Clinical trials are the gateway between the laboratory bench and the pharmacy shelves.
by Anna C. Christensen
Originally published in the Fall 2018 issue of Act Against Cancer
The next time you pick up a prescription at a pharmacy, take a moment to appreciate the contents of that translucent orange bottle. Feel the weight of it in your palm. Tap a pill into your hand, roll it between your fingertips. Behind that little pill is a history of big ideas, one in which countless students, postdocs and research scientists designed painstaking experiments and were likely frustrated by failures.
But they persevered until they accumulated enough evidence to turn their molecules into medications.
Before being mass produced by pharmaceutical companies and distributed to your local corner drugstore, however, that drug had to prove itself in a series of clinical trials, an essential component of medical research involving the careful testing of experimental therapies, devices, screening methods, prevention methods and other types of care. Although they mostly assess the safety and effectiveness of new drugs, trials can also be used to evaluate other strategies for improving health, such as new technologies for imaging tumors or diets specially designed to reduce cancer risk.
At the University of Arizona Cancer Center, the Clinical Trials Office oversees the trials that give participants access to care they might be unable to find elsewhere in the community. A team of compassionate clinicians manages the “front of the house,” caring for patients, while the “back of the house” hosts a flurry of administrative activity as a squad of specialists makes sure bills are paid, contracts are negotiated, and trials are run in accordance with legal and ethical requirements.
“Drug discovery is not easy,” says Daruka Mahadevan, MD, PhD, co-leader of the UA Cancer Center Therapeutic Development Program. “If it were easy, everybody would be doing it.”
Fortunately, the University of Arizona is teeming with scientists following numerous leads on drug candidates — compounds that show potential to treat cancer. After rigorous testing, an elite few make their way to the clinical trial stage, at which point they might become the subject of an investigator-initiated trial, a clinical trial spearheaded by UA Cancer Center members.
“Investigator-initiated trials are the most important to us,” says Daniel Persky, MD, director of the Clinical Trials Office. “We take an idea, which often comes from one of our collaborators in the lab, and put it in the clinic to test if it works and is safe in the patient.”
These trials are shining examples of the University of Arizona’s team-oriented atmosphere.
“Collaboration is the driving force in developing drugs, through scientists at the bench working closely with investigators in the clinic,” says Hani Babiker, MD, associate director of the UA Cancer Center Early Phase Clinical Trials Program.
Funding for these trials comes from diverse sources. Individual philanthropists’ gifts can accelerate a scientist’s research, helping propel it into the human-treatment stage. Additional money might come from grants awarded by nonprofit organizations or federal sources. Sometimes, pharmaceutical companies step up to help foot the bill.
“The biggest challenge is to get the funding to take a drug from preclinical studies to the clinic, which costs several million dollars,” says Dr. Mahadevan. “An investor and a passionate investigator have to be willing to take it on.”
To convince companies that investment in our investigator-initiated trials is worth their money, UA Cancer Center physician-scientists might have to go back to the lab. Compiling more enticing preclinical data could make the difference in attracting pharma funding.
“If the drug hits the target really well and there is an unmet need, chances are very high that you can take it all the way to the clinic,” reports Dr. Mahadevan.
In addition to investigator-initiated trials, the Clinical Trials Office helps run trials for pharmaceutical companies or the National Institutes of Health.
Pharmaceutical companies design their own trials, often enlisting UA Cancer Center investigators to take part in a larger effort in which investigators from across the country — or even around the world — follow the same protocol. Results from patients far and wide are combined into a single robust data set that can clarify the safety and efficacy of a drug.
“When you put a lot of minds together, things move better,” says Dr. Babiker of these types of multi-institutional studies.
Although pharmaceutical companies benefit from the minds at the UA Cancer Center, it’s vital that patients benefit as well.
“The trials ideally need to serve both a need of our patients and a scientific need,” Dr. Persky says.
Finally, other clinical trials are federally funded to ensure the public gets its money’s worth from their tax dollars.
“The National Institutes of Health support the trials that pharmaceutical companies would not be conducting, and that serve the needs of the population,” says Dr. Persky. “Our institution has always participated very heavily in these trials. They are important to serve the mission of treating cancer.”
It’s just a phase
Clinical trials are typically conducted in three phases. After a molecule shows promise in the lab, phase I studies are the first to be performed in humans, giving participants access to new treatments that might later be hailed as medical breakthroughs.
According to Dr. Babiker, “One of our missions is to move the science toward developing new drugs, specifically for cancers for which we don’t have a lot available.”
These trials usually only enroll 10 to 30 volunteers, and might last only a few months.
“Phase I trials use very careful dosing and very close monitoring of patients for side effects,” Dr. Persky says. “The goal is to establish safe doses of the drug.”
“We’re mainly looking at the best dose,” adds Ruth Cañamar, who manages the Early Phase Clinical Trials Program. “Our center has been very successful in opening trials quickly, as well as enrolling the subjects needed to complete a trial. This ability has created a great working relationship with pharmaceutical companies and continues to bring more novel drugs to our cancer center and the region, accelerating the pace of novel drug development.”
Assuming that a drug seems safe in phase I, researchers can advance to phase II, during which anywhere from 30 to more than 100 volunteers receive a dosage established in the first round of trials.
“The goals of phase II trials are to see how effective the drug is, as well as to get more information about the safety,” Dr. Persky says.
Investigators hope to predict a drug’s safety and effectiveness based on a patient’s biomarkers — chemicals in the body that could help us predict who is most likely to respond to a drug and who might be at risk for serious side effects.
“The U.S. Food and Drug Administration is now approving biomarker-driven trials in early-phase trials prior to randomized trials, a major achievement for trial designs,” Dr. Mahadevan says. “This offers benefits to a lot more patients.”
Researchers will celebrate a successful phase II trial by advancing to phase III, which can enroll hundreds or even thousands of participants. Patients are “randomized” — randomly chosen, like flipping a coin or rolling dice — into experimental groups and control groups to see how the innovation compares to standard treatment. The results illuminate which approaches work best, incrementally pushing medical science forward, one trial at a time.
“Phase III trials are done to get a drug approved by the FDA,” Dr. Persky says. “The goal of the trial is to evaluate outcome — ideally overall survival, but sometimes survival without disease.”
After phase III, the FDA may bestow its final approval on a drug — but the investigation doesn’t stop there. Phase IV studies follow thousands of patients to obtain real-world effectiveness and safety data for the approved drug. Researchers can learn long-term survival rates and detect rare side effects.
Rising up to challenges
Clinical trials are becoming more complex as our understanding of cancer grows.
“The cancer field is changing,” Dr. Persky says. “We now understand that any one cancer is actually a collection of several different cancers. Instead of one trial, now we have five trials with smaller groups of patients.”
To recruit enough volunteers, investigators need to form good relationships with community physicians, who can refer potential participants. These physicians, however, can sometimes be reluctant to let their patients go. Some clinical trial investigators tackle this problem with proactive community outreach.
Says Ms. Cañamar, “Dr. Mahadevan goes out in the community and says, ‘When you first diagnose a patient, think outside the box. See what is available here at an academic medical center.’”
“We hope that our oncologist colleagues in the community would recognize our trials earlier on, to afford patients the opportunity to be enrolled,” Dr. Babiker adds.
And, as clinical trials proliferate, the Clinical Trials Office is steadily expanding its staff to accommodate demand.
“Clinical trials require more and more work every year,” Dr. Persky explains. “There are a lot of requirements to collect data, a lot of checks and balances to keep patients safe, and to provide all the information necessary to evaluate if the drugs are effective. It is very much a team enterprise.”
Ms. Cañamar credits the Clinical Trials Office’s success to “the passion that everyone on our team brings to the table” — health-care providers who ensure that clinical trial participants receive the best of care, and behind-the-scenes specialists who fire on all cylinders to tame mountains of paperwork.
Despite myriad challenges, the Clinical Trials Office is staffed with people ready to face them. By successfully shepherding a new drug onto pharmacy shelves, this team represents just a few of the folks who helped turn an idea into a tangible item rolling around in an orange bottle.
Photo 1: Daruka Mahadevan, MD, PhD. Photo: Kris Hanning
Photo 2: Hani Babiker, MD. Photo: Kris Hanning
Photo 3: Melissa Lim (left) and Ruth Cañamar. Photo: Kris Hanning
Image: Graphic by Steve Tkachyk, text by Anna C. Christensen