Culture and language are important considerations in clinical research and have gained new prominence in the context of multi-national trials. Global Communicator consulted with the experts at ProPhase, a New York City-based training, research, and development organization, about some of the issues inherent to global trials and how they help their clients to successfully cross cultural and linguistic borders.

Question. Can you describe what your company's role is during a multi-national study?

A. ProPhase provides pharmaceutical company sponsors, CROs, and related organizations with expertise and services to support psychiatry, neurology, sleep, and pain medicine trials. One of our major activities is investigator training and certification, with a focus on establishing and maintaining high levels of inter-rater reliability. We manage this process for all outcome measures including diagnostics, symptom severity scales, quality of life instruments and many others. ProPhase also supports scientific design and review of protocols, instrument selection, licensing and development, online compliance and learning management, and statistical and psychometric analysis. These are all aspects of clinical research that require a high degree of expertise and specialization. By working closely with scale authors our highly integrated multi-national team of clinicians, scientists, and management professionals supports all phases of drug development.

Q. As research activities have expanded into emerging regions of the world, the issue of site training and preparation has emerged as a critical component in a study's outcome. What are the necessary steps for delivering high-quality training on a global basis?

A. The first step in training on a multi-national/multi-regional level is the understanding and comprehension of local concerns and issues that investigators and patients will face. Too often, we see a "one-size-fits-all" approach to training. One example is the assumption that either all investigators have high levels of English fluency - or more commonly that providing minimally translated training materials is sufficient to ensure comprehension. High-quality linguistic translations are essential and are most effective when coupled with careful review and customization of the entire training and certification process. The training and certification process needs to take into account the interaction between cultural factors, symptom expression, and the distinctive nature of CNS trials.

Q. Why is it critical for drug development companies to consider culture when fostering meaningful communication with patients, physicians, project teams, and other stakeholders?

A. Culture, context, and environment have a profound impact on the way illness is perceived, explained, and expressed. Failure to account for these differences in studies often impairs relations between parties. In addition, variability in pharmacokinetic and pharmacodynamic mechanisms as a result of culture, context, and environment increase the risk of side effects and adverse events in some populations. Moreover, channels of communication operate differently according to social and cultural norms within and between populations. For example, good clinical practice topics, such as true and informed consent, and the physician - patient relationship may impact what is or is not possible in a study.

Q. Russia and Russian-speaking populations figure prominently in clinical and research studies. Do you have examples of English vs. Russian language training successes in terms of comprehension?

A. In truth, the most critical issues in training Russian investigators to participate in clinical trials are the same issues that inform the training of investigators anywhere in the world. These issues include language barriers, clinical training and experience particular to a given investigator population, and conceptual incongruities in the face of what are purported to be universal symptoms and diagnostic categories.

Q. Another country of central importance to global trials is India. India is an immensely diverse and heavily populated country - a potential challenge for recruitment. Does English suffice as the "official" language for trials in India?

A. Many sponsors new-to-work in India bring with them the assumption that since English is the primary language of medical training it should suffice as the "official" language for the trial. 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. Consent forms and other materials at the screening level are frequently translated into one of the many local languages. However, once the patient has been enrolled and randomized, the availability of non-English materials in terms of case-report forms (CRFs), clinician administered scales, or even patient-reported outcomes (PROs), may shrink. For this reason, only in exceptional cases can English be seen as sufficient for clinical trials in India.

Q. Are there cultural factors to consider, as well?

A. Yes. 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 may be 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 in this area may lead to deficient and unreliable data as well as uncomfortable investigator and patient participants.

Q. In addition to language translation, what are some of the tactical options you employ (or recommend your clients use) to address language barriers? How do these tactics compare in terms of cost, practicality, and training effectiveness?

A. In addition to traditional training methods (such as standard didactic training and reviewing diagnostic and symptom features) we have engaged in two new and exciting initiatives, specifically "Applied Training" and "Data Monitoring". Briefly, Applied Training involves the careful review of an investigator's clinical interview technique by an expert clinician. Language competence and clinical competence do not always produce cultural competence in clinical interview technique or scoring rationales. Whenever possible we strongly prefer to use expert trainers who have experience using the clinical instruments with patients in the same settings (i.e., same country or region). Our trainers provide specific feedback to investigators and help to assure that there is consistent communication and a consistent message.

Data Monitoring, carried out by partner organizations such as CROnos (www.cronosccs.com) is a process that uses computer-based algorithms and direct clinical interface to ensure that raters produce accurate data for the duration of a clinical trial. The algorithms work regardless of language or culture, however the manner in which investigators are engaged must be considered with respect to the rater's cultural and theoretical background as this can inform how they may have assigned scores to a scale. Theoretical constructions such as negative symptoms in schizophrenia may be characterized as unitary or discrete depending on which part of the world someone was educated in. Certain scale items may also be considered in different ways depending on how they are expressed by patients, e.g., lower expressed emotionality in certain eastern cultures and greater somatic complaints among individuals diagnosed with depression from some Central American countries. Data-monitoring serves to identify where these types of presentations may be a function of culture versus where there are problems in the assessment of the disorder itself. This helps to ensure that all international data for an indication is being gathered in a systematic manner.

Finally, we have several ongoing projects to collect data from investigators regarding their perception of how different instruments, methodologies, or techniques may operate in their sites or regions. We then incorporate what we learn into future efforts and make recommendations regarding study design and instrumentation.

Q. What are the challenges that you see in developing new regions and countries for inclusion in clinical research in the future?

A. The existence of regulatory infrastructure adequate to meet FDA requirements contributes to the absence of many countries from the pharmaceutical clinical trial world. Both time and money are needed in order to seek out new regions and willing participants. In particular, for new regions psychometric and other aspects of scale validity are a major challenge that requires extensive preparation before launching a study with a new population. It is often worthwhile for sponsors to begin this process in non-drug or exploratory studies, even before beginning an early stage clinical program - certainly the costs of doing so proactively outweigh the risks of having regulators request validity data on an instrument after database lock.

Q. Is there anything you would like to add?

A. Thank you for this opportunity to discuss issues that we consider important to the valid outcome of global trials. If you have any questions, please do not hesitate to contact us (information below).

About ProPhase
ProPhase is a therapeutically focused training organization engaged in educating mental health professionals on practical applications, administration and interpretation of psychometric rating scales. With roots in educating within academia, combined with expertise in psychometrics, clinical research experience, thorough knowledge of clinical utility of rating scales, and a highly talented team of trainers, ProPhase brings unique and unmatched value to rater training in the pharmaceutical industry. For more information, contact Ashleigh DeFries, Director, Research & Training Development, at ProPhase.