Tooling Up for Clinical Trials

Clinical trials represent an expensive and time-consuming barrier for pharma firms. Can the proliferation of IT tools keep clinical trials manageable in the face of growing regulatory demands? Neil Davey investigates…

The pharma sector may be busy inventing remedies for society’s ailments, but that’s not to say that it doesn’t have its own particular maladies in need of a cure. And if there’s one particular cause of discomfort, it is the clinical trial process. Clinical trials form the largest single cost centre for new drug development, and each additional day a drug spends in clinical development is estimated to cost from US$600,000 for niche drugs up to US$8 million for a blockbuster. But with clinicians and regulatory agencies requiring more data from trials than ever before, each trial phase has become increasingly complex, ramping up the amount of time a drug developer remains out of pocket. As a result, costs are climbing at an alarming rate, with Frost & Sullivan suggesting that the cost of clinical development has increased by some 40 percent over the last 10 years.

“It can take a lot of time because it is challenging to design protocols and recruit patients, but it is also to do with the complexity of the information,” says Greg Johnson, VP Global Data Management at PRA International. “You have got a number of participants – you have got the investigator site, the sponsor organizations, you have typically got CROs and other vendors – all involved in the collection of the information. And when you have a lot of different parties gathering together complex data, there tends to be a lot of iteration in getting that accomplished.”

With so many new drug development initiatives ultimately rejected and never making it to market, pharma firms are understandably under pressure to increase the efficiency of the clinical trials process, either shortening the time it takes to bring a successful drug to market or identifying bad drugs that will never reach the market more quickly. And improving the collection and management of the spiralling amounts of data has proven to be at the core of streamlining the process. Clinical trials were traditionally very manual and paper-based activities, with the majority of information residing in forms that collected patient information and trial data. But as pressure has grown on the industry to speed up the procedure, there have been tremendous efforts in terms of automating these processes.

As with any other sector, by automating specific tasks of paper-based systems, firms can increase accuracy (in this case of their research data) and save time and money. But other tools more specific to the clinical trials process have also emerged in recent years that have further streamlined operations, many of which are based on the internet. “Web-based tools have proven to provide tremendous benefit to the clinical trials process,” acknowledges Dave Kubersky, Managing Director of Ness Life Sciences and Specialty Solutions Group. “From improving data collection speed and accuracy to reducing costs across the entire cycle, new tools and technologies have now reached a level of maturity and stability that benefit the entire process. Due to the distributed nature of trials as a whole, leveraging the ubiquity of the web makes tremendous sense.”

Data transfer

Electronic patient reported outcomes (ePRO) provide a perfect example of how these tools have aided pharma firms in recent years, having demonstrated reductions in variability and increased study power in clinical trials. Studies by Invivodata, for instance, suggest that ePRO can dramatically increase the integrity of patient reported outcome data by driving over 90 percent patient compliance and, as a result, reducing error variance by 33 percent. The advent of electronic data capture (EDC) has also been of similar value, particularly in terms of speeding up the transfer of data.

Traditionally, the investigator documents the trial results on a case record form that is collected by the CRA a month later, with the data then entered into the study database. Inconsistencies in the data may then be questioned from that database, which go back to the investigator to be answered. This is obviously a time-consuming process. But if you have web-based electronic data capture then the investigator can input the information straight to the database, with intelligence built-in to ensure that certain input errors are also avoided. Therefore, it significantly cuts the length of time it takes to get clean and well-processed data. Most companies have now used this kind of technology on studies. Andy Lawton, Head of Biometry and Data Management at Boehringer Ingelheim, explains how remote data capture (RDC) has been integral at his organization.

“Implementing RDC in a consistent way across all trials gives us a great benefit,” he says. “In the paper arena there is an issue regarding what is on the paper and what is on the database. Now that we are in a remote data capture situation, you can say at any time that the only thing that is outstanding is what the investigator hasn’t entered yet. And so you can make decisions on the data earlier – you can see whether the patients are being recruited and whether they are the patient population you wanted rather than having to wait 60-90 days for the patients’ data to come in-house, be entered, be processed and then ready to look at it. You have that instant view on the data and thus you can make decisions earlier. Now we have set ourselves a target for when every trial in the phase II-IV area will be RDC so that we can get the real benefits of data coming to us quicker.”

Information revolution

While technologies such as EDC and RDC support clinical information needs, clinical trial management systems (CTMS) are being leveraged to support the managerial and administrative side of running clinical trials. This often addresses areas such as patient/subject status tracking, patient/subject scheduling, billing and invoicing, milestones, and related reporting. With the US CTMS market poised for five-year compound annual growth rate of nearly 13 percent according to Life Science Insights, culminating in CTMS software licenses amounting US$360 million, CTMS will be playing an increasingly integral role in clinical trials.

“Clinical trial management systems encompass a broad array of tools, which include electronic clinical record formats (eCRFs) through clinical trial supply chain management (to ensure that samples for double-blind trials are delivered correctly, on time),” says Srivathsan Aparajithan, Director of Life Sciences and Healthcare Solutions at Marlabs. “From the perspective of time taken to complete a trial, these tools obviously help reduce the overall time period. When one includes patient recruitment as part of the clinical trial process, the impact is even higher, because web recruitment of patients can cut down the time it takes to assemble the right profile of patients for the trial. And eventually translates to reduction in costs of carrying out the trials.”

With a raft of automated tools and web-based solutions available for pharma firms, clinical trials have been revolutionized in the past decade. “Anything that allows you to get the data in hand quicker and to have all the parties who are trying to collaborate together be able to look at the same data in real-time is going to make things simpler,” says Johnson. “You are trying to reach decisions quicker. At the macro level you are trying to decide whether a chemical entity works or whether you want to go forward with a study. But even within the context of an individual study, you are testing the assumptions that the study was set up around – how fast you are going to recruit, how many queries you are going to generate – all of those different assumptions you started out with are being tested. And the folks working together on that need to be able to look at what is actually happening and compare it to the assumptions and adjust their plans as they go forward. You are doing that in an iterative process – sending data back and forth and exchanging e-mails is not the same as being able to, for instance, pull up an EDC screen and look at the same information in real-time together.”

Holy grail

Nevertheless, the tools are not without their problems. In some cases, the solutions that have been introduced to address problems have even introduced new complications. EDC, according to Kubersky, is a case in point. “Historically, when everything was done on paper there were a lot of inefficiencies so EDC was seen as a way to automate this to a significant degree,” he highlights. “However, they can introduce new issues whereby data management can become more complicated with regards to the provisioning of lines and what needs to be required at site level. So while EDC is a benefit it can also create a new set of inefficiencies.”

But there are other more fundamental IT limitations at present. “If you are looking to streamline, I don’t really believe that any single point solution can help,” continues Kubersky. “One of the big inefficiencies is the fact that in the clinical space there really does not exist today an equivalent of an ERP for clinical. So there are a lot of point solutions that support discrete processes but there is no overall process.” The proliferation of clinical trial technology in particular has created new issues, suggests Lawton. “We’re still using too many systems,” he explains. “We haven’t got what I would consider a total killer application that really integrates many of our problem areas into one. And so we are still looking for that Holy Grail solution that will bring in all our data from the different areas and bring those together.”

Fortunately, developments in standardization are afoot that could aid the whole data integration process and ultimately further streamline processes. Work by the Clinical Data Interchange Standards Consortium (CDISC) to create a clinical data interchange protocol in particular should ease the problems, especially as organizations such as the Association of Clinical Research Organizations (ACRO) and the FDA have become increasingly involved in the standard. “Integration hopefully should become easier because the industry has finally got together and agreed on commonly used standards,” suggests Ruediger Dorn, Industry Director for Pharma, CPG and Process Industry at Microsoft. “And the same standards can also be used to communicate between the pharmaceutical companies and the regulatory agencies. So there are standards in place around safety reporting and there is work done around how the clinical data is recorded in to the central databases of the FDA, etc. So data standards can help a lot to facilitate that and also as it is now based around XML, the internet standards have enabled communication between the various entities and definitely accelerated that process."

Providing relief

Despite a few technological teething problems, the future for the clinical trial process looks to be clear. Procedures will inevitably become increasingly electronic, increasingly automated, whilst efforts to integrate the tools will become a priority. “Integrating all of these products into one and getting the most efficient processes to work with them is going to be revolutionary,” says Lawton. “We still deal with paper in many areas and so to eliminate that and move to an all-electronic environment would be a great benefit. And on top of having good reporting tools, we are going to implement a good data warehouse that is going to securely hold the data and bring in line good processing standards to it in terms of good program control for the programs that you use to report on the clinical trials. All of this will help enormously.”

With the pharmaceutical sector in another major transition period in its evolution, the streamlining of clinical trials can only become more important. Indeed, while regulatory agencies may be demanding ever tighter clinical trial stringency, it may be other pressures altogether that demand greater reliance on existing IT tools, and the leveraging of emerging clinical software. “It seems like the era of the blockbuster drug is coming to an end and increasingly it is becoming apparent that pharma companies will have to look for extremely targeted drugs,” says Srivathsan Aparajithan.

“This requires a rethink on the way clinical trials are planned and managed. There will be a lot more molecules that will need to be tested, patient recruitment to trials will have to get even more refined, there will be geographical challenges to reach samples to sites. The pharma industry has all the tools required for this, right from clinical trial management through data analysis, to regulatory submissions. But given the large number of molecules involved, tools like portfolio management will gain prominence. Also business intelligence tools that permit predictive analytics and financial reporting will become important and will become an integral part of the clinical development process.” Indeed, whilst the challenges associated with clinical trials are certain to continue to rise, the pharma sector can take heart from the fact that IT continues to evolve, providing some relief from the pain of the clinical trial process.

Clinical trials, regulatory bodies and software vendors – an unholy but necessary alliance
By Dr David Hardison, Chairman of the Board of the Clinical Data Interchange Standards Consortium (CDISC).

Regulatory changes within the clinical trials process continue to pressure the life sciences industry, which is cautiously trying to evaluate these emerging standards. In the US, the FDA has begun to heavily influence IT and process decisions with guidance such as 21 CFR Part 11. To date, the industry's response has been one of ‘bolt-ons’ to the existing process and solutions, rather than revisiting the clinical business as a whole. The result is often 25-30 software applications requiring integration, support and maintenance. Now that the business case has been accepted (FINALLY!) for moving away from paper, more than 100 electronic data capture (EDC) solutions are being offered to add to the complicated, multi-vendor environments that exist in many companies.

While EDC is an important component of a data acquisition strategy, a need exists for an enterprise clinical trial system of production taking the company from pre-trial planning and set-up, through the trial itself and into the submission stages. This system includes regulatory compliant capabilities for data acquisition, data aggregation, data analysis, reporting and submission with workflow transparency into investigative sites, CROs, labs and sponsor companies. This is an iterative process that demands far more comprehensive awareness of the clinical, data management, statistical and regulatory requirements than previously considered in the point processes and solutions.

Let us unravel some of this Gordian Knot and try and discover the primary pressure points and what, if any, relief can be brought to bear. The three primary drivers are; regulations, the pharmaceutical companies themselves, and vendors of software and services solutions.

The FDA, through its support of the Clinical Data Interchange Standards Consortium (CDISC), has signalled that this is the direction in which it is heading. The FDA has also mandated compliance to 21 CFR Part 11. This FDA 'Final Rule' was published in 1997 and establishes requirements to ensure that electronic records and electronic signatures are trustworthy, reliable and generally equivalent substitutes for paper records and traditional handwritten signatures. It is important to consider what type of records Part 11 applies. The regulation mandates what records must be maintained; the content of records; whether signatures are required; how long records must be maintained.

So what do the pharmaceutical companies want? If worldwide R&D costs, according to various sources, come in at around $60 billion a year and clinical trials represent the largest slice of this budget, there is a lot of money to be saved by speeding up the process. Gartner Group estimates there could be between a 30 -35 percent reduction in time to approvals with the use of technology. The companies also want more drugs in process managed cost effectively. CFO's are tired at throwing money and manpower at every little problem or buying the latest application.

Pharma companies want compliant systems that will improve current business process through speeding up the clinical trials process at a lower total cost of ownership. The question is how will the pharma companies reduce the current 25 or 30 non-standard point applications that are in use today to three or five? The answer is a core information management architecture covering both data and documents that is standards-based, simple to use, easy to access and capable of working with the latest compliant applications. The information architecture is the glue between the business processes and the applications.

Now to the vendors, the third driver – or point of pain in this conundrum.
The FDA has some very interesting words to say on the subject of vendors, words worth remembering as the need for enterprise clinical trials platforms heats up. The FDA in many cases does require the validation of software for its intended use. 'The agency believes that commercial availability is no guarantee that software has undergone “thorough validation” and is unaware of any regulatory entity that has jurisdiction over general purpose software producers.

The agency notes that, in general, commercial software packages are accompanied not by statements of suitability or compliance with established standards, but rather by disclaimers as to their fitness for use. The agency is aware of the complex and sometimes controversial issues in validating commercial software. However, the need to validate such software is not diminished by the fact that it was not written by those who will use the software.'

The vendors would be well served to vigorously support the emerging standards, and, more importantly, incorporate them into their products. However, vendors alone will not solve these problems. Specialist support and consultancy organisations in conjunction with users and vendors, all keeping a close watch on regulatory and standards agencies, will reap vast rewards in this market. Those that meet global requirements will reap significant economies of scale. Those that take a piecemeal approach are destined for failure on a far larger scale than previously understood. This goes without saying for pharma companies and regulators, as well.