The globalization of clinical trials no longer is a matter of speculation; it is a fact. Each stage of a drug’s life cycle is touched by language, culture and national infrastructure specifics. Culture and language have gained new prominence in the context of multinational trials.
As much as 40% of all drug trials in 2005 were conducted in emerging markets, up from about 10% in 1999. Trials continue to shift to emerging markets such as China, Russia and India in the search for more patients, lower costs and faster recruitment. Moreover, many of these countries have centralized health systems, meaning that hundreds of patients with similar symptoms are found in the same place, with larger numbers of both study-naïve and treatment-naïve subjects as compared to other regions.
In order for drug development companies to continue to research novel compounds, to reach new patient populations and to do so in a responsible and constructive manner, it is critical to understand the unique role that culture plays and how to use this understanding to foster meaningful communication with patients, physicians, project teams and other stakeholders.
The best way to appreciate the issues inherent to global trials is to consider the different aspects of trial conduct and what these basic concepts mean in another context — another country, region or culture. For example, the physician/patient relationship and the meaning of consent may vary, as well as intercultural communication and language barriers as they relate to the trial. Doctors, patients and vendors may respond differently to varying levels of formality and also have different priorities or concerns.
The role of language and culture
Russia and Russian-speaking populations figure prominently in clinical and research studies. Over the past five years, ProPhase, a New York City-based training, research and development organization, has conducted a series of studies to evaluate the comprehension and research performance of clinicians in Russia following training exercises on psychiatric patient evaluation. The clinicians were asked to evaluate symptoms of schizophrenia and their severity as presented in a series of training videos featuring patient interviews. A selection of videos was produced in the United States in English with translated transcripts provided to aid comprehension. The remaining videos were produced in Russia, featuring Russian interviewers and patients. The clinicians-in-training were mixed in terms of their English language fluency. While the clinicians who were the most fluent in English outperformed their peers in their evaluations of the videos in English, everyone performed better when watching and evaluating the fully Russian videos. The increase in accurate judgment was particularly notable for those symptoms that are more subjective and rely on observation (“negative” symptoms).
In subsequent analyses, clinicians-in-training across Europe and Asia universally have indicated a preference for training materials in their native tongue, regardless of their knowledge of English. However, such programs become increasingly difficult to produce for countries such as Singapore and India, where multiple languages and dialects coexist within a single group of trainees or investigators. Moreover, the disparities in performance may not be driven purely by language but may be intertwined with experience, culture or a difference in conceptual framework.
One country of central importance to global trials is India. India is an immensely diverse and heavily populated country (Figure 1), a potential challenge for recruitment. Many sponsors new to work in India bring with them the assumption that since English is the primary language of medical training and the education system in general, it should suffice as the official language for the trial. While consent forms and other materials at the screening level are translated into one of the many local languages, once the patient has been enrolled and randomized, the availability of non-English materials in terms of case-report forms, clinician administered scales or even patient-reported outcomes (PROs) may dwindle.
While clinician English fluency is exceptionally high in India, patients may be unable to participate fully in the program without full linguistic support and forward planning. However, language alone cannot resolve all of the issues encountered during clinical trials in India. As with many world populations, certain topics may be socially and culturally inappropriate for direct questioning techniques and investigation. Investigators in a trial may be reluctant to broach particular topics with their patients, and patients are unlikely to answer such questions if asked. It is incumbent on those designing trials, administering training, and providing linguistic and cultural support to consider potential problem areas prior to executing a trial and to plan for contingencies and modifications. Negligence may lead to deficient and unreliable data as well as uncomfortable trials and patient participants. Conducting trials in countries such as India raises additional complications that trial designers must consider in depth. For example, different relationships and rationales for taking medications and seeking medical services may create a perception of noncompliance — a term that fails to capture or address the local reasons for discontinuation.
Regulations and guidelines
Regulations may prohibit or limit what one can say about a drug, its availability or competing compounds. In the United States, the Food and Drug Administration (FDA) has language requirements for documentation and filing. Also in the United States, there are national standards on Culturally and Linguistically Appropriate Services, developed by the Office of Minority Health, US Health and Human Services, as well as mandated protection for patients with limited English proficiency.
From a global trials perspective, Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, recording and reporting trials that involve the participation of human subjects. Compliance with this standard provides public assurance that the rights, safety and well-being of trial subjects are protected and that the clinical trial data are credible.
Free and informed consent lies at the heart of ethical research involving human subjects. It encompasses a process that begins with the initial contact and carries through to the end of the involvement of research subjects in the project. Failure to properly obtain informed consent is one of the most commonly cited violations at research sites. Seven of eight warning letters from the FDA sent to clinical investigators between May and September 2009 specifically mention failure to properly obtain informed consent, most often as a result of having participants sign an outdated version of consent forms. Some problems inadvertently arise when translating consent documents into a new language. Content can either get omitted or be translated incorrectly. During translation, many terms become difficult to understand, even for health care professionals.
Among different documents given to a research subject, informed consent documents may be some of the most important. Their wording is carefully monitored by institutional review boards, also called research ethics boards in some countries, in accordance with GCP principles. According to GCP, the language used in the oral and written information about the trial, including the written informed consent form, should be as nontechnical as is practical and should be understandable to the subject or the subject’s legally acceptable representative and the impartial witness, where applicable.
In order to help ensure a patient’s understanding of the trial and realize free and informed consent, the translated version of the informed consent documents should preserve the original content and style. This includes everything from font size and footer information to descriptive nonmedical terms, if that’s what was used in the source document. Precise translation equivalents must be used for key terminology to avoid critical mistakes. For example, replacement dose is not the same as additional dose, and study or research does not equal treatment. Specifically, as it relates to Indian languages, the terms symptoms and signs are often translated using the same word, while more accurate words are available. Inflammation and infection are also commonly mistranslated words.
But sometimes the names of diseases or other medical terms should remain in English despite their translations being available in the local language. This would occur if the term is not readily used or if more people are aware of the English term than the Indian language term. The linguist must use judgment to maintain a balance between the need to explain and popularize new medical terms versus understandability of the translation.
Further, cultural values differ from country to country, as well as from community to community. For example, in some cultures it is important that researchers talk about the trial with and possibly obtain permission from the patient’s family and local community before attempting to obtain consent for participation in a clinical trial. According to findings from a study published in the Journal for Medical Ethics on community-based trials and informed consent in rural north India, the majority of the community interviewed could decide about participation only after discussing it with other community members. Only a third of all respondents could take an exclusively independent, nonconsultative decision. In the case of the few women interviewed, this number was even lower. Most believed they would be unable to decide for themselves.
PRO instruments are the only measurement tools that report what the patients experience as it relates to their treatment, symptoms or quality of life without it being interpreted by the physician. For an instrument to be used in multicountry studies, it must address the same concepts in all languages in order to make it possible to pool data and compare results. This is done through a series of steps involving multiple teams of translators, editors and in-country clinical researchers, as well as cognitive debriefing groups to ensure accuracy across languages, dialects and cultures. However, once the English version is translated into another language, the possibility of inconsistencies arises. This is particularly true when there are a number of different languages spoken throughout the trial sites and trial countries.
Translation and linguistic validation of PROs must follow a rigorous multistep process that typically includes dual forward translations of the instruments, followed by their reconciliation into a single forward translation. The next step consists of a back translation, which is then compared to the original source text. Based on the back translation findings, mistakes and ambiguities are corrected in the single forward translation. Then, for some languages, the translation is adapted into the local language dialects.
With so many linguistic differences and cultural nuances — even within the same country — it is crucial to validate trial documents for accuracy. A method used to confirm consistency is linguistic validation of the translated questionnaires through pilot testing on real people, also called cognitive debriefing. For each target language (TL), typically an in-country focus group is run by a professional bilingual moderator using a structured interview approach. Each focus group consists of native speakers of the TL across demographics to make up a general population for the testing, the results of which are reviewed by in-country research teams and implemented into the final version of the translated PRO instruments. At times, cognitive debriefing takes place via individual interviews. Benefits of conducting focus groups and interviews include the ability to uncover areas of cognitive difficulties, grammatical and translation mistakes, expressions that may sound offensive, and cultural irrelevancies.
Effectively managing â€¨pharmaceutical translation
To reach non-English speakers, pharmaceutical companies typically outsource to language specialists in the medical translation industry. Depending on the volume of languages and documents to be translated, this can sometimes result in working with multiple vendors. To ease and expedite these projects, it often helps to centralize the translation process and work with as few translation vendors as possible, managing content across multiple languages, locations and translation providers via content management systems and translation memory tools. By centralizing translation management via one department, a core contact team or even a designated project manager, organizations can streamline their translation procurement efforts more effectively and often less expensively. This will help organizations to manage multiple languages and numerous translation vendors or vendor locations, thus resulting in faster turnaround times and fewer translation errors.
In today’s increasingly global clinical â€¨trial environment, incorporating language and culture into the drug development process plays an important role in meeting product demands. Communication problems, proper drug usage, and issues of true and informed consent can occur in any and every setting and are potentially compounded in multi-national trials.
Planning should include expense and time estimates for translating documentation to and from local languages, especially for clinical trial forms and documents, and should factor in costs and time for developing language strategies. Develop a communication strategy that outlines what methods will be used to address the language and cultural factors most important to the project outcome, as well as to anticipate how confidentiality, language proficiency and other legal regulations may affect the trial.
It is also advisable to obtain guidance from local experts and organizations with area-specific knowledge regarding disease concepts and cultural and linguistic issues. Careful forward planning in global studies can be essential to success and particularly in activities such as start-up training and when dealing with certain specialized areas of medicine such as psychiatry, neurology, oncology and pain management.