international clinical trials - threats and opportunitiesaz9194.vo.msecnd.net/pdfs/131202/10503...

International Clinical Trials - Threats and Opportunities

Eugen Trinka

Universitätsklinik für Neurologie, Salzburg

Paracelsus Medical University

American Epilepsy Society | Annual Meeting

Disclosure

American Epilepsy Society | 2013 Annual Meeting

• E Trinka has acted as a paid consultant to Eisai, Medtronics, Bial, Gerot-Lannacher, Biogen, and UCB.

• He has received research funding from Austrain Research Foundation (FWF), Jubiläumsfond der Österreichischen Nationalbank (ÖNB), European Union, UCB, Biogen, sanofi-aventis, Bayer, Red Bull and

• speakers’ honoraria from Bial, Cyberonics, Desitin Pharma, Eisai, Gerot-Lannacher, Böhringer-Ingelheim, Sanofi, GSK, and UCB.

• Owner Neurconsult Ges.m.b.H

Learning Objectives

• To understand the basic principles, strengths and weaknesses of the most common clinical trial designs

• To identify the most critical biases in clinical trial design

American Epilepsy Society | 2013 Annual Meeting

Agenda

• Do we need international trials?

• Current trial designs

– Monotherapy trials in newly diagnosed epilepsy

– Add on trials in drug resistant patient

• Globalization of trials

• Methodological issues

• Conclusions

Reasons for international trials

• Two thirds of patients are seizure free on currently available ASDs, but may suffer from tolerability problems

• Lack of RCTs for many seizure types, epilepsy syndromes, and status epilepticus

• Little information on etiology specific responsiveness

• Antiepileptogenic and disease modifying drugs are currently not available

• High numbers needed, especially in newly diagnosed epilepsy

• Licensing of ASDs regulatory trials

Marson and Wiliamson Curr Opinion Neurol 2009; French et al. Epilepsia 2013; Friedman and French Lancet Neurol 2012;

Straus et al. Evidence Based Medicine. How to practice and teach EBM. Elsevier Churchill Livingston 2005

Best research evidence

Own experience

Patients‘ values and

circumstances

The decision making process is in the heart of health care: both individual treatment decisions and public health

• EBM requires the integration of the best research evidence with our clinical expertise and our patients‘ unique values and circumstances

– valid and clinically relevant

– basic sciences

– patient-centered clinical research

– power of prognostic markers

– efficacy and safety of therapeutic and preventive regimens

Evidence from research

RCTs

Synthesis

Retrospective studies and case observations

Meta-analysis and Cochrane Reviews

Original published articles in peer reviewed journals

Modified from: Straus et al. Evidence Based Medicine. How to practice and teach EBM. Elsevier Churchill Livingston 2005

Prospective uncontrolled trials

Regulatory trials

Agenda







• Conclusions

Straus et al. Evidence Based Medicine. How to practice and teach EBM. Elsevier Churchill Livingston 2005

Best research evidence

• Randomised controlled trials (RCT):

Monotherapy in newly diagnosed epilepsy

Add on treatment in refractory patients

RCTs face substantial barriers:

• Randomness of seizures

• Regression to the mean

• Inability of patients to recognize seizures

• Small effect sizes in newly diagnosed and in refractory patients

Which population do we study?

0.6%

0.4%

Newly diagnosed epilepsy

Drug resistance

1. seizure

Monotherapy

alternative Monotherapy

Poly- therapy

Monotherapy studies

• Placebo controlled mono RCTs are ethically unacceptable due to established AED Declaration of Helsinki

• Active controls

– non-inferiority design: EMA1

– superiority design: FDA2

• EMA accepts equivalence (non-inferiority) with an added value for the patient1

• FDA requires superiority (but: pseudo-placebo or historical controls are “acceptable”)2

1: EMEA: http://www.emea.europa.eu/pdfs/human/ewb/056698en.pdf; 2: Leber Epilepsia 1989

Superiority design

OXC VPA

50%

% seizure free

57% 54%

p = 0.2

The absence of proof of difference is not

the proof of absence of difference

Negative in terms of superiority does not allow the conclusion of non-inferiority

It is wrong to say:

“Both substances have the same efficacy”

1: Christe et al. Epilepsy Research 1997

N=249; 56 Wk

Zonisamide: Monotherapy study design • 582 patients aged 18–75 years, newly diagnosed with partial epilepsy

CBZ, carbamazepine; ZNS, zonisamide

Screening 2 weeks

Titration 4 weeks

Flexible dosing period 3 x 26 weeks

Maintenance period

26 weeks

Down-titration or transition to

double-blind extension

(Study 314)

1200 mg

800 mg

400 mg 400 mg

200 mg

600 mg

100 mg

200 mg

300 mg

200 mg

400 mg

500 mg

CBZ

ZNS

0 mg

0 mg

Baulac et al. Lancet Neurology 2012; 11:579-88

Active controls in non inferiority design

• Selection of test drug

• Optimaler Gebrauch der Vergleichssubstanz

• Non-Inferiority Grenzen

• Ergebnisse und Analysen

– Welche Population wurde eingeschlossen?

– Wie groß ist die Wirksamkeit der Vergleichssubstanz

– Gesamte Daten ITT und per protocol (PP) sowie non inferiority Analysen

• Assay sensitivity (Testvalidität), Robustheit der historischen Data (comparator vs placebo)

• Ethische Fragen

– CBZ-IR1,2, PHT1

– LEV (non inferior to CBZ-CR, class I3 and III KOMET6)

Class 1 studies in ILAE Guidelines4

– VPA ?

– LTG (SANAD study: efficacy (time to treatment failure) > CBZ, OXC, GBP, TPM5, class I PGB7)

1: Mattson et al. NEJM 1995, 2: Chadwick et al. Lancet 1999; 3: Brodie et al. Neurology 2007; 4: Glauser et al. Epilepsia 2005; 5: Marson et al. Lancet 2007; 6: Trinka et al. JNNP 2012, 7: Kwan Lancet Neurol 2011

But: absence of knowledge of the size of the treatment effect compared to placebo

Active controls in non inferiority design

• Auswahl der Vergleichssubstanz

• Optimal use of comparator on-Inferiority Grenzen






• Ethische Fragen

1: Brodie et al. Epilepsy Res 1998

STEP ONE: Time to treatment failure

LEV

LTG CBZ-SR

1: Werhan, Trinka and Krämer, Data on file; http://clinicaltrials.gov/show/NCT00438451, Aug 16th 2012

OR 1.838 (95%CI: 1.092-3.093) for LEV vs. CBZ-SR



• Non-Inferiority margin






• Ethische Fragen

- Δ

T–C

Δ Non inferiority margin - clinically irrelevant - a priori defined

Test substance is better

Difference T - C

standard substance is better

0

Active controls in the non inferiority design

Non Inferiority margin: absolute vs relative

60%

6 month seizure free

40%

20%

Relative 20%

Absolute 20% -33%

relative -50%

relative

-30% relative

Comparator’s efficacy Comparator’s treatment effect over placebo

Placebo Effect: 20%

Newly dignosed epilepsy: what is the treatment effect?

Relapse risk

6 m

on

th r

emis

sio

n

Treatment effect

2 seizures, normal EEG and MRI

10 seizures, EEG c spikes and abn. MRI Placebo

Testdrug

Modified from: Marson and Williamson Curr Opin Neurol 2009

Assay Sensitivity



• Non-Inferiority Grenzen





• Assay sensitivity

• Robustness of historical data (comparator vs placebo)

• Ethische Fragen

60%

6 m

on

th r

emis

sio

n

45%

30%

15%

75% T

C T

C

P Placebo X

Withdrawal to Monotherapy Study Design1,2

1: French et al. Epilepsia 2010; 2: Friedman and French, Lancet Neurol 2012

French et al. Lamotrigin XR conversion to monotherapy; first study using a historical control group. Neurotherapeutics 2012; 9: 176-184

Sperling et al. Conversion to monotherapy with eslicarbazepine acetate in adults with partial-onset seizures: results of a North-American study AES 2013 Poster 3.293

Pazdera et al. Conversion to monotherapy with eslicarbazepine acetate in adults with partial-onset seizures. AES 2013 Poster 1.228

Typical Add on Design

Baseline

8 wk

Taper Titration*

4−6 wk

Randomization

Treatment phase

12 wk

Placebo

100 mg

200 mg

300 mg

• fixed dose and fixed titration scheme

• short treatment period

• categorized endpoints: 50% responder rate

• continuous endpoints: median %-seizure reduction

Marson et al.BMJ 1996, Cramer et al. Epilepsia 1990

76

51

21 1923

9

0

10

20

30

40

50

60

70

80%

%

% % %

%

Which patients are included in RCTs?

Baseline

8 wk

Randomisation

„….patients with refractory partial onset seizures (POS)“…

432 Pts. from 2 epilepsy centers

Most common exclusion criteria in RCTs 2002-2007

Tlusta et al. Epilepsia 2008

Which patients are included in RCTs?

Baseline

8 wk

Randomisation

„….patients with refractory partial onset seizures (POS)“…

Syndrome specific diagnoses are not considered

Generalised epilepsies are underrepresented

Etiological stratification is not acknowledged and entry information (EEG, MRI etc) is irreversibly reduced in RCTs

What do we compare?

Treatment phase

12 wk

Placebo

100 mg

200 mg

300 mg

• Selection of dose to reach the endpoint

efficacy first

• after licensing, lower doses are often recognised to be sufficient

• higher doses may be well tolerated (rarely)

Typical Add on Design

Placebo

3: Ryvlin et al Lancet Neurol 2011

30

25

20

15

10

5

0

Pla

ceb

o r

esp

on

se r

ate

s (%

)

Year of publication

2002 2000 1998 1996 2004 2006 2008

Are placebo responder rates rising over time?

2009 2010

Guekht et al, Epilepsy Behav 2010;17(1):64-9 Sperling et al, Epilepsia 2010;51(3):333-43 Gil-Nagel et al, Acta Neurol Scand 2009;120(5):281-7

Brodie et al, Epilepsia 2009;50(8):1899-909 Elger et al, Epilepsia 2009;50(3):454-63 Halasz et al, Epilepsia 2009;50(3):443-53

Placebo

Perampanel 8 mg

Perampanel 12 mg

Median percentage reductions in seizure frequency per 28 days in the Full ITT – Double-blind Phase versus Baseline

P=0.51

P=0.52

P=0.001

P<0.001

Non-North America North America

-40

-30

-20

-10

0

-50

48 59 53 73 74 80

Effect size in different regions

French et al, Abstract AAN 2011; Neurology 2012; 79:589-96

Agenda







• Conclusions

1: Glickman et al. NEJM 2009; 2: Yusuf et al. Clin Trials 2008; 3: Dilts et al. J Clin Oncol 2006; 4: Zhang et al. Trials 2008

“Pharmaceutical and device companies have embraced globalization as a core component of their business models, especially in the realm of clinical trials.”

• 15% annual increase in FDA regulated investigators based outside the US since 2002 and 5.5% decline in US based investigators1

• increasingly bureaucratic and expensive regulatory environment in wealthy countries has not been shown to benefit patients and reseach mission2-3

• major concern is ethical oversight: 90% of published trials in China 2004 did not report ethical review and only 18% reported informed consent4

• imbalance between RCTs in developing countries and extrapolation of results in developed countries1

• Social ecology and genetic makeup of trial populations

Geographical distribution of HLA alleles

HLA-B*1502

• Prevalent in South-East Asia

• Rare or not present elsewhere

• Highest prevalence = ~12%

HLA-A*3101

• Prevalent in Europe / Americas

• Less common elsewhere

• Highest prevalence = ~40%

http://www.pypop.org/popdata/

Agenda







• Conclusions

RCT: methodological problems

• Naive positivism

• Patient selection

• Bias: Sponsorship

• Publicationbias

• Peer review

• Framework for false positive results

• Problem of Induction and Allsätze





• Publicationbias

• Peer review



Inclusion and exclusion criteria are not representative for the population we have to treat.

Open studies (SANAD; KOMET) are prone to bias before randomization.

Syndrome diagnosis is often not acknowledged: all patients with “generalized seizures” LGS, JME, CAE?





• Publicationbias

• Peer review



Lexcin et al. BMJ 2003; Heres et al. Am J Psychiatry 2006





• Publicationbias

• Peer review



Turner et al. NEJM 2007


• Naiver Wissenschaftspositivismus




• Publicationbias

• Peer review



Mooneshinge et al. PLOS 2007; Ioannidis PLOS 2005

Small studies2

Small effect size

Large number of tests

Flexibility in design, definitions and endpoints

Financial interests

The hotter the field... 1





• Publicationbias

• Peer review



, inductio

Inference from particular to general

x(C(x) A(x))

All argumernts of unobserverd matters of fact depend upon the relation of cause and effect

J. Mittelstraß, Enzyklopädie Philosophie und Wissenschaftstheorie Bd.1, 609, , Metzler 1995





• Publicationbias

• Peer review



French et al. Epilepsia 2007, Shorvon Epilepsia 2007, Panayiotopoulos Epilepsia 2007

• Fundamental and clinically relevant questions in clincal practice cannot be answered by RCTs:

• Comorbidity: Depression, sleep disturbances, COPD, cardiovascular diseases, etc.

• Gender: pregnancy, oral contraceptives

• Epilepsy syndrome

• Idiosyncratic AEs?

Limitations of EBM

•FBM and aplastic anemia (AA)

– at 1:3000-5000 15000 have to be included to observe 1 AA4

•VGB and concentric visual field defects

–1997 first case report

–1995 VGB vs. CBZ: 41% had visual field defects6

•Postmarketing experience LTG:

-TEN: RR > 141

-Hypersensitivity syndrome

-Agranulocytosis2

-Seizure aggravation3

1: Mockenhaupt et al. J Invest Dermat 2008; Neurology 2005; 2: Fadul et al. Epilepsia 2002; Ural et al. Epileptic Disorders 2005; Solvason et al. Am J Psychitr 2005; 3: Thomas et al. Brain 2006, Trinka et al. JON 2002; 4: Pellock et al. Epil Res 2006; 6: Kälviläinen et al. Arch Neurol

1995

• N=1721, unblinded, randomised

• Newly diagnosed “..CBZ was deemed to be standard treatment...“

• CBZ, GPB, LTG, OXC, TPM

• Time to treatment failure(TTF)

• Time to one year remission

Marson et al. Lancet Neurology 2007

1. How effective are the AEDs?

2. Which AED is the best choice for newly diagnosed epilepsy?

• N=1688, unblinded, randomised

• Newly diagnosed “..VPA or CBZ was considered to be standard treatment...“

• LEV, VPA, CBZ

• Time to treatment failure (TTF)

• Time to one year remission

Median daily dose: LEV 986.6 mg; VPA-ER 986.5 mg; CBZ-CR 588.5 mg

HR (2-sided 95% CI): 0.90 (0.74–1.08), p=0.258

Trinka et al. JNNP 2013

Opportunities and next steps

• Foster innovation and access to therapies, while ensuring that clinical research is conducted in populations in proportion to the presumed markets

• Assure integrity of the research wherever it takes place

• Streamline regulations governing trials and reduce redundancy in the systems

• ICH-GCP guidelines are valuable, but some issues are “subject to interpretation (“…adequately monitored…”)

• Characterization of trial populations and sites registries

• Pharmacogenomic data registries

Conclusion

• Long term solution will require input from stakeholders in academia, industry, and regulatory agencies around the world

• RCTs are as good as the regulatory authorities want them to be changing of the landscape has began: ILAE Task Force on Regulatory Issues

• New trial designs to reduce exposure of drug resistant patients to placebo

• Complementary pragmatic trials

• Prevent “international trials” from getting “globalized”

• We do not have a better method…….“all arguments for evidence are a circulus vitiosus and all counterarguments are pseudo-contradictive“ modified after Stegmüller

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