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When a process works, it’s natural to try to repeat it rather than recreate or rethink it. This holds true in running clinical trials to develop new drugs: the main path to FDA drug approval is often the same path that led to the prior drug’s approval.

For decades, the foundational basis for determining if a drug should be approved is whether its benefits outweigh its known and potential risks for the intended population. At its core, this is a quantitative risk-benefit analysis. It is not a patient-centric evaluation and it does not emphasize individual patient quality of life as a significant factor.

It’s time to start shifting this strategy and instead approach drug development not only through balancing efficacy and safety, but also by taking into consideration the broader needs of patients as individuals.


Cancer drugs are good examples of this challenge. They have traditionally been developed with a focus on eradicating cancer cells and shrinking tumors to undetectable levels, and certain levels of toxicity are the tax assumed for the realized benefit. The cost to the patient in terms of tolerability, ease of use, compliance with the therapy, and quality of life are not always the primary driving factors in development decisions. But drug developers must begin implementing these considerations into their algorithms.

At a fireside chat at the SVB Leerink Therapeutics Day in Boston this summer, Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, commented on the need to incorporate the patient’s perspective to develop better designs for clinical trials. A few months later, speaking at the Breakthroughs in Medicine conference, she said, “The science is fabulous, but that’s not enough.”


The implication of Woodcock’s statements, at least in part, is that there are better ways to approach drug development to benefit individual patients, help them stay on treatment, feel better, and live longer. Drug developers need to take a lead in achieving this goal.

New and creative solutions, such as figuring out better dosing and treatment schedules, can be the difference between a potent drug associated with severe side effects and one that patients are willing to take long enough to maximize the benefit. We’ve seen successful examples of this before.

In the early 1990s, there were limited treatment options for women with breast cancer that was resistant to available chemotherapy agents. The introduction of taxanes like paclitaxel and docetaxel marked a significant advance in treatment.

Although taxanes are now a cornerstone of breast cancer therapy, they were initially too toxic for most patients. Since then, the average dose has been reduced, dosing schedules have been optimized with lower doses administered more frequently, and taxanes are now being used to enhance other treatments. These adjustments have led to promising results and have allowed more patients to be treated for longer periods of time than in those early days.

Cancer drugs may work well when given daily, continuously, and indefinitely. But they may also work at least as well — and with lower toxicity — if given less often. A class of cancer drugs known as histone deacetylase inhibitors was among the first to be used with an intermittent regimen, in which a high dose is followed by a rest period intended to allow the body to recover from side effects.

When the FDA approved Yervoy, the first checkpoint inhibitor marketed in the U.S., in 2011, it was highly effective but only in a small subset of patients with advanced disease. And as with many new therapies, there were new treatment challenges, due in large part to immune-related toxicities. From subsequent experience and clinical trials has emerged a better understanding of how to use immunotherapies. One approach is to use flexible dose regimens, which have successfully expanded the number of patients who can benefit from Yervoy.

My company, MEI Pharma, is investigating alternative schedules that could not only improve the overall risk-benefit ratio but more broadly take into account the needs of patients as individuals. An example of this can be found in our development of ME-401, an investigational drug candidate that blocks phosphoinositide-3 kinase (PI3K) delta, a key pathway in the proliferation and survival of B-cell malignancies.

While some of our trials use continuous daily dosing, others use an intermittent dosing regimen. The latter is based on understanding drug concentrations in plasma and tumors, as well as understanding the renewal cycle of key immune cells thought to be related to potential toxicities.

Our decision to evaluate an intermittent regimen with ME-401, which leveraged immune modulating learnings from the Yervoy experience, aims to identify an approach that can achieve clinical benefit and minimize the adverse events that challenge other PI3K-delta agents. So far, these adjustments to dose and schedule are demonstrating promise in mitigating toxicity and in deriving extended benefits from treatment.

Instead of considering the best comparator compound and the easiest way to copy past programs, drug developers need to become more nimble and innovative. There isn’t a one-size-fits-all solution for improving therapeutic approaches and clinical trial designs. But creating novel and effective alternatives to drug administration and dosing is one way to help put patients at the heart of clinical trials and deepen the understanding and appreciation for the characteristics of a compound.

Study designs for drug candidates that are more patient-centric will be a next step in leading a paradigm shift toward a patient-centered approach to drug development.

Richard Ghalie, M.D., is senior vice president for clinical development at MEI Pharma.

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