T H E I M PA C T O F L A N G U A G E + C U LT U R E IMPLEMENTING MULTINATIONAL RANDOMIZED CLINICAL TRIALS MONIKA VANCE CEO | SANTIUM ISCTM AUTUMN CONFERENCE 2017 Hotel Le Meridien Etoile - Paris FRANCE September 1, 2017 ISCTM Chair: Amir Kalali MD ECNP Chair: Eduard Vieta MD
PRESENTER DISCLOSURE Monika 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 TRIALS The U.S. Food and Drug Administration Perspective Data most impacted by language and cross-cultural challenges. U.S. + EUROPE World’s most prolific clinical trial data collectors. Growth of International Clinical Trials Based on total registered CT Investigators 100% 90% 234,000 Trials 195 Countries 80% 70% 60% 50% Growing Global Activity 40% 30% 47% non-US research sites 20% 20x more trials; 2x non-US raters (since 2005) 10% 0% 80% NDAs include non-U.S. data U.S. Non-U.S. ClinicalTrials.gov [website] (Jan 2017). Trends, Charts and Maps [webpage]. Retrieved from www.clinicaltrials.gov/ct2/resources/trends#MapOfStudies 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.
FACTORS IMPACTING CNS TRIAL SUCCESS We resolve only what we learn to understand. Data Management + Analytics Cultural norms Expertise & Experience Timelines Region Data entry & management practices Trial execution Site selection methodology Expertise/Experience Sponsor + Research Study design CRO Site PI involvement Service provider Attrition selection practices Endpoint Measurement Quality of ratings/scores Strategy Qualifications Informed consent Informed consent Budget Supportive Aims environment for Target accuracy subjects Rater Cultural origin Biases Clinical training & Titration experience Drug Language skill Language Managing subjects’ & Expectations Efficacy proficiency caregiver expectations Cultural Communication with subjects/caregivers Religion Diagnostic framework Outpatient vs. inpatient Mechanism of action & specificity Attrition Informed consent Disorder Subject Symptom presentation Caregivers Economic benefit Diagnosis Demographics Trust / rapport Psychopathology with rater Etiology Inclusion / exclusion Adherence 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.
CULTURE + DATA DISSONANCE Assessment, Measurement and Trial Design in Cross-Cultural Conflict Data Interpretability RCTs - Ideal for inquiries in somatic medicine & highly problematic in CNS: Hypotheses based on emic clinical knowledge, inductive & abductive logic. UNDERSTANDING ETIOLOGY AND PATHOGENESIS What do we understand about the disorder? What does LIMITATIONS decompensation look like at measurable critical stages? VARIABLE DIAGNOSTIC CLASSIFICATION SYSTEMS This IS normal ICD 10/11 (51%) vs DSM (44%)*; not cross-culturally validated EMIC CLINICAL TRAINING Variable perceptions - pathology, cultural disorders, clinical profile, symptom severity and treatment prioritization. IMPACT OF CULTURE ETIC PRIMARY OUTCOME MEASURES Data Interpretability ClinROs + PROs: Subjective, culturally-biased, variable in psychometric quality; rarely adapted to converge with cultural norms. *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
POWER DISTANCE UNCERTAINTY AVOIDANCE PDI - Acceptance of unequal UAI – Tolerance for ambiguity distribution of power INDIVIDUALISM - COLLECTIVISM INDULGENCE - RESTRAINT IDV – Preference for group- IND – Indicator for happiness (focus based organization on fulfilment in simple joys of life) Assessment of Society’s Persona MASCULINITY - FEMININITY LONG-TERM ORIENTATION MAS – Success emphasis on LTO – Consideration of tradition + task vs person progression + actions/challenges Geert Hofstede’s Cultural Dimensions Effects of Culture on Emic Societal Values + Communication + Behavior CROSS-CULTURAL DIFFERENCES ASSESSMENT METHOD Hofstede, G. (1980). Culture's consequences: International differences in work-related values . Beverly Hills, CA: Sage.
INFORMED CONSENT Communicating Potential Risks + Benefits = Understanding Cultural Differences Maximize Subject Recruitment Opportunities 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) SOCIAL CONSTRUCT RELIGION STIGMA • MDs held in high regard • Limitations in acceptable treatments • Disclosure of diagnosis + prognosis • Husband / Family / Community approval • Special needs re: body contact, skin • Women, children, elderly rights exposure, inquiries about physical/ • Illiterate mental health, healthcare provider, • Not competent to give consent (i.e. spiritual healer + rituals, etc. mentally ill) 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
GAMBLING DATA INTEGRITY ClinRO + PRO + Informed Consent Linguistic Validation 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. LIMITATIONS CLINRO + PRO TRANSLATION EXPERIENCE TRANSLATION Unquestioned acceptance of ingenuous IN EXPERTISE instructions from sponsor/CRO impacting COMPANIES psychometric integrity and quality of translation. PSYCHOMETRICS + TRANSLATABILITY • Internal expertise in psychometrics is rare. Expertise + Resources • Conceptual assessment for linguistic equivalency varies in quality (i.e. conformance + performance) LOCAL “CLINICAL EXPERT” NETWORK “ Never trust the translation or • Linguists - medical translation certification interpretation of something without first • Variable network of MDs – variable fluency, trusting its interpreter.” availability, and relevant expertise ACCESS TO RATER + SUBJECT GROUPS Suzy Kassem ― Philosopher, Writer and Poet Linguists tasked with CD; challenges with informed consent and availability of MDs. Also use sponsor’s study sites’ resources.
PATIENT-REPORTED OUTCOME MEASURES Protecting Data Integrity in Ethnically Heterogeneous Countries LINGUISTIC VALIDATION CONSIDERATIONS Psychometric Design Basics READING LEVEL COMPREHENSION CULTURAL RX ASSUMPTIONS Normal 12-yr old Items represent equivalent US Level: Gr. 6 Communication style construct of target disorder literate adolescent Simple (i.e. visual + somatic symptom Items are translated with conceptual Layman terminology reporting) Descriptive equivalency Expectations for change Subjects are fluent in official national language(s) Perception of change Subjects are natives or accultured residents of target country
CLINICIAN-REPORTED OUTCOME MEASURES Protecting Data Integrity in Ethnically Heterogeneous Countries LINGUISTIC VALIDATION CONSIDERATIONS Psychometric Design Basics READING LEVEL CULTURAL COMPREHENSION RX ASSUMPTIONS Western (US-based) Advanced Skilled + Technical Items represent equivalent diagnostic + symptom profile construct + translated with Academic Medical terminology frameworks conceptual equivalency Technical Medical idioms & Raters are locally trained or euphemisms accultured Rater training adequately calibrates cultural differences Raters are fluently bilingual (English + Subjects’ Languages)
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