clinical research with a focus on psychiatry/neurosciences feam spring conference, dublin, 28th –...

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




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


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


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


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


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


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


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



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

clinical research with a focus on psychiatry/neurosciences feam spring conference, dublin, 28th –...

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