International Clinical Trials
February 2010 - The economic downturn has forced pharma companies large and small to re-examine many business practices. Boom times forgive inefficiency; recessions punish it without mercy. Continued reliance on old, familiar habits may put many pharma companies at risk. This is especially true of clinical research, where timelines and costs strain patience and budgets in the best of times.
One response to the economic downturn is to accelerate the rush to conduct clinical studies offshore. However, savings from conducting studies in lower-cost areas are far from automatic. Furthermore, adding a multinational dimension compounds the challenges of managing clinical studies. Every aspect of operations must overcome the friction of different languages and cultures, and the inevitable complications in communications and logistics. All such factors have the potential to increase the difficulty of even the most routine study operations. Enrolment is often slow; study management finds out about many unanticipated issues and problems only later – sometimes much later. As a result, it takes more than the customary levels of management attention and team-wide effort just to keep a multinational study moving. However, during a severe recession it is not enough simply to exhort managers and team members to focus more intently and to work harder. Meeting such challenges requires new adaptive techniques, the application of the adaptive approach to study operations as well as study designs, and a more time-sensitive and information-driven approach to study management.
Information with which to Manage
In most large multinational studies, management have access to information on enrolment progress and the number of queries generated; however, the information is general. You know that enrolment is lagging behind goals, but you have little or no information about why. Some sites or countries may be enrolling faster than others, but there is nothing in study reports to explain the reasons. Sites in one country may be generating a disproportionate number of queries, but there could be a hundred different explanations, and there is no information pointing to one explanation rather than another. In some cases, there may be more detailed reports, but they come too late to support corrective action – the damage is done by the time the report reaches management.
The engine of management is knowledge – knowledge that goes beyond the bare essentials to provide a basis for decisions that correct problems or exploit opportunities. Management is about decision making. In a large multinational study, management is particularly dependent on receiving frequent updates of detailed information about what is going on in different countries and at different sites. Furthermore, distributed management is essential in large multinational studies – there are too many issues and too many decisions in too many places for a lone decision-maker in a central office to understand and resolve. Thus, the information required to manage larger multinational studies must be timely, accurate, actionable, and role-specific. The information must also flow to management continuously. Sporadic updates and reports at wide intervals are not good enough.
Resisting the Temptation to ‘Throw People’ at large Multinational Studies
When study operations are scattered around the planet, though, how can studies ensure a continuous flow of timely, accurate, actionable and role-specific information? The first impulse in managing large international studies may be to increase the size of the study team out of proportion to the patient population. Adding more bodies is certainly a plausible strategy for managing studies that involve large populations in multiple countries. Adding more bodies also makes it easier to use the telephone for frequent contacts with distant and often new colleagues. The voice at the other end reveals a kind of information that email usually lacks – the reassuring sound of a calm, sincere voice with facts close at hand, or the evasive, embarrassed, or indifferent tone of someone who would rather not acknowledge serious issues or who has decided the study is not a high priority. Voice conversations with distant sites are more reassuring than email, at least until the study team has established relationships of trust with distant investigators and monitors.
The trouble with managing large international trials by expanding the study team and relying heavily on interpersonal communications is that the human quotient goes way up. There are more people communicating and performing more tasks in keeping with personal habits, styles, and preferences. Interpersonal communications may be reassuring, but it requires consistent effort and initiative from multiple individuals, and adds another layer in the process of creating central reports that reflect the status of operations. The higher the human quotient, the greater the risk of variation and error in study processes. For all the stated reasons, increasing the human quotient is not the best way to manage large multinational trials.
Another reflexive approach to managing larger multinational studies is to count on a webEDC system to provide all the information management needs. However, webEDC systems generally concentrate on collecting patient information rather than tracking operational performance and providing managers with information with which to manage. It is rare for webEDC systems to provide management information that is timely, accurate, role-specific and actionable. Neither staffing up nor relying on webEDC for management information is a reliable approach to running efficient studies despite the challenges of distance, time zones, and different cultures and languages.
The Right Way
The solution to the problem of managing large multinational studies is a combination of defining study processes with greater precision, and implementing those processes to the greatest possible extent with technology that closely tracks study activities, preferably in near-real-time. If implemented well, technology can be of immense assistance in managing large multinational studies. Requirements for technology to manage such trials include:
- Rapid, accurate data capture and validation with technology such as the digital pen
- Automatic generation of performance metrics on all operations that affect costs and timelines, including enrolment and query processing and resolution
- Continuous reporting that requires little or no effort by site personnel and keeps monitors and management current
- An integrated trial management system that operates as a near-real-time control panel for the entire study
- A custom study website that keeps all sites up to date with the latest revisions of study forms and procedures, as well as performance metrics that allow individual sites to compare their performance with that of their peers
- Study management that uses detailed information to help sites meet goals rather than just to apply pressure
The Underappreciated side of Adaptive Research: Operational Adaptations
One of the hottest buzzwords in clinical research is adaptive. In common parlance, adaptive research denotes the use of data collected during a study to modify the study’s design in midcourse. The most common technique for adapting study designs is sample-size re-estimation. Based on midcourse data about parameters such as size of the treatment effect, studies can adjust sample size up, to ensure the ability to detect a difference between the test drug and the comparator, or down, to avoid testing the experimental drug on more patients than necessary. The key principle is increasing efficiency by making midcourse changes based on data collected during the study.
The goal of design adaptations is to increase efficiency. However, design flaws are not the greatest source of inefficiency in clinical studies. That distinction belongs to major aspects of operations, including enrolment, query processing, site management and closeout. Maximising efficiency requires not only making judicious use of design adaptations, but addressing operational problems head-on. Applying the adaptive principle to study operations provides even greater benefits than applying the same principle to study designs. For example, using technology such as the digital pen not only for collecting patient data, but also as a basis for generating near-real-time performance metrics on enrolment can greatly increase efficiency. Such performance metrics can identify the most effective enrolment strategies, messages and media quickly, allowing study managers to focus resources where they are most productive. In one STD study, a single site came up with the most effective recruitment strategy – posting flyers in nightclub restrooms. Early identification of this strategy enabled study managers to encourage all sites to adopt the same strategy, resulting in faster enrolment (see Figure 1).
A One-two Punch for Greater Efficienty
Used separately, design adaptations and operational adaptations can each improve efficiency. However, the greatest improvement comes from using both types of adaptations in a single study. Because design adaptations are not appropriate for every study, use of these techniques should be selective, targeted to individual study needs, and often applied at intervals, as with sample-size re-estimation halfway through a study. By contrast, the use of operational adaptations should be continuous and comprehensive, improving all major aspects of study operations as soon as timely performance metrics indicate an opportunity for improvement. Operational adaptations use continuous tracking of day-to-day activities to manage clinical studies to new levels of efficiency.
The combined use of design and operational adaptations is a one-two punch against inefficiency, allowing study managers new levels of agility in responding to changing circumstances. This agility is exactly what study managers need to keep complex multinational studies on time and on budget. A recent international study of metastatic breast cancer provides an example.
Case Study of the Agile Approach: Saving one Year on a Multinational Study
Enrolment in oncology studies often presents challenges, as a recent article in The New York Times illustrates (1). However, adaptive techniques, both design and operational, can greatly accelerate enrolment despite the challenges. The technique of sample-size re-estimation modifies the study design to ensure that no more patients are enrolled than necessary.
Adaptive enrolment modifies enrolment strategy and tactics dynamically based on near-real-time performance metrics, by site AND study-wide. The recent multinational study of metastatic breast cancer enrolled faster by combining sample size reestimation and adaptive enrolment.
The study used sites in the US and other countries. Close monitoring of enrolment metrics such as screen failure rate allowed dynamic adjustments in enrolment strategy. Because of known enrolment challenges of previous mBrCa studies in the US, study managers anticipated the need to move to add sites in Russia and other countries with minimal delay if US enrolment did lag behind targets. As feared, enrolment at US sites was slow – an average of less than one patient per site per month. However, near-real-time performance metrics quickly showed the severity of the problem. Rather than making modest adjustments in the enrolment approach at US sites, the study rapidly added a total of 27 sites in six countries. Managing these sites with the aid of timely enrolment metrics allowed 282 patients to be recruited in nine months, making the study the fastest enrolling mBrCa study to date. The adaptive technique of sample size reestimation contributed to time savings by reducing the number of patients required to demonstrate a difference between the test drug and the comparator. Enrolling the right number of patients with the most effective recruitment techniques is what allowed setting a new enrolment benchmark in this therapeutic area.
The mBrCa study relied on an advanced, integrated trial management system with streamlined processes and a wide array of performance metrics and standard reports. Appropriate infrastructure also played an important role, made possible by a digital pen system for rapid data capture and almost immediate data reporting via the internet. Technology played an essential role; however, technology ultimately allowed a more proactive approach to study management that used continuous information updates to inform timely management decisions. The decisions made the dierence between the success of the study and yet another sad story about an important study experiencing long delays because of missed enrolment targets. Another factor contributing to the success of the study was the determination of study management to provide support to help sites succeed wherever possible. Study managers did add new sites when necessary, but also helped each site perform to the best of its ability.
The drug industry can achieve its greatest possible chance of success in multinational studies with a combination of more proactive management and the use of technologies and processes that provide stakeholders with a continuous flow of timely information. The objective is to optimise both study design and operations to achieve efficiencies at every step of the clinical development process. This means factoring adaptive methodology – and a technology platform to support it – into study protocols during the earliest planning stages, and making sure each component of multinational trials functions with maximum agility. To adopt such an approach, the role of management must change from the historic model of keeping hands off and awaiting the outcome, to a style that is for more active and engaged. Multinational studies in the depths of recession demand nothing less.
- Kolata G, Lack of study volunteers hobbles cancer fight, The New York Times, 2 August 2009