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The process of bringing a new molecular entity or device to market has historically been long, costly and both paper and people intensive. Clinical trials play a substantial role in this development process with costs for a single clinical trial potentially reaching $100 million.1 These high costs are compounded by an inability to totally recoup the investment due to limited patent exclusivity timelines. Because the patent time clock starts ticking very early in the process, there is often only 8 to 13 years to earn back the sums invested in the product’s development by the time marketing approvals are obtained.2 Consequently, biopharmaceutical and device sponsors must push to introduce new drugs to multiple markets simultaneously so as to recoup the astronomical development costs quickly.
Finally, the complexities of the highly specialized drugs and devices being developed today to support the growing trend of personalized medicine bring their own set of challenges. Investigators for these global studies need to excel not only at specific medical specialties, but also at recruiting and enrolling the proper patient pool for the trial while still navigating the changing tide of the regulatory seas. Thousands of patients and hundreds of sites in many different countries are becoming the norm.
This all points to ever-increasing demand for experienced investigators. Yet, according to a 2012 site study conducted by Tufts CSDD, of the 15,000 unique site locations worldwide, a “high proportion” of them were overseen by “novice principal investigators,” who did not remain. High turnover rates created even more costly subsequent site selection and management costs.3 Also, according to a 2012 CenterWatch report, the fraction of most active, FDA-regulated principal investigators (defined as those who complete more than two 1572 forms each year), has dropped from 29% to less than 23% during the past five years.4 One of the biggest reasons is that these investigators incur high fixed costs, making it difficult to stay afloat for very long. The economy is another factor, in addition to old practices, complex protocols, flat study budgets, more demanding workloads and competition for studies with inexperienced investigators who accept unrealistic grant amounts. All of these factors have forced veteran principal investigators to scale back or go out of business.
Consequently, sponsors are now highly motivated to create an easier, more streamlined study startup period for investigators, while still speeding up the timetable and decreasing costs. Perhaps the most obvious place to start is in the essential document collection process. Clinical study startups require intense collaboration among the sponsoring life sciences company, contract research organizations (CROs), investigators, the ethics committees and many other outsourced providers; regulatory oversight on many different levels; and documentation at every step. On average, more than 10,000 different documents over the course of three years are involved in every new trial, which all require time and effort to manage.
There is some movement in the life sciences industry away from the slow paper systems that have been used for decades. And, although the spreadsheet era of clinical trial start-up process management is not totally behind us, software systems are appearing as replacements. In fact, 2012 survey data from the DIA TMF Reference Model group showed a 12 percentage point increase since 2010 in the number of respondents currently planning, building or evaluating an electronic Trial Master File (eTMF). Many of these eTMFs are currently available, but like many eClinical technologies, have now grown into cloud technology.
Clinical Trial Remedy is in the Clouds
Cloud technology, where software is web-based rather than installed on each individual hard drive or in a sponsor’s or CRO’s data center, can offer document exchange on demand wherever permissioned users can connect to the Internet. Unlike traditional installed software, cloud technology software does not require the capital or technological support commitment. It offers a pay-as-you-go subscription payment model, is enhanced regularly and relies on a single code base so that everyone is running the latest version all the time.
In the clinical world, sponsors, CROs, and study investigators across the globe can access a cloud-based eTMF with a single dashboard from any device and from any department. New team members from any organization can be brought online in minutes. Authorized users can access documents in the eTMF, make changes and send them back to the central repository in the cloud. This is in direct contrast to paper management systems where content can get stuck in one silo or another and the manual hand-offs between these siloes create information overload. Simple questions like “where are we today?” and “what other documents are missing?” and “is our TMF inspection ready?” become difficult to answer.
Tracking documents manually can also lead to inaccuracies, missing documents and overall lack of document control. These paper and email systems also lack mechanisms for a proper audit trail – especially for today’s more complex and expansive trials. Electronically captured data is the obvious alternative for the TMF but it still must, of course, comply with the FDA’s Code of Federal Regulations (CFR), 21 CFR Part 11. This regulation is applicable to records in electronic format and demands the use of validated systems to ensure accuracy, reliability and consistency of data with the use of secure, computer-generated, time-stamped audit trails to independently record the date and time of operator entries and actions that create, modify, or delete electronic records.6 But even validated electronic TMFs can be limited. If they are built using client/server platforms, they require sponsors to provide VPN hook ups or even individual laptops pre-loaded with the eTMF application to all users. The cloud allows sponsors to avoid this because of the web and can enable collaborative workflow between sponsors, CROs and investigators in real-time, resulting in a more complete and accurate audit trail.
Furthermore, since the cloud documentation is centralized, everyone works ‘on the same page,’ with visibility that can lead to better quality data and documentation, and avoid possible downstream effects that could undermine the study and decrease efficiency when it comes to health authority inspections. Cloud-based eTMF users can pinpoint missing documents or spot issues such as non-performing sites causing delays, and resolve them proactively.
Because many systems can be integrated in the cloud, sponsors can step-up the use of cloud technology to encompass the entire clinical trial process. Instead of many disparate systems, therefore, there is just one, complete eClinical solution. However, the tools still require integration to work together if the various software is not from the same vendor. The collaboration between partners and team members continues from shipment of the investigational drug or device to enrollment of subjects and through execution of the protocol. The monitoring of sites and accumulation of data can work under the same collaborative spirit, reducing study errors and further study delays.
The Cloud’s Long-Term Forecast
The Food and Drug Administration (FDA) and the European Medicines Agency (EMA) now require electronic submissions of a highly structured, electronic common technical document (eCTD).5 The FDA also more recently started requiring all submissions labeling to follow a structured product labeling (SPL) format – an overdue step towards more clearly defining the rules for use of electronic systems.
All told, these regulatory changes are helping to drive the industry’s adoption of eTMF systems in the cloud while successful use of cloud eTMF systems are helping to dispel any concerns around their efficiency. For example, cloud technology solutions can be developed to comply with the FDA’s Part 11 regulations out of the box without additional validation or an add-on application, overcoming another concern. Security measures for validation and firewall breaches, as well as back-ups are standard practice and no longer cause for any cloud anxiety.
The real issue is can the industry embrace the new technology tools that have the power to minimize the enormous impact that growing study size, complexity and global reach has brought to clinical trial start-up? Paper spreadsheets and installed software tools are no longer viable under today’s cost pressures and urgency to successfully complete widespread clinical trials. Cloud technology offers an environment where collaboration, document management and visibility can flourish, reducing costs and facilitating speed to trial.
Source: Robert Deming, 2013. http://mywingspan.com/why-cloud-makes-sense-for-tmf/