Schindler: Steering a Course Change at Merck
By Deborah Borfitz

In the early 1990s, as a senior biostatistician at the Genetics Institute (later acquired by Wyeth), Jerald Schindler, DrPH, found himself pining for statistical gear to bridge all the pesky stops and starts of drug development. He envisioned a continuum of data crunching from the earliest dose-finding studies to the final dose-testing trials that count toward product registration. Assumptions would be checked while a trial was in progress, rather than at its conclusion a year or two later, and the protocol would be altered accordingly. 

Though Schindler didn't know it at the time, he was describing what has since been termed "adaptive clinical trials." He was, in fact, responsible for establishing the vision for the underlying eClinical infrastructure that has allowed Wyeth to do its pioneering adaptive trials. He then became a big advocate of the concept as a consultant presiding over the pharmaceutical research division of Cytel, a position he left at the end of March.

As the new vice president of late-stage clinical development statistics at Merck & Co., Schindler will be giving the adaptive approach its most serious exposure yet. "Part of the reason I'm here is to...look for opportunities to do dose ranging and Phase II/III trials," he says. Currently, Merck has a "relatively small number" of adaptive trials completed and in progress in different phases.

"In my view, adaptive clinical trials make sense everywhere," says Schindler. "There are different opportunities at different stages. Early on, you want to identify products that are likely to continue and find the right dose regimen and patient population. You start with a blank slate and over time explore a lot of ideas and eliminate ones that don't look promising. In a later stage, you...start with a few doses and identify the best of the few."

As with any major shift, the key challenge will be overcoming inertia issues. Adaptive trials require an investment in upfront planning "to do simulations and understand the different options and their implications," says Schindler. Merck will continue to develop its "worldwide common infrastructure so all [trial-related] data flows into similarly structured databases," thereby allowing the re-use of simulation and data analysis tools. Adaptive trials demand "a lot of data analysis, and quickly. You may need to do three or four small analyses of the data. If it's painful to do, you will run out of resources quickly."

One type of frequentist adaptive trial, known as a "group sequential trial," has gained wide acceptance over the past 30 years. "These trials usually contain a small number of interim analyses with the option to stop the trial, or discontinue a treatment arm, based on how various patient groups, on different drug doses, are faring," says Schindler.

The alternative Bayesian statistical approach deals with new data as it comes in and estimates the probability that the drug is effective. The blending of data with prior ideas makes the methodology a bit controversial. The required computing power is also overwhelming, although tools to do Bayesian analysis have improved substantially over the past two decades, says Schindler.

"Adaptive clinical trials can be done in a frequentist way, a Bayesian way, or a mix of the two," says Schindler. But the new adaptive approach to clinical development establishes a process for making interim decisions during the drug development process that "takes advantage of all the information you have all the time." Conceivably, a drug could journey through clinical development based on a combined adaptive proof-of-concept/dose response trial and then an adaptive, multiple-dose Phase III trial that "ends enrollment into groups that don't do as well and focuses on the dose or doses that will make it to market."

Adaptive drug development across the entire portfolio "enables companies to allocate resources among all products based on real-time results from the ongoing clinical trials," says Schindler. "The combination of the adaptive process with portfolio management will likely be the next step in the evolution of the adaptive approach."

Invivodata Marks Twenty Years of the eDiary
By Ann Neuer

Back in the 1980s, clinical researcher Saul Shiffman would often walk into his waiting room and notice study volunteers hurriedly filling out the past two weeks of patient diaries. "This is an experience that every researcher who has ever worked with paper diaries can relate to," says Shiffman, co-founder and chief science officer for invivodata.

That observation and the nagging doubt that this type of belated recall probably led to highly inaccurate and essentially useless information were the driving forces behind Shiffman's creation of the eDiary, the first handheld device meant to improve the caliber of patient reported outcomes (PRO). At this week's Drug Information Association's (DIA) Annual Meeting in Atlanta, invivodata will begin celebrating the 20 year anniversary of the eDiary, a simple-to-use device that lets study volunteers easily record needed study data as close to the event as possible while preventing them from tampering with the data or entering them inaccurately or after the fact.

"When we started to develop eDiary, we did it from the perspective of what was needed for clinical research. The emphasis was on the patient, not the technology," comments Shiffman. Together with Jean Paty, a student of Shiffman's, the two recognized that offering patients a way to gather data in a natural setting using a reliable portable device had to yield better results than a paper system fraught with fake diary entries.

When eDiary first appeared on the scene, industry stakeholders immediately saw the value of the tool and began contracting with Shiffman at the University of Pittsburgh to provide eDiary programming and services. There were industry skeptics, of course, who questioned whether the technology was robust and whether patients would accept it. "The technology was very robust by the standards of the time, and we found that patients actually preferred the eDiary to paper," says Shiffman.
 
The first eDiary trial was a smoking cessation study, but before using the device, Shiffman and Paty launched a small pilot study to try to understand how patients would interact with it. Shiffman comments, "We actually gave each patient a diary to take home and watched how they worked with it. We de-briefed them and then fed that information back into how we developed the software. The patient experience was the central driver of the development."

Over the next decade, Shiffman and Paty continued to develop the eDiary at the University of Pittsburgh and publish and present their work documenting the value of accurate collection of PRO data. Finally, in 1999, as eDiary collected its one-millionth ePRO record, invivodata was created. Doug Engfer, president and CEO, co-founded the company with Shiffman and Paty. They had worked previously with Engfer, who was then president of The Windward Group, a software developer that enabled eDiary to begin using Palm technology.

In 2004 the company named the product DiaryPRO, and as Engfer explains, "We really started to see traction around that time, in 2003 - 2004, and it's continuing. We have touched 10 times as many subjects today as we had in January 2004. At that time, we had been involved with 5,000 subjects. Now we've reached 50,000." According to Engfer, as of January 2004, invivodata had processed five million patient records, and by January 2007, that number had jumped to 150,000,000. "In the first half of 2007, we've closed more than twice as much business as we had in the same period in 2006," Engfer states.

The company is privately held and does not disclose revenues, but Engfer says that revenues are following increases in subject numbers.

As use of eDiary continues to grow, it's not surprising that it has reached the radar screen of the FDA. In February 2006, FDA produced a draft guidance, Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims. The guidance states that FDA plans to review study protocols to determine that stakeholders are taking measures to ensure that patients make diary entries at the appropriate time so as not to threaten the accuracy of PRO data. Complementing this draft guidance is a new guidance issued in May 2007, Computerized Systems Used in Clinical Investigations, to make sure that the hardware/software combinations are validated and perform reliably in clinical trials.

"We believe that these guidances will drive additional growth, and once more people transition to electronic diaries, they will start to see the potential for scientific improvement," says Shiffman.

Schindler: The New Era of Drug Development
By Deborah Borfitz

A main concern of U.S. and European regulators is the potential for bias to creep into an adaptively designed Phase III trial via communications with investigators and patients about whether a particular dose is working, says Jerald Schindler, vice president of late-stage clinical development statistics at Merck & Co. "It's hard to prove you didn't influence [future data], so you need to lock data down and keep it separate from those who conduct the trial."

Regulators are clear that, with early-stage trials where blinding is not a big issue, "companies can look at almost anything they want within reason," says Schindler. Consequently, it pays to "learn a lot about a drug early, when the bar is lower."

Just about every pharmaceutical company today is doing the newer types of adaptive trials -- including those that involve Bayesian statistics -- or talking about it, says Schindler. "Some companies will not do well, and give up. The others -- and presumably Merck will be among them -- will figure it out and zoom ahead."

This new level of skill required for successful adaptive trials will give companies a major competitive advantage over companies that fail to develop the necessary skills, says Schindler. "At Merck, we have been adding to our already strong statistical capabilities by selecting talented statisticians to join our statistical staff with the desire for close collaboration with the clinical research departments."

That translates into a lot of positives in the years ahead, and not just in terms of adding efficiencies to the business of drug development, says Schindler. "The fact that we have better information earlier is a big deal." Adaptive trials can lower the risk of clinical development, in the aggregate, by "identifying losers early." They can improve public health. Effective treatments will get to market sooner. Companies also won't give up on useful compounds simply because of bad guesses on dosing.

"One of the side benefits [of adaptive approaches] is that they require close collaboration among everyone who helps run a trial...making the whole process more efficient," says Schindler. "Information should be shared when people need to know it."
 
Schindler adds, "What I'd like to do at Merck is help influence how drugs are developed. [The company] has a pipeline filled with potential products. All of us here need to find a way to develop good products in the most efficient way and get them to market. The adaptive approach will go a long ways toward doing that."

It also makes the job a whole lot more interesting. "As the decision-making process is driven more and more by understanding emerging signals in the clinical data, the role of the statistician becomes even more important," says Schindler.

Related stories:
Adaptive Trials a Strain on Organizations

Biting the Adaptive Trials Bullet

Real-Time Trials

Study: Who's Paying Affects Trial Results

UPI | In head-to-head trials of two drugs, the one deemed better appears to depend largely on who is funding the research, a new U.S. study said. more

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