Launching Global Clinical Trials

White Paper Launching Global Clinical Trials Best Practices for Efficient and Cost-Effective Translations September 2007 | White Paper | Copyright Lionbridge 2007

White Paper At a Glance Successful global clinical trials require early consideration of the costs, complexities, and risks of communications. Best practices for clinical trials translation ensure your global trials are efficient, cost-effective, and successful in all markets.

Executive Summary The target market for conducting global clinical trials has changed significantly in the past 12 to 18 months, moving beyond pharmaceutical early adopters to the mainstream marketplace. This shift has placed a heightened focus on the language challenges and complexity of running a global clinical trial. More and more companies are moving toward ascending regions, such as India and China, to launch global trials, and are naturally looking at the downstream benefits these locations offer – access to large, drug-naïve populations, lower trial operating costs, and the ability to rapidly recruit suitable participants. This focus on end-benefits, however, fails to consider the deep challenges of the launch process itself, and companies who are not yet globally-proficient are likely to underestimate the critical role translation plays in that effort. Translation should be considered in the beginning, during the planning phase of the global clinical trial. It is important that all parties involved have a realistic expectation of the costs, complexities, and risks of the translation process. Companies that are not making these calculations face unnecessary delays and cost overruns. Third party outsourcing organizations that underestimate the cost and delivery schedule of clinical translations often have to revert to the sponsor company to renegotiate costs. This can significantly delay the execution of a trial and make the outsourcing organization appear ill-prepared. This white paper highlights the language challenges found in a global clinical trial and offers a number of best practices for managing the translation effort. Failure to adequately plan for translation introduces several new risk factors that must be considered in today’s highlycompetitive pharmaceutical market.

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Issues and Challenges of Global Trial Communication Over the past few years, pharmaceutical companies and Contract Research Organizations (CROs) have significantly changed their launch plans for global clinical trials. Regulators are demanding ever-increasing population pools, longer-term monitoring, and more trials. In response, the pharmaceutical industry is seeking access to larger, drug-naïve populations, a wider range of diseases, lower trial operating costs, and suitable candidates for rapid recruitment. This change in strategy has pushed the market boundaries farther and farther across the globe into the so-called ascending markets of Eastern Europe, Asia, and Latin America. According to Thompson CenterWatch, 20 to 30 percent of clinical trials are now being conducted in the ascending regions. India is a particularly popular choice, just behind China and ahead of Russia. Pharmaceutical companies are also developing relationships with key physicians and clinicians in these locales, since they are in the best position to ultimately promote and prescribe a trial drug when it comes to market.

Countries such as India and Conducting a trial on a global scale assumes a China, though popular from a certain amount of risk and introduces significant cost and patient recruitment management challenges, many of which can be perspective, bring special attributed to communication. In India, for language and cultural example, there are 11 languages spoken by more challenges you will need to th than 25 million people each, with a 12 language consider during the clinical spoken by just under that number. This makes it trials planning process. challenging to recruit a patient population because it does matter where in the country you recruit from and if you are prepared to deliver materials in multiple Indic languages. As the pharmaceutical industry pursues multi-geography clinical trials, translation has become a critical step and a potential roadblock in the global clinical trials process. While the overall cost of clinical trials may be lower in some markets, it is important to address how you will communicate with all of the participants in your trial. Virtually all of the materials involved in the clinical trial, including the Investigator’s Brochure, Clinical Study Protocol, Subject Information and Informed Consent Form, Clinical Study Reports, Patient Reported Outcome (PRO), and the Case Report Form, will need to be translated into the target languages of the participants. Once the trial is underway, the patient diaries and other in-country trial materials will need to be translated back into the trial language to ensure accurate data collection and analysis. Clinical trials translation differs significantly from other types of translation. When translating standard materials like a user guide for a computer, a linguistically correct translation is perfectly acceptable. The associated terminology is reasonably standardized across the world, and there are fewer nuances in meaning.

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In the clinical trials process, the terminology is truly unique to the individual trial and is filled with industry specific language and technical terminology. When this material is developed for patient participants, it has to be understood at the most basic level so that a patient can participate in a trial appropriately. In these cases, simply having a translator in-country is not enough; translators must be certified clinicians such as doctors or biochemists who understand both the language of the end-user and the language of the trial. The translation of clinical trial protocol demands a mastery of medical and pharmaceutical language.

Planning for Translation Rapid expansion into diverse cultures and languages adds significant complexity to the clinical trials process. It changes the risk profile dramatically and cannot be overlooked. If economic models and risk scenarios are built for the trial but the data inputs do not include a true consideration of the cost, complexity, and risk of translation quality, the trial’s end goals will be jeopardized. The issue of language is as critical to the process as patient screening or any other trial planning element. It is important that everyone involved in the clinical trial have a clear understanding of why translation is best addressed during the planning phase. For example, so much attention is paid to initial patient recruitment and the design of the Case Report Form that the importance of translation is often overlooked. With the Case Report Form, issues such as word phrasing, definitions, and spacing may arise during translation that will impact the form’s overall design and usability, as well as how quickly the trial can be deployed. Addressing these issues during trial planning reduces rework and extra expense later on. Virtually every component of the trial should be evaluated to determine if it should be translated and the impact on trial quality if it is not. Most critical are all of the materials that will be provided to your patient population and physician sponsors in advance, as well as during and after the trial. If you merely translate these critical materials after the fact, you might have linguistically correct translations, but the documents will be missing key nuances, making the materials difficult to understand and potentially inaccurate. Companies that have committed to multi-geographic clinical trials are most likely undertaking some form of translation, since it is rarely desirable to recruit a population that is purely bilingual — typically with English as a second language. While bi-lingual studies are acceptable in parts of Europe and even countries like India and Singapore, by accepting only bi-lingual participants into your study, you are unnecessarily narrowing your potential patient pool. To reach mono-lingual study participants, some amount of translation is required. While the overall direct cost of the translation project is small when compared to the trial’s scale, the choice of how to do the translation work will have a dramatic impact on how quickly the trial can begin. If the trial is ready to begin but the translation is not, the resulting delay of one day, one week, or one month will have a palpable monetary effect on the cost of the trial. Multiple trial sites coming online simultaneously are critical and require a clear understanding of the clinical trials process.

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If the translation process becomes the bottleneck to beginning a trial, there are financial penalties to consider. It is estimated that bringing a compound from the lab and into the market can cost from $800 million to more than $1 billion. This means that every delay in getting the drug to market can mean hundreds of thousands of dollars in lost revenue opportunity; or worse, the difference between a blockbuster drug and a complete market miss.

Best Practices for Clinical Trials Translation As a result of our work with global Clinical Trials, we have developed the following best practices to ensure a seamless process with the desired results.

Develop a Comprehensive Translation Strategy at the Outset Plan for the complexities of language early in the clinical trials process. Do not assume that every bilingual or multilingual person can be a translator. Further, do not assume that someone who is very good at translating product documentation can make the transition to translating highlysophisticated clinical trials terminology. Asking an in-country marketing team to handle the translations is also not a recommended option. While members of the team may be bilingual, they may not truly understand the trial’s nuances and goals, nor do they have the time to go through the PRO in detail. Build in time to streamline the communications effort, and secure a translation partner who has the scale to be your centralized resource for multi-geography patient locations and regulatory filings. Large scale translation partners have the ability to scale quickly based on the project timelines and bring the required language resources to the project (shortening total translation time). They also have the ability to deliver clean, consistent data across languages because they are looking at the entire project. This pushes project management to the translation partner instead of forcing you to manage it in-house. A global partner can ensure that translators are appropriately trained and certified and can source translators in all languages.

Establish and Follow Standardized Processes While the nuances of each step may vary, be sure to execute a complete translation process that includes: ƒ ƒ ƒ ƒ ƒ

forward and back translations a clinical review harmonization cognitive debriefing pilot testing

While standard translation projects will often go through a translation and then one subsequent review cycle, clinical trial translations add several critical steps to ensure the final translations are acceptable and ISPOR/Type II compliant. This is most notable in the translation of the PRO

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instrument. Much of the trial’s data validity and subsequent analysis hinges on the patients’ comprehension of PRO questions, how well their answers comply with those questions, and how effectively the material has been translated for analysis. The approach to translation affects the validity of the study, so it is important to have a complete and standardized process to ensure quality and reduce risk.

Optimize the Review Process to Shorten Review Cycles The area that is most problematic in clinical trials is the translation review process. These reviews are often conducted by in-house staff, each with other full-time responsibilities. As a result, even though the translation is complete, the final review cycle can take as long as 7 to 15 weeks. This is a significant roadblock that can have a material impact on the trial. For clinical trials where a cognitive review is necessary, the delay in review times increases exponentially. Critical to shortening this step is enabling reviewers with online tools that will make conducting the review easier; or outsourcing the review to an independent resource altogether. Typically, large-scale translation providers can assist by providing independent reviewers to conduct the language QA process. Keeping these resources and processes separate from the translators ensures the objectivity of the QA effort. Reviewers must also pay close attention to PROs and the data in the patient diaries. Forms that are poorly designed and/or translated can lead to patient misunderstanding and inaccurate data. When reviewing these materials, reviewers must have a clear understanding of what the patient is reporting. Success of the trial drug hangs on both the presentation of the question (nuance) and the accuracy of the patient’s response.

Conclusion There is no shortage of examples of how things can go wrong in translation in all industries; but, it is much easier to alleviate these challenges in clinical trials if you plan for them during the initial design phases. The worst possible outcome of a bad translation is a serious adverse patient reaction (SAE); however the more likely problem is delay. If the translation process becomes the bottleneck to launching the trial, this can have serious downstream effects, including lost revenue and the difference between a successful drug and a market miss. As a result, the pressure to move quickly, but carefully, in all phases of the drug lifecycle is immense. Regulatory bodies are demanding greater scrutiny over drug discovery and clinical trials. More trials with more participants only drive up the cost of drug discovery and delivery, increasing the associated risk and potentially slowing down innovation. As pharmaceutical companies and CROs look to streamline the parts of the chain they can control, they will look to the clinical trials process as a key competitive advantage. We expect that trials will only go more global, with patients being recruited on an even greater scale. Pharmaceutical companies and CROs that can rapidly recruit a global patient population and deliver clean, high quality data will have a massive market opportunity. Translation is critical to that effort.

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Lionbridge welcomes the opportunity to explore the value our Clinical Trials Translation solutions can bring to your organization and we invite you to contact us for an initial discussion about your global objectives and how we can help you achieve them. Visit us at www.lionbridge.com/clinicaltrials.

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Contact Information About Lionbridge Lionbridge Technologies, Inc. (Nasdaq: LIOX) is a leading provider of globalization and testing services. Lionbridge combines global resources with proven program management methodologies to serve as an outsource partner throughout a client's product and content lifecycle — from development to globalization, testing and maintenance. Global organizations in all industries rely on Lionbridge services to increase international market share, speed adoption of global products and content, and enhance their return on enterprise applications and IT system investments. Based in Waltham, Mass., Lionbridge maintains solution centers in 25 countries and provides services under the Lionbridge® and VeriTest® brands

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