S. Anne Montgomery, Leah J. Rosin, and Cheryl Scott

Abstract

"Outsourcing drives innovation." That's what industry consultant John Vogel told BioProcess International when we discussed clinical-trial-related outsourcing with him. It was an intriguing idea. New Technologies: What we are seeing in the pharmaceutical service provider arena is that there are a lot of new technologies and a lot of new providers offering those technologies." He offered examples including electronic patient diaries, which allow patients to record their symptoms and could remind them to take their medication or provide a means of contacting someone if they need help. In the packaging/labeling area, interactive voice response systems (IVRS) allow you to manage clinical supplies more efficiently."

Such systems are good for clinical investigators, who can use the automation to determine what medication a given patient should be assigned to, then find out which blind-label box would be appropriate, and for sponsor companies - which can use them for just-in-time delivery of supplies. IVRS and other electronic data systems have been around for a number of years, Vogel said, "but in the clinical arena, we still rely a great deal on paper and pen." CROs are among the first to adopt such new technologies - and to create standards for them. The problem was that "each sponsor was developing its own version of electronic data capture," Vogel told us. "The study sites would have to train their personnel in using as many as a dozen different schemes, and they might have a whole bank of computer terminals dedicated to each individual sponsor."

Now companies are realizing that they aren't necessarily qualified to develop the best electronic data capture approach. "An outside service provider that has experience working with many different types of studies and sponsors in different countries may have a better perspective on what the ultimate electronic data capture approach should be." This should ultimately increase the use of electronic systems overall. Another subject that's getting a lot of discussion is so-called smart packaging. "Essentially," Vogel said, "it's putting an electronic chip in a package to record when a patient accessed a medication unit." That can help in interpreting data, especially those associated with erratic clinical responses or bioavailability. "It may be that a patient isn't taking the medication as directed."

Increasingly, sponsors are testing their drugs in seniors, which presents certain challenges in packaging. "If they have to struggle with a dosing unit," Vogel explained, "they are more likely not to be compliant." Such patients may even decide to drop out of a trial for such reasons. "We have to develop packaging that's easier for seniors to deal with. On the other hand, we're increasingly concerned about child safety."

Adaptive trials:
Clinical trials are most often double blinded, but the labeling on each drug unit has a flap that a doctor can open in the event of an emergency to disclose the contents (drug or placebo). But how can patients find out that information in a need-to-know situation - e.g., if a child has gotten into the package? Electronic data may make that easier. Both the industry and the FDA are now talking about simplifying study procedures, designing trials for interim analysis rather than waiting until the end. If data indicate that one study group is achieving a better therapeutic benefit than the others, the study can be adjusted before it's over. "That's being done right now in some severe disease areas. It's being done in some HIV-AIDS trials."

Such adaptive trials, Vogel said, present new challenges in terms of supply. "I'm sure that there are some vendors or prospective vendors out there trying to think of new technologies or services that could simplify providing clinical supplies for adaptive trials."

Globalization:
Some clinical research organizations are looking into lesser-developed countries either to find large numbers of patients or to find people who haven't been treated with other drugs for a given disease. "When we go abroad, we talk about so-called virgin patients: those who have a certain disease and have never been treated for it."

Clinics in such countries are interested in conducting these studies because it provides access to drugs they wouldn't otherwise have access to. It may also involve the pharmaceutical sponsor or CRO having to give the institution certain instruments and technologies that they need to do the job. Another positive factor here, Vogel says, is that "in certain populations, people are highly compliant." In some places, patients take direction better than in others. "If a doctor tells them to do something," he added, "they do it."

Postmarket surveillance:
The notion of the adaptive trial could lead to sweeping change: Instead of conducting phase 1, phase 2 and then phase 3 trials, companies may think more in terms of a continuum. "A big part of that," Vogel cautions, "is adequate safety evaluation. We're trying to find ways of getting better markers for safety during a clinical trial program. You never really get a good grasp on safety until a product gets out on the market and into very large numbers of people." A major concern is whether a very significant adversity will end up occurring very infrequently. Such events may not show up until a product has been on the market for six months or more, and tens of thousands of patients have been treated, rather than the 2,000-3,000 that would be in a clinical development program. "So another area that is expanding, in terms of CRO business, is the continued evaluation of safety and effectiveness after a drug is approved."

Most modern FDA approvals carry a requirement to conduct continued research (so-called phase 4 or postmarketing trials). Not too long ago, Vogel reported, the FDA commissioned one of the large consulting organizations to look into this issue. Among the results were that, for postmarket studies mandated, over a third of biotech companies had not conducted theirs (1). "FDA is saying, 'You've got to do some more studies once we approve this.' Sponsors are saying, 'OK,' and nothing happens. Now if I were head of regulatory affairs for a pharmaceutical company, and the FDA told me to do something, I don't think I'd view it as voluntary." In response to those findings, last year senators Charles Grassley (R.-Iowa) and Christopher Dodd (D.-Connecticut) introduced a bill to transfer the current FDA Office of Drug Safety to a new Center for Postmarketing Drug Evaluation and Research, which would presumably provide better follow-up (2). An important part of the FDA's critical path initiative (3) that is involved in efficacy as well as safety is the advent of associative clinical safety biomarkers. "We're now beginning to develop an understanding to identify potential biomarkers that might be associated with adversity or even therapeutic benefit." Genentech's breast cancer treatment Herceptin is a good example of this.

In testing, it was discovered to work very well with a certain subpopulation of women who had a particular genetic biomarker. Improved understanding of the human genome will only further such endeavors. Another associated development is microdosing - so-called phase 0 studies. A considerable amount of toxicology evaluation must be performed in several species prior to an IND for a phase 1 study. In a "phase 0" trial, the dosage used would be so small that it represents, theoretically, no risk of toxicity. Because most biologics are molecules that are already produced by human bodies, toxicity can be less of an issue with such products to begin with. Vogel pointed to a particular technology that would be needed for microdosing studies, accelerated mass spectrometry, which can detect material at very small concentrations. "This is a very interesting and exciting area now," he said, because with many products, "you can make a significant investment, then you dose humans, and they don't even absorb it. It just kind of goes in and out. And that's clearly not going to warrant any further development." Microdosing can weed out such weak candidates. "Certainly some CROs are making a significant investment in that area."

References

• 1 Conspiracy of Silence: How the FDA Allows Drug Companies to Abuse the Accelerated Approval Process, 1 June 2005, Congressman Ed Markey.
• 2 The FDA Safety Act of 2005, S930, 5 April 2005; Consumer's Union letter to Grassley and Dodd.
• 3 FDA Announces Partnership with Critical Path Institute to Conduct Essential Research to Spur Medical Innovation, 16 December 2005.

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