Trial time: Q&A with Ralph Venhaus
Ludwig’s director of clinical trials management on the importance of rigorous safety and efficacy testing
Why are clinical trials so important for cancer research?
Bottom line: The only way to find out if a new cancer treatment works is to test it in cancer patients through clinical trials. Clinical trials are the last component of a long drug research and development process that usually starts with discovery and involves extensive preclinical testing in cell culture and animal studies. All of the standard, recognized cancer treatments we have today are a result of this research and development process.
Here at Ludwig, we are primarily involved with phase 1 and early phase 2 clinical trials, which test a new drug or treatment first in a small group of cancer patients to initially evaluate safety and appropriate doses before going into larger trials to determine its actual efficacy. We also investigate a drug’s mechanism of action or biomarker profile in such trials. Every trial we perform is the result of a discovery that investigators believe indicates a viable concept for a new treatment. Eventually, all cancer treatments must prove to be effective and have an acceptable safety profile in appropriately designed and conducted clinical trials with a larger number of patients before they can be made widely available to the general patient population.
Why are so few patients enrolled in clinical trials?
While the majority of children with cancer do participate in clinical trials, the participation rate of adults is still extremely low – only about 3% overall. Many clinical trials have to be closed owing to a lack of patients.
This is unfortunate but can be explained. There are a lot of barriers to patient recruitment. Probably the biggest hurdle is that most of the trials are concentrated in the big academic centers, but the majority of patients are treated outside these centers and often don’t even know about clinical trials. Oftentimes, a patient’s physician isn’t aware of trials in their geographic area or they might not have the time to discuss the possibility of a trial with the patient. Patients and their doctors also worry that participation in a trial might be too great a burden for patients and their families. And there’s even the issue of medical liability.
And patients themselves often don’t want to be a test subject for an experiential treatment. They’re afraid they might get a placebo and not receive any treatment at all, or that participation in a trial is a last ditch effort. However, when a placebo is indeed used, it’s often given together with the best standard treatment available; this ensures that the patient receives an active treatment and allows us to compare standard treatment alone to standard treatment with the new treatment. The use of placebos without a standard treatment is only ethically acceptable in patients who would not receive any standard treatment at all – for example, during a period of time when a patient is closely monitored by their doctor, but no specific medical treatment is indicated until symptoms develop or change.
The elderly is another population that is underrepresented, as physicians are more apt to refer middle-aged or very young patients to a clinical trial. Elderly patients are more likely to have medical histories that make them ineligible to participate in a trial, as they often suffer from other physical ailments in addition to cancer. All this results in too many trials chasing too few suitable patients in too few treatment locations. And you end up with a fairly large number of trials that can’t be completed due to lack of enrollment.
These are major issues, but Ludwig is being proactive about them. In our trials, we take great care not to unreasonably restrict the enrollment criteria for patients. For example, we do not generally use age as an exclusion criterion, as long as the patient appears healthy enough to tolerate the treatment. We are also reaching out to smaller community hospitals and treatment centers, where the vast majority of patients receive their standard of care. It’s a way for us to engage some of the 97% of patients who might otherwise not have access to a trial.
What do you think about trials that test multiple drugs?
These so-called ‘basket studies’ are a great idea because they allow you to efficiently match patients whose cancer has a specific target for treatment with drugs, irrespective of the type of cancer they have, thus accelerating the development of new targeted therapies. They also speed enrollment, allowing many screened patients to enter the study, which means the investigators will get answers faster on whether experimental drugs work. These studies give patients the best chance for treatment of a deadly disease because everyone gets some type of therapy. So instead of starting with multiple clinical trials, you start with one trial—the basket—in patients with different cancer types, allowing patients to enroll in cohorts or groups suited to their specific tumor indication.
Finding the right basket to put them in is done by genetic profiling, evaluation of biomarkers or other selection criteria. Having many drugs and treatment baskets available under the cover of a single study is an efficient way to keep overhead low, patient recruitment high, data collection and analysis efficient, and patients interested and focused.
What is most gratifying about your job?
The patients. We know that patients have benefited from the clinical trials we’ve been involved with. At the end of the day, it’s gratifying to see something work, which allows patients to live longer and enjoy a reasonable quality of life. It’s heartening to hear stories like the one about the patient with stage 4 melanoma whose life expectancy was 10 to 15 months before the trial. This patient is still alive 10 years later. That’s what it’s all about.
Tell us a little about your work prior to joining Ludwig in 2002?
I was educated in Germany and received my bachelor’s degree in chemistry from the University of Dortmund and my medical degree from the University of Heidelberg. During my five years in medical school, I had the advantage of working almost full-time as an emergency medical technician in hospital emergency rooms and intensive care units, which gave me invaluable experience. After medical school, I specialized in anesthesiology and intensive care and became board certified. All together, I spent 10 years in emergency rooms, operating rooms and intensive care units. I loved the work, but after some 4,000-plus anesthesiological procedures in windowless rooms, I jumped at the opportunity to join ASTA Medica as a jet-setting clinical pain researcher learning how to do clinical trials. This is what brought my family and me to the United States in 1990, where I founded and directed the company’s US medical affairs department. It was here that I first became involved in cancer trials, which eventually became more and more the focus of my work.
I’m an entrepreneur at heart, and my next move was to Coley Pharmaceutical Group in Wellesley, Massachusetts, a privately held biotechnology company that was later taken over by Pfizer. I was the third employee and tasked with establishing and leading their worldwide clinical research operations. In my three-year stint at Coley, I was primarily involved in developing innovative products that stimulate the immune system via TLR-9. I assembled a rather large team of 30 researchers and we completed over 10 studies in that time period. It was through our immunology work that I first met Lloyd Old and Eric Hoffman. In 2002, they asked me to join Ludwig as head of clinical affairs and oversee the expansion of its clinical research capabilities. Four years later, I assumed responsibility for regulatory affairs also, and in 2010 became director of clinical trials management and chief medical officer.
How did you become a motorcycle enthusiast?
As a small kid, I loved the BMW bikes the cops rode in postwar Germany – white with blue “Polizei” emblazoned on them. As a big kid in college, a ride down the Autobahn on the back of a friend’s bike got me hooked, and I got my first one a few months after that ride. And it’s still my favorite way to commute to the office!
Do you have any other secret hobbies or passions we should know about?
At home, in New Hampshire, I do all my own landscaping and I am an expert in building retaining walls, so front loaders and backhoes are a big part of my weekends and vacations. I also do my own carpentry, plumbing and electrical work, which is good because I bought a piece of property in Virginia on a lake several years ago that I’m now developing. Nevertheless, despite my strong affiliation with construction work, I do intend to hold on to my day job.
How did you become an anesthesiologist?
I guess childhood experiences had a profound effect on me. The city I was born in – Hagen, in the Westphalia region – was in ruins after the war, and many of the buildings had been completely destroyed. My preschool was right across the street from the Catholic Marienhospital, and since there was no fence separating the school from the hospital, I would run over every time an ambulance would arrive with a patient. There were no emergency ramps, so patients had to be hand carried on stretchers up the stairs. I witnessed a lot during the three years I spent there. I distinctly remember one day when they brought in a patient who was in agonizing pain. He repeatedly cried out to the emergency technicians, “Please, give me anesthesia. Please, give me anesthesia.” More than anything, I wished I could do something for him. That must have stuck in my brain and I consider myself very lucky to have been able to live my dream and to pursue a profession that I’m still passionate about after all these years.