Managing Clinical Trials

"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.

Oncology clinical research scientist recommends a nuanced preclinical study process to speed drug development

Medelis has just published the third issue of "Peer Perspectives in Oncology," our free Q&A series focused on issues that face Chief Medical Officers today: rising costs, optimum patient accrual, targeted therapeutics, patient safety, FDA regulations, efficacy, budgets, and timelines.

In "Preclinical Trials:  A Nuanced Approach to Get Into the Clinic Faster," Dr. Mike McGarry describes a nuanced preclinical process that can help a CMO get into the clinic faster.  This approach hinges on a strategic, well-defined rodent model, quality data, and ongoing integration between the pre-clinical, regulatory and clinical teams.

Dr. McGarry, VP of Preclinical Studies at Medelis, is a preclinical research scientist with 35 years of experience generating high quality animal-based data.  In the interview, he provides a detailed inside look at the issues that can speed or derail the oncology preclinical phase:

• Critical factors for a CMO to understand and evaluate during this step in the drug development process
• Regulatory assessments and how to avoid hitting a preclinical wall
• The nuances and complexities of animal models, tumor selection, and other variables
• How to keep the preclinical, regulatory and clinical teams involved in feasibility dialogue
• The typical preclinical process and the questions a CMO should be asking at each step
• Additional requirements unique to oncology preclinical trials
• What to look for in an outside preclinical team.

The abstract is free, and you can download it here.  You can also download the first two issues in the series, "The Complete Phase 1b:  A Proven Approach to Getting to Phase II Faster," an interview with Dr. Dan Von Hoff, and "Patient Safety in Clinical Trials," a discussion with Dr. James Gourzis.

Insight: Preventing a Preclinical Dead End

Oncology preclinical studies are commonly viewed as straightforward investigations run exclusively by researchers.  Tasked with finding molecules that stop cell growth, researchers often operate independently without true integration with the preclinical, regulatory and clinical teams.

Dr. Mike McGarry, a preclinical research scientist with 35 years of experience generating high quality animal-based data, advocates for a more synergistic approach.  In an upcoming issue of "Peer Perspectives in Oncology," he weighs in on the typical preclinical process and shares insight that can help CMOs extract more useful information that aids drug development and speeds overall progress to phase I.

One of the big issues Dr. McGarry commonly sees is a chasm between a sponsor’s preclinical and clinical teams.

"Preclinical researchers are extremely technical and scientific; they’re focused on microscopic details of various tissue or organ side effects," he explains.  "On the other side, the CMO is pushing to move a drug forward while managing costs to meet the company’s targets.  That forward momentum can create friction with the conservative, tentative nature of the research scientist who is watching the nuances unfold and has perhaps a very different perspective on the trial."

Without close communication and integration, preclinical experimentation can lead to a regulatory brick wall, a scenario no CMO wants to experience.

"I’ve spent most of my career in preclinical experimentation, and it's an expensive funneling process," he continues.  "You start with thousands of compounds and eventually narrow it down to the one that warrants close scrutiny, hopefully making it into clinical study and application. As you’re narrowing the field, the preclinical team also has to focus on the end goal or you can easily end up in a place that has no utility."

For a CMO, the answer is to get more involved in the preclinical process to gain insight, lead the study direction and prevent the silo effect from derailing a promising drug.

"There needs to be ongoing, seamless communication and integration among the clinical, regulatory and pre-clinical teams," he adds. "Communication affects the quality of results to be reported and thus the usefulness of the data.  Each team should be actively involved in feasibility dialogue at each step in the study."

The complete interview is one of several slated to be published this summer.  You can sign up to be notified via email here.   

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.