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Antiquated reporting of adverse events in clinical trials is costing pharma billions and forcing it to seek new pharmacovigilance solutions.

By Mark D. Uehling

November 19, 2004 | Following the autumn withdrawal of Vioxx, a cox-2 inhibitor with $2.5 billion in annual sales, Merck took three hits. First was the wrath of investors — they pushed Merck's stock down 33 percent in less than a month, as 276,000 Vioxx patients were abruptly switched to safer anti-inflammatories. Then came rumors of the sale or merger of the company.

The third blow: Merck's revelation that information about Vioxx safety problems had been a total surprise. Some epidemiologists estimate that Vioxx may have caused up to 27,000 heart attacks and 7,000 deaths. "It was totally out of the blue," insisted Merck chairman and CEO Raymond Gilmartin. "I was stunned."

Gilmartin's comment confirms what many have long suspected: a colossal failure to understand and deploy pharmacovigilance and safety-tracking technology in clinical trials. Sadly, that's hardly unique to Merck. Whether drugs such as Baycol, fen-phen, Seldane, and Rezulin are withdrawn by manufacturers or the FDA, the cost can range from millions to billions in fines and legal settlements. The list (see "When Good Drugs Go Bad," page 34) is either dangerously long, in the view of industry critics who say the FDA is too chummy with the industry — or blessedly short, considering the hundreds of products approved for sale. As with other clinical tasks, rusty, homegrown applications litter the industry. Antiquated, paper-based collections of safety data from around the world can jam the gears of the best systems.

Paper Waits 
For now, as the lawyers circle over the limping Merck, it would be interesting to know whether the Vioxx safety reports were recorded on paper or electronically. (European physician-investigators for the company are said to be especially computer-phobic.) If on paper, were any patients unnecessarily exposed to the drug while faxes and forms were entered into the computer? Merck declined to comment.

The FDA Warehouse Overfloweth 
Reports of adverse events are straining the FDA staff and budget. But Congress wants the industry to keep using paper. The FDA can only encourage digital submissions.

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With the industry comfortable with paper and the U.S. government stingy in its funding of more modern safety systems, the frontier is being defined by the Europeans. The European Medicines Agency (EMEA) will require the electronic submission of safety reports by November 2005. As Sabine Brosch, EMEA's deputy head of pharmacovigilance, told Drug Information Association (DIA) meeting attendees last summer: "The volume of data is low, but we are making progress."

Although the FDA still has some glitches to work out, it is attempting to synchronize with the European approach to safety data — and simplify the reporting process as much as possible. Only 21 percent of urgent safety reports to the FDA in 2003 were submitted electronically.

The FDA's aged systems are undergoing improvements but remain clunky and kludgy in ways that make it difficult for the industry to submit data electronically. For example, the size of attached files is limited, and PDFs can be sent only on physical media (not via e-mail), or to a special electronic FDA drop-box called the Gateway. "We have had some problems with the Gateway," Roger Goetsch, FDA director of regulatory affairs, said at the DIA meeting. "We're still dealing with paper. Our regulation says: paper."

The FDA also declined to explain the pace of modernization of its safety systems, or its plans to encourage the industry to supply more reports electronically. At DIA, however, Goetsch said, "We know [the amount of reports] is going to go up 10 to 15 percent a year. We can't hand-type these in. We need to put them in electronically."

Pfizer's director of regulatory affairs, William Gregory, is more descriptive of the FDA's predicament. He said, at DIA, "The workload regulators have in front of them is rather staggering. The paper systems just don't cut it when it comes to responding to public health crises and deciding on next steps. The number of reports will increase over time, not because our products are less safe but because we have newer products and we have expanded products."

When Good Drugs Go Bad 
With months or years needed to process data on paper, better technology could help companies withdraw dangerous medicines more quickly.

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Pfizer's system was developed with help from Intrasphere Technologies of London and New York. Before, as Pfizer's Robert Mozenter said at the DIA, "It was easy to get data in. It was hard to get data out." Now that's changed, and any field in the database can be queried and reported on. Pfizer is using EMC storage and Veritas software, coupled with safety software from Aris Global. "We also have the ability to move the data from a document to a PDF or a Word document," says Valerie Vandevoorde, Pfizer's director, group leader, regulatory reports.

Synergies with EDC? 
Many vendors privately feel that the pharmaceutical industry could use technology more skillfully, which would not only save money in legal settlements (because fewer illnesses or deaths would occur before a drug's withdrawal) but also preserve some of the industry's tattered public reputation.

Few vendors are willing to state that in plain English, however. An exception is Jeffrey Green, CEO of Cleveland-based Datatrak International. "Patient safety is priceless, and everything else in clinical trials is secondary," Green says. "This industry is still processing its information largely by hand, with three-ring binders. Since you cannot react to what you don't know, it is not difficult to appreciate electronic data capture (EDC) could improve a company's ability to be as responsive as possible to patients enrolled in clinical trials."

Green continues: "It is somewhat contradictory to observe so many people with portable devices that can immediately capture e-mail, while waiting three to six months for up-to-date results in a clinical trial as paper works its way through the system. In 2004, capabilities exist to do a more diligent job of patient surveillance. We can all elevate the standard of practice based upon a foundation of data awareness."

Green cites an NIH study in which it took clinicians months to first learn that some patients were having strokes and then halt the study. The reason for the delay: double data entry, the Olympian stenographic practice that still occurs every day at every company in the industry. "The side-effect profile was buried in paper files waiting for double data entry," he says. "In 2004, not having immediate awareness is difficult to justify."

To be fair, clinical trial sponsors do occasionally discuss safety and pharmacovigilance systems at industry conferences. Wolfgang Schuman, head of corporate drug safety at Schering AG, described the evolution of his company's efforts at DIA as "a major re-engineering process."

Schering has several global centers handling safety and pharmacovigilance: 50 employees based in Berlin, 30 out of the United States, and 20 in Japan. "All these people at the sites have full access to the data," Schuman says, "not just the headquarters." The reason? To allow an individual to be aware of all the safety issues surrounding a particular drug.

Elsewhere, alas, the situation is an unfortunate replay of technology adoption across the industry. To wit: The industry's dissatisfaction with commercial offerings in the clinical space has meant that safety systems (like many others) tend to be hybrids of paper, fax, and electronic reports.

For Brad Gallien of Oracle Clinical, the simple reporting of data is becoming less of a challenge after a major investment in technology to track adverse-events reports. Senior director, product management for AERS, Oracle's safety product, Gallien estimates that half of the big pharmas have homegrown, proprietary safety systems. He can't comment on the capabilities of those systems, but having a commercial application to manage a welter of requirements worldwide can provide peace of mind. "We can handle all the international reporting requirements in a single database," Gallien says, including those in Japan.

Significantly, the Oracle Clinical safety application integrates well with two other applications in the suite — software to manage clinical data and to ensure standardized medical terminology, called TMS. "All of these applications need to be able to summarize and manage their data against a standard nomenclature such as MedDRA," Gallien notes. Why do drug companies need a rigid digital thesaurus to span the organization? Because "headache," "migraine," "hangover," and related terms need to be recorded and aggregated consistently before the data can be sent to the FDA.

Beyond generating reports, most industrial-strength safety systems also need a way to export data so that co-workers inside and outside the company can manage what are now two streams of information about the same patient. One stream was in the original generic clinical system, the other routed to the safety or regulatory teams for further processing.

Explains Gallien: "The information is compared between the safety system and the clinical-trial system for consistency." Oracle AERS has an out-of-the-box integration with Oracle Clinical. "We can run a report within AERS to know that every clinical case in AERS has been compared to the clinical data management system — and manage any discrepancies that may evolve."

Clintrace: New Architecture 
At Oracle's archrival Phase Forward, Kathryn Roy, vice president of marketing, says the big news is that the Clintrace safety tool offers a new architecture to be used across the company's product line. All users can now be connected to the same data via the Internet and assigned suitable role-dependent levels of access. That will facilitate global management of safety data.

Roy of Phase Forward: "There's no going back."
With so many different workflows beloved across the industry, Phase Forward knew its technology had to be adaptable. "We invested a lot in the configurability of the user interface," Roy says. There's also more flexibility. "Traditional safety systems are closed and proprietary," she says. "Customers can change reports. We can change reports and change them much faster."

Roy acknowledges resistance to electronic systems, especially among smaller customers. But she believes the industry is coming to understand that the FDA is under pressure to process safety data, and will eventually pass on that pressure to sponsors. "There's no going back," Roy says. "The regulatory authorities understand that their ability to protect the public is tied to better adverse-event reporting."

Further efficiencies may depend on the usage of other technologies, especially EDC, which is used by fewer than half of the customers who install Clintrace for safety data. Roy is diplomatic about the fact that many customers want to work with paper and license her tools à la carte — say, choosing just EDC software or a safety tool. But everything will work more smoothly if less paper is flying around. "EDC is a pre-requisite for speedy adverse-event reporting," Roy says. "It's EDC that helps you with early detection."

In some cases, the industry watches for problem drugs with trained experts and databases, not software. MetaWorks is not as well known as Oracle or Phase Forward; the company analyzes the medical literature and cleans FDA safety data obtained under the Freedom of Information Act. The MetaWorks database has more than 200,000 entries, and data on some 3 million patients.

Matt Reynolds, MetaWorks' senior director, risk management and safety services, says his company recently analyzed a drug for Aventis in response to questions from the FDA. "It was a lot quicker and cheaper than doing a clinical trial," he says. "The efficacy was comparable to their competitor, and they did not have any increased liver safety issues." This evidence helped Aventis persuade the FDA not to pull the drug off the market.

Some vendors, such as Medidata and Outcome Sciences, are trying to incorporate the tracking of safety data into their more generic applications in the EDC arena — and eliminate the need to install massive safety systems. "Pharmacovigilance must take place not just during drug development, but should be aggressively pursued in the post-marketing environment," says Jules Mitchel, president of Target Health.

Mitchel's company "recommends that proactive online registries be created at the time of drug approval to collect safety data from sufficient numbers of patients until a true risk-benefit analysis can take place. The technology exists, and this approach has been used in several countries worldwide. It is time for the U.S. to set an example."

Can Your Software Do This? 
The safety-reporting and pharmacovigilance niche is served by both specialty vendors and EDC companies. Homegrown applications created by and for sponsors are still a major factor.

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Medidata's CTO Glen de Vries concedes that his software cannot yet export forms to the FDA or automatically generate abstracts of patient diaries. "A large part of the clinical data required for safety reporting is already present in our eCDM platform," de Vries says. "Leveraging the availability of data in EDC can catalyze a significantly streamlined process." Customers, he says, are requesting this tighter integration of EDC, clinical data management (CDM), and safety databases.

Even before safety data are collated and cleaned, a complementary analysis is increasingly occurring in a proactive manner. Predictive statistical techniques, loosely dubbed "pharmacovigilance," can identify significant trends in small numbers of patients before they come to the attention of ambulance chasers. Using pharmacovigilance software, a handful of medical adverse events may spur a company to order a new clinical trial or additional study of FDA data. Pharmacovigilance can determine if six rare tumors that pop up in patients taking Lipitor in Denver are cause for a national panic or no big deal.

Back to Quality of Data 
For an industry leader such as Relsys, the potential of pharmacovigilance is obvious. The company says its pharmacovigilance systems can "mine multiple data sources to prioritize potential issues, assess performance against similar cases in the database using the MedDRA hierarchy, build a knowledge base against which to measure future drug performance, issue early alerts, and even escalate issues based on pre-determined business rules."

At Aris Global, Mark Loudon, director of regulatory compliance, says that while the key algorithms are identical across the industry, what is critical is the quality of the data plugged into those algorithms. "Signal detection is useless unless it is done on a full pool of data," Loudon says. "Unless you scan the horizon, you have tunnel vision." Aris Global's pharmacovigilance tool "is designed to pick up signals that humans wouldn't necessarily be able to detect."

Whatever the statistical tool in hand, the importance of centralized data cannot be overlooked. A few years ago, Loudon helped a major pharma company deal with a question from the FDA. At issue: For unknown reasons, a researcher abroad keeping the data was not responding to telephone calls. So Loudon hopped on a plane and visited his office. The safety data had been painstakingly penciled into a paper spreadsheet of the type favored by accountants. Once headquarters found out about that, the drug was quietly dropped.

Of course, the handwritten data might have been impeccably accurate. "But there is no audit trail associated with data," Loudon says, "nothing to connect it back to the original case report forms. Had the data been centralized, and had we known where all the data were, we would have been able to determine our course of action much more quickly."

At smaller companies in the industry, Loudon believes, there is a curious bravado about tracking regulatory and safety filings in binders or Microsoft Excel. But in Europe, he notes, companies will soon be required to submit safety data 90 days after the end of a trial. Right now, many companies can't manage that task in a full year. When Loudon tells U.S. managers about the 90-day deadline, he hears laughter — nervous laughter. "I don't know if these people are using paper or electronic systems," he says, "but they seem to think it's a big deal to get it done in a year."


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