenses
Baptiste van Helmont, 1626
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.
History of antipsychotic treatment
1900
'40
'50
'60
'70
'80
'90
2000
Risperidone
Molindone
Ziprasidone
Loxapine
Olanzapine
Aripiprazole
Chlorpromazine Haloperidol
Clozapine
Quetiapine
Fluphenasine
Iloperidon
Trifluoperazine
Reserpine
Thioridazine
Jean Delay
Pierre Deniker
Perphenazine
Atypical antipsychotics,
Conventional,
2nd Generation
Classical neuroleptics,
1st Generation Antipsychotics
Source: Lieberman J, et al., APA Annual Meeting, May 2001
Schizophrenia
Clinical Antipsychotic
Outpatient Health European First
Trials of Intervention
Episode
Outcomes
Effectiveness Cost Utility of the Latest
Schizophrenia
Antipsychotic Drugs in
Trial
Schizophrenia
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 Research with a Focus
on Psychiatry/Neurosciences
The main points of the presentation:
 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
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 with a Focus
on Psychiatry/Neurosciences
The main points of the presentation:
 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
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 with a Focus
on Psychiatry/Neurosciences
Methodological pitfalls:
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
Exclusion of real world conditions:
Human rights
1Papakostas
•
•
•
•
•
Alcohol&drug abuse
Comorbidity
Suicidal thoughts
Other treatments
Severity of illness
GI and Fava M, Eur Neuropsychopharmacol 2009
2Khan A et al, CNS Neurosci Ther 2010
3Kemmler G et al, Arch Gen Psychiatry 2005
4Hofer A et al, J Clin Pharmacol 2000
Antidepressant vs Placebo
response rate
53.8
146 mns 182 CT
N=36 385
37.3
95% CI
Source: Papakostas and Fava, 2009
Publication year and response rate
Response rate
antidepressants
1980-1989
1990-1999
Verum
2000-2007
Placebo
N=36 385
262 verum-placebo pair comparisons
Source: Papakostas and Fava, 2009
Factors influencing signal detection
Response to placebo in CNS studies
PANSS total score
change from baseline (placebo)
Placebo response in acute clinical studies of schizophrenia
Placebo response correlates with the time when the study was conducted
1993 1996 1997 2001 2002 ~2000-1 2000-3 2004-5 2004-6 2004-6 ~2007-8
Kemp AS et al. Schizophr Bull 2010; 36:504–509
Kinon et al. Curr Opin Psychiatry. 2011 Mar;24(2):107-13
Factors influencing signal detection
Placebo-verum difference in HAMD
Response to placebo in CNS studies
130 DB RCT
betwen 1981-2008
N=35122
Verum N=23157
Placebo N=11965
Publication year
Khan A et al., CNS Neurosci Ther 2010
Factors influencing signal detection
Response to placebo in CNS studies
40
40
AD group HAMD0
PL group HAMD0
AD group HAMDdecrease
PL group HAMDdecrease
30
HAMD
HAMD
30
20
20
10
130 DB RCT
between 1981-2008
N= 35 122
Verum N=23157
Placebo N=11965

10
Khan A. et al.,
CNS Neurosci Ther 2010
0
0
Publication year
Factors influencing signal detection
Response to placebo in CNS studies
40
AD group HAMD0
40
PL group HAMD0
AD group HAMDdecrease
PL group HAMDdecrease
HAMD
HAMD
30
30
130 DB RCT
between 1981-2008
N= 35 122
Verum N=23157
Placebo N=11965
20
20
10
10
NS
Khan A. et al.,
CNS Neurosci Ther 2010
0
0
Publication year
Multiple overlapping factors
which impair signal detection




Design of a study
Type of facility (level, qualification of raters, blinding)
Patients’ characteristic (severity, suicides, comorbidity, comedication)
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?
(V2) (IVRS)
HAM-A
InteractiveIVR
voice
system
OBS HAM-A
(V2)
Doctor’s
rating
Number
Number
of patients
Number
Number
of patients
70
60
50
40
30
20
10
35
30
25
20
15
10
5
0
0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54
HAM-A total
Totalscore
Score
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54
Total Score
HAM-A total
score
HAM-A was used as a screening for inclusion and as an outcome measure in the relapse prevention study.
The graph on the left indicates that inclusion criterion was HAM-A total score „at least 20“ 
Source: Feltner et al, NCDEU, 2001
Multiple overlapping factors
which impair signal detection












Design of a study
Type of facility (level, qualification of raters, blinding)
Patients’ characteristic (severity, suicides, comorbidity, comedication)
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
Clinical Research with a Focus
on Psychiatry/Neurosciences
The main points of the presentation:
 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
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 nonmedical 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
Hurdles in the current process prevent fast and fair
access to novel treatments in CNS
Bottlenecks
Regulatory
approval
Public / private R&D
and regulatory
Market
entry
Pricing and
reimbursement
Patient
use
Clinical delivery
Knowledge
feedback
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
• Disease awareness is limited and
the share of voice for CNS is low
• Health authorities hold back highprice treatments in some countries
• Uptake depends on a variety of
factors, incl. attitude of providers,
nature of innovation, budgeting, etc.
• Role of effectiveness studies not
clear but essential to assess relative • Providers are under pressure of
therapeutic value
cost-containment measures
• Pricing and reimbursement schemes • Widespread implementation of
are not considered flexible enough
guidelines often time consuming
to allow retrospective price
• Lack of standardized patient
increases
registries affects disease knowledge
• Payers continue to focus on cost• Clinical learning from trial and in-life
containment measures
settings are insufficiently fed-back
Number of clinical trials applied for in EU
№ trials
5200
5000
4800
4600
4400
№ trials
4200
4000
3800
3600
2007
2008
2009
2010
EU CTD concept paper 25/2011
The cost of a new drug development
Million $
 9x!
Morgan S et al. Health Policy 100 (2011) 4–17
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
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)
To analyze the impact of CTD, a consortium created
by the European• Forum
for Good Clinical
Practice
Reduction
of planned
number of participants
(EFGCP) and comprised of the European Clinical
in EU trial applications (DG Sanco statistics)
Research Infrastructure Network (ECRIN), the
– for
2007:
535,000
European Organization
Research
and Treatment
of Cancer (EORTC), –
Ethics
Committee
of the Medical
2009:
358,000
University of Vienna, and Hospital Clinic I de
Barcelona, established the Impact on Clinical
• Reduction of proportion of world’s
Research of European Legislation (ICREL)
pharmaceutical CT in UK (BMJ 2009)
– 2000: 6%
– 2009: 2%
• EU trials (ICREL statistics)
– More costly
– More difficult to plan, start and conduct
NEGATIVE IMPACT - FACTS (2)
• Particular problems in multi-national, noncommercial trials in cancer, paediatrics,
transplantation (PLoS Medicine 2009)
• Striking decrease in number of drug
development companies formed in Europe
(EuropaBio 2010)
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
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
Clinical Research with a Focus
on Psychiatry/Neurosciences

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
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