Key Takeaways
- The FDA may borrow ideas from Project Optimus to improve dose finding studies for rare disease treatments.
- Dose optimization is increasingly important in rare diseases because the patient populations are so small that additional studies often are not possible if a dose fails, FDA officials said.
- Like oncology patients, rare disease patients care about finding the right dose in addition to gaining access to the treatment.
The US Food and Drug Administration appears to be applying some of the thinking behind the Oncology Center of Excellence’s Project Optimus dose optimization initiative to rare disease drug development.
At a 29 October workshop titled Opportunities to Improve Dose-Finding and Optimization for Rare Disease Drug Development, which was hosted by the Duke-Margolis Institute for Health Policy, FDA officials stressed that dose optimization is just as important in rare diseases as in more common conditions. The FDA also said dose optimization may in some ways be a more urgent priority for rare diseases because the smaller pool of patients means fewer chances to run new studies if an initial dose fails.
While not formally unveiling any new initiatives, the workshop’s theme mirrored Project Optimus' mandate that patients care about finding the correct dose, in addition to obtaining access to new therapies as soon as possible.
Office of Clinical Pharmacology Director Issam Zineh described the tension between making treatments available as quickly as possible versus having “sufficiently elucidated the determinants of treatment response variability in a way that allows us to optimize therapeutic use at the individual patient level.”
The tension is universal in drug development, but there is “a kind of exceptionalism in rare diseases,” he said. Rare diseases “often don’t have the numbers to unequivocally answer questions about dosing and regimen optimization.”
Rare diseases also have a “tremendously urgent specter of unmet medical need” and can include access challenges. The issues are exacerbated for extremely rare, or N of 1, conditions.
“We have to be very skeptical of any position that de-prioritizes good dose-finding … because of some claim that patients care more about access than they do about getting the dose right,” Zineh said.
“In fact, we have taken that paternalistic posture before,” he added. “Engagement with patients with severe and life-threatening conditions doesn’t necessarily reveal that preference to be the case.”
“While of course clinical benefit is a priority, patients also value regimens that reduce pill burden and/or reduce dosing frequency, regimens that enhance tolerability and/or decrease either the frequency or the severity of short- and long-term toxicities, that prevent or mitigate drug-drug interactions, that would eliminate food requirements, that could allow for optimal use during pregnancy or when pregnancy is desired or may occur, and of course that reduce costs,” Zineh said. “Some of these concerns are addressable through dose optimization.”
Zineh said the HIV/AIDS drugs in the 1980s and 1990s were one example, but also mentioned a more recent experience.
“Even in oncology, where it’s long been presumed that patients would desire a drug with any survival advantage, we see a very clear patient voice that says they are not willing to trade quality of life necessarily for quantity,” Zineh said.
Focus On Gathering More Data From Each Patient
OCE launched Project Optimus in 2021 in recognition of the reality. The model was clearly front of mind for the conference organizers, who included a presentation by Division of Biometrics V statistical Team Leader Joyce Cheng on recommendations in the oncology dose optimization guidance finalized earlier this year.
Zineh argued that many of the themes of recent endpoint development work can improve dose finding. With fewer patients to study, developers must concentrate on gathering more data from each patient, and supplement the work with other approaches like modeling.
“In many ways, the same approaches can be leveraged to address all of these questions,” Zineh said. “They include optimized clinical trial designs, biomarker discovery and validation, the development and application of non-clinical models of disease, as well as drug-response, and quantitative methods, including empirical and mechanistic modeling and simulation strategies, as well as the use of real-world data.”
Standard Approaches May Not Be Feasible
Robert Schuck, director of the Office of Clinical Pharmacology’s Division of Translational and Precision Medicine, agreed that standard approaches to drug development may not be “applicable or feasible” for rare diseases.
That is “as true for dose-finding studies and dose optimization as it is for any other aspect,” he said.
Schuck also said dose optimization is “critical” in rare diseases because “it is very hard to re-do a study if we don’t get things right.”
In common diseases, an efficacy trial may indicate a dose is too low, so the sponsor can simply conduct another study with a higher dose. But Schuck said “With rare disease studies, that is nearly impossible.”
“We really need to enter those larger studies with the most informed dose that we can possibly do,” he said.
