Today, clinical trials have to comply with rigorous rules and ethical compliance. Clinical trials are highly structured, and in addition to efficacy, they also determine side effects, interactions and long-term effects.
For Heidemarie (also known as Heidi) Kletzl, Clinical Pharmacologist, and Yumi Cleary, Pharmacometrician, this level of rigor is absolutely necessary and makes every success that much sweeter, especially in the case of rare diseases, where treatment options are often scarce.
“We work in a strictly regulated environment to ensure we gather the necessary data in a safe manner without undue risks for the patients,” Heidi explains. “It usually takes from six months to a year to plan and set up a trial, and it can take several years to enrol patients and collect the required data. All these highly controlled procedures are important because in the end we need to be sure that the medicine is working as intended and is safe.”
The design and operational execution of a modern clinical trial varies depending on the focus of the research; it usually assesses whether a medicine or a device is functional and fit for purpose, or determines the improved quality of life.
If a disease has a fast and high mortality, scientists must balance the intense desire to get a new medicine to the patients quickly while adhering to the requirements of a clinical trial.
“Clinical trials guarantee the utmost rigor in assessing the value of a potential new medicine,” says Heidi, “but we need to move fast, especially for patients living with severe life-threatening diseases where time is of the essence.”
So, the team asked: What if there is a better way?
Phase I - researchers test a new drug or treatment on a small group of healthy people to evaluate safety, dosage range and identify side effects.
Phase II - usually a small group of patients (often between 50 to 300 patients, depending on the disease) receive the medicine to evaluate safety and efficacy at different dose levels.
Phase III - larger groups of patients, often 1000+, are tested to establish safety and efficacy in the respective disease for the new medicine.
Phase IV - after a treatment has been given regulatory approval (i.e., market authorisation), information on the risks, benefits and best use, as well as data on people who have been taking the drug for a longer time, is gathered from doctors and patients.
For the development of a new medicine in a disease with high morbidity, the clinical team conceptualised a new approach: combining Phase II and III into a single clinical trial. In order to shorten its timeline and carry it out successfully, the team, and external partners, worked tirelessly on weekends.
Moreover, because the most severe form of that disease affects infants, with symptoms appearing within months of their birth and death usually occurring before their second birthday, the data from the clinical trial needed to come from infants.
Typically, the appropriate dose — the critical aspect to making sure a medicine is effective and safe — is determined after conducting a Phase II study, with a large group of patients. However, in this fast-tracked small trial in infants, the appropriate dose was determined based on ongoing data monitoring and dose adjustment for each individual infant during the study.
With this approach, the time between the first dose given to a human being to submission for approval was reduced from around ten years, which is often required for the standard development path, to less than four. “It was so gratifying to see how many patients' lives were saved because we were able to employ this bold and innovative clinical trial design,” says Heidi.
“It was very stressful,” Yumi adds, “I was nervous, especially working with babies, but in the end, being a part of the team bringing a treatment to market that will save many patients, including children’s, was the highlight of my career at Roche.”
For their outstanding work to bring a new molecule to patients in an unusual think-out-of-the-box manner, Yumi, Heidi, their colleagues from the Roche project team and their external partners received two awards, from the British Pharmacological Society and the Society for Medicines Research respectively in 2021.
Yumi and Heidi gather data from the trial’s participants’ blood, then develop a model and run multiple simulations in order to determine the appropriate dose. But they are only two of the hundreds of people needed to develop a new medicine and to deliver it to the patient—from those who bring the trial subjects on board to the medical teams who care for them to data management teams, bioanalytical lab personal, toxicologists, statisticians, medical writers and biometrics teams. Not to mention the tireless efforts from charities and research organisations to raise funds and disease awareness.
“Just as it takes a village to raise a child,” Heidi says, “it takes a very big team to run a clinical trial successfully.”
While modern clinical trials have come a long way since the battlefield, there is always room for improvement. “And we won’t stop innovating and working together,” Heidi promises, “to continue to take clinical trials to even bigger new heights.”
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