As sponsors search for patients abroad, technology clearly matters—but not every clinical trial on the planet is ready for electronic data capture
By Mark D. Uehling
May 19, 2004 | A couple of years ago, a prominent American biotech company found its pediatric trial for rhinitis behind schedule, with 30 clinical sites worldwide struggling to enroll suitable patients. That's when Novotech, an Australian contract research organization (CRO), got involved. "We got our sites up and running very quickly," says Alek Safarian, Novotech's founder and managing director. "The top-recruiting sites worldwide were in Brisbane. They helped close the study out three months earlier than it would have otherwise."
In this case, Australian investigators were not tripping over each other to find suitable patients. In fact, the Australian sites recruited patients so quickly they were audited for compliance with FDA regulations — and passed with flying colors. Safarian notes that there are still physicians in Australia who decide about participating in a trial on scientific grounds — not for revenue. "The environment in the U.S. is highly commercialized," Safarian notes. "It's very competitive. When you look at a lung cancer study and you go to major institutions, you're often competing with other ongoing studies at the same time."
|Sweating the Small Stuff
|What may not be obvious about global trials is that minor details, gone awry, can erase the advantages.
It's hardly news that sponsors are taking the quest for patients into every corner of Asia, Europe, and Latin America. The rule of thumb is that cost savings may be 30 percent to 50 percent compared to trials in the most developed countries, with patients accruing at rates two or three times faster. As Joseph Anderson,
a consultant from Waife & Associates, explains (see "Sweating the Small Stuff" ), the "patient densities" are greater, especially for "naive" patients who have not been treated with other medications.
'Model this Stuff'
But it is increasingly clear that technology is allowing the most adroit participants to differentiate themselves. "You can recognize the enrollment goals are not being met," said Mark Goldberg, president of Perceptive Informatics, at the recent Bio-IT World Conference + Expo. "You can model this stuff in real time, play with it. What if we added five sites in Italy and those sites had a projected enrollment rate of two patients per month?" Goldberg is talking about not merely collecting clinical data, but also working with them proactively around the world, where perhaps 20 percent of research dollars flow (see "Going Global").
|In 2003, approximately $5.7 billion was spent overseas, amounting to 17% of the $27 billion spent on R&D by members of PhRMA, the industry's lobbying arm.
Oddly enough, technology deployed abroad matters for both the software-oriented world of electronic data capture (EDC) vendors and the service-oriented world of CROs. Both classes of companies are scrambling to name the most exotic locale in which they've recently opened or expanded an office, whether in Mumbai (PPD, Covance) or Beijing (Quintiles). As in the United States, there is no argument that technology matters, in the form of helpdesks, overnight shipping of lab specimens, or Web-enabled training in English.
But is EDC, in particular, ready for Poland or China? Take Ming-Wei Wang, president of SiniWest, a San Diego-based CRO. As an occasional partner with Celera Genomics and Applied Biosystems, Wang lives in Shanghai and has helped Western companies run five clinical trials in China since SiniWest was founded in 1993.
Wang is not well versed in the arcane details of EDC. Paper remains the standard technology for collecting clinical data in China, he says — even if it means using FedEx to send boxes of case report forms across the Pacific. A physician himself, Wang says Chinese patients are less suspicious of the medical establishment than their counterparts in the West, and thus sign up for trials more readily. "Some patients don't want to be guinea pigs, but most people are quite comfortable," Wang says.
Cultural re-education of trial sponsors may be more necessary. "They think China should be cheaper. It is relatively cheaper," Wang says. "But if you want to do something compliant with FDA requirements, you have to spend money. You have to have the infrastructure supporting that." In his case, that means people.
The biggest quirk of going overseas to find more patients is that the main tool to find them here — advertising — is off limits. "Pharmaceutical and biopharma companies have been quite unsophisticated about how they think about patient recruitment overseas," says Matthew Kibby, head of metrics and evaluation at BBK Healthcare. Direct appeals to patients are banned by European law. Even physician-to-physician communications are tightly regulated.
One typical response to the situation, Kibby says, has been resignation or hopelessness. Instead, he proposes, a country-specific approach can recruit plenty of patients — without the significant expense of print, radio, or TV ads. "What you have to do is have a centralized coordination and a tailored approach to every country," he says.
The good news is that the national health services and bureaucracies in Europe can be persuaded to permit centralized communication with physicians. Elite medical opinion leaders can also be contacted readily. "It's quite easy to reach out to a large number of them," Kibby says.
Without advertising as a tool, execution is everything. Consider PRA International. Since the Virginia CRO was founded in 1996, it has acquired firms in England, France, and Spain, as well as a Canadian company with offices in California, Brazil, and South Africa. Earlier this year, PRA opened an office in Budapest; its fastest-growing office is in Poland. With 2,500 employees on five continents, the company delivers clinical information to customers in the same manner worldwide.
That's facilitated by a single IT environment, tightly standardized around the globe. "When we go into a new office and set it up with IT infrastructure, we do a wholesale replacement of pretty much everything. There is some upfront cost. But there are huge benefits in that we can staff a project flexibly across the globe," says Cindy Keppner, PRA's director of IT. She explains that employees anywhere in the world can walk (or log) into another PRA office and know how to get started. "This helps us with the patient recruitment and investigator recruitment. It gives us a competitive edge."
Just like Southwest Airlines, which uses only the Boeing 737, PRA staffers worldwide use the same Dell hardware and BMC support-desk software. Within Russia and Brazil, Dell business units can ship laptops to the most remote areas reliably. Says Keppner: "The systems are the same. The file structures are the same. The business processes are the same." Using the company's wide-area network, built on Microsoft's Terminal Server infrastructure, employees in British Columbia can pitch in when the work in Mannheim, Germany, is piling up.
In general, she says, the telecommunications infrastructure for broadband is nonexistent or priced out of range in Europe. The fallback option — dial-up access to e-mail — is also expensive.
And a few non-IT surprises have affected her PCs and servers. "Germany has something I find intriguing," Keppner says. "German air conditioning is what they call it. It means taking outside, ambient air and circulating it through the building. It is more of a venting system." On occasion, she has arranged extra cooling equipment.
Surprisingly, given PRA's single-minded focus on a common IT environment, it has yet to standardize around a single strategy for EDC. When required to use that technology by a sponsor, it does. But paper remains the most common option.
'Doctors Like Paper'
There are similar feelings about EDC from Geoff Kitson, a consultant at ProPharma Partners Ltd. of London. (The company has a close affiliate in California.) In principle, Kitson agrees that EDC is a valuable, potent technology. But he's also seen it go awry. "The versions I've used have caused more grief than anything else," he says.
But Kitson outlines one approach that uses a facsimile — a common way to relay data back to a more developed country. It's kludgy, he acknowledges, using the same optical character-recognition software that scans standardized test forms. But it works. In much of the world, Kitson says, "Doctors like paper. It's one of the biggest reasons EDC falls down. It's still relatively interruptive to the doctor-patient relationship." Kitson is a bit more excited about handhelds one day infiltrating the clinical trial than the desktop computer.
At Phase Forward, a leading EDC supplier, the paper and electronic collection of data internationally is not only going well — it is a key part of the company's strategy. The sense of scope, scale, of global reach is one of the ways the company tries to distinguish itself from smaller rivals with no foreign presence.
The company has 90 people in London, where a helpdesk runs 24/7/365, in 17 languages. It has real working offices in Paris and Tokyo. Even some of Phase Forward's larger competitors are able to afford little more than a single office across the Atlantic. A substantial percentage of its clinical trials are done overseas, with similar numbers of trials done just in the United States and just internationally.
Do It Yourself?
Countering conventional wisdom, Phase Forward estimates that high-speed phone lines in some parts of Argentina and Brazil can be installed in three to 10 days, far faster than the 10 to 21 days needed in the United States. The company doesn't depend on other firms elsewhere, handling basic provisioning itself.
There's a similar technical philosophy in Basel, Switzerland. Biomit, a CRO, is simultaneously an EDC company. It developed its own Web-based software to gather clinical data in Russia, Hungary, and elsewhere. An impressive 60 percent of Biomit's trials are run using EDC, which the company perceives as a core competitive edge. "EDC is one of our unique selling propositions," says Andrin Cerletti, Biomit's business development manager. "We had it from the start. We are currently running a transplant study that is being conducted with 1,300 patients. That's really where the EDC can show its muscles."
Cerletti says investigators at clinical sites like the technology, which requires only a dial-up connection and a browser. At the end of the process, Biomit exports its data in Oracle- and SAS-friendly formats.
The company was founded in 2001 and has completed only a handful of studies. Today, it has 50 employees in Switzerland, Hungary, and Germany. But growth is so strong that in four years, the company expects to triple in size. Included in its base price are 15 basic statistical reports that can be run off the Internet as the data are coming in. Other reports are available at an extra charge.
In the United States, even in Europe, Cerletti says, there is a misconception that paper is somehow safer. "They think that when you go overseas to Europe, you lose control," Cerletti says. "With EDC, you are more in control of your data. That is one of the biggest misunderstandings."
Cerletti declines to comment on the approach of the two giant European companies, Bayer and Novartis, which give each clinical site a laptop dedicated to clinical data collection. But he does say: "We think that if you have [the software] locally on some specific hardware, you have to validate each and every machine, which does not make sense and is very costly. We just validate one server. The data are transferred as soon as the investigator taps the submit button. No data are stored on the local hard drive."
Biomit has done a handful of trials in Brazil and Thailand, but Cerletti says the story in Eastern Europe is especially interesting. So eager for the business, so attuned to the arrival of inspectors from U.S. or European regulatory agencies, these sites in former Communist nations often exceed the standards of more advanced countries to the west.
"The standards will go up. We can do studies in Eastern Europe with the same standards that we would use here in Switzerland. These countries are taking efforts to have even higher standards than what the EU has. It's annoying," Cerletti says, half-joking at the prospect of being upstaged by a bedraggled Slavic republic just liberated from Soviet neglect. "It will take time, but people will get convinced that you can have high-quality studies in Eastern Europe at a good price."