Michael Smyth

The FDA realized the need to modernize clinical trials as part of its Critical Path Initiative, with the goal to better prepare investigators to safely and effectively perform clinical studies of investigational products. The European Medicines Agency is working on ways to streamline clinical development, for example, with a recently released draft, "Reflection Paper on GCP Compliance in Relation to Trial Master Files (Paper and/or Electronic) for Management, Audit, and Inspection of Clinical Trials," 

. The paper hints at and paves the way to move towards a fully electronic trial master file process.  

While sponsors, regulatory authorities, and CROs are collaborating, initiatives to streamline the interactions required during clinical trials for investigative sites are happening in a limited fashion at best. This is due to the sparse tools and high level of administrative activity. 

 Over the past 10 years, clinical trials have become more global, driven by changes in regulatory timelines to start up studies faster, provide better access to study subjects, and reduce costs.  

More studies are seeing an increased number of investigative sites with fewer subjects per site, as compared to Phase II and Phase III studies conducted a decade ago. This impacts not only the sponsors and CROs, but global investigative sites as well in a number of ways. 

One such result would be an increased administrative burden with paper. While more than 75% of 121 global investigative sites TransPerfect surveyed in October 2011 confirmed they use electronic data capture, 100% of the sites shared that regulatory binders and essential documents are still handled on paper. The majority of the sites indicated this was a sponsor/CRO requirement, even though the sites prefer to receive documents electronically. 

There would also be a greater struggle to support multiple vendors. In a recent survey presented at the DIA 2013 Annual Meeting, data showed that sites typically work with between six and 10 different vendors when executing a study. Multiply this across studies and the number of vendors and contact points can be quite large, not to mention the number of passwords to be maintained.  

Lastly, there would be a more cumbersome record archival and retrieval process. In order to comply with regulatory record retention requirements that differ by country, many sites keep investigative site files stored and archived in either their institution or in off-site storage. In the event of an audit, sites that share archival and retrieval would find it challenging to retrieve certain files—and some sites even indicated they would be unable to find documents. 

There are a few best practices that stakeholders in the clinical trial process can be doing to evolve and adapt to these changes. One such change is to implement paperless regulator binder and essential document processes. From study startup through closeout, today's global e-clinical solutions provide opportunities for a completely paperless process.  

Another option is to improve flow by using one study phone number. Regardless of the number of vendors involved, sites should use one phone number either globally or locally.  

Today, call flow and routing in an IVR would allow for one number and based on the menu, support multiple languages and support for all vendors. This would triage calls to different vendors involved in study support as needed, eliminating the need for the site personnel to call different numbers.  

Finally, it helps to establish one centralized portal. Currently, vendors retain their own portals, resulting in one study with many different portals. Giving sites one global portal with different security rights allows investigative sites and study teams to go to one place for any study or program information. This reduces it to one password per study and if the portal is used across studies, even further streamlines work for the sites.  

Transforming clinical studies processes will require critical thinking outside of the 20-year-old box.  

The good news is there is technology available to help. The implementation of best practices for clinical study and development conduct can streamline administrative burdens for investigator staff as well as study teams, and hopefully yield reduced costs in conducting global clinical development.  

—Michael Smyth, General Manager, TransPerfect's Life Sciences Solutions Division, e-mail: 

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The implementation of best practices for clinical study and development conduct can streamline administrative burdens for investigator staff as well as study teams, and hopefully yield reduced costs in conducting global clinical development.

Paperless Clinical Trial Optimization—Thinking Outside the Box

Over the past five years, the number of clinical trials conducted outside the United States by pharmaceutical, biotech, and medical device companies has increased significantly, either as a result of global clinical programs or because of the need to meet specific country requirements for registration. Many factors have contributed to this increase, including the need to find treatment-naïve populations and patients with the relevant disease indication, the adoption of Good Clinical Practice (GCP) regulations outside the United States, and the relatively low costs of conducting trials in less developed countries. For many organizations, including trial sponsors and the CROs that are contracted to execute part or all of these trials, such favorable conditions have made the decision to go outside the United States to conduct feasibility studies and clinical trials an easy one.   

The United Kingdom, Western Europe, Russia, and other Eastern European countries have become especially popular over the past several years for conducting development activities (see Figure 1).

  As life science companies dedicate a greater percentage of their R&D budgets to these regions, countries have worked to accommodate further clinical research and development by establishing better regulation and infrastructure. As highlighted in a 2007 CRO Survey by Jefferies (see Figure 2), the distribution of clinical development spending across the various regions was predicted to change drastically between then and 2010, with the U.S. forecasted to lose its majority status, while the Asia/Pacific and emerging markets such as South America and Africa were estimated to see gains of 50% or more in their allocation.

The growing popularity of the Asia/Pacific—China in particular—cannot be denied. A 2006 study conducted by A.T. Kearney (see Figure 3) that sought to determine the most attractive clinical trial locations, considered a number of factors, including patient pool, cost efficiency, regulatory conditions, relevant expertise, and infrastructure and environment. Each of these factors was rated on a scale of one to 10, and a composite score was generated to rank the countries plotted against the United States. After accounting for all factors, the most attractive location to perform trials outside of the United States was China, closely followed by India.

Figure 1. The global rise in clinical research activity over the years.			

China was ranked highest in the Kearney survey primarily due to its high cost-efficiency and plentiful patient pool. Cost estimates for Phase II and III trials, which are typically the most time-intensive and expensive aspects of the clinical development process, can range anywhere from 10% to 30% of the costs of conducting those same trials in the United States. 

Figure 2. Results of the survey show the difference between 2007 spending by region and spending expectations by 2010. 			

While costs in China are generally lower, the large patient population makes it exceptionally attractive from a cost standpoint. In the United States, competition for patients can be fierce, with multiple companies often vying for the same patients. Since the cost per-day of not having a product on the market can be enormous, many companies are forgoing the better U.S. regulatory oversight and infrastructure to take advantage of China's enormous treatment-naïve populations—a benefit that can significantly shorten the patient enrollment period. Today, China has a population of over 1.3 billion people (dwarfing the U.S.'s 300 million), the majority of whom are treatment-naïve.

Furthermore, as China continues to develop economically, more Chinese will begin to emulate the Western lifestyle and culture. This means that for organizations looking to provide treatment for the disease indications prevalent in the West, Chinese patient populations are now more suitable than in the past. Data shows that Chinese people are eating more and exercising less, increasing the incidence of cardiovascular disease, which is now the most frequent cause of death in China. According to data from IMS Health, five of the 10 fastest growing therapy classes in 2003 encompassed treatments for illnesses of the cardiovascular and central nervous systems, with another three in respiratory, anti-inflammatory, and anti-ulcer drugs.

In addition to the epidemiological changes occurring in the Chinese population, there are a number of factors that make China an ideal environment for patient recruitment. First, treatment of serious maladies is often concentrated in major hospitals, making it easier to recruit patients and study investigators than it is in the United States, Europe or Japan, where potential study patients visit local physicians. Second, within the Chinese culture (more so than in the West), physicians are highly respected and trusted. As a result, patients are more likely to enroll in a trial if their physician recommends it, virtually eliminating the need for the subject recruitment materials that are essential to successful recruitment in the United States and Europe. 

While China has a lot of attractive features that make it a big draw for organizations conducting clinical trials, the country still has many challenges to overcome before it can become the go-to destination for clinical development and testing. One issue is a lack of investigative sites that meet the regulatory standards of the United States and Europe. 

Figure 3. Final rankings for the 15 countries rated in the 2006 survey in top-down order of most attractive to least attractive. 			

In 2004, the Chinese State Food and Drug Administration (SFDA) passed a regulation that required organizations to utilize only sites that have achieved GCP certification. However, as of April 2007, only 242 investigative sites in China had achieved this certification.

  Even though China has a surplus of potential patients, the lack of GCP-certified sites means that subject recruitment is often localized to a handful of locations—and it is not uncommon for several pharma companies to be competing for the same pool of patients. As a result, recruitment is often strained in a country where people are its most plentiful resource. 

This dearth of GCP-certified investigative sites adds up to a difficult state of affairs when it comes to patient recruitment. In fact, the current recruitment landscape in China looks a lot like that of its Western counterparts: In the United States, many pharmaceutical companies and/or their CRO partners will utilize the same study sites for a clinical trial rather than placing studies at different sites or training and developing new investigative sites that may have better access to the necessary patient populations. To fully capitalize on China's advantages, industry will need to invest some time and money in building and developing adequate investigative sites and training on-site personnel. 

In addition, it is widely held that there is a long time required for approval of a clinical trial application by the Chinese regulatory authority. To that end, the extended time allows sponsors to better prepare for these subject recruitment and other multicultural challenges. 

In addition to coping with infrastructure and expertise issues, companies that choose to conduct trials in China must be prepared to handle the country's many cultural and linguistic differences. As written by Liang Kong, Project Manager at APEX International Clinical Research: "Sponsors should expect and prepare for language-related misunderstandings during the planning and conduct of a multinational clinical trial. In China, almost all of the submission documents for the SFDA and Ethics Committees (ECs) should be in Chinese, including the protocol, Investigator's Brochure, and Informed Consent Form—which can increase costs and time. Repeated feedback to correct errors in translating administrative and research documents also increases the time sponsors spend on a project."

According to Merick Su, Drug Safety and Medical Information Manager for Bayer Healthcare in China (BSP China), "Finding the right physician often takes a long time." Chinese physicians may find it difficult to understand the clinical protocols, which are written in English. "A lot of companies will translate the protocols in Chinese but the physicians are still expected to fill in all the information in English," says Su. Unfortunately, many of the companies that initiate the trials make the false assumption that all site personnel speak English fluently. 

While many of the 242 GCP-certified site physicians might speak some English, trial conduct would be streamlined if all study-related information were in Chinese. Meeting these language requirements will become increasingly important as the infrastructure and personnel conditions improve in China. Right now, study investigators will typically participate in clinical trials in addition to their daily duties as a physician. As more investigative site personnel are added to support clinical trials, language barriers are likely to become even more of a challenge, as most of the new personnel will speak, read, and write English to an even lesser degree than the study investigators. 

According to David Hardison, Vice President of the Life Science Division of SAIC and Chairman of the Board of CDISC, "In terms of language challenges in China, given the multiple languages and the real possibility of patients and trial staff having differing dialects, remedial measures may be needed to reconcile these differences in the trial. Indeed, language errors could very well increase the submission/trial cycle. All documentation to the medicine governing body in China (SFDA) will have to be made in Chinese. ...All documentation instructing local CRAs (e.g., phlebotomy kit instruction, etc.) will also have to be translated into Chinese, increasing the length of time to ramp up a trial."

  Given these obvious linguistic needs, pharmaceutical companies must build additional time for translation of these materials into their study timeline. 

Organizations should also consider the ways in which language barriers can affect the use of ever-evolving clinical trial technologies such as Interactive Voice Recognition (IVR), Electronic Patient Reported Outcomes (ePRO), Electronic Data Capture (EDC), and Clinical Trial Management Systems (CTMS). EDC, for example, is now being used in 35% of global clinical trials, particularly in Phase I and Phase II trials.

  Investigative site personnel spend a significant amount of time filling out and submitting patient data to pharmaceutical companies for eventual analysis. Because this data is so crucial to the regulatory process, it's essential that these EDC systems are adequately translated and that site personnel receive training in their own language. 

"Asia-Pacific sites have less EDC experience, but sites are universally keen to become involved in EDC. Training must be in the local language. A one-hour English presentation at the investigator meeting is not satisfactory. Sites may need more training in 21 CFR Part 11 and local EDC-specific SOPs," said Graham Bunn, Medidata's Vice President of Strategic Alliances for the EMA.

Also, because most site personnel are more comfortable with their native language, all software user interfaces, documentation, and eLearning materials should be localized into the relevant Chinese dialect(s). Doing so will markedly improve compliance and the quality of clinical data. Ideally, the Clinical Research Associates (CRAs) that oversee the investigative sites would also speak the local language, which would enable them to provide in-language training on protocol procedures and data collection methods. 

As the number of niche clinical trial technologies continues to multiply, an increased burden will be placed on sites where English is not the primary language. However, there are a number of things sponsors and their CRO partners can do to lessen that burden. As discussed, translating clinical trial documentation, localizing technologies, and providing adequate in-language training can go a long way toward improving the efficiency of non-English speaking sites. In addition to removing language barriers, streamlining the administrative process associated with recruitment and data submission can also alleviate burdens on sites. 

As the number of parties involved in each trial continues to increase (which will occur naturally as trials employ more third-party providers of language, technology, and clinical services), investigative sites will need to manage a greater volume of forms and documentation—often in multiple languages. Sponsors are starting to realize the inherent advantages of advanced technologies that allow all trial stakeholders to collaborate and access documentation in a central location on the Web. These technologies, which require no IT overhead and can be set up in hours, make exchanging regulatory documentation and filling out forms much faster (and often cheaper) than completing the same tasks using global express mail.  

These Web-based collaborative technologies allow sponsors, CROs, other vendors, and site personnel to securely access all trial information (study protocols, investigator brochures, etc.) as well as all forms requiring completion by site personnel. Advanced solutions even assist with the auto-completion of some of the regulatory documentation, minimizing errors and significantly reducing administrative burdens during the start-up phase of a trial. If the stakeholders involved speak different languages, some of these systems offer a user interface that can be customized to each user's native language. It's also possible to set group security features that allow for each stakeholder to have separate access settings (e.g., Chinese personnel will only have access to Chinese-language documentation). 

When every day counts, as is always the case with clinical trials, these time-saving technologies can be a tremendous boon for sponsors and CROs, while also helping to break down the linguistic and cultural barriers associated with conducting trials on a global level. 

Pharmaceutical, biotech, and medical device companies, as well as CROs that execute trials on their behalf, are increasingly looking for emerging markets where clinical development can be conducted more rapidly and cost-effectively than in the United States. Thanks to its large patient pool and low costs, China has emerged as the one of the most attractive locations to perform clinical trials outside of the United States. However, companies that decide to conduct trials in China need to account for language and cultural issues in the planning stages of each clinical trial in order to avoid the need for stop-gap measures down the road. 

This may include localizing any clinical trial documentation into the relevant Chinese dialects, employing multilingual CRAs to interact with and train site personnel, and utilizing technologies that promote collaboration between all stakeholders. To date, many pharmaceutical companies have successfully executed clinical trials in China, and it is expected that the number will only increase as time goes on. Those companies that plan well in advance for the cultural, linguistic, and administrative challenges associated with executing trials in China will significantly speed the time to market for their products in development. 

is General Manager, Life Sciences Solutions, at TransPerfect, Three Park Avenue, 39th Floor, New York, NY 10016, email: 

1. Wachovia Capital Markets, Initiating On The Pharma Services Sector, Nov. 27, 2007. 

3. A.T. Kearney, "Make Your Move: Taking Clinical Trials to the Best Location," 

http://www.atkearney.com/index.php/Publications/make-your-move.html

4. M. Rosenberg, "China Population: The Population Growth of the World's Largest Country," 

http://geography.about.com/od/populationgeography/a/chinapopulation.htm#

5. PriceWaterhouseCoopers, White Paper, "China: Prescription for Growth," 2004. 

6. L. Kong, "Clinical Trials Opportunities in China," 

http://appliedclinicaltrialsonline.findpharma.com/appliedclinicaltrials/article/articleDetail.jsp?id=416539&sk=&date=&pageID=5

7. "Keeping Tabs," Future Pharmaceuticals, 2007. 

8. D. Weng, Globalization and Patient Recruitment, Future Pharmaceuticals Podcast, 2007. 

9. P. Ward, "EDC Progress Steady for Europe and Asia," 

http://appliedclinicaltrialsonline.findpharma.com/appliedclinicaltrials/Articles/EDCProgress-Steady-for-Europe-and-Asia/ArticleStandard/Article/detail/432022

Cultural, technological, and practical issues that need to be addressed to increase success.

Michael Smyth

Articles

Paperless Clinical Trial Optimization—Thinking Outside the Box

The China Experience