Phase IV Specialist: Device Maker Chooses Outcome

Here's a clinical trial koan. Suppose you have an eligible, eager patient. Do you need a site? Are you sure?

Maybe not, says Richard Gliklich, president and CEO of Outcome Sciences. In Phase IV trials, he believes, technology and a remote physician could be more than adequate to gather high-quality data and conform to good clinical practice (GCP).

The Cambridge, Mass., company recently announced its role in creating a 250-site registry for adult patients with normal pressure hydrocephalus (NPH). NPH is characterized by an abnormal accumulation of fluid in the brain; it affects 250,000 patients in the U.S. Partners on the registry include the American Association of Neurological Surgeons and Codman & Shurtleff, a firm that makes therapeutic and diagnostic devices for the condition. Many of Outcome's trials have hundreds of sites and tens of thousands of patients.

Gliklich says his ability to serve investigators has given him a leg up on rivals (e.g., etrials and Ninaza) that are also expert on Phase IV projects. In the case of a disorder like NPH, he notes, there is abundant pediatric data on the condition, but the new registry is likely to change what physicians know about managing adults. "It is going to be giving the sponsor and the advisory panel a view into how the disease entity changes with a new therapy and a broader application for the device," says Gliklich.

He adds that his company's reporting capabilities to individual investigators have been significantly enhanced, to the point where surgeons can drill down not only into populations and subpopulations of patients (their own or those of other physicians), but also to the records for individual patients. "We're trying to drive value to the sites and physicians to make it worth their time to participate," says Gliklich.

Which brings us to the patient without a site. All its work in Phase IV means that Outcome Sciences has frequently encountered post-marketing trials where the patients appeared out of thin air. With certain diseases, Gliklich explains, patients know they have a condition - cancer, rheumatoid arthritis, and erectile dysfunction come to mind. Safety surveillance or other FDA-mandated studies could be massively cheaper if physical sites were not necessary.

Thus in the first part of 2005, Outcome Sciences will roll out new Web-based software called PatientDATA. Under the hood, PatientDATA will draw heavily on the data and software of Veritas Medicine. PatientDATA amounts to an electronic or digital site for research, a concept new to this reporter. The software will identify, consent, qualify, and enroll patients online - and then collect their data. "There are physicians in the mix - they just function virtually," Gliklich explains. "We are doing this within a GCP approach. It could be utilized for an S-NDA or to meet a risk profile."

A related area of Phase IV growth is studies of personalized medicine or, to use another phrase, controlled distribution. These are trials in which demographic, clinical, or genetic characteristics qualify or disqualify specific patients. "[That is] an area that is growing very rapidly for us," says Gliklich. "In the next few years, we will start see approvals based on narrow characteristics."

Outcome Sciences has long integrated data from interactive voice response (IVR) systems, patient diaries, and facsimiles. But now it is also enabling more administrative functionality in its core application. "There are things we've done that enable you to avoid a clinical trial management system (CTMS)," Gliklich notes. He's hesitant to call his system a CTMS, but says it can handle sophisticated enrollment reports, data analysis, 1572 forms, curriculum vitae, protocols, investigator meeting schedules - and money. "Sites can see what they're owed. That improves expectations," Gliklich notes.

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Insightful Clinical Statistics, Insightful Software

Jose Pinheiro's job is to help the company tweak its strategy for clinical trials. As a senior associate director at Novartis, he can get a little busy writing scripts doing SAS programming for less-statistically sophisticated users in the company. And therein lies the rub. Because some of those users, as much as they enjoy Pinheiro, would rather do the work themselves.

Based in East Hanover, New Jersey, Pinheiro hardly takes offense at that - in fact, like the rest of us, he'd like to take on the most urgent and difficult chores and enable decision-making. And while Pinheiro respects and uses SAS, he clearly prefers S+ from Insightful Software.

"The SAS environment - why it's so successful - is that it lends itself naturally for repetitive work," notes Pinheiro. "However, if you want to try new methodologies, I don't think SAS is the most effective programming tool."

As an example of what he's talking about, Pinheiro cites a question from within the company about a particular trial: When is it preferable to randomize patients centrally versus randomizing them when clinical sites telephone into an interactive voice response (IVR) system? As Pinheiro recalls, "It was a simple question: When do you recommend that we do one or the other?" No commercial software or academic paper addressed the question.

So Pinheiro wrote a little application in S+. By putting in a few variables - the number of patients, treatments, and clinical sites - the program typically shows an inflection point at about 1,000 patients. "What we wanted in the end is to have the trial statistician have the ability to make a recommendation," says Pinheiro. "Having the proper software tools can make the life of statisticians and managers a lot simpler. They don't have to know S+."

Pinheiro addressed the user group meeting for Insightful this fall, and that occasion provided an opportunity for a reporter to catch up with Michael McConnell, the company's tireless champion in the life sciences (there are also significant markets for the company's tools in the insurance and financial industries). Among other things, McConnell sells software for microarray analysis.

But some of the company's tools are quite focused on clinical trials. Which is why McConnell immediately waded into a larger debate about statistical tools that can help sponsors design shorter, cheaper trials. Some quantitative sophisticates prefer group-sequential analysis; others prefer adaptive design. McConnell is in the former camp. "We've had this product out for a long time," McConnell says, referring to his S+SeqTrial product. "It's kinda fun to see to the surge of interest in it."

"There are ways that we can take an interim look at the data," he said. "If you've got high efficacy or no efficacy, you can stop the trial early."

His competitors - not just SAS but Cytel, which is run by a Cambridge, Mass., professor - are doing their best to put very sophisticated mathematics into a user interface that just about anyone can use to model different clinical scenarios. The emphasis here is not just the analysis of the data at the end of the trial, but to work with the information during the trial and before it starts - and in ways that won't make biostatisticians at the FDA blanche. Both Insightful and Cytel believe regulators and sponsors are looking upon their tools with increasing interest.

For his part, McConnell is a charming, razor-sharp advocate for his tools. "There are a lot of SAS programmers using thousands of lines of code to do things that people can do with one line of code in S+," he says. "We're going to stop a lot of silliness."

But the last thing he's trying to do is offend the most expert, devoted SAS users. "We use their software in association with interactions with our clients. We've figured out how to make them work together. The user never has to leave SAS, but can get all the S+ statistical and graphical reporting from within the SAS environment."

One of the more interesting talks at the meeting was a presentation by Keith Nieforth, a PharmD in the clinical pharmacology department at Hoffman-La Roche. Nieforth told the audience that he's been able to use Insightful S+ environment to standardize and automate reports that once took scientists . . . well, forever.

Said Nieforth: "Way too much time is spent formatting graphical and tabular output. Should scientists be doing this? My opinion is no. We can automate it with tools like S+. There is quite a bit of time that can be saved.We're not talking about minutes. With some studies you can spend four to six hours doing this. Sometimes the formatting is a nightmare. There is quite a bit of time that can be saved."

Modeling Trial Supplies: Tourtellotte Consulting

Ed Tourtellotte is a former Ernst & Young person, a programmer's programmer who's hung out his own shingle as a consultant. He stopped by to show off a new Tourtellotte Consulting application, tcVisualize. It does one thing: It simulates fluctuating drug supplies during clinical research using a map-based, geographical interface.

As tcVisualize runs, it's fascinating to see a map of Europe with half a dozen bar graphs gyrating up and down like the cylinders of an internal combustion engine. Tourtellotte's program models the prospective enrollment and randomization of patients - and the sites' subsequent use of placebo and drug. As patients enroll or drop out, the supplies change, the colors in the bar graphs flicker from red to green. Problems pop up in Italy as the bars in Spain stay green.

The tcVisualize software can handle either central or center-based randomization. It can be told the schedule for patient visits and dosing, for trial caps and costs, for when drugs expire. Colleagues in pharmacy, clinical and support can see the ramifications of a particular protocol - and the effects of any changes to that design. All simulations can be saved and repeated, or run again with a bit of real data from an ongoing trial.

tcVisualize simulates the supply of medication to clinical sites using a geographically-oriented interface.

The preciousness of any drugs synthesized for research cannot be overemphasized, Tourtellotte believes. When supplies are awry, he says, direct, out-of-pocket costs may exceed $70,000 per day. "The costs are enormous. You cannot get the pharmacy to produce new stuff quickly." In some cases, the health of patients may be in jeopardy if supplies run out. And if there is too much drug, money has been wasted on manufacturing. "The hidden cost is the cost of other drugs you didn't manufacture," says Tourtellotte. "The ROI screams. This is going to help you today."

In black and white, that quote is a bit misleading - Tourtellotte himself is an extremely quiet, careful, moderate soul. Having said that, he does tote around a gorgeous Voodoo laptop that is bright orange and the only PC I've ever envied as an unrepentant Apple partisan.

The tcVisualize application has a drag-and-drop tool to add a new clinical site in, say, Atlanta. Behind the scenes, however, the software uses GPS coordinates to correctly position a new supply depot or clinical site. Using GPS allows users to load a list of 200 sites automatically and have each site accurately appear on a map on screen. That functionality could be tied into shipping or tracking systems in the future. The program can receive data from other clinical applications in XML format. Users can also add their hunches about whether a particular country tends to have a high rate of enrollment or not; one slider adjusts the anticipated variability to apply to the simulation overall.

"This predicts the conduct of the study, and predicts the supply permutations in advance," says Tourtellotte. In a past life, he built a homegrown interactive voice response system for a major pharmaceutical company. (He says the system has now been used in 100 trials but won't name that company.) tcVisualize can be licensed for $450,000, which includes training, support, and upgrades for a five-year term. Tourtellotte Consulting is based in Framingham, Mass. Its website does not have an abundance of information; the firm's phone is (508) 872-4245.

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