Mitigating the Challenges Of Global Trials

The globalization of clinical trials presents several benefits and challenges for biopharmaceutical firms. On the one hand, the growth in global clinical trials provides opportunities to improve patient recruitment, reduce development costs, and test new products in nations they will be sold. On the other hand, global trials pose unique challenges that must be overcome, such as how to implement e-clinical technologies and manage clinical supply chains worldwide. This article will review the factors driving the globalization of trials and the issues faced by e-clinical technology companies and supply chain providers related to managing Interactive Voice/ Web Response Systems (IVRS/IWRS), patients, and clinical supplies on a global basis, particularly in “emerging” regions.¹

Factors Driving the Globalization of Clinical Trials
A variety of financial, logistical, and clinical factors have propelled the growth of global clinical trials. Among the most important is the need to access patient populations in high growth markets. Data provided by IMS Health and KPMG indicate that ethical biopharmaceutical sales growth rates will remain in the 3-6% range in Western Europe and North America while growing at double digit rates in emerging areas between 2011-16. The percentage of sales in the US and the top 5 European nations will decline from a combined 61% to only 44% by 2016, while emerging regions (led by China) will increase from 10% to 13% in the same timeframe. Moreover, China will move up rapidly to become the second largest market for ethical pharmaceutical products by the end of the decade.²

The need to improve productivity and reduce clinical trial costs are two critical factors that have driven the globalization of R&D. Studies indicate that the cost of recruiting, treating, and managing patients in emerging nations, particularly in Asia are significantly lower than in the West, although increasing at a more rapid rate. Still, the cost per visit in Phase I-IV trials from 2009-2011, according to TTC-LLC, is 64% less expensive in China and 68% less in India than in the US (not counting the expenses related to sponsor oversight), with Phase III costs being the most significantly lower, particularly in India.³ In a similar study, KPMG concluded that the four least expensive nations to manage trials were India, China, Mexico and Russia.⁴ Meanwhile analyses of the Clinicaltrials.gov database conclude that the percentage of trials in emerging regions is growing at a much faster rate than in the West, with a compound annual growth rate (CAGR) of 4.8% in Asia and 2% in Latin America compared to -.01% in the US from 2007-2011.⁵

Finally, an examination of regulatory activities and quality issues reveals the extent of growth in emerging regions. In the past few years, the FDA and EMA have significantly increased their inspections abroad to keep pace with the trend of the R&D internationalization. For example, from 2010-2011 CDER inspections in Asia-Pacific increased from 12% to 21% of all agency inspections, while those in Europe decreased from 67% of all inspections outside the US to 52% in the same period.⁶ The issue of quality has also been a focus of the Association of Contract Research Organization and other groups which have concluded that data quality, patient safety, and overall study administration in emerging regions is comparable to many Western nations because of the harmonization of GCP guidelines worldwide, the growth and influence of regulatory agencies outside the West, improvements in infrastructure, and global study oversight by international technology companies, CROs, and Supplies Management firms. All of these factors contribute to lower costs, comparable quality data, and reduced timelines in trials involving emerging regions.⁷

Growth of e-Clinical Technologies In Emerging Regions
Given the dramatic increase in the number of trials conducted in emerging areas during the past ten years, it is no surprise to learn that the fastest growing segment for e-clinical technologies is in “Rest of World” regions, such as Asia-Pacific, Eastern Europe, Latin America, the Middle East, and Africa, with a combined CAGR of 16.6%.⁸ But implementing e-clinical technologies and managing clinical supplies in such regions presents a variety of challenges for sponsors of global trials, technology providers, and clinical supplies management firms.  The remainder of this article will focus on the application of one e-clinical technology (IVRS/IWRS) and the critical role it plays in global trial management.

The two main functions of IVR/IWR systems are to manage patients and investigational drug products during a clinical trial. In terms of patient management, such systems have traditionally been used to screen, enroll, randomize and assign medicine to subjects participating in the study. More recently, the role of IVR/IWR has been expanded to larger aspects of patient management including compliance, electronic Patient-Reported-Outcomes (ePRO) and messaging. IVR/IWR systems also manage the patient’s visit calendar, blinding/unblinding, and other patient management functions depending upon the requirements of the protocol.

Complementing its patient management functionality, IVR/IWR systems plays an integral role in managing medicines during the trial, including assignment of kits, ordering of drugs for sites, managing product expiration dates, as well as tracking the distribution and inventory of investigational drugs from study launch to eventual reconciliation and destruction of the product at the end of the trial. In short, IVR/IWR systems play a key role in patient management and the accountability of all study drug inventory during the trial.

Impact of Globalization on IVRS/IWRS and Clinical Supplies Management
Some of the most significant challenges in managing IVR/IWR systems on a global basis arise during the pre-study period when user requirements and plans are generated for the technology.  Depending upon the complexity of the protocol a number of issues need to be considered. First, how many languages are required and what level of effort in translations is required? Given that IVR/IWR is procured only a few months ahead of trial launch, it is important to determine if all languages are required at study go-live. If sites will be coming on in stages, clients may make a decision to launch the system with certain languages and bring others live following launch. To help mitigate the impact of languages on timelines, market-leading IVR/IWR firms have libraries of prompts in foreign languages, which can speed the process of translation.

A second key challenge in the pre-study period involves assessing technology requirements for sites and patients. Has a feasibility study been conducted to assure that particular sites have access to computers, the Internet, or toll-free lines? If phone access is an issue, it may be necessary to distribute calling cards to sites so that they can access the IVR. Do sites prefer to receive IVR/IWR confirmations via fax or email? Such considerations need to be addressed early in the planning stages.

Trials that incorporate ePRO add further challenges to successful implementation of IVR/IWR systems. If the study involves collecting patient-reported-outcomes with an IVR/IWR system, similar site considerations regarding access to the Internet and international or national toll-free lines also apply to patients. And if patients are going to receive reminder calls, emails, or text messages, it must be determined when such reminders can be sent and to which device.  Hence an understanding of technology infrastructures and user preferences for technologies in various regions is very important, and something that market leading technology companies manage proactively for clients.

Technology challenges also arise due to the complexity of the study design or its unique protocol requirements. For example, adaptive trials may require the changing of treatments arms or dose ranges. Such issues not only complicate the system’s development but also have an impact on supplies management. This challenge is best managed by companies that provide integrated IVR/IWR technologies, forecasting capabilities, and supplies management services (see Figure 1 for the role such firms play in a clinical trial). During the requirements gathering process and ensuing system-build, project managers who understand packaging and labeling regulations on a country-by-country basis can help a sponsor better coordinate its supplies and technology strategies to enable “just in time” labeling and other flexible options that enhance trial productivity, particularly in adaptive or complex trials, such as those involving drug pooling. In the case of the latter, having an integrated team of technologists and global supply chain experts work with the sponsor on requirements gathering and system development planning is key, as drug pooling works best when the technology and supplies provider have open channels of communication and can act swiftly to pool drug between various local and regional depots while nimbly managing labeling requirements. Moreover, such firms help to inform decisions relating to depot strategy (the use of central, regional, and local depots) which can impact the design of the IVR/IWR in studies involving product pooling.

IVR/IWR providers and supplies firms also face the challenge of managing time zones in global trials. Decisions need to be made prior to the study regarding windows for drug expirations, inputting laboratory data into the IVR/IWR to determine patient dosing levels, and managing patients who are entering ePRO data into the IVR/IWR from different parts of the world. Even how the date is represented inside the IVR/IWR needs to be examined prior to study go-live. Some countries use different conventions for dates, such as putting the month before the day. When entering dates manually this can create big issues. As a result, most IVR/IWR companies have moved to graphical calendars that allow users to select the date and time by clicking rather than through manual entry. In sum, working across time zones adds complexity to the design of the IVR/IWR and supplies strategy.

Even Mother Nature must be considered when designing your IVR/IWR and associated supplies strategy, as contingency planning is vital for the success of supplies management. Are there climate or terrain challenges that will delay the shipment of supplies to sites? Are certain label types better suited for shipment in humid or tropical conditions? If the product is a biological entity (e.g., monoclonal antibody, vaccine), what special packaging and shipping arrangements must be taken to maintain cold chain management and monitoring on an international basis? Moreover, a working knowledge of specific customs houses’ processes and procedures, as well as the quality of couriers on a global basis needs to be considered. Can they deliver under adverse conditions, such as during hurricanes? If not, what workarounds are possible? All of these considerations — and many more — must be addressed to optimize an IVR/IWR system and have it well coordinated with supplies strategy.

A new set of challenges present themselves once the global study goes live, many of which involve supporting sites.  A trial is a living and evolving thing that requires adjustments to the IVR/IWR, which is why such systems are not a “set it and forget it” technology. Therefore it is essential to have 7/24/365 multi-lingual technical help support for sites and sponsors. It is extremely important that a help desk request is resolved immediately because sites typically call when an issue impacts their ability to manage a patient who is visiting the site (e.g., randomizing, dispensing and dosing medication). Failure to provide immediate resolution to a password or system functionality problem can result in the necessity to re-schedule a visit or interfere with medication dosing. Such delays have a ripple effect on trials, often resulting in timeline and quality issues.

Training site professionals and patients to use IVR/IWR systems is also paramount to the success of a global trial. Site staff located in emerging areas may not be familiar with such systems and may require hands-on or other methods of training. IVR/IWR providers who possess global experience understand the significance of having training materials translated into foreign languages for sites and sponsors. Such suppliers also understand the importance of having web training programs and practice (staging) environments available for naive users to learn the technology prior to using it during the trial. Such support must be available at all times during global trials.

In terms of managing clients, live global trials require 24-hour access to project managers and specialists who help sponsors with key clinical supplies support services, such as ordering drugs, managing expiration dates, as well as setting and re-setting trigger levels.  In the case of complex studies involving pooling of drug, changes in treatment arms, or significant laboratory testing as part of the screening process, having access to project managers at any time is essential to clients. Finally, since clients spend most of their time reviewing IVR/IWR reports rather than actually executing transactions in the technology, it is essential that suppliers have little to no system down-time. This provides assurance that sites can access the system at all times and that data is refreshed in near real-time to empower sponsors with information while making trial-related decisions.

In conclusion, global trials present a variety of challenges that must be overcome for the successful execution of patient and supplies management. Many of those challenges involve managing diverse foreign languages, cultural issues, regulatory bodies, customs houses, time zones, geographical and climate concerns, and other matters. Having an IVR/IWR provider that has significant experience both in managing technologies and supplies globally is essential to overcoming such challenges,  as the integration of those functions dramatically improves the pre-study planning and eventual administration of the trial once it goes live. 

References

1. The term “emerging” markets is evolving and unclear. While it is typically applied to nations in Central and Eastern Europe (CEE), Asia, Latin America and Africa, evidence is mounting that many nations in those regions, particularly in CEE and Asia have modernized their technology infrastructures and become very experienced in clinical trial management while also comparing favorably with Western nations in terms of education levels, quality of life, state of medical care, skill levels of workers, and other factors.
2. IMS Institute for Healthcare Informatics, “The Global use of Medicines: Outlook Through 2015, published May 2011.
3. TTC, Grant Plan Database, www.ttc-llc.com, April 2012, cited in Parexel Biopharmaceutical R&D Statistical Sourcebook, 2012-13, pp. 162-163.
4. KPMG, “Competitive Alternatives: KPMG’s Guide to International Business Location Costs,” 2012.
5. Parexel Biopharmaceutical R&D Statistical Sourcebook, 2012-13, pp. 215-219.
6. Parexel Biopharmaceutical R&D Statistical Sourcebook, 2012-13, p. 220.
7. ACRO, “The Case for Globalization: Ethical and Business Considerations for Clinical Research,” 2009. Also see, “Value of Insight Consulting, “The Case for Globalization: Ethical and Business Considerations in Clinical Research, July 2009.
8. Global Industry Analysts, “eClinical Trial Technologies: A Global Business Strategic Report,” 2012.

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Todd Kole, R.Ph. is vice president, Clinical Project Services at Almac. Joseph Bedford, Ph.D. is director of Marketing at Almac. He can be reached at joe.bedford@almacgroup.com.