By Deborah Borfitz

Investigator-initiated (mostly post-marketing) studies are "a black hole" for major pharmaceutical companies, according to Jeff Williams, CEO of Clinipace, in Research Triangle Park, N.C. "The investigator is funded and then they wait and hope [that] the study gets completed on time, [that] they get insights from the trial...and [that] they get data that is publishable. Often, they get none of that back."

Part of the problem, Williams says, is that companies are compelled to have a "hands off" relationship with investigators so as not to influence study results. Left to fend for themselves, investigators submit data "on an Excel spreadsheet or 4-by-5 cards."

Based on data from the FDA, investigator-initiated trials (IITs) accounted for about 62 percent of the 12,778 total active investigational new drug applications (INDs) at year-end 2004, reports Kenneth Getz, senior research fellow with the Tufts Center for the Study of Drug Development: "Each year, 1,395 new investigator-initiated INDs enter clinical testing." Oncology, central nervous system, and immunologics are the top three therapeutic areas. Grant sizes range from $50,000 to millions.

Medical science liaisons (MSLs), being pharmaceutical companies' main point of contact with investigators in the field, facilitate IITs by keeping investigators on task with agreed study milestones, says Jane Chin, Ph.D., founder and president of the Medical Science Liaison Institute in Los Angeles. If requested, the liaisons help investigators build an awareness program with their colleagues. Technology can also help investigators streamline study reports and pharmaceutical companies track IITs "in a compliant manner."

One solution being tried by top-five firms is to provide investigators with Tempo, Clinipace's Web-based platform, Williams says. "Our product is extremely flexible, configurable, and there's a huge simplicity factor. It has a clinical workflow engine that can map to any clinical protocol. We're involved with our first few investigator-initiated trials now," including a $30 million project. Williams says he won't be ready to offer up particulars for a few months, but that Clinipace will "support the overall management of the [IIT] process."

IITs present unique and costly challenges, says Chin. Universities believe they should own the rights and risks to the information collected, since the study idea originates with one of their investigators. But the drug under study is owned by the supporting pharmaceutical company. Further, it is sometimes difficult to tell if the pharmaceutical company in fact approached the investigator with the idea - violating the very definition of "investigator-initiated." There are also different levels of risks and responsibilities, depending on whether the investigator or company is the designated sponsor.

"Companies are concerned about compliance," says Chin. "If federal regulators look at a trial, the company has the burden of proof that the [study] idea really came from the investigator, bears scientific merit, and wasn't used as an incentive to reward or induce a physician to use the company's products."

Of course, pharmaceutical companies are also busy with registrational trials for new indications. Because efficacy and safety data coming from a small number of patients "can be exaggerated," an IIT can potentially detract from a larger, ongoing trial involving the same drug - in some cases, creating the need to build in an additional variable, says Chin. "That, in itself, is not good." The outcome of an IIT can also create "unwelcome media attention" for a company.

The IIT itself may languish if the investigator is involved in 10 other trials, adds Chin, since the burden of data management falls on the study coordinator or research nurse. Famous doctors may be distracted by too many other demands to meet recruitment promises. "By the time a clinical study finally completes, the data may no longer be clinically relevant," says Chin.

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Deborah Borfitz, is a Vero Beach, Fla.-based freelance writer who previously contributed to the clinical trials publication CenterWatch. She is co-author of Informed Consent, covering the risks and benefits of volunteering for trials. She also writes extensively about healthcare trends, marketing, business development, and Internet intelligence.

Product recalls are practically a way of life for some companies, and not just those that manufacture prescription drugs. In a review of medical device recalls reported on the FDA website for the first six months of 2004, it was found that nearly a quarter of the 170 recalling firms subsequently had repeat incidents involving the same or similar products.

Reasons for the recalls ran the gamut from labeling errors to failure to meet product specifications, and potential or real product contamination problems.

The firms corrected the specific nonconformance, but apparently never recognized or eliminated the root cause, surmised Lisa Ensign, director of clinical and study solutions at Denver-based NetRegulus.

Presumably, the companies experiencing multiple recalls are not clients of NetRegulus. Its Web-based software, NetRM, includes data-management applications for each regulatory process in the product life cycle -- including clinical data collection, post-market reporting of adverse events (pharmaceuticals) and complaints (devices), and manufacturing oversight of non-conformance and audit processes, Ensign says. Quality and study data are stored all in one place, making trends -- good or bad -- easy to spot.

That's the kind of holistic approach advocated by Boston-based AMR Research in a February 2006 report examining costly compliance trouble at Boston Scientific. Quality and manufacturing compliance, it said, need to be centrally developed and coordinated. A "tighter integration of technology is required to sense, correct, prevent, and report effectively" on nonconforming events. Life sciences companies, generally, are admonished for "still trying to manufacture Six Sigma quality products from Three Sigma manufacturing processes."

NetRegulus does proportionally more post-marketing surveillance than traditional clinical solution providers, says Ensign. "All companies need to look at long-term adverse reactions, but particularly those with products taken chronically or implantable devices that remain in the body more or less permanently."

Regulatory compliance, overall, is equally costly to drug and device companies, says Ensign, consuming about 50 percent of their operating budgets. So it's a big deal fiscally as well as ethically.

Recently, NetRegulus has seen "a significant increase" in customers using its system for post-marketing surveillance activities, says Ensign. "This is being driven from many fronts: new regulations, public pressure as a result of some high-profile recalls, and increased emphasis and focus from the FDA," which "emphasizes an integrated view of the product quality experience from conception to retirement."

In the future, these activities will happen more or less routinely with any new product, says Ensign. She notes that the proportion of new molecules required to be tracked post-approval already jumped from 30 percent to 70 percent between 1998 and 2003.

Industry benefits from this trend because "[companies] may be able to do shorter clinical studies by agreeing to do post-marketing surveillance," Ensign says. It also "makes good business sense from a risk mitigation standpoint. [Companies] would rather detect a problem upfront than have it explode on them and be forced to take action."

Regulatory compliance may be costly, but nonconformance is even more so. The loss of brand equity can take years to recoup.

By Deborah Borfitz

Doug Engfer, CEO of invivodata, says its electronic diary (eDiary) isn't just a handy means to collect patient reported outcomes (PROs) data. It's a behavior management system that "guides patients to comply with a study protocol." In fact, invivodata guarantees 93 percent or better compliance with its DiaryPRO eDiary.

This figure mirrors the finding of a National Cancer Institute-funded study revealing a mere 11 percent of paper diary entries were made according to protocol. Researchers expected a fair amount of "parking lot compliance," wherein patients retroactively made entries right before seeing the doctor, says Engfer. What they didn't anticipate was that half of all patients would make entries ahead of schedule.

Surprisingly, paper diaries are still far more prevalent than electronic ones. "If patients filled them out when they were supposed to, paper diaries would be ideal," says Engfer. "But patients seem more intent on procrastinating or, worse yet, reporting data in advance that they think will please their doctor." That can provide conflicting results that lead sponsor companies to either abandon a drug or run bigger, more expensive studies.

The eDiary movement got a boost early last year from the FDA's draft PRO guidance outlining the requirements for selecting a PRO instrument, says Engfer. The guidance gave further credibility to electronic PRO (ePRO) data as a means to evaluate drugs and biologics as well as the specific capabilities of eDiaries to time- and date-tag entries on studies involving off-site data collection.

DiaryPRO utilizes data collection software on a Palm device that accompanies patients wherever they go, says Engfer. "The software itself interviews patients at prescribed times or allows them to enter data when they experience symptoms." At night, the device sits in a special cradle to recharge and "silently phones home" with diary entries maintained in a backend database. Physicians are notified of wayward participants via Web-based compliance reports.

Since 2000, invivodata has secured more than $24 million in financing to support its growth and expansion globally, says Engfer. The vendor has had 20 consecutive growth quarters. Business volume has roughly doubled, and revenues now balance operational costs. The product suite also includes SitePRO for clinic-based data collection.

In terms of bookings, invivodata just completed its most successful quarter, says Engfer. "We're running about 80 studies right now and are involved in dozens of programs [involving drugs or biologics] that have been or are about to be approved by the FDA." As of 2006, invivodata is capitalizing on its scientific and regulatory expertise by offering sponsors guidance on clinical trial protocols through its PRO Consulting business.

Its primary competitor, PHT, has been around a few years longer and focuses primarily on the technical performance of its eDiary, says Engfer. "We feel...you need to keep the process simple and collect high-integrity data unobtrusively. We're dealing with kids as young as five and people in their 90s."

Engfer says invivodata has a trio of partnering themes. One is to integrate databases and processes with other "best-of-breed" eClinical providers like Medidata, Phase Forward, and DataLabs. A few months ago, invivodata made its debut in Japan using its partnership with sales force automation vendor Dendrite International to ship and manage ePRO devices, run the helpdesks, and ensure that the right protocol-specific software gets installed on devices.

The second partnering theme is to absorb data from other sources, such as respiratory readings from a device produced by VIASYS Healthcare, into DiaryPRO or SitePRO, Engfer says. The third is to provide the training necessary for major contract research organizations to handle eDiary study management and support so invivodata can focus on product development.