Most people hear about clinical trials when they enter phase III, when researchers need larger pools of participants and when there is more knowledge about the drug or treatment plan.
However, so much more goes on behind the scenes to reach that third phase — and so many more improvements can be made to streamline the journey to get to phase III. High data quality, better safety decisions, reduced trial operation costs and faster study execution can all be key to making early phase trials more successful.
There are several clinical research organizations (CROs) and trial developers who are looking to change their approaches to the early phases of development. Learn how technology and new scientific knowledge are improving phases I and II.
Reviewing Early Phase Trial Design From a COVID-19 Lens
It helps to use the COVID-19 vaccine trials as examples of high-level best practices.
During the first wave of vaccinations, most Americans received a two-dose vaccine, manufactured either by Pfizer or Moderna. Concurrently, Johnson & Johnson wrapped up the phase III trials of its one-dose vaccine, which the FDA approved for emergency use in February 2021.
That was good news for public health experts. “If we can have a vaccine that is a single dose, the J&J vaccine would become, without doubt, the vaccine of choice for the world,” says Carlos del Rio, a professor of medicine at Emory University.
Significant testing was necessary to determine whether a one-dose vaccine was safe, and what its efficacy was. That’s what researchers explored during phase II of the Johnson & Johnson trials — dosage levels and the vaccine’s safety.
Phase III of that trial helped determine what a safe single-dose shot would look like and how it would be administered. Johnson & Johnson conducted two phase III studies for this vaccine, each with 40,000 volunteers. Compare that to the 805 participants for phases I and II combined.
Smaller phase I and phase II studies are designed to protect the general population. Researchers have to make sure the dose and active ingredients are completely safe before reaching out to a phase III participant pool of thousands.
But what happens when researchers don’t have thousands of willing participants to participate in early phase trials? How can researchers improve the early phase experience so it is more effective and better for the patient?
This is where data comes in.
Early Phase Trials Are Getting Smarter
Only a small portion of early phase trials ever get pushed into phase III research and onto drug approval. Some researchers spend years working on a treatment option and testing it, only to receive inconclusive data that can’t be pushed forward.
In an article for Antidote, Eian Kantor explains that just 33 percent of clinical trials even make it to phase III — compared to 70 percent that pass on to phase II from phase I. The small group of trial participants could spend several months in a trial that never gets approval to move forward.
However, there is a growing movement to retool how researchers conduct early phase trials. This can create better patient outcomes, prevent waste and help research organizations save money.
“Phase 1 clinical trials ... have changed significantly in just the last few years,” says Dr. Lynne Eldridge, a physician and patient advocate. “With the advancement in precision medicine, which allows treatment to account for individual genetic differences, it's likely that phase 1 clinical trials will continue to offer more promise for individuals rather than simply studies performed to see if a drug is safe.”
Those promises include helping potential treatments get to market faster. Further, a reimagining of early phase trial design in this context could allow teams to work more quickly.
“The sooner we can be confident that a drug or a dose of a drug either works or doesn’t work, the sooner we can either advance that drug or stop evaluating it in patients,” says Rob Lenz, vice president of global development at Amgen. “To me, that’s a great example of patient centricity.”
Precision Medicine Is Changing the Clinical Trial Process
Precision medicine uses only a handful of patients to evaluate the effectiveness of a treatment option. In some cases, these might be one-person trials, or “n of 1 trials.” Using a smaller sample might seem counterintuitive, but precision medicine increases the chances that a treatment might actually work.
“When the industry refers to ‘precision medicine,’ it means a targeted, individualized approach to disease prevention, diagnosis, and treatment,” says Wayne Bowden, VP of partnerships and strategy at Biorasi. “This individualized medicine can be directed and differentiated around a patient’s own genetic makeup, lifestyle, or specific reaction to the environmental stimuli around them.”
Precision medicine forces researchers to conduct more research and do more planning when designing the early phases of a clinical trial. Because there is a smaller sample, researchers need to make sure the data isn’t corrupt or tarnished by outside factors.
“In order to create a platform for precision clinical trials of target therapies, we need to develop assessments of genetic factors, environmental impacts, and gene-environmental interactions,” explain WebMD CMO Dr. John Whyte and James J. Gillespie, a professor at Saint Mary’s College.
These precision trials are made possible because of large-scale clinical trials. Doctors can use the data from more common conditions to inform their decisions around rarer issues and use the information to drive better results.
“I think the common conditions have the opportunity to learn a lot from us rare diseases because we’ve always dealt with small populations,” says Sharon Terry, CEO at Genetic Alliance. Terry’s two children were diagnosed with a rare genetic disorder in the 1990s, leading her to conduct her own research, identify the genetic cause, and develop diagnostic tools and clinical trials for it.
Developers Should Balance Advancements With Patient Care
Ending a trial early can be viewed as a setback for some patients, who might not be willing to sign up for another trial or could feel worried about their future treatment plans.
“Loss aversion is a key principle in behavioral economics,” says Judith Garber, a health policy fellow at the Lown Institute. “Put simply, we feel the loss of something greater than we feel the gain from something. This matters in clinical practice because if a patient thinks there is something that will help their condition and then they don’t receive the intervention, they will perceive it as a loss.”
Poor experiences in clinical trials can lead to lower recruitment rates, something the industry is already struggling with.
“Patient recruitment is an industry-wide challenge—only about 3 percent of American cancer patients participate in clinical trials,” says Tandy Tipps, vice president of the Precision Oncology Site Network. “The recruitment and retention of qualified participants are essential for meeting timelines, budgets, and overall trial success.”
Essentially, speeding up phases I and II — even with better data that allows drug and treatment developers to find the best possible options faster — can have ripple effects if patients aren't prepared for the change or aware that new processes can affect their eligibility.
“Even simple conversations with patients about the value of clinical research can change the way they think about participation,” write Jennifer Byrne and Amanda Wright at Greater Gift, along with Jane Shen, president of the Board of Directors at Wake Forest Healthcare Venture.
Greater Gift conducted a survey as part of its Hero’s Journey Art Project. It polled attendees before and after viewing the installation on whether they would participate in clinical trials. Before the experience, only 25 percent said they would. Afterward, 40 percent said they would be somewhat willing to participate.
CROs need to focus on how they engage with patients, especially in their early-trial experiences.
The next decade could potentially hold some dramatic changes in early stage clinical trial design. A growing focus on precision medicine will mean smaller volunteer groups to help researchers identify treatments for rare conditions. Today’s CROs and industry leaders continue to test what works best for patients in early trial design and what drives the best possible data to advance treatment and care.
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