SAFETY ISSUES RESULTING FROM POOR TRANSLATION OF CLINICAL TRIAL DOCUMENTS

1. SAFETY ISSUES RESULTING FROM POOR TRANSLATION OF CLINICAL TRIAL DOCUMENTS When Science Meets Regulation and Culture Dorit Eldar, M.D., Medical DirectorBQT Biomedical Translations, Petach Tikva, IsraelYehudith Wexler, ChairpersonBioForum Group, Ness-Zionna, Israel Acknowledgements: Stanley G. Garbus, M.D., Garbus Consulting

2. TABLE OF CONTENTS INTRODUCTION PART 1: Poor Translation of Clinical Trial Documents – Safety Risks to the Participant PART 2: Poor Translation of Clinical Trial Documents – Safety Risks to others PART 3: Common problems of poor translation PART 4: Understand the cost of poor translation PART 5: Fundamental Skills Needed for High Quality Translation of Clinical Trials Documents

3. INTRODUCTION Use of poor translation results in poor language in general • Art Beetles?

4. INTRODUCTION – cont. • Literature, cinema, poetry… • The press • השטחים הכבושים / המשוחררים? Use of poor language affects us in many levels, including sub-conscious levels

5. INTRODUCTION – cont. • Medicine החיים והמוות ביד הלשון Body = גוף? גופה?

6. INTRODUCTION – cont. • Medicine - cont • Effective communication between patient and provider of medical care is critical to the delivery of safe, high-quality care. • Patients have to understand the questions they are asked and the information that is given to them. • Studies have shown:Patients with low language proficiency are at increased risk of experiencing an AE. The issue has been studied in countries with a high proportion of new immigrants whose knowledge of English is limited – US, Canada, Australia (1, 2). Lately such increased risk is present also in the European Community due to greater patientmobility (3). Johnstone MJ, Kanitsaki O. Culture, language and patient safety: making the link. Int J Qual Health Care 2006; 18: 385-388 Divi C, et al. Language proficiency and adverse events in US hospitals: a pilot study. Int J Qual Health Care 2007; 19: 60-67 Groene O, et al. Quality requirements for cross border care in Europe: a qualitative study of patients', professionals' and health care financiers' views. Qual Saf Health Care 2009; 18: Suppl i.15-i. 21

7. INTRODUCTION – cont. • Medicine - cont Hence the safety of patients participating in a clinical trial may be jeopardized because of their poor language proficiency and also because of faulty translation of trial related documents. • Any inconsistency between the original text and the translated one may lead to lack of comprehension or to misunderstanding, bad decisions and dangerous activities • Inaccuracy may be critical • Use of high language may lead to misunderstanding, withdrawal of the subject's consent, irrelevant concerns and unnecessary fears • Omission of text – may be dangerous

8. INTRODUCTION – cont. Documents written by of for the Sponsor Translator Documents to Local Readers: candidates, patients, investigators, study staff, ECs, authorities, etc. Documents written by local parties: physicians, authorities, EC, etc. Sometimes the client’s expectations from the translated document cannot be reached by the market since the combination of professional translation and biomedical knowledge is not common

9. Every document has a purpose INTRODUCTION – cont. ONE fundamental purpose: To inform (the participant – ICF the attending physician – Form 11 the study team – patient diary the investigator – investigator’s brochure…)

10. The purpose determines the target reader. Thus, Every document has its target readerExamples: INTRODUCTION – cont. Informed Consent Form – the candidate / volunteerProtocol synopsis – the investigators and study staffIB – the investigatorsSafety reports – the safety boardEC correspondence – investigator/ sponsorPatient diary – the patient / and study staff Patient emergency card – anyoneLetters -the attending physician, etc.

11. Each target reader has its characteristics INTRODUCTION – cont. Examples: The candidate / patient / participant / volunteer: “the layman”, lacks medical background, has an 8th grade reading level, sometimes is sick, sometimes suffers from side effects, is under a lot of stress, surrounded by advice giversThe sponsor, investigators and members of safety boards: professionals, extensive medical background, specifically in the study’s subject, busy, high academic reading level The study staff - medical background, busy, academic reading level

12. The information, vocabulary and style of the document should be adjusted to the target reader INTRODUCTION – cont. The translator should know the characteristics of the target reader in order to create a document which fulfills its purpose. If the translator does not know your reader – he/she should not translate. Not knowing the target reader is dangerous and may lead to crucial safety risks.

13. Safety risks to who? INTRODUCTION – cont. • Examples: • The volunteer • The volunteer's partner • The volunteer pregnant partner • The unborn child • Family members (including children & elderly) • Family friends • Neighbors / The community • The society / the study • The environment • ANYONE ENGAGED OR INVOLVED IN THE STUDY

14. PART 1: Poor Translation of Clinical Trial Documents - Safety Risks to the Volunteer 1. Hazards in medication therapy (both when self administered or given by others) – Increase occurrence or severity of AEs Examples: poor translation of: - Prescription and administration of the trial medication: name, dosage, route of administration - Signs and symptoms to be looked for - failure of the clinical trial team to elicit participant's symptoms - Steps the volunteer or family may take to prevent or minimize AEs - Explanation of how and by whom the AE will be treated, and to what medical and chronological extent - Explanation of how the study drug affects the standard treatment the patient is receiving

15. PART 1: Safety Risks to the Volunteer – cont. The participant's limited ability to understand documents at a level that permits effective interaction with the clinical trial team leads to • failure of the participant to act as instructed • disparities in prescription and administration of the study preparation • reduced likelihood for appropriate follow-up and treatment of the underlying conditions and/or of side effects of the trial It is CRUCIAL for these explanations to be translated clear and accurately in a language understandable by the staff, patient and family

16. PART 1: Safety Risks to the Volunteer – cont. 2. Risks due to cultural differences, not properly adjusted by thetranslation Examples: • English text invites people to a clinic examination. In some countries this should be modifies to house calls (in order to cover a family disease). • Food / beverages prohibited in certain religious (alcohol). • Is “room temperature” the same in Israel and Norway? • Questionnaires – risk of scoring differently than others around the globe Verbal memories – recalling lists of words BUT – words like “mink” and “lawn” are not usable in Israel, “cottage” means cheese, China” means only a country • Letter fluency - naming as many items as possible that begin with that letter

17. PART 2: Poor Translation of Clinical Trial Documents - Safety Risks to others Examples: The participant's partner: misunderstanding regarding diet, sex relations (contraception - when, for how long, which?), behaviour, daily activity, mood Participant's pregnant partner:unclarity regarding hazards to pregnancy / fetus Unborn child of a participant / participant's partner: genetic hazards to future generations Family members and friends: errors in translation of storage and precautions required Community: errors in precautions – infections, contaminations. Society / Study: errors in reporting safety data to be analyzed for registration, development of drug resistance Environment: errors in instruction of disposal of radioactive ingredients, TB live vaccines

18. PART 3: Common problems of poor translation • Lack of professional medical background • 1a. Medical vocabulary – using the right term: • Example - anatomy: • Both breasts (pupils) are equal and reactive to light and accommodation. • Example: pathology: • Occasional, constant infrequent headaches(Occasionally, infrequent persistent headaches)

19. PART 3: Common problems – cont. • More Examples: • She had no shaking chills, but her husband states she was very hot in bed last night. (She had no shaking chills but her husband states that she had high temperature / fever in bed last night). • When she fainted, her eyes rolled around the room.(When she fainted she rolled her eyes around the room). • Discharge status: Alive, but without my permission(Discharge status: Alive. Discharged without my permission).

20. PART 3: Common problems – cont. • 1b. Jargon – new areas ahead of language • Language in science is dominated by 2 contradictory trends: • Greater international unification - globalization of scientific English • Growth of field-specific jargon - new terms to express new knowledge • “Jargon” allow specialists to communicate precisely with one another. • Removing jargon or substituting it with another phrase can affect interpretation. • Cat  scan – is it “searching for kitty?

21. PART 3: Common problems – cont. Problem – same words used in different jargons mean different things (What is Plasma? Is it in the cell? Is in the blood? Is it a sterilization device or a part of your TV screen? THE DECISION IS DEPENDANT ON KNOWING THE TARGET READER!

22. PART 3: Common problems – cont. • Slang – a popular jargon • Doc • Over the counter • Gay participants – are they merry?! • The pelvic exam will be done later on the floor(The pelvic examination will be done later, in the ER department (which is always on the ground floor and often called “the floor”). • Dr. Smith felt we should sit on her abdomen(Dr. Smith felt we should discuss her abdomen (ד"ר סמית חשב שצריך לשבת על הבטן שלה). • Outpatient - A patient who has fainted?

23. PART 3: Common problems – cont. • 1c. Acronyms and abbreviations • FDA, ICH, IEC, IRB, WHO, EMEA, PI, MedDRA, CRF, AE/SAE… • Professional background enables choosing the right full term for the reader: • Example: • FDA: Food & Drug Administration ? / Functional Data Analysis ? / Florida Dental Association ? / Foreign Disaster Assistance ? / Frequency Domain Analysis ? / Federal Disaster Area ? • And knowing when they suit the professional reader • Example: • The SOP reg. an AE of abnormal AST (SGOT) or ALT (SGPT) levels, but normal AUC or AUC(0-t), requires using the ANCOVA model. BMI, BP, Bpm, HR, EF and ECG results will be documented in the CRF. IV PKs, even when NCS or WNL will be expressed in mgs per mls.

24. PART 3: Common problems – cont. 2. Lack of knowledge of local and international health regulations, clinical trials procedures, lack of commitment to GCP requirements Example: Length – a profound problem! knowledge of local and international health regulations, clinical trials procedures, and GCP requirements enables quality suggestions of shortening, if requested.

25. PART 3: Common problems – cont. • 3.Lack of linguistic skills: • Tense • The past tenseprevails in biomedical reports, except for “general truths,” which are written in the present tense. • The medication improves weakness. • The medication improved weakness. • Future tense should be used in protocols but may confuse issues about standard practices. • Environmental controls will be set to maintain temperatures of 18o to 26oC. • Environmental controls are set to maintain temperatures of 18o to 26oC.

26. PART 3: Common problems – cont. • Numbers • Doses, timetable of procedures, amounts of blood to be taken, etc.: • Inaccuracy may be critical, even fatal. • Commas simplify the reading large numbers (23,450 vs. 23450) but: • Many Europeans use the decimal point as a comma, rather than a period (e.g. 23,450 means 23.450)

27. PART 3: Common problems – cont. • Never trust the auto speller – read again!: • Examination of genitalia reveals that he is circus sized.(Examination of genitalia revealed that he iscircumcised). • While in ER, she was examined, x-rated and sent home.(While in ER she was examined, X rayed and sent home) • The lab test indicated abnormal lover function.(The lab test indicated abnormal liver function). • The skin was moist and dry • (The skin was mostly dry)

28. PART 3: Common problems – cont. • 4. Lack of translation skills: • 4a. Lack of outmost preciseness • Using the signs > / < / = / ± / ≥ / ≤ in translating inclusion / exclusion criteria • The patient has no previous history of suicides.(The patient has no previous history of suicide attempts.) • On the second day the knee was better and on the third day it disappeared. (On the second day the knee was better and on the third the pain / swelling disappeared.)

29. PART 3: Common problems – cont. 4b. Lack of computer skills Use of different programs, (online and hard copy) dictionaries, templates. High knowledge of implementation of footers, remarks, comparison of documents, tabulating etc.

30. PART 3: Common problems – cont. • 4c. Inconsistency • Typical of documents with multiple contributors (protocol, clinical report, ICF). • all along the document internal consistency is important regarding: • Language - level and terms used • Style • verb tense • Structure

31. PART 3: Common problems – cont. Inconsistency – example: The study product will be given to the subject by the investigator. The study doctor will administer the investigational preparation by injecting the experimental solution to the participant. After receiving the pharmaceutical experimental product, the patient will be requested by the physician to lie down in order to receive additional trial drug. The participant, the PI, the study drug – one term!

32. PART 4: Understand the cost of poor translation Physical / emotional harm Misconduct of the trial Money Time

33. PART 5: Fundamental Skills Needed for High Quality Translation of Clinical Trials Documents– minimizing errors and safety risks • A translator who knows the target reader • with: • 1. Professional medical background (vocabulary, jargon, acronyms, abbreviations; knowing when and how to seek dictionaries, text books, specialists' assistance • 2. Profound updatedknowledge of relevant local andinternational regulations and procedures (The ability to simplify the text, the knowledge to suggest solutions) • 3. High linguistic skills (tense, grammar) • 4. High translation skills (outmost accuracy, computer skills, consistency)

34. Thank you for listening!