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International Clinical Trials

The Road Ahead

As cloud computing, digital identities and cost concerns all apply pressure to clinical research, eClinical providers look to respond with solutions that are agile and affordable.

The clinical research community is on the brink of unprecedented advances in medical science, but at the same time research productivity is steadily eroding. Recent data show that studies are becoming more complex, taking longer, and retaining fewer patients, while only 16 per cent of the drugs entering the clinical pipeline are likely to gain FDA approval (1,2).

eClinical systems are at the forefront of strategies to reverse the erosion of research productivity. The FDA has impelled conversion to eClinical systems with a draft guidance on eSource documentation that essentially supports moving all clinical data into a single, massive system with an audit trial (3). While the guidance is new, the advantages of such an approach have been discussed among drug developers for the last 25 years.

Despite its theoretical advantages, the promise of large eClinical systems has not been matched by real-world performance. After more than two decades of trial and error with integrated eClinical systems, the research community has identified several common pitfalls and is moving towards new solutions for effective, flexible and affordable eClinical systems.

Benefit for All Users

A frequent frustration for eClinical sponsors has been the push-back from study site members, many of whom have resisted the transition from paper-based to digital systems. Why would study sites prefer to push paper when the whole world is going digital? The answer lies in how – and for whom – eClinical systems have been developed.

In the traditional ‘waterfall’ approach to system development, user requirements are created by clinical trial analysts, functional requirements are drafted by the IT department, and systems are built and tested by those creating them. Adherence to this approach ensures that software can be validated in a quality regime per regulatory requirements. An approach such as this produces eClinical systems that function well and provide study managers with the data and reports they want. However too often, these systems do not meet the needs of study sites for simple, intuitive tools. Instead, study sites have encountered eClinical systems that are complex, training-intensive and difficult to access. When such systems create more, not less, work than the paper alternatives, resistance by study sites is predictable.

eClinical providers have responded with a new generation of systems designed with end-user needs evaluated at the beginning, middle and end of system development. This solution may seem simple, but requires constant advocacy for study site users, so that their needs are not subordinated to the ever-present demands of IT and study management.

Flexible Use

eClinical systems can make clinical activities more efficient and accurate, but that doesn’t mean they make sense for every trial, such as small Phase 1 trials that can be effectively managed using paper, email and phone calls. At the other end of the spectrum, Phase 3 global trials can involve upwards of 200 study sites, and Phase 4 safety monitoring trials can span five years or more. Clearly, this is not a one-size-fits-all area of enterprise, and the challenge is to determine what level of eClinical automation produces value in various study settings.

Determining eClinical value can be highly technical and include valuations of queries, invalidated data and other sources of inefficiency in clinical trials. It may be more practical for study managers simply to focus on areas of study operations that are known to be the sources of error, major components of the planned trial, and amenable to quality improvement using eClinical solutions.

The cost of eClinical systems must also be taken into account, including allocated/committed, variable direct and variable indirect costs. The latter includes lead time to ramp-up eClinical systems, training time for users, and the potential need for parallel paper-based systems. Value-based assessments may not be practical to conduct for each study. A more sensible approach is to develop a standard tool that computes value based on study variables and suggest an optimal mix of eClinical support. Alternately, study sponsors can assign trials to three or more levels of scale and complexity, and apply a standard mix of eClinical resources within each level.

Modular Design

Early visionaries of eClinical sought the development of large integrated systems that support a full array of clinical trial operations, spanning CTMS, EDC, RTSM (IVR/IWR,) ePRO, document management and more. The hope was that large integrated systems would yield sundry benefits, including fast and accurate data transfer across functional areas, combined metrics and sophisticated performance reports. However, with experience, it has become apparent that such large-scale systems are inherently complex and expensive, with long lead times to develop, and a mixed record for delivery.

In response to this, many eClinical providers have shifted to the development of systems that are modular and interoperable. Modular design involves development of separate functional modules for CTMS, EDC and others that can stand alone or work with each other, allowing study sponsors to easily adjust the mix of eClinical systems to study needs. Major eClinical providers such as BioClinica, Medidata and Parexel now offer ‘suites’ of eClinical products, available as a menu of applications built on a common framework.

Interoperable Systems

The prime attraction of a single, massive eClinical system is that a consistent data set can be used across various functions, streamlining data management, reducing errors and improving study quality and efficiency. Similar benefits can be achieved with separate, yet interoperable eClinical systems that work seamlessly with each other to exchange data and harmonise activities. Interoperability goes hand-in-hand with modular and hosted solutions, and virtually every major eClinical provider professes to be interoperable. But despite lofty claims and many legitimate advances, most drug developers today utilise a patchwork of unconnected eClinical systems, sometimes from the same vendor.

Data standards are the foundation of eClinical interoperability, and CDISC, the Clinical Data Interchange Standards Consortium, was formed in 1997 “to develop and support global, platform-independent data standards that enable information system interoperability”. CDISC has promulgated several data standards, notably SDTM and CDASH, which have gained traction with study sponsors, especially in recent years (4). However, true CDISC-based interoperability among eClinical providers has remained elusive, with the most common barriers cited as lack of understanding of standards, high cost, domains not covering sufficient data, and lack of regulatory guidance (5).

Similar initiatives include the Metrics Champion Consortium, which has pursued standardised metrics to improve clinical trial performance, and the SAFE Biopharma Association, which has developed a digital identity and signature standard to support transformation to a fully electronic environment for clinical research. Similar to CDISC, these standards have generated successful pilots and expanding membership, but practical barriers remain and achieving interoperability among eClinical systems is a continuing challenge (6,7).

A general trial portal can complement other eClinical platforms and serve as a starting point for interoperability. General trial portals include features such as training and communications centres, as well as study documents and resources. A trial portal can also accept data feeds from other eClinical platforms and post key study metrics from multiple systems on a common dashboard, providing study team members with a current, consolidated view of study status. The ePortal can support single sign-on (SSO) to other eClinical platforms, providing end users at study sites with a more convenient way to access and comply with all study systems. A trial ePortal can serve as a conduit for data streams from multiple eClinical platforms, and potentially convert heterogeneous data feeds into a standardised, unified data set. In this way, a general trial portal can serve as a foundational contributor to an eTrial master file.

Hosted Services

The IT departments of large biopharmaceutical companies have traditionally preferred to operate eClinical systems from servers installed within their company networks. This penchant for control reflects the heightened pressures placed on biopharma companies for security, privacy and regulatory compliance. Technology has evolved, however, so that hosted eClinical systems, such as Software-as-a- Service (SaaS), offer several advantages over installed systems. Hosted services by definition do not require on-site installment and are already functionally validated, so they are faster and less expensive to ramp up. It’s also easier and less costly to maintain systems that are hosted by the eClinical providers who developed them. And, of course, hosted eClinical systems do not require customers to purchase and operate a multitude of servers.

eClinical providers have strived to win the confidence of study sponsors with hosted services that are highly compliant and secure. To gain ground, hosted eClinical systems must be flexible enough to support a wide range of study designs. To deploy quickly, systems must support rapid provisioning, with pre-built forms and import functions, and systems must be easy to populate with study information such as study documents, third-party data, branding, training modules and study communications.

The next phase in study sponsors off-loading eClinical duties to vendors, and this year’s hottest trend in IT is cloud-based computing, using third-party providers of data processing, storage and software. Using efficient, large-scale IT resources can yield benefits in cost and flexibility, and the cloud approach also facilitates centralising data, managing access, and sharing data among collaborating parties. These aspects are convergent with modular design, interoperable systems and digital identities, as discussed. Additionally, the assemblage of very large data sets into a central, coherent environment has profound implications for data analytics that could identify trends and efficiencies, transforming clinical trials. Cloud computing is also compatible with another end goal of eClinical systems: creation of an electronic Trial Master File, or eTMF.

Another recent innovation in eClincial systems is the selfservice SaaS platform. The eClinical provider Merge has introduced a ready-to-use platform that supports a menu of comprehensive eClinical functions (8). After training on the system, study managers can access a web interface to mix and match services, configure their workflow, and populate these platforms. The unique aspect is that customers use the platform ‘as is’, with no additional programming by the vendor.

Colliding with this self-service approach is the need to match the workflow of individual studies. Wide variability among companies, departments and study designs all serve to undermine the use of templated workflows. To match study operations, either a self-service eClinical system must be highly flexible, or study designs must conform to eClinical functions. Indeed, some eClinical thought leaders believe that for the next phase of eClinical to succeed, studies must be designed around eClinical systems, and that process change is needed to revolutionise the conduct of clinical trials (9,10).

Affordability

The consensus view is that the costs of drug development have spiralled to a tipping point, elevating the issue of affordability for eClinical systems. Most major biopharmaceutical companies are restructuring their research programmes into smaller decentralised units, and diverting a larger share of research capital into partnerships, alliances and stand-along acquisitions. The smaller buyers of eClinical systems generally operate in a more constrained funding environment, and are likely to prefer systems that are flexible, agile and most importantly, affordable.

eClinical system affordability is a challenge that must be met on several fronts. Cloud computing can play a part, lowering IT resource costs by an estimated 25 per cent (11). Another tactic is to build eClinical systems for reuse so they yield value over multiple instances. This calls for disciplined study design and use of templated systems that require minimal work to use for the next study (8). Quality compliance, validation and documentation are costly, and eClinical systems must be designed for use without a major cycle of re-validation for each next study. Drug developers need to resist the temptation to make design changes to eClinical platforms and avoid layering on non-core ‘wish list’ functionality. Consistency and affordability go hand-in-hand. The final frontiers of affordability are the design of clinical trials and the definition of workflows, both with efficiency of study systems in mind. As cost becomes more of a driver in drug development, the idea that studies should be designed around systems, and not vice versa, is likely to gain traction.

Conclusion

We live in a period of unprecedented, rapid change. Mobile devices, apps, texting, search engines and social media are but a few of the technologies that have transformed modern life in just a handful of years. In clinical research, cloud computing, digital identities and cost pressures are among the transformative forces looming on the horizon. eClinical systems must not only be ready for forces we see coming, but for unforeseen change as well, because the event horizon is only a few years hence. The iPad, first sold in April 2010, has become the most rapidly adopted device in history, and is now a prevalent digital device in clinical settings. Many eClinical developers are scrambling to develop solutions that work not only with the iPad, but the iPhone, Android, and other mobile devices and operating systems. These mobile technologies have one thing in common: a few years ago, no one saw them coming.

Most importantly, eClinical systems must address research productivity and play a role in yielding more market success from the $65 billion spent annually on biopharma R&D. To achieve that, eClinical systems must be designed for affordability and provide the foundation for a process change towards more efficient, successful trials. Clinical trials themselves may need to be re-designed around efficient use of eClinical systems, as part of a new, more productive R&D paradigm.


References
  1. Tufts Center for the Study of Drug Development, Impact Report: Growing protocol design complexity stresses investigators, volunteers, 10, January/February 2008
  2. Tufts Center for the Study of Drug Development, Impact Report: Large pharma success rate for drugs entering clinical trials in 1993-04: 16%,11, (4), July/August 2009
  3. US Food and Drug Administration, Guidance for Industry: Electronic Source Documentation in Clinical Investigations, December 2010
  4. CDISC Website, Mission and Principles, www.cdisc.org/missionand- principles
  5. CDISC Journal, CDISC: Adoption Trends, Benefits and Addressing Barriers, Friggle W, Li F, Labout S, Kush R, October 2011
  6. AstraZeneca, AstraZeneca Implementation of SAFE Digital Signatures, 25 February 2007
  7. Metrics Champion Consortium, Inc, AstraZeneca and ERT Case Study: Utilizing a Multi-Phased Approach to MCC ECG Performance Metrics Implementation, 2008
  8. Merge Healthcare Incorporated, Merge Announces Release of eClinical OS Platform at DIA Conference, Press release, 25 June 2012
  9. Nick Lucus, MD, Foresight, an INC Research Publication, An Honest Look at the eClinical Process: What Can We Learn from Best Practices Outside the Industry? 1,(5), February 2009
  10. David M Connelly, Touch Briefings, The Challenges of Data Capture and Data Management – a CRO Perspective, 2007
  11. Pharmaceutical Technology.com, Ahead in the cloud – a new home for clinical trial data, 31 January 2012





 

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Bill Cooney founded MedPoint Digital in 1990 and continues to lead its strategic growth in digital platforms for clinical research. Prior to launching MedPoint, he helped start up a division of Publicis Healthcare and worked in marketing positions at Wyeth and Abbott, including as Business Unit Manager for the Depakote franchise. Bill speaks at numerous industry events and publishes articles in medical industry journals on topics ranging from Sunshine Act compliance to cultural challenges in conducting trials and interoperability across digital systems.
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