Drug Development As A Progression Through Stages: A Patient-Centric Approach To Progress
People living with Parkinson’s disease urgently need better treatments, both for symptom relief and to slow disease progression. The pathway for new drugs to reach patients relies on successful testing in randomized, placebo-controlled trials. Without rigorous trials, we would not have confidence in the safety and effectiveness of most of the drugs (and devices) that are currently available for Parkinson’s disease.
The core principles for drug testing go back to the 1962 Amendment to the Food, Drug and Cosmetics Act which required that new drugs approved for use by the Food and Drug Administration be both safe and effective. The Amendment describes core concepts including “substantial evidence” based on “adequate and well-controlled investigations” as the basis of which a drug will be considered have the effect “it is represented to have under the conditions of use proposed in labeling.” Over time, the idea of clinical meaningfulness summarized as an effect on how patients “feel, function or survive” has also become a core principle. This formulation can be traced back to a 1977 supreme court opinion by Thurgood Marshall, who wrote, “In the treatment of any illness…a drug is effective if it fulfills, by objective indices, its sponsor's claims of prolonged life, improved physical condition, or reduced pain.”
While rigorous and time-honored, the traditional clinical-trial approach can be expensive, slow and may not place enough weight on the underlying biology that is the root cause of diseases. As a result, clinical trials have been modified over time to accommodate emerging biological concepts of disease and the need to test drugs as efficiently as possible. The objective of these modifications is to accelerate drug approval for serious conditions like Parkinson’s disease and Alzheimer’s disease by centering on underlying molecular pathology. Trials that use biomarkers of the disease process as outcome measures could potentially be shorter and require a smaller number of participants, leading to a more efficient process.
The new approach has many advantages, but it also has unexpected consequences that may conflict with the core principles of drug approval. One is that a new therapy could be considered effective even if there is no discernable evidence of clinical benefit, (i.e. no potential to impact clinical features of disease), at least in the short term. Another is that clinical trials would not necessarily need to be conducted under the intended conditions of use, i.e. not in patients who have clinically recognizable form of disease.
How can we reconcile the biological aspects of disease with patient-centered trials to approve treatments that both address biology and what matters to patients?
A critical element will be establishing a clear connection between the underlying biology of the disease and its clinical impact on patients. This includes understanding the pathology of the disease, its mechanisms, and how specific treatments work. Gathering the evidence to support these connections may exceed the scope of any single drug development program or pharmaceutical company, though the industry will be a key partner in bridging this gap. Instead, a collective body of scientific evidence will be necessary, much of which will likely come from longitudinal studies across the full spectrum of the disease, such as the Parkinson Progression Marker Initiative. This evidence will rely on existing biomarkers of disease pathology and, ideally, a new generation of biomarkers that additional reveal disease mechanisms.
A second key element is thinking about drug development as a progression through stages. The first step is to conduct trials based on the new paradigm that confirm effects on underlying biology and then conduct trials that return to the traditional paradigm to show that the treatment helps patients with active symptoms. These trials would be in appropriate patient groups and using patient-centered outcome measures. Ira Shoulson, who died last year, could be considered the father of modern therapeutics for Parkinson’s disease. Dr. Shoulson was a tireless advocate for patient-oriented outcomes. He referred to this mission as “listening to the patient’s voice.” Today, that might seem like an idealistic gesture—quaint, perhaps—but it is a stance that still has much to teach us.
Better treatments for Parkinson’s disease are desperately needed to relieve the burden of the disease itself, and to ease the strain it places on families and loved ones. Emphasizing biology is critically important for finding drugs, particularly those that address disease progression. However, the only way to know a drug has a clinically meaningful effect in its conditions of use is to test it in patients in need of better treatment and listen to what they say about how well it works.
Andrew D. Siderowf, MD, MSCE is Associate Professor of Neurology at the Pennsylvania Hospital Department of Neurology in Philadelphia. He has spoken at past World Parkinson Congresses and will join the WPC Research Spotlight 2025 series on Tuesday, April 15, 2025. Register here for the series.
Ideas and opinions expressed in this post reflect that of the author(s) solely. They do not reflect the opinions or positions of the World Parkinson Coalition®