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Paul Bleicher, MD, PhD, is chairman and chief scientific officer for Phase Forward.
Pharma companies are committed to using electronic data capture in clinical trials. Technology adoption will continue to grow, as FDA and consumers want faster safety data.
The pharmaceutical industry has entered the "enterprise era" of electronic technologies for clinical development. While 70 to 80 percent of clinical trials are still paper based, many of the largest pharma companies have committed to doing virtually all their clinical trials using electronic data capture (EDC). Technologies for collecting and mining safety data are being heavily adopted as FDA and the public demand better, faster access to safety data. And industry stakeholders are developing a growing appreciation for the way electronic tools contribute to higher data quality, faster and more effective access, greater cost effectiveness, and shorter clinical development timelines.
These tools, of course, are just the beginning. The industry is accelerating adoption of many additional technologies, including integrated trial management systems (ITMS), communication portals, and many other solutions that address clinical development workflows. In the pilot phase are automated authoring of protocols, clinical trial simulations, electronic informed consents, electronic institutional review board (IRB) processes, and electronic budgeting and payment systems. Ideally, these functions and others will be integrated into a single clinical development system, allowing data to flow smoothly among them, facilitating better decision making, and optimizing study results. (See "The Emerging Value Chain".) But for the moment, most are stand-alone "point solutions," or at best, partially integrated. Companies are faced with a strategic question: Should they adopt these technologies as they exist today, or wait for the development of a fully integrated clinical development system?
To date, no pharmaceutical company has been able to create a fully automated clinical development process. The integrated software necessary is not yet available, and no companies have achieved the standards, process knowledge, and commitment needed. On the other hand, the industry has evolved to the stage where electronic solutions are an accepted—even expected—part of the mix.
A single clinical development system would allow data to flow smoothly among various functions.
Today's e-clinical tools tend to be stand-alone systems. But they are gradually integrating a number of related processes, from protocol development, site initiation, and subject enrollment to data collection, monitoring, analysis, and regulatory submission. Companies such as GlaxoSmithKline, Schering-Plough, Eli Lilly, Novartis, Bayer, Procter & Gamble, and others have openly discussed the value they aim to achieve with electronic data capture. Almost every company using such EDC systems hopes to integrate them with software that controls other parts of the development process.
Some within the industry suggest forgoing upgrades of individual technologies as they wait for a unified e-clinical system that will manage all functions of clinical development. Whether they are considering an enormous project within their organizations or a giant consulting assignment to systems integration specialists, they should be aware that this road is littered with spectacular failures. The Federal Bureau of Investigation paid more than $113 million for software meant to unify its case management process. Reportedly, the software delivered was outdated and will only be used to help design a completely new system. This story echoes in the halls of major pharmaceutical companies as well.
Smart sponsors and contract research organizations (CROs) are not waiting for a finished e-clinical system. Instead, they are moving ahead by incorporating one or more integrated electronic solutions to improve the clinical trials process, today. The first and key step is automating the painful paper process of data collection between sites and sponsors. The supply chain methodology used in manufacturing has important lessons for clinical development in the "manufacture" of its key product—the new drug application (NDA) or biologic license application (BLA).
Supply chains integrate the flow of information among internal and external network participants throughout the procurement, production, distribution, and customer interface stages of manufactured goods. They enable aggressive inventory management, customized product delivery, and just-in-time manufacturing, which revolutionized the automobile industry. In addition to a supply chain, the pharmaceutical industry must manage a value chain: the procurement, production, assembly, and distribution of data. Data shapes the path from a "hit" in the discovery process to a label claim on a package insert. This value chain is at the core of pharmaceutical development. This value chain has been managed in the past by legacy processes and a few modern systems. Clinical development, the final common pathway of all potential new medicines, is beginning to wake up to the need for an optimized value chain.
Linking supply chains and value chains can spur the drug development process. Consider, for example, the supply problems in clinical trials of new biologics, especially when drugs are manufactured in pilot plants. Often, the supply and stability of a study drug from such plants are very limited, leading to delays in starting crucial Phase II clinical trials. There simply isn't enough study drug available to leave a supply at every investigative site for months, while the sites wait for new patients. By linking the EDC system with fulfillment data, sponsors can have a study drug shipped overnight to clinical sites as patients enter a study.
Global regulatory changes are driving the move to EDC technology. In 1997, when FDA issued 21 Code of Federal Regulations (CFR) Part 11, the Electronic Records, Electronic Signatures Rule, the agency began to create an electronic regulatory environment. Since then, FDA has established the Data Standards Council to coordinate the use and maintenance of common regulatory data standards throughout the agency. For data interchange and archiving, the agency now uses standards developed by Clinical Data Interchange Standards Consortium (CDISC). It has named CDISC's Study Data Tabulation Model as a standard format for data submitted in product applications. FDA plans to require electronic data submissions for NDAs, amended new drug applications (ANDAs), and BLAs. Also, FDA is now accepting electronic patient-reported outcomes (ePRO) from wireless handheld devices.
The Role of EMR
The electronic regulatory environment was expanded when The International Conference on Harmonisation (ICH) created the electronic common technical document (eCTD), a new version of the CTD, which contains information about the safety of a product. The (paper or electronic) CTD is required in Europe, and FDA strongly encourages its use, especially in online applications. According to the ICH, the eCTD should serve as the basis for the safety issues identified in the Pharmacovigilance Specification—a summary of the identified and potential unidentified risks of a drug.
And there are more developments. In March 2005, FDA issued Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment, an industry guidance for detailing safety signal identification and development of a pharmacovigilance plan. According to the guidance, sponsors may want to consider developing electronic registries, which are organized systems for the collection, storage, retrieval, analysis, and dissemination of information on individuals exposed to a specific medical intervention. By creating registries, sponsors would be able to evaluate safety signals identified from various sources, and analyze factors affecting the risk of adverse events.
Still on the subject of safety, the European Medicines Agency (EMEA) now requires sponsors to submit data electronically on suspected unexpected serious adverse reactions (SUSARs) to EudraVigilance, the European data processing network. EudraVigilance has enabled EMEA to implement electronic data exchange of Individual Case Safety Reports (ICSRs) on marketed products, using data standards outlined in ICH guidelines. In addition, EMEA requires sponsors to make electronic submissions to the European Clinical Trials Database (EUDRACT), a clinical trial registry.
These recent developments are just the most important among many regulatory developments that encourage the adoption of ECD and related systems in the pharmaceutical industry. Eventually, the electronic submission requirements will become so pervasive that they create a competitive threat for companies whose enterprise technology does not meet the reporting challenge.
Many pharmaceutical companies long ago implemented an enterprise resource planning (ERP) system on the business side. The ERP system often dovetails with the clinical side, if only at familiar points like the hiring and payment of contract workers, the procurement of basic medical supplies, and standardization of contracts, liability agreements, and so on.
The (Gradual) Road Ahead
To proceed down the road to fully electronic clinical development, systems must incorporate more elements of the clinical data core into one system that supports business and clinical decisions at the same time. For example, benchmarking the activities of external vendors and investigative sites with respect to quality, enrollment and efficiency of previous trials would improve the selection of outsourcing partners, such as CROs.
Tiered project management of operational activities, data, and documents The backbone of a future clinical ERP system is likely to be an intranet-based roadmap that contains the plans for a complete NDA or BLA. For every new project, the system would create the outline of the NDA and have placeholders for the documents and decisions that are needed at various stages in the clinical development process. As the process unfolds, the system indexes and cross references all documents, including versioning, background, discussion, and data for pre-clinical and clinical steps. The process of drug development itself is performed through the software, not documented by it. Eventually, the ERP also might serve as a management tool for creating a general development plan for investigative compounds or devices.
Real-time analytics Businesses, including pharmaceutical companies, use real-time data to spot trends and improve operations. As investigative sites collect more and more electronic data, such real-time analytics (RTA) promise to shape best practices on the clinical side. Researchers who review data in real-time can not only detect disturbing patterns such as clusters of adverse events, they can also modify the design of a study in midstream. When incorporated into study designs and analysis plans, adaptive randomization allows the size, randomization schema, and other study parameters to be adjusted based upon pre-defined parameters of the data, provided data are collected in near real-time, such as in an EDC system.
Content management throughout the NDA process Multimedia and Internet companies use enterprise content management (ECM) to archive and recycle bits and pieces of information in the production of Web sites, e-learning, and other media products. The NDA is a promising target application for ECM.
Most pharmaceutical companies have adopted some type of ECM to keep track of the immense flow of documents in an NDA, but such information is seldom shared across the larger clinical enterprise. Tools developed for searching/ indexing content and managing digital rights can be adapted easily to the NDA or BLA environment. Much of the content used in NDA reports is repeated, more or less verbatim, in dozens of different places. Clinical protocol language is similarly reused repeatedly. ECM makes it possible to create content libraries full of passages that can be recycled over and over. ECM libraries also can be used for automated protocol development and other report writing.
New possibilities will emerge as automated reporting, electronic medical records, EDC, and automated alerts of serious adverse events begin to interact. (See "The Role of EMR".) But progress toward more sophisticated ECM and ERP systems is sure to remain gradual.
The completely integrated, fully electronic clinical development system will not just appear one day, completely formed. (See "The (Gradual) Road Ahead.") Instead, expect the continued improvement of existing point solutions, and eventually, the integration of these solutions. Overall development will be driven by the value of each individual solution. Pharmaceutical companies that are first to put electronic clinical development solutions online are likely to be first to integrate their systems—and first to reap rewards from an improved value chain.
Paul Bleicher, MD, PhD is chairman and founder of Phase Forward. He can be reached at firstname.lastname@example.org.