By Maxine Bookbinder

July 29, 2016 | The goal of clinical trials is to develop and market superior therapies with maximum efficiency at minimum cost. But doing so depends upon the ability to successfully complete every trial step with nuanced behind-the-scenes timing, skill, and precision. These rarely-noticed mundane, yet critical technological processes are taken for granted but are an integral part of today’s pharma landscape.

The engineering, biology, and management virtuosi who turn these visions into realities view their work as contributions to their local communities and the global greater good. “What we are offering is a separation from how things are done. We are offering new options for people,” says Ed Tourtellotte, 4G Clinical CTO, the architect of what he calls the world’s first configurable Interactive Response Technology and designer of the clinical trial supply simulator tcVisualize and Trident IWR.

A stream of initials—IVR (Interactive Voice Response), IWR (Interactive Web Response), IMR (Interactive Mobile Response), IxR (Interactive x Response) and IRT (Interactive Response Technology) and RTSM, or Randomization and Trial Supply Management, are used to describe critical services required by every complex clinical trial. According to the 4G website, RTSM, which co-founder, CEO, and former Army ranger David Kelleher says is a $750 - $1 billion industry, is “the backbone of clinical trials” and allows biopharmaceutical companies to dispense medications, supply sites, and assign patient treatments more rapidly and efficiently, while removing the risk of human errors.

This inventive system is based on an elementary premise updated for multifaceted trial needs: reading, writing, and math, or more precisely, natural language processing (NLP) that, combined with custom clinical trial intelligence, reads and interprets written RTSM specifications and, within minutes or seconds, builds a deployable system automatically.

Iain Dowlman, Vice President, Logistics Solutions, PAREXEL, describes RTSM as a service, purchased on a trial-by-trial basis, that performs centralized services such as randomization, medication allocation, automated resupply of investigational products at sites and depots, emergency unblinding, and centralized patient recruitment and progression metrics. PAREXEL has been using RTSM since the 1990s for patient screening and randomization, medication dispensation, automated resupply of sites and depots, real-time metrics, expiry date management, and drug reconciliation. It acquired ClinPhone in 2008, which provides RTSM services for the complexity of different development phases, study types, and geographical regions.

Constantly evolving innovation and increasingly complex technologies have mandated the need for, ironically, simplified trial procedures. “Third generation IRT (RTSM) systems are running out of runway, and the most critical aspects of large phase 2 and 3 clinical trials – randomization, drug dispensing, and site resupply – continue to be poorly supported across the pharmaceutical industry,” says 4G’s Tourtellotte.

4G, a clinical trials technology company that accelerates the development of new pharmaceuticals, is the latest vendor to enter the RTSM cyber landscape. The company plans to work with pharma and bio-technology companies in study phases II and III and to have an FDA-validated service in September.

“The name of this type of system has evolved with generations,” says Kelleher. “RTSM describes it more accurately, so that is what we are using now.” We’re making the entire drug development process faster by improving that little piece of the world: the build, test, and release of this system, which can typically take up to 12 weeks per trial. If you need to change specifications or correct errors, you eat a lot of time. We will reduce that time to less than four weeks.”

The 4G team says it is not actually increasing the speed of drug transport, but improving the efficiency of the transportation, all through the complex supply algorithms and NLP. “Instead of using the traditional, weeks-long approach of writing system specifications and handing them to a developer to code the system, 4G carefully writes a structured specification and uses NLP to read specific words and understand and incorporate these words into meaning,” says Tourtellotte. “If you write a specification and build with a smart editor, the system can build itself. You write specifications and press ‘build.’” Specifications can be easily changed by altering a paragraph or inserting a missing word; this new data is then immediately a part of the system.

The ability to make quick changes simply by tweaking the language, such as changing a paragraph or adding and deleting words, allows for flexibility and efficiency, says 4G Chief Operating Officer Christine Hurley. Older generation systems can’t adapt to modifications such as adaptive trial designs and patient changes as easily as RTSM.

4G’s work begins with a trial design or protocol. The team then builds a specification to ensure the details of the trial design are implemented accurately. The 4G RTSM platform, Prancer, reads the specifications once and creates the functioning RTSM system instantly. Sponsors can then validate that the system is created as specified. Double-blind instructions remain the same; patient 123 retrieves encoded test kit ABC from nurses who don’t know which patients are receiving drugs or placebos.

The RTSM system also keeps track of drug supplies at every clinical trial site. Traditionally, a supply manager calculates resupply thresholds; the 4G system does this and immediately sends out new supplies before they are needed, saving time and “eliminating human error,” says Hurley. The software system forecasts trial drug supply by calculating supply quantities; through advanced math algorithms, the system can determine supply levels at every site, adjust them automatically, and send product as needed. “Our clinical supplies forecasting functionality encompasses a number of parameters, including expected numbers of sites and patients, patient enrollment rates, supply thresholds, and withdrawal rates.”

According to Hurley, reporting with RTSM is simple; data listings provide quick access to all system transactions, such as shipment, patient, and supply inventory listings. “We are structuring our reporting to be much more user-centric meaning that, instead of being presented with a blank screen and a list of reports to choose from, we are offering our users dashboards that help to answer the question, ‘What do I need to do today?’ The dashboard shows recent system transactions, data elements that might need attention, upcoming milestones, etc. with easy links to take action where needed.”

The software allows users to set risk or performance-based supply confidence dial levels. “From a business point of view,” says Kelleher, “a user typically cares about inventory levels, cost and delivery accuracy and not the details of how to optimize those variables. The capability allows a user to set those business tolerances and adjust them quickly. For example, 99% on-time delivery will require higher inventory levels and cost, whereas certain scenarios may allow for a reduced on-time delivery metric, reducing inventory and cost requirements.”

4G’s role in clinical trials is to efficiently and accurately control patient randomization and drug dispensation through randomization of sites nationally and globally. The key innovation, says Kelleher, is being able to set up the software quickly and alter it instantaneously when necessary. This can reduce trials by weeks, saving money and delivering therapies to market sooner. “It’s a common belief that every day of delay of a late-stage trial is worth $1 million in unrecoverable lost revenue. We are doing our part to get drugs to market faster and to save lives.”

PAREXEL’s Dowlman agrees that the development of RTSM has improved the clinical trial process. For example, sponsor companies have real-time access to up-to-date recruitment figures and can automatically close recruitment when predefined thresholds are met, avoiding over-recruitment. It has also advanced the use of complex randomization algorithms, including a range of adaptive techniques such as more efficient resupply processes, significantly reducing the amount of medication overage needed to effectively conduct a clinical trial.

“Our ClinPhone RTSM is a ‘full service’ offering,” says Dowlman. “All hardware is hosted by PAREXEL. This is important since RTSM is often on the critical path for treating patients and as a result the system needs to be available 24/7/365. To access the system, the end users simply require a phone or a computer.”

Of course the system is always changing. In a blog posted at Applied Clinical Trials, “Three Generations of RTSM,” (September 17, 2015) Tourtellotte noted that 3rd generation RTSM had run into the problem of “constant innovation to keep up with trial designs, spiraling complexity daunting away those same sorts of people who suffered in generation two.”

But for now, RTSM is increasingly being seen as an essential part of the management of clinical materials, says Dowlman. “With increasing integration with medication tracking technology, including temperate monitoring systems, the future of RTSM is likely to be the development of full traceability of medication from creation to destruction.”