OR WAIT null SECS
It is increasingly important for clinical trial personnel to break through the obstacles that language and culture present when conducting trials away from their home countries.
Clinical trials conducted in multinational and multicultural environments are increasing and include more nontraditional sites in Asia, Latin America, and Eastern and Central Europe. There appear to be clear economic advantages to performing trials in emerging markets. This article addresses how differences in infrastructure, language, and culture within multinational clinical trials can quickly cost time and real dollars. Citing current examples from industry, the article offers tips for controlling clinical trial costs and discusses how to prepare for these differences and manage them as they occur.
The cornerstones of clinical trial research include infrastructure (facilities, equipment, and ancillary personnel), a pool of subjects, and investigator experience. The sponsor faces the costs of subject and investigator recruitment, data analysis, record keeping, adverse events, informed consent, and addressing protocol related audit findings.
Since 1990, the scope of global research has grown from 28 to 79 countries, and the number of investigators conducting FDA research worldwide has multiplied 16 fold1. The International Conference on Harmonization E5 allows the use of foreign data in drug approvals. Nontraditional sites attract sponsors with the promise of lower costs for subject recruitment and investigator compensation. Some aspects of clinical development may cost less in nontraditional markets, but other aspects can cost more. For example, sponsors may have to invest in building new infrastructure, training more personnel, and traveling more frequently to monitor study sites and to build relationships with local regulatory bodies.
Language and cultural differences among subjects and investigators may also necessitate staffing changes to accommodate differences in culture. Project cycle time may be increased by repeated interaction to correct translation errors. Schedules may have to be adjusted to accommodate differences in medical practice.
Clinical trial managers who apply project management techniques to foreign clinical trials will first identify the goals of the clinical trial plan, and then examine the effects on cash flow elements. In Central and Eastern Europe, Asia, and Latin America, subject recruitment is likely to be faster than in traditional sites in the United States, Western Europe, Canada, Australia, and New Zealand. Many of these countries also offer a vast pool of treatment-naive subjects and equivalent or higher prevalence of diseases for which treatments are being developed.
Despite these advantages, infrastructure needs at nontraditional sites may require sponsors to build clinics and supply computers and sample refrigeration systems. Telecommunications may be less reliable, requiring more international travel for trial managers and team members. Finally, seasonal differences, holidays, and national vacation schedules can significantly affect clinical development timelines.
Managers should use a checklist (see sidebar) to compare the infrastructure costs of conducting a clinical trial in different regions. They may also use this checklist to factor in the likely financial impact of language and cultural differences.
Sponsors are relying increasingly on English as a global language. Local physicians, however, work with patients in their native languages. The cost implications of this dichotomy include the cost of translating protocols, informed consents, questionnaires, source data, adverse event reports, and even training content.
Potential costs associated with translation errors are even more significant. Repeated feedback to correct errors in translating administrative and research documents leads to increased cycle times.2 And if key terminology is left open to individual interpretation, a whole study may be compromised.
Some sponsors may say there is no need to worry about language barriers because they require English fluency in their clinical development team. However, it may be useful to consider the caveat, If there is one message, and 100 people to communicate with, one will have 100 messages, unless one is careful. Most people using English professionally are not native speakers. About 1.2 billion people may speak English as a second or foreign language, while only 380 million can be counted as native speakers, a ratio of 3:1.3 What are the vocabulary and grammar qualifications that make one an English speaker? Do high marks on a written test ensure equal competence when English is used in face-to-face meetings or teleconferences? Sponsors should expect language related misunderstandings during the planning and conduct of a multinational clinical trial and prepare for them.
How might mistakes show up in the process of a clinical trial, and how serious are they? Consider the common misunderstanding of dose and dosage, or serious and severe, even among native English speakers. It is more likely that these may be misunderstood and misapplied with nonnative speakers, with potentially significant impact. Unaddressed misunderstanding could compromise the integrity of the whole study and result in a multi million dollar error. Sponsors can avert misinterpretation by making all definitions explicit, through the use of a standard glossary, and through simultaneous translation during investigator training.
Culture is a largely unspoken, shared agreement on deep values within a community. Culture is manifested as social patterns of speech and behavior. Many emerging clinical trial sites differ from traditional markets in that deep values within the culture favor the community over the individual. Social status is revered, as are behaviors geared toward building long termrelationships.
Cultural values and behaviors present benefits and challenges for those sponsoring multinational clinical trials, in terms of internal management and external relationships with subjects, investigators, and regulatory bodies. Internally, sponsors may have to opt for more senior personnel to be involved. Externally, cultural differences influencing medical practice and patient behavior are likely to show up in the course of a clinical trial in key areas such as subject enrollment and compliance, scheduling subject visits, investigator compensation and training, informed consent, adverse event reporting, source data, auditing, and internal communications.
These examples show how language and cultural differences may require additional attention and resources during a multinational clinical trial.
Subject enrollment and retention is often faster and easier in nontraditional markets. Sponsors are drawn to these markets by the abundance of treatment-naÃ¯ve subjects within large urban centers with a hospital infrastructure.
One study estimates that in the United States, 66% of subjects enroll independently of their doctors. In Latin America 80% of subjects are offered enrollment by their doctors.4 This difference is important when preparing recruitment plans and materials.
Religion may also affect enrollment, for example, in a trial requiring a complete sexual history from women in a predominantly Catholic country. If the basic premise of a trial is at odds with a sites culturally prescribed ethics (whether derived from religious or secular principles), a sponsor may consider selecting a different site, or modifying the protocol. Another option here may also be to use an experienced local partner for protocol preparation and subject enrollment.
Subjects in some countries are very compliant and eager to attend all study visits. They tend to listen to their doctors and follow orders unequivocally. In Russia and Japan, for example, a culture of compliance dictates that patients follow doctors orders explicitly. This tradition presents a benefit to sponsors enrollment is quick and retention is high.
One corollary to this culture of compliance is that subjects (in Russia and Japan, for example) may not readily report adverse events. They may not complain, because they don t want to jeopardize their status as a participant or lose access to medical treatment or they may be too sick. Investigators may need training to actively solicit adverse events from subjects.
The culture of compliance may also create difficulties in documenting informed consent. Japanese and Russian subjects and their families traditionally prefer the attitude of I put myself in your hands, doctor. A full informative discussion of risks requires investigators in those countries to break the pattern of treating patients without sharing with them the sometimes frightening details of their illness.
In countries with low literacy, permission may not be documented on a form.6 Regulators may have difficulty confirming that subjects received proper information about risks and benefits, and that their participation was not coerced.
Sponsors need know about differences in medical practice. In Latin America, a typical physician schedule includes hospital rounds in the morning, and afternoon work in private clinics. Hospital staff, required to help a principal investigator during subject visits, may only work in the morning.
Source data may not be saved. If they are, they may be illegible, handwritten notes in the local language, making translation difficult. The sponsor can opt to remain at the site or to find another where source data is traditionally kept. If there are other benefits for staying at a particular site, sponsors may need to budget additional resources to train site personnel on standard operating procedures (SOPs) for source data and quality standards, to supply computer equipment and computer support, to provide templates to ease recording, and to ensure that site staff members are computer literate.
Investigators may be participating in a clinical trial because it increases their status in the community, a powerful incentive in relationship-based cultures like India and Latin America. Sponsors may solidify investigator dedication by including key regional investigators in scientific publications and presentations at conferences and symposia.
Investigators and subjects often use local languages during their interactions. Data and hospital records may be recorded in the local language, requiring translation.
Local expressions for symptoms and ailments may be translated literally, misleading data analysts. For example, in some developing countries, subjects may describe a respiratory infection with a phrase that literally translates as stomach moves in waves, suggesting a problem with the stomach, rather than with breathing.9 Literal translations may require sponsors to send repeated queries for clarification. Worse, sponsors may not recognize the report as an error, compromising the study.
Cultural differences influence investigator training, in terms of choosing who participates in the training and which learning methods and support materials will be effective with that audience. Resident physicians in Latin America may fill out the case report forms themselves, a role that defines them as important audience members. Sponsors must also consider hierarchy when inviting participants. Superiors may feel overlooked if they are not invited when subordinates are, even if it is the subordinates who actually need the training.
Learning methods also vary. Americans and Canadians often prefer to jump to the end of a lesson. Pacific Rim learners may prefer a sequence featuring theory followed by a learning experience. Europeans may favor a high volume of detail and structure.
To address variations in language fluency, sponsors should also address the content of training materials. If published in English only, sponsors may benefit from providing them to participants in advance, so that they have a chance to prepare comments and questions for the meeting. Graphics and diagrams may also be used to bridge language barriers, although care should be taken to consider the cultural appropriateness of images. Sponsors may consider publishing some key training materials in local languages. Finally, if simultaneous translation is used during the training, sponsors should ensure that the translator is also technically fluent in the appropriate medical field, and allot twice the amount of time they normally would for that portion of the training.
Input errors and varied terminology may lead to duplications in reporting, and other inconsistencies that are difficult for auditors to interpret.
One alternative is for sponsors to invest in a computer-based audit management system with key words for major findings and centralized templates for reporting findings and documenting action plans.
Differences in cultural values, specifically around collaboration and hierarchy, play a role in the degree of cross-functional involvement in developing protocols and staffing quality assurance teams. In general, individual and department roles may be more specifically defined, and more senior people may be involved than in comparable organizations in the United States.
In Japan, for example, protocols are approved at a high organizational level, and development may involve specialists from Clinical Development, Statistics, Regulatory Affairs, and Drug Supply. In contrast, Western companies enlist broad support, adding Quality Control, Drug Discovery, Project Planning, and Marketing to the protocol development team.
In contrast to the United States, physicians are routinely among the staff of German Quality Assurance departments.11 Finally, cultural differences influence rigorous regulatory compliance, which affects the projects target standards. The Japanese, for example, may tend to set standards of quality assurance so high that partners fear they are unachievable.
A sponsor may choose to globalize quality assurance by taking some concrete steps including a Partnership Approach within the clinical trial organization. International management teams share responsibilities for preparing audit plans, budgets, workload distribution, and strategy. Furthermore, auditors from corporate management partner with those from site quality assurance into joint audit teams to help smooth out language and cultural barriers at lower levels in the organization.
Sincere respect for unique cultures and their differences is the first step in building best practices for conducting a multinational clinical trial. Applying a partnership approach to build supportive external relationships is likely to serve sponsors well, especially in relationship-based cultures. Sponsors should continually seek opportunities to develop relationships with local regulators, as well as with investigative sites in academia, public hospitals, and private institutions. Investigators, study coordinators, and clinical development team members should experience training about the cultural differences they are likely to encounter, and learn appropriate ways to handle those differences.
Accurate translation is the key to handling language-related issues. Training materials and forms should be prepared in local languages, and a simplified version of English is recommended for international meetings and correspondence. Sponsors should also choose translators who are technically fluent in the terminology of the relevant medical field.
Sponsors who prepare for differences between national infrastructures, languages, and cultures, and who allow for the unexpected, will succeed in controlling costs and cycle times and in building strong development teams around the world.
1. Office of the Inspector General Report, The Globalization of Clinical Trials (OIG, Washington, DC, September 2001).
2. Clinical Trial and Regulatory Best Practices in Japanese Affiliates of Multinational Firms (Pittiglio Rabin Todd and McGrath. 1503 Grant Rd., Ste. 200, Mountain View, CA, 94040).
3. Barbara Wallraff,What Global Language, The Atlantic Monthly, November 2000, 5264.
4. Eduardo Motti, Implementing Clinical Studies in a Traditional vs. a Non-traditional site, DIA Annual Meeting, June 17, 2003.
5. Khin Maung U, How Regulators See Clinical Data from Diverse Countries in a Single Study, presented at the DIA Annual Meeting, June 17, 2003.
6. Carolyn Rugloski, Training Considerations When Conducting Global Trials, proceedings of the DIA Annual Meeting, June 17, 2003.
7. Diego Glancszpiegel, Clinical Trials in Latin America, Applied Clinical Trials, May 2003, 3841.
8. Jorge Guerra, How Pharma Companies (and CROs) Decide on the Placement of International Clinical Studies, proceedings of the DIA Annual Meeting, June 17, 2003.
9. John Murray, interview on Fresh Air, National Public Radio, July 9, 2003.
10. Beat Widler, How Can We Bring More Structure into the Audit Process and into Audit Reports, proceedings of DIA Annual Meeting, June 19, 2003.
11. Hans Poland, How to Globalize Clinical Quality Assurance, DIA Annual Meeting, June 19, 2003.