Preparing for Growth in Neurodegenerative Treatment Opportunities: How Clinical Teams can Best Position Study Design and Strategy to Reach Study Participants

Advances in the understanding of neurology and neurological diseases have led to significant progress in the development of treatments for neurodegenerative diseases. While patient enrollment and retention for clinical trials in this field can be challenging, CROs with the right expertise, tools, and passion can help sponsors implement successful, cost-effective studies that minimize site and patient burden. The knowledge, expertise, drive, and passion of the entire PPD team make it easier on our clients and clinical trial patients and sites, and our innovative thinking makes it possible to bring breakthrough therapies for neurodegenerative diseases to the market as quickly and cost-effectively as possible.

Current Clinical Research in Neuroscience: Focus on Curative Treatments

Neuroscience is a fascinating area of research, and knowledge and awareness of the pathways in the brain have fortunately grown tremendously in recent years, which has contributed to growing understanding of the molecular aspects of many neurological and neurodegenerative disorders. From the Decade of the Brain Initiative (1990–1999) to the more recent International Brain Initiative (IBI), various global efforts in the last decades aimed to enhance public awareness of the benefits to be derived from brain research and from international research collaboration for CNS disorders. The number of new medicines discovered and brought to market in the last 20 years is not only reflective of these advances but also highly impressive. Indeed, in all areas of neuroscience, new approaches to treatment are evolving dramatically in response to the rapid progress being made today.

In addition, more changes are expected going forward, given that COVID-19 infections appear to have an impact on the expansion of neurological diseases. The virus is known to affect neurological systems, and in addition to milder but persistent neurological manifestations, some patients may develop severe conditions, including cognitive impairment, pain, sleep disorders, stroke, and in rare cases Guillain-Barré syndrome.

One positive outcome has been that many Big Pharma companies have reentered the neuroscience space, and much of the new efforts are focused on identifying curative treatments, specifically disease-modifying treatments (DMTs) and cell and gene therapies. This trend spans models in neuroscience indications and particularly in neurodegenerative disorders.

This new focus on finding cures rather than looking to treat symptoms is quite exciting, because these diseases are debilitating and no effective DMTs have yet been developed. In addition, neurodegenerative disorders are rather personal. Nearly every single person is close or relatively close to someone who suffers from Alzheimer’s disease, Parkinson’s disease, or another form of neurodegenerative disorder.

Right now, the industry is on the “doorstep” of finding solutions for neurodegenerative diseases. There is still much to learn, but the more we uncover, the more we understand what we do and do not yet know, which guides our efforts to obtain the required knowledge. As a result, within the near future, the industry will be in a position to leverage that understanding to find drugs that will effectively treat patients. Ideally, advances similar to those achieved in neuroinflammatory disease over the past 10–15 years will be realized for Parkinson’s disease and Alzheimer’s disease over the next 10–15 years.

Complexity Creates Challenges

Neurodegenerative diseases are particularly complex. There are at least 143 candidates in clinical trials for the treatment of dementia and Alzheimer’s disease, many of which operate by unique mechanisms of action and at least 132 candidates are in phase I, II, and III studies for Parkinson’s disease. That diversity reflects the complexity of the disease and the fact that it involves many different systems within the brain.

One aspect of the complexity of neurodegenerative diseases relates to their progression through different phases. That can lead to tremendous variability in patient experience and symptoms and complicate the evaluation of outcomes. There has been movement in clinical trials toward pre-identification of patients or even enrollment of prodromal patients that do not yet exhibit the full gamut of symptoms, with reliance on genetic status becoming increasingly important. The goal is to reduce the variability of the patient population with respect to the disease phase and thereby hopefully increase the success of these studies.

In addition, the degree of information sought from individual clinical trials has increased significantly. Studies in the past focused mainly on clinical responses, such as a specific symptomatic effect. For instance, trials for Parkinson’s disease in the late 1980s, 1990s, and early 2000s focused on treating symptoms and dealing with the treatment-related complications and/or late side effects often observed with these medications.

Later in the 2000s, after the Decade of the Brain and beyond, there was more of a focus on tracking disease evolution. Treatment of symptoms is extremely important for the patient, but a greater understanding of disease mechanisms typically leads to increases in the complexity of clinical studies. In Parkinson’s disease, for example, outcomes went beyond basic symptoms, such as rigidity, dyskinesia, tremors, and the ability to perform daily activities, to exploring biomarkers and trying to advance clinical exploration beyond symptom improvement and into disease progression.

In order to run these new trials targeting disease progression, new diagnostic criteria have been agreed upon and new outcomes measures have been validated to assess disease progression. Additionally, the target populations have shifted to earlier stages of neurodegenerative disease and presymptomatic study subjects.

For elderly patients, it is important in these newer clinical trials to balance the number of outcome measurements with patient burden. There may be great interest in many aspects of the disease within a clinical trial, but the patients involved are often frail, aging, and suffering. It is not reasonable to make them withstand a six-hour clinic visit for testing and scales. The moment they get tired, the inaccuracy in test assessment dramatically increases, and the data become less reliable.

For patients with early or presymptomatic disease, there is more leeway in trials that involve patients that are earlier with respect to disease progression. However, many of these people are still working and still cannot afford eight-hour doctor visits on a regular basis. These patients are driven to support finding a cure or treatment, but, realistically, they typically do not have the time to be away from the office for a full day every four, six, or even eight weeks.

PPD works with study teams, patients and caregivers on this issue of balance, because there is genuine excitement around the possibilities for new outcomes measures. The expansion and explosion of digital technologies for use in clinical trials is helping tremendously. For instance, from a Parkinson’s trial perspective, there is the opportunity to remove some physical tests, measures, and scales that require the patient to be in the office and replace them with wearable or other devices that provide real-time data that are not only objective but give better visibility into the patient while reducing the patient burden. In fact, it is comparable to shifting from a fixed picture, as taken during scale assessment at a short and specific time of the day in the office, to a movie, with technologies that can capture thousands of data points during a long period of time while the patients carry on their regular lives.

The industry is not only on the doorstep of new treatments but on the precipice of new approaches to conducting clinical trials. The idea of leveraging external methods to passively collect data that can inform the clinical picture about the patient is on the verge of widespread acceptance. That technology has the potential to transform how clinical trials are run, and PPD is at the forefront of implementing and leveraging these new solutions, including wearable devices.


Overcoming Enrollment and Retention Difficulties

The challenges of enrollment and retention vary depending on the type of neurodegenerative disease. For instance, with Alzheimer’s disease, it is necessary to confirm the pathology on the basis of specific biological or imaging biomarkers in a clinical research setting. Patients also must have cognitive and functional performance established and meet unique inclusion/exclusion criteria. Recruitment rates in clinical trials are still very low, and recruitment takes between 1.8 and 3.8 times longer than the treatment phase. To understand this major challenge, PPD is conducting a patient and caregiver survey on clinical trials to hear what matters most to people living with the disease and their caregivers. The survey results will help to understand how clinical trial design and conduct need to be optimized to increase enrollment and retention.

Furthermore, the temptation on the part of teams planning clinical trials on neurodegenerative diseases is to use the same sites repeatedly and take advantage of the experience gained by the staff. With common diseases like Alzheimer’s and Parkinson’s, however, it is easy to reach the maximum number of patients that can participate in a clinical trial. That impacts enrollment as well. The exhaustion of patient pools resulting from conducting too many trials targeting the same populations at the same site is a major reason for sites declining to participate in clinical trials, but a lack of sufficient staff can also be a contributing factor.

PPD is overcoming this challenge by establishing research sites at large medical facilities with broad capabilities and access to large numbers of new Alzheimer’s and Parkinson’s disease patients. We are continually expanding our site database to add new sites and new investigators that are experts in the diseases we are studying, know their patients, and have some experience in clinical research. We provide support to these sites and investigators through additional training on clinical research and more relevant scales and newer digital technologies, along with closer follow-up. We also continue to leverage our key, established sites that have highly experienced staff who can offer guidance. Linking sites that are geographically close to establish research networks also facilitates patient selection and staff training.

This approach reflects an investment in the future while simultaneously providing an effective solution for present challenges. It allows more trials with more patients to be conducted today and ensures that the sites are well-positioned to conduct patient-centric, decentralized trials. The key is for the patients to have trust in the relationships they have with their physicians and/or neurologists.

It is also important to note that the expansion to more sites allows us to address not only the issue of patient enrollment but also patient retention. With the new disease-prevention studies and trials that go beyond symptom treatment to include disease-modifying therapies, it is more important than ever to keep patients enrolled over the full term, which can in some cases be two or three years. Patient engagement throughout the course of the study is critical. Patients must know what is being done and why and what outcomes are expected. Patient engagement in the basic science and objectives of the trial, as well as the bonds between patients and site staff, is key for patient retention.

Contract research organizations (CROs) must deliver data and regulatory documents that clients can submit to regulatory authorities when seeking marketing authorization for their drug candidates. The data are generated by conducting clinical trials with patients, and patient retention is essential for generating valid data. As much data as possible must be collected to achieve an analysis with a level of sensitivity sufficient to allow confident decision-making. When a patient drops out, that data is then missing and must be imputed using statistical processes that can reduce the accuracy of the data analysis.

The patient experience and patient burden are at the center of how we approach clinical trials, because there is a direct link between patient retention and data integrity. We take the time to know who our patients are and then determine which sites are best suited to see them, given the process and protocol. We also invest time in optimizing processes as much as possible in consideration of the burden to patients. Part of that effort is establishing the optimal balance between the desire to add more outcome measures and the need to avoid overcomplicating the process for the patient. It is worth noting that as much as 50% of all academic clinical trials are never published, a number that may be higher for industry-sponsored trials. Even within the published papers, a significant number of the “exploratory outcomes” are not typically included, and in many cases these outcomes have no real scientific use, despite the increased patient burden they cause. In the end, PPD focuses on trial optimization, streamlining the process, and selecting the best endpoints for the patient and the sponsor in order to generate the best data.

Rare disease studies are often linked to specific sites, because only certain centers specialize in these rare illnesses. For studies of rare neurodegenerative diseases, rather than having large numbers of patients that must be funneled to the right sites with sufficient personnel and research equipment, the problem can be in finding patients willing to participate. Consequently, there is a need to establish relationships with these sites. Patient selection takes place at the sites, often in conjunction with patient advocacy groups. To address the specific enrollment needs for rare diseases, PPD has established relationships with a significant and highly valued group of rare disease sites and with many different patient organizations. We take a very personalized approach with these specialized sites and work closely with advocacy groups to benefit from the unique insights they have on general developments regarding the diseases they focus on.


Wearables Driving Revolution in Movement Disorder Trials
For movement disorders, wearables will enable a revolution in the way we study patient symptoms. They allow ongoing study of patients while they go about their daily lives, significantly reducing the patient burden while providing real-time data gathered in real-life settings. As wearables allow a continuous monitoring of disease parameters, it provides access to information about how movement issues wax and wane throughout the day — information that cannot be collected in a 45-minute doctor’s visit or even a four-hour session for a clinical trial.


Researchers will no longer be limited to collecting data at fixed points in time; they will be able to track patients for long periods, generating large quantities of data that can be analyzed using artificial intelligence and machine learning. As these devices get more sophisticated, they will provide even more valuable information that will help drive the development of effective treatments.

Protocol Optimization at PPD

In general, only 40-50% of clinical trial data is used for registration or publication. The question then becomes: If more than half of the data isn’t going to be used, why generate it? What is needed is an optimization of protocols to ensure that only relevant data are produced and unnecessary work is eliminated, to remove any unnecessary burden on both the site staff and patients.

The protocol optimization process at PPD involves exploring the protocol and the schedule of events and includes an automated method for estimating the amount of time required and the cost per procedure and the number of procedures needed per patient visit to determine site and patient burden. It also compares the protocol to peer protocols (both PPD and external) to determine what is outlying and different (not that different is necessarily negative). Input is included from patients and site staff regarding their insights on the complexity of the protocol.

This information is mapped to the specific endpoints, and the result is a summary of what is relevant and what is secondary to the goals of the trial. The information on time and cost for each item helps sponsors to evaluate which tests might not be truly relevant when considering real day-to-day life for the site and the patients. The ultimate result is a streamlined protocol focused on collecting the primary and key secondary endpoints that will minimize the patient burden when still providing the results necessary to make decisions about the drug candidate.

In one case, PPD looked at a protocol for a client that was struggling to run a trial. During the protocol optimization process, it was discovered that both the site burden and patient burden were quite high when patients were enrolled, owing to the number of procedures and time required to complete them. At the first visit, there was a lot of data coming in, and a high volume of scale assessments had to be performed. In addition, the site was expending tremendous effort to recruit and enroll patients into the study. However, the sites were not being compensated for this front-loaded time expenditure. That misalignment was only revealed by taking the holistic view afforded by PPD’s protocol optimization process. Streamlining of the protocol to reduce the site and patient burdens and modification of the site payment structure to allow compensation for time spent were recommended as a result.

That is why PPD developed the protocol optimization process as a real way to generate value for sponsors. It also takes about 18 business days to complete — less than a month overall. On average, we achieve a 9% reduction in complexity and a 12% reduction in patient burden. These reductions translate directly into reduced costs and higher enrollment rates.

PPD is Well-Positioned to Support Neurodegenerative Disease Clinical Trials

PPD has had great success supporting clinical trials in neurodegenerative diseases, because we filter built-in science and clinical knowledge through to our very passionate implementation teams that work hard to ensure not only that clients get what they need but that clinical sites and patients are also properly supported. Some of our team members are neurology patients taking drugs that PPD helped to develop. Others have children with neurological disorders. Everyone is driven to develop new drugs that help patients lead long and successful lives.

We also have in-house physician–experts that are still practicing, understand trends in treatment and the patient experience, and continue to see and treat patients. Our patient solutions department works to identify the best mechanisms for reaching out to patients. PPD has also forged close connections with many patient advocacy groups in order to understand what matters most to patients and how we can better support them during clinical trials.

Continuous interactions between teams from different departments with different areas of expertise ensure the development of optimal solutions. In addition, using unique tools, such as protocol optimization, disease and clinical trial simulator technologies, and our accelerated enrollment solution system, PPD is able to define optimum sample sizes and generate unique quality data and clinical outcomes that can be plugged into regulatory documents in a fast and efficient manner. We help pharma companies design their clinical protocols to ensure that site and patient burdens are minimized and patient enrollment and site engagement are boosted. The result is quality and value realized with speed.

In essence, the knowledge, expertise, drive, and passion of the entire PPD team makes it easier on our clients and clinical trial patients and sites, and PPD’s out-of-the-box thinking makes it possible to bring novel medications for neurodegenerative diseases to the market as quickly and cost-effectively as possible.

Alberto Lledó, M.D., Ph.D.

Dr. Lledó provides strategic counsel and direction to internal and external programs and teams, regionally and globally, for all aspects of the clinical research work and all phases of studies in the neuroscience therapeutic area. He is also the scientific and medical lead at PPD’s Movement Disorders (MD) and at the Multiple Sclerosis (MS) Pillar teams. Based in Barcelona, Dr. Lledó joined PPD in 2017, with more than 22 years of experience with global medical leadership roles in big pharma and as a CMO of a UCL academic spin-off company in London. Dr. Lledó clinical and research focus are in the areas of MD (Parkinson’s disease, Tauopathies, Huntington’s Disease, RLS, etc.) and other neurodegenerative disease. He has also significant experience in multiple sclerosis, pain, and peripheral neuropathies. Dr. Lledó has kept doing part-time clinical practice, as a neurologist, throughout all his pharmaceutical career.