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 highly-
competitive 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.

Conducting a trial on a global scale assumes a Countries such as India and

certain amount of risk and introduces significant China, though popular from a
management challenges, many of which can be cost and patient recruitment
attributed to communication. In India, for perspective, bring special
example, there are 11 languages spoken by more language and cultural
than 25 million people each, with a 12 language
th challenges you will need to
spoken by just under that number. This makes it consider during the clinical
challenging to recruit a patient population trials planning process.
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 bi-
lingual — 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.

September 2007 | White Paper| Copyright Lionbridge 2007| WP-526-0907-1 | Page 4

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 highly-
sophisticated 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 forward and back translations

ƒ a clinical review
ƒ harmonization
ƒ cognitive debriefing
ƒ 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.

September 2007 | White Paper| Copyright Lionbridge 2007| WP-526-0907-1 | Page 6

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.

September 2007 | White Paper| Copyright Lionbridge 2007| WP-526-0907-1 | Page 7

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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www.lionbridge.com