Shaping the future of clinical data management

The way in which clinical trial data is gathered, collated and shared has changed dramatically over the years, moving from the time-consuming paper-based approach of the early 1990s to the use of sophisticated electronic systems today. As each technological advance happens, however, new issues arise in regard to the integrity, security and validity of data.

Though the change has been enormous, it has not necessarily happened quickly or easily. In the 1990s, attempts by the likes of Bayer and Novartis to capture data electronically met with success, but there was initial resistance, not least because the internet was not as fast or accessible as it is today, and the need for proprietary systems made electronic data capture (EDC) cumbersome.

Since internet-based approaches became viable, progress picked up pace, really taking off in the 2000s, While paper case report forms were replaced by eCRFs, paper patient diaries started to be abandoned in favour of PDAs, as well as web or phone-based solutions, to capture electronic patient-reported outcomes (ePROs). Nevertheless, these ePROs raised concerns from regulatory authorities because good clinical practice requires investigators to stay in control of the data at all times, which is in question when patients are entering information electronically and data is passed between external internet servers. This issue has only been solved in recent years, with the 2009 FDA guidance.

The next step will be to take data directly from electronic health records (EHRs). A lot of progress has been made in implementing EHRs in the US, but Europe has also made progress, which will make it far easier to access and analyse patient data. Nevertheless, it is clear that as technology enables the easier capture of more accurate data, regulatory issues - as well as cost issues - will still remain.

"Technology moves faster than regulation, which takes ten years to catch up. There has been constant adaptation of the rules for the last 20 years, and no pharmaceutical company wants to adopt technology that regulators might not accept, as a new drug could be rejected because of unacceptable data management," says Dr Pierre-Yves Lastic, senior director of data privacy and healthcare interoperability standards for Sanofi R&D and chair-elect of the CDISC board of directors.

"With the move to EHRs, the gap between regulations and technological capability will still remain, but now, issues like privacy and data protection become important. It must be ensured, for instance, that sponsors cannot access trial data stored and transmitted electronically, or that hacking does not result in the theft of patient data. EDC involved regulations for control, but now ethical aspects are more prevalent," he adds.

The Clinical Data Interchange Standards Consortium (CDISC) is a global, open, multidisciplinary, non-profit organisation that has established standards to support the acquisition, exchange, submission and archive of clinical research data and metadata. Its mission is to develop global, platform-independent data standards that enable information system interoperability to improve medical research.

Lastic believes that the adoption of industry-wide standards will help ensure that technological advances deliver the speed, efficiency and accuracy gains that will improve the outcomes of clinical trials.

"EDC has certainly reached a level of maturity where the capture becomes more efficient, less expensive and faster, but it took time, partly because of the resistance to change. But if you look at the numbers you find that regulators are asking for more from sponsors, which pushes up costs. It is hard to show the ROI for new technology, as speed and quality improve but costs do not necessarily fall," he remarks.

Setting the standard

CDISC has led the way in moving the pharmaceutical sector towards industry-wide data standards, which Lastic believes would simplify the approval process for new drugs by harmonising the data and streamlining research processes from the initial protocol through analysis and reporting.

"Any industry standardises processes for efficiency. You don't want to waste time and money reinventing the wheel with every clinical trial. To get up-to-date information, one needs standardised sources of data, no matter what the industry. In the 1990s, however, we saw all large companies had optimised processes around in-house standards, but now that is changing," he says.

"One reason is that regulatory authorities are under more scrutiny, especially since drugs like Vioxx were taken off the market for safety issues. Regulators want to compare data between companies, like comparing Vioxx with similar drugs to see if there are similar problems. That comparison was hard because of the different terminology and data formats used by different companies."

Arthritis treatment Vioxx (rofecoxib) was recalled in 2004 after studies indicated higher rates of heart attacks and strokes were uncovered in patients using the drug, compared with a placebo. Merck pulled a drug off the market that had seen total sales of $2.5 billion in over 80 countries. Shortly afterwards concerns were raised about Pfizer's Celebrex, which ceased to be marketed direct to consumers for over a year.

"Another driver really important in the last five years is the failure of any one company to find better treatments for neurodegenerative diseases like Alzheimer's, cancer, tuberculosis and other big public health issues. So, there is more collaboration between companies, and these efforts are yielding some promising results. So, the need to standardise data across the industry is not only for safety, but also for efficacy," states Lastic.

"Also, CROs are involved in increasing numbers of clinical trials, and they have an interest in using industry standards as opposed to tailoring their processes for each individual client. There are also new laws governing the comparison of the efficacy of drug treatments in the same therapeutic area, which have implications for the price that can be charged for a new drug."

It seems clear that beyond the usual issues of cost and performance that drive standardisation in many industries, the pharmaceutical sector is increasingly compelled to move towards standards for clinical data collection and analysis by regulatory pressure and by the need to work together to tackle some of today's major health issues. The question, therefore, is why progress
has not been quicker.

An uneven road to standardisation

As Lastic says, the pharmaceutical industry is not one that readily embraces change. This is not necessarily a criticism, but a necessary reality in an industry that is heavily regulated, and which invests huge sums of money in developing drugs when only a few will make it to market. Changing to industry-wide standards will involve a considerable investment of time and money, so drug companies need to know that the benefits will justify the expense and will significantly improve the efficiency and the outcomes of clinical trials.

"One of the biggest barriers is that large companies have developed their own processes based on their own standards, so they are reluctant to adopt a new standard. It takes a long time to see the pay-off in terms of efficiency, and it means a lot of work for a lot of teams within each big pharma company," remarks Lastic.

To counter this inertia he points to research from Gartner, which over the years has encouraged the move towards standards. In 2007, Gartner research suggested that CDISC standards save time and money, and also have an impact on the effectiveness of clinical studies by enabling the aggregation of information into a repository where it can be reused for trial simulation, knowledge-based trial design, improved safety surveillance and efficacy analysis.

"Studies by Gartner and others on costs also show that the earlier you use standards, the bigger the cost advantage. If a company puts data into the right format for regulators at the end of the trial, then they are effectively adding an extra step of transforming the data, which takes more money and more time. The cost of a trial is lower if you embrace standards earlier," says Lastic.

Slowly but surely this message seems to be getting through. A recent survey by CDISC, for example, showed that over 80% of companies that responded had implemented or were in the process of implementing the study data tabulation model (SDTM).

SDTM defines a standard structure for human clinical trial data tabulations for submission to the FDA as part of a product application. It was selected as the standard specification by the FDA in 2004, and all data submissions are expected to conform to this standard. It is the standard that has, so far, been most widely adopted [see Figure 1, above left], but is just one part of the much broader palette of standards that CDISC has produced, covering everything from the terminology used in clinical trials to archiving and sharing of data.

The goal now is to increase the adoption of the full array of standards, which will happen only with the continued collaboration and cooperation of pharmaceutical companies, CROs and regulators.

"The problem is that when companies say they are implementing the standard, we don't know how far along they are with the process. But we can say that adoption is progressing fast," says Lastic. "There remains a lot for us to do at CDISC. We are part of the work mandated by the FDA that looks more at the efficacy aspects, when previously the focus was on safety aspects. We are also engaged in efforts to make the standards easier to implement and use. We are working more user guides, case studies and training programmes. We are pushing standards forward, and there is no doubt that they will profoundly change the industry."