Managing Clinical Trials

Adaptive Trial Design for Phase I, Phase II

Adaptive trial design is a hot issue in the drug development community. Adaptive conferences and web seminars abound, and suddenly, every consultant or vendor to the industry has become an adaptive expert. The FDA and EMEA are also much more receptive to adaptive trials than they were a few years ago. 

However, the picture is a shade different from what the industry had expected. Originally, much of the focus was on adaptive phase III trials as well as on seamless phase II/III trials. Those are, indeed, successfully being implemented today. But the real action is in phase II dose-finding trials and even in phase I trials for safety.

In today’s new issue of Peer Perspectives in Oncology, Medelis talks with Ranganath Nayak, Ph.D., the CEO of Cytel, Inc., about the benefits, opportunities, and challenges presented by adaptive trial design in phase I and phase II studies. Cytel has designed more adaptive trials for industry sponsors than any other service provider and in virtually every therapeutic area, including medical devices.

Dr. Nayak begins by discussing why adaptive trial design is gaining so much momentum in early stage studies. "First, adaptive trials are most helpful when you do not know enough at the beginning of a trial to design it with confidence," he says. "This is much more likely to be true in phases I and II than in phase III.  

"Second, the best way to make expensive phase III trials more successful is to do more thorough work in phases I and II," he continues. "Getting the dose right through well-designed phase I and phase II trials is the best way to maximize success in phase III, which then leads to a higher rate of NDAs. “

Dr. Nayak offers insight and expertise on a variety of issues surrounding adaptive trial design, including:

• Commercial, ethical, and budgetary benefits of the adaptive trial model;
• Statistical and data issues;
• Changing to the adaptive model across multiple sites;
• Safety issues to consider;
• Budgeting for an adaptive trial;
• Dealing with independent decision-making bodies;
• Patient consent and communication issues;
• Medical supply logistics;
• Other best practices and planning issues.

Download the abstract here; you’ll also gain access to the other issues in the series, and we’ll notify you of future publications as well.  

"Context of vulnerability" and its role in targeted drug development

Renowned cancer researcher Dr. Daniel Von Hoff and his team at TGen are fervent believers in a new approach to developing novel therapies for patients with pancreatic cancer. Their rationale, dubbed “context of vulnerability,” is a powerful new drug development paradigm that’s generating impressive results.

Medelis has just published a free downloadable interview with Dan (download it here) as part of our “Peer Perspectives in Oncology” series.  In the abstract, Dan explains how this model has already led to promising discoveries and is changing the future of oncology drug development. 

“Context of vulnerability,” a term coined by TGen’s Spryo Mousses, Ph.D., refers to the genetic configuration in a patient’s tumor that makes it susceptible to a specific drug.  “Context of vulnerability provides the genetic rationale for a targeted therapy,” Dan explains.

In the abstract, he provides examples of context of vulnerability in use.  “One way to establish the context of vulnerability is to work backwards from the result,” he says.  “For instance, in a phase I or phase II trial, you treat a certain number of patients, and when someone responds, you have to ask yourself, ‘Why did that patient respond?  What was the vulnerability in this specific tumor or patient?’  The patient either had a genetic lesion or tumor stroma that was susceptible to the drug in some way.”

Dan explains that context of vulnerability can improve a sponsor’s chance of seeing efficacy during an early-stage trial with a much smaller n.

“If you let context of vulnerability guide drug development, you would put only those patients who have the appropriate susceptibility to the drug on trial,” he emphasizes.  “It’s essentially how Herceptin® got approved with an n of 480.  If they hadn’t pre-selected patients for the context of vulnerability, estimates say that it would have taken about 23,000 patients to get the drug approved.”

Throughout the interview, Dan addresses many of the questions and opportunities presented in this model:

• How context of vulnerability provides a genetic rationale for a targeted therapy;
• How to establish a patient’s context of vulnerability;
• How using context of vulnerability to guide drug development can improve your chance of seeing efficacy with a much smaller n;
• Incorporating context of vulnerability as the oncologist’s “sixth vital sign;”
• A case study of context of vulnerability in use and how it improves patient care and new agent development;
• The gap between known contexts of vulnerability and available therapeutics;
• How CMOs can flip their drug development planning to leverage this approach;
• Feedback from the FDA, national and international groups;
• Targeted therapeutics and the future of oncology.

The abstract is the fifth in Medelis’ “Peer Perspectives in Oncology” series, and you can download the entire series here.  You’ll receive email notices when future issues are published as well.

Dan Von Hoff discusses "The Complete Phase Ib"

Medelis has published a free new downloadable abstract, "The Complete Phase Ib: An Approach to Getting to Phase II Faster," an interview with renowned oncology investigator Daniel D. Von Hoff, M.D. 

"The typical phase I approach is essentially serial drug development, which involves running multiple separate trials,” Dr. Von Hoff explains at the beginning of the interview.  "Each site at each trial adds a layer of time, cost, and management oversight. What I call 'the complete phase Ib' is a simple solution that essentially tests the various drug combinations in one phase Ib with multiple arms run in parallel.

"For example, assume you have good preclinical data on a single agent that may be more effective in combination with another agent—for example, a monoclonal antibody plus gemcitabine (GEMZAR®)," he explains. "Most Chief Medical Officers anticipate that the pivotal clinical trials will be standard therapy with or without the new drug, and they prepare for that eventuality by conducting a phase I trial of the combination. Typically, this involves launching five, six, or sometimes more combination phase I trials. Each trial has to be negotiated and managed separately, and each must have its own protocol, adding layer upon layer of cost and effort.

"The strategy I'm suggesting eliminates all these separate serial trials because it puts the combinations into one phase Ib trial."

Dr. Von Hoff offers a detailed look at this approach and the many benefits to sponsors, patients, and investigators, including:

• Patient accrual and treatment benefits
• How the approach can "rescue" patients
• Dosing strategies
• Logistical considerations
• Cost and timing considerations
• Effects on phase II studies
• Reactions from the FDA investigators, sponsors and patients

The abstract is the second in Medelis' "Peer Perspectives in Oncology" series.  In the first issue, "Patient Safety in Clinical Trials," Dr. James Gourzis discusses recent issues in patient safety and the role of sponsors, CROs, IRBs, DMCs and the FDA in ensuring patient safety in future clinical trials.

You can download each of the interviews here.  You’ll receive email notices when future issues are published as well.