T H E I M P A C T O F L A N G U A G E + C U L T U R EIMPLEMENTING MULTINATIONAL RANDOMIZED CLINICAL TRIALS

ISCTM AUTUMN CONFERENCE 2017

Hotel Le Meridien Etoile - Paris FRANCE

September 1, 2017

ISCTM Chair: Amir Kalali MD ECNP Chair: Eduard Vieta MD

MONIKA VANCE

CEO | SANTIUM

PRESENTER DISCLOSUREMonika Vance | CEO | Santium

I have relevant financial relationships with the concepts described, reviewed, evaluated, or compared in this presentation.

Commercial Interests & Consulting Fees – Financial compensation from Santium, with 100% ownership interest and income

generated from international healthcare and pharmaceutical industries, and government agencies; providing services related

to clinical outcome assessment.

Speaker Honoraria – None

Potential Conflict of Interest – None

GLOBALIZATION OF CLINICAL TRIALSThe U.S. Food and Drug Administration Perspective

47% non-US research sites

20x more trials; 2x non-US raters (since 2005)

80% NDAs include non-U.S. data

Growing Global Activity

U.S. + EUROPE

World’s most prolific clinical trial data collectors.

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Growth of International Clinical TrialsBased on total registered CT Investigators

U.S. Non-U.S.

Ayalew, K. (Sept. 2014). FDA Perspective on International Clinical Trials; Rate of Increase for FDA Regulated Investigators: 2000-2014 [PowerPoint Presentation]. Retrieved from www.fda.gov/downloads/drugs/newsevents/ucm441250.pdf.

ClinicalTrials.gov [website] (Jan 2017). Trends, Charts and Maps [webpage]. Retrieved from www.clinicaltrials.gov/ct2/resources/trends#MapOfStudies

195 Countries 234,000 Trials

Data most impacted by language and cross-cultural challenges.

FACTORS IMPACTING CNS TRIAL SUCCESSWe resolve only what we learn to understand.

Sponsor + CRO

Research Site

Subject

Rater

Trial execution

Expertise & Experience Timelines

Site selectionmethodology

Disorder

Region

Outpatient vs. inpatient

Study design

Symptom presentation

Diagnosis

Titration

Drug

Efficacy

Demographics

Inclusion / exclusion

Expectations

Economic benefit

Diagnostic framework & specificity

Supportiveenvironment for

subjects

Cultural norms

Aims

Expertise/Experience

PI involvement

Quality of ratings/scoresQualifications

Clinical training & experience

Managing subjects’ & caregiver expectations

Attrition

Attrition

Budget

Biases

Service provider selection practices

Language skill

Psychopathology

Note: This diagram is an example of select elements to demonstrate level of complexity. It is not intended to represent a complete set of contributing factors affecting trial success.

Endpoint MeasurementStrategy

Language proficiency

Trust / rapport with rater

Adherence

Cultural origin

Etiology

Mechanism of action

Data entry & management practices

Informed consent

Informed consent

Religion

Cultural Communication with subjects/caregivers

Data Management + Analytics

Caregivers

Informed consent

Target accuracy

ClinROs + PROs: Subjective, culturally-biased, variable in psychometric quality; rarely adapted to converge with cultural norms.

ETIC PRIMARY OUTCOME MEASURES

Data InterpretabilityAssessment, Measurement and Trial Design in Cross-Cultural Conflict

What do we understand about the disorder? What does decompensation look like at measurable critical stages?

UNDERSTANDING ETIOLOGY AND PATHOGENESIS

ICD 10/11 (51%) vs DSM (44%)*; not cross-culturally validated

VARIABLE DIAGNOSTIC CLASSIFICATION SYSTEMS

CULTURE + DATA DISSONANCE

RCTs - Ideal for inquiries in somatic medicine & highly problematic in CNS: Hypotheses based on emic clinical knowledge, inductive & abductive logic.

LIMITATIONS

This IS normal

*Evans, S. C., et al (2013). Psychologists’ perspectives on the diagnostic classification of mental disorders: Results from the WHO-IUPsyS Global Survey. International Journal of Psychology, 48(3), 177–193. http://doi.org/10.1080/00207594.2013.804189

Data Interpretability

IMPACT OF CULTUREVariable perceptions - pathology, cultural disorders, clinical profile, symptom severity and treatment prioritization.

EMIC CLINICAL TRAINING

UAI – Tolerance for ambiguity

UNCERTAINTY AVOIDANCE

IND – Indicator for happiness (focus

on fulfilment in simple joys of life)

INDULGENCE - RESTRAINT

LTO – Consideration of tradition +

progression + actions/challenges

LONG-TERM ORIENTATION

POWER DISTANCE

INDIVIDUALISM - COLLECTIVISM

MASCULINITY - FEMININITY

PDI - Acceptance of unequal

distribution of power

IDV – Preference for group-

based organization

MAS – Success emphasis on

task vs person

Geert Hofstede’s Cultural Dimensions

Hofstede, G. (1980). Culture's consequences: International differences in work-related values. Beverly Hills, CA: Sage.

CROSS-CULTURAL DIFFERENCES ASSESSMENT METHOD

Effects of Culture on Emic Societal Values +

Communication + Behavior

Assessment of Society’s Persona

INFORMED CONSENTCommunicating Potential Risks + Benefits = Understanding Cultural Differences

• MDs held in high regard

• Husband / Family / Community approval

• Women, children, elderly rights• Illiterate• Not competent to give consent (i.e.

mentally ill)

SOCIAL CONSTRUCT

• Disclosure of diagnosis +

prognosis

STIGMA

• Limitations in acceptable treatments

• Special needs re: body contact, skin

exposure, inquiries about physical/

mental health, healthcare provider,

spiritual healer + rituals, etc.

RELIGION

NUREMBERG CODE + DECLARATION OF HELSINKI (1964)

“In any research on human beings, each potential subject must be adequately informed of the aims, methods, anticipated benefits and

potential hazards of the study and the discomfort it may entail.. He or she should be informed that he or she is at liberty to abstain from

participation in the study and that he or she is free to withdraw his or her consent to participation at any time. The physician should then

obtain the subject’s freely-given informed consent, preferably in writing.”” – excerpt; (emphasis added for this presentation)

Maximize Subject Recruitment Opportunities

Nijhawan, L. P., Janodia, M. D., Muddukrishna, B. S., Bhat, K. M., Bairy, K. L., Udupa, N., & Musmade, P. B. (2013). Informed consent: Issues and challenges. Journal of Advanced Pharmaceutical Technology & Research, 4(3), 134–140. http://doi.org/10.4103/2231-4040.116779

Unquestioned acceptance of ingenuous instructions from sponsor/CRO impacting psychometric integrity and quality of translation.

CLINRO + PRO TRANSLATION EXPERIENCE

• Linguists - medical translation certification

• Variable network of MDs – variable fluency, availability, and relevant expertise

LOCAL “CLINICAL EXPERT” NETWORK

• Internal expertise in psychometrics is rare.

• Conceptual assessment for linguistic equivalency varies in quality (i.e. conformance + performance)

GAMBLING DATA INTEGRITY

Expertise + Resources

PRO Guidance + ISPOR Method – practical mechanical approach. In its

entirety, absolutely minimal method for translating PROs. Too minimalistic

for ClinROs designed to measure complex constructs.

LIMITATIONSIN EXPERTISETRANSLATION

COMPANIES

“ Never trust the translation or

interpretation of something without first

trusting its interpreter.”

Suzy Kassem― Philosopher, Writer and Poet

ClinRO + PRO + Informed Consent Linguistic Validation

PSYCHOMETRICS + TRANSLATABILITY

Linguists tasked with CD; challenges with informed consent and availability of MDs. Also use sponsor’s study sites’ resources.

ACCESS TO RATER + SUBJECT GROUPS

PATIENT-REPORTED OUTCOME MEASURES

READING LEVEL

US Level: Gr. 6

Simple

Descriptive

COMPREHENSION

Normal 12-yr old

literate adolescent

Layman terminology

CULTURAL

Communication style

(i.e. visual + somatic symptom

reporting)

Expectations for change

Perception of change

RX ASSUMPTIONS

Items represent equivalent

construct of target disorder

Items are translated with conceptual

equivalency

Subjects are fluent in official

national language(s)

Subjects are natives or accultured

residents of target country

Protecting Data Integrity in Ethnically Heterogeneous Countries

Psychometric Design Basics

LINGUISTIC VALIDATION CONSIDERATIONS

CLINICIAN-REPORTED OUTCOME MEASURES

READING LEVEL

Advanced

Academic

Technical

COMPREHENSION

Skilled + Technical

Medical terminology

CULTURAL

Western (US-based)

diagnostic + symptom profile

frameworks

Medical idioms &

euphemisms

RX ASSUMPTIONS

Items represent equivalent

construct + translated with

conceptual equivalency

Raters are locally trained or

accultured

Rater training adequately

calibrates cultural differences

Raters are fluently bilingual

(English + Subjects’ Languages)

Protecting Data Integrity in Ethnically Heterogeneous Countries

Psychometric Design Basics

LINGUISTIC VALIDATION CONSIDERATIONS

LANGUAGE + CULTURE TRIALSThe colloquialism + heart and soul of its people

* Erwin, S.M., Osgood, C.E. (1954). Second language learning and bilingualism. Journal of Abnormal and Social Psychology, 59, 139-146. |

Lambert, W., Havelka, J., Crosby, C. (1958). Language Acquisition. Journal of Abnormal and Social Psychology, 56, 239-2

Linguistic – 1-3 years immersion in local

community

Clinical - 3-5 years emic immersion in active

clinical practice treating relevant disorder(s)

BILINGUALISM* + LOCAL CLINICAL IMMERSION

PROs - Grade 6 reading level

ClinROs – Advanced academic, medical,

and Western DSM terminology

LANGUAGE + EXPERTISE

Heterogeneous subject group in each country

Unique ethnocentric behaviors and reporting

styles of somatic and psychological symptoms

+ perceptions

LANGUAGE + CULTURE + SYMPTOM-REPORTING

ClinROs and PROs developed in North

America

Mapped to American DSM taxonomy

Etic perspective to foreign raters

CULTURE + PSYCHOPATHOLOGY

Translators + Raters Translators + Raters

TRANSLATING CULTURALLY-SENSITIVE CONTENT

SUMMARYLANGUAGE + CULTURE IN MULTINATIONAL CLINICAL TRIALS

UNDERSTANDING CULTURAL

DIFFERENCES

VALIDATE ALL

TRANSLATIONS

QUALIFY FLUENCY IN RATERS

+ TRANSLATORSDEFINITELY TRANSLATE

CLINRO MEASURES

Make communication

with international raters

and subjects crystal

clear

Ensure cultural

sensitivities are

addressed

Use the existing guidance

the linguistics community

uses to assess adequate

fluency

Don’t leave your raters to

acculture themselves to your

standards; give them the

tools they need to make the

transition easier.

Hofstede’s Data + Scale (select countries)

COUNTRY POWER DISTANCE INDIVIDUALISM MASCULINITY UNCERTAINTY AVOIDANCE

LONG-TERM ORIENTATION

Philippines 94 32 64 44 19Mexico 81 30 69 82China 80 20 66 40 118India 77 48 56 40 61France 68 71 43 86Hong Kong 68 25 57 29 96Poland 68 60 64 93Turkey 66 37 45 85Portugal 63 27 31 104Czechia (Czech Republic) 57 58 57 74Spain 57 51 42 86Japan 54 46 95 92 80Italy 50 76 70 75S. Africa 49 65 63 49USA 40 91 62 46 29UK 35 89 66 35 25Switzerland 34 68 70 58Sweden 31 71 5 29 33Denmark 18 74 16 23Israel 13 54 47 81Austria 11 55 79 70

0-20 21-40 41-60 61-80 81-100 101-120

Hofstede, G. (1980). Culture's consequences: International differences in work-related values. Beverly Hills, CA: Sage.

CROSS-CULTURAL DIFFERENCES

PhilippinesMexicoChinaIndia

FranceHong Kong

PolandTurkey

PortugalCzechia (Czech Republic)

SpainJapan

ItalyS. Africa

USAUK

SwitzerlandSweden

DenmarkIsrael

Austria

Filter: Power Distance

Power Distance Individualism Masculinity Uncertainty Avoidance Long-Term Orientation

Implicit Global Benchmark

PDI IDV MAS UAI LTO

Data Interpretability = Cultural Differences + Communication

Hofstede, G. (1980). Culture's consequences: International differences in work-related values. Beverly Hills, CA: Sage.