Medical Device Link.

Originally Published PMPN April 2005

CLINICAL TRIALS PACKAGING

Will high-profile safety concerns mean new demands?

Christina Elston, Contributing Writer

PHOTO OF AN AUTOMATED CLINICAL TRIAL LABELING LINE COURTESY OF CLINICAL TRIAL SERVICES.

FDA-approved drugs are facing some tough scrutiny. On December 23, 2004, FDA issued a public health advisory recommending caution in the use of Cox-2 inhibitors such as Vioxx, Celebrex, and Bextra in light of evidence that the drugs may increase the risk of heart attack and stroke. In February—just weeks after FDA announced formation of an independent Drug Safety Oversight Board—manufacturer Biogen Idec voluntarily removed Tysabri from the market following one patient death and one serious complication. Tysabri is a new treatment for multiple sclerosis that had received accelerated FDA approval in November 2004.

These events may rattle patient confidence in the safety of pharmaceutical products. They will likely prompt pharmaceutical companies to provide greater transparency in clinical studies. They may also prompt the expansion of clinical trials to larger patient populations and increase emphasis on patient compliance. Providers of clinical trials packaging could then face new demands due to these efforts to improve the trials' effectiveness and drug safety.

EXPANDING PATIENT POPULATIONS

FDA may begin requiring larger, longer animal studies, followed by larger Phase II and Phase III studies, predicts Joseph Urban, RpH, MBA, senior director of ProClinical Pharmaceutical Services (Phoenixville, PA). "I believe the companies will be asked to address safety concerns with additional statistical evaluations of side effects," he says. "Additionally, I see them pressing for more genomics and pharmacogenetic evaluations on the patient population to further determine the genetic makeups of those who can safely be treated with the experimental agent and of those for whom the agent would have adverse effects."

Some packagers are already seeing an impact. "Our customers are taking a look at how they are going to conduct these studies now that these safety issues have come into play," says Frank Lis, senior vice president and general manager for global clinical supply services at Cardinal Health (Somerset, NJ). One of the company's customers was considering expansion of one Phase III study from a population of 15,000 patients to 20,000 patients. "Adding another 5000 patients represents a significant growth in cost," Lis points out.

Larger studies mean increased cost and increased time to market, agrees Jeff Hallquist, director of sales at Fisher Clinical Services Inc. (Allentown, PA). "We may see fewer new drug approvals," he says. The resulting loss of incremental revenue at pharmaceutical companies would likely increase pressure on packaging companies to reduce costs, Hallquist and other packagers note.

A MORE GLOBAL REACH

The Med-ic Digital Package uses RFID tags to track medication usage. (click to enlarge)

Patient populations may also be expanded in a global sense, according to Lis, who says Cardinal Health is increasing its capability to support studies in global populations. Markets in India, Asia, and South America will all likely see increased numbers of clinical trials. "Our clients say it's cheaper to do studies in these regions than it is in Western Europe," Lis explains, adding that those are also markets pharmaceutical companies would like to reach with their products.

The globalization of studies won't necessarily have an impact on which packaging options pharmaceutical companies choose, says Scott Houlton, vice president of Quintiles Clinical Supplies (Mount Laurel, NJ, and Kansas City, MO). But it may have an impact on outsourcing in the packaging industry. "There are fewer players that are able to support a global study," Houlton explains. "You're going to see some of the niche players lose some of their competitiveness."

AUTOMATION AND EFFICIENCY

Financial pressure could also increase emphasis on cost-cutting measures, such as automation and supply-chain management. These haven't been relied on heavily in clinical trials packaging, but they may begin to look more attractive.

"Automation is going to be critical when you're looking to package these larger studies," says Lis. Automated packaging for products in double-blind Phase III studies—which require a two-panel label—was absent, he says. However, Cardinal Health recently co-designed and purchased new equipment to handle both printing of variable text and label application, increasing productivity fivefold over the previous manual application.

Updating outsourcing models is another way to improve efficiency, says Hallquist. Five years ago, he says, large pharmaceutical companies did not outsource their varied clinical trial functions to a single provider. But things are changing as cost pressures increase. "Being able to integrate across those multiple areas is now seen as a way to decrease cost and gain efficiencies," Hallquist adds. Companies are looking for full-service providers offering consolidated site initiation kits that might include, in addition to the investigational drug supply, case report forms, training videos, and other ancillary supplies such as glucose test meters, pipettes, and clinical chemistry kits.

With a single provider handling storage, distribution, procurement, and site inventory management, there are fewer shipments, fewer touch points, and fewer transactions. "This can present a tremendous value over a multiyear global study," Hallquist says. "Five years ago, we were seen as a clinical packaging company," he adds. "Today we're a clinical supply-chain manager."

THE PATIENT-COMPLIANCE FACTOR

Packages that record the time and date a patient accesses medication, and thus provide a measure of patient compliance, could also be in increased demand—if the technology is seen as worth the cost.

Med-ic CertiScan software from Information Mediary Corp. captures data from Med-ic Electronic Compliance Monitor blister packages on clinical patient compliance. This calendar reveals patient noncompliance during a hypertension drug study. (click to enlarge)

"Patient compliance (or lack thereof) during clinical trials undermines IND [investigational new drug] effectiveness, leading to higher recommended doses," says Allan Wilson, MD, PhD, president of Information Mediary Corp. (Ottawa, ON, Canada), makers of the Med-ic Digital Package. "This is underscored by the large number of medications for which dosing recommendations are scaled down after approval on the basis of large-scale patient experience." Reducing patient noncompliance during clinical trials by using an electronic compliance monitor will result in more-accurate postapproval dosing recommendations and reduce the incidence and severity of side effects, Wilson says.

"How reliable could the data [from a trial] be if we don't have an indication of whether and when the drug was taken?" asks John Smit, northwestern regional manager of MeadWestvaco Healthcare Packaging (Mebane, NC). In creating its Cerepak product, MeadWestvaco partnered with Aardex, creator of the software and analytical services that allow viewing and manipulation of the data. They have also developed an inexpensive reader to work with the product, says Smit. "This technology will allow you to eliminate those patients who really shouldn't be a part of the data you're evaluating," Smit says.

Lis of Cardinal Health says it isn't certain how large a role clinical trial patient compliance played in problems with the Cox-2 inhibitor drugs, but insists this factor can't be ignored. "The issue, again, is around expense," says Lis. "Not many pharmaceutical companies have wanted to spend the additional money yet." If compliance is found to have played a role in recent high-profile cases, "that might make companies decide the benefits are worth the cost," Lis adds.

"We have seen some clients interested in the technologies," says Quintiles' Houlton, "but those technologies are not developed and widespread enough to be cost-effective, especially for a large study. If you've got six sites, it's no big deal. If you've got 600 sites around the world, it's a very big deal." The fact that an industry standard for the technology has not yet emerged could also make companies reluctant to invest in the equipment, Houlton says.

COMMUNICATION AND MONITORING

In the meantime, simpler measures such as improved communication with patients may also come into play. "I see the advent of more blister packages with warnings and diaries and toll-free numbers to call with questions directly on the package and label," says ProClinical's Urban.

Wallet-style packaging for blisters can help patients follow their regimens. Photo courtesy of Clinical Trial Services. (click to enlarge)

Increased attention to label design may also be in order so that warnings about possible side effects are clearer to patients. Packaging products in blister cards, rather than in bottles, offers a better venue for presenting this information. Compared with the size of a label on a bottle, "you probably have at least five times the amount of available space," says Philip Diamond, vice president of marketing, Clinical Trial Services (CTS; Audubon, PA, and Craigavon, UK). Fitting the same amount of information on a bottle often requires pullout or folding labels that patients tend to tear off and lose after the first reading, he adds. Blister packs—especially calendar-type packs that highlight when to take medication in a pictorial sense—also improve compliance because patients know exactly when to take each dose, says Diamond.

Patient monitoring via phone-in electronic diaries could also become more popular, he adds. These allow for "very sharp analysis and control of the data," because the information is transmitted directly into monitoring systems. Along with providing patients an additional reminder to take their medication, it allows companies to learn about serious side effects more quickly, and discontinue studies if necessary. "It's a way of being able to switch off a study faster," Diamond says.

The above possibilities represent continuations or accelerations of trends already in motion. How quickly products supporting those trends will see increased demand will depend on FDA's conclusions about why some questionable products have reached the marketplace. Industry, says Houlton, is positioning itself to handle whatever impact transpires. "We have the capacity, the flexibility, the global reach to meet their needs."

Copyright ©2005 Pharmaceutical & Medical Packaging News