|By Tré LaRosa
For anybody with a neurological condition, it can be very frustrating to not have answers or a treatment plan that is improving their life. It can feel that medicine and science take too long to find solutions that have a tangible positive effect on patients’ lives. So why is it this way, with science and medicine often taking years or decades before patients can have access to a therapeutic that significantly helps them? In this blog, we’ll discuss those challenges, why they exist, how they hamper progress, and why resolving them would have a profound effect on the treatment of neurological conditions.
It takes time to generate enough evidence
Medicine is both a scientific field and a field unto itself. Medicine, then, operates within the same framework as science in that medical decisions must be guided by evidence-based decision-making. But science, for all its positives, is often not as quick as we would like it to be. This isn’t necessarily from lack of trying, but legitimate, rigorous science requires extensive evidence to ensure therapeutics are safe and effective. This means therapeutics are often investigated in the lab before they get investigated in animal models, and then promising evidence must exist in animal models before clinical research can be ethically conducted. Medical research is guided by firm ethics, guidelines, and processes at every phase of the process. Often, patients — and even doctors and scientists themselves — can feel that these guidelines and processes are too bureaucratic and burdensome and limit medical advancement, but these safeguards exist to ensure structural legitimacy and trust between the patients and the medical system.
Not every aspect of treating patients requires extensive research and approval. For example, medical devices that present minimal risk to the user, such as an ankle brace or elastic bandage, are defined as Class I and are usually exempt from the Federal Drug Administration’s (FDA) regulatory processes. Other devices, such as wheelchairs or implantable pacemakers, go through more stringent research and regulatory processes since these are usually life-saving, life-sustaining, or directly implanted into bodies. In terms of treating conditions, this distinction is important as it demonstrates the varied regulatory processes in place that are meant to be proportionate to the level of risk or benefit to the patient. Medications, on the other hand, since they can have extensive effects on the body, must go through more extensive regulatory processes. These processes, and the reality that it takes time to accrue enough evidence to ethically advance therapeutics through each phase, is one challenge when treating any condition. Science is a study of how the world works; medicine, though, is the treatment of human beings. Most scientists are motivated by both an intrinsic desire to better understand how the world works and how to utilize those findings to make life better, but while that desire is decent, patients are immediately affected and that’s where doctors operate, within the liminal space of what we do scientifically understand and what we don’t.
Some challenges are systemic; they are realities of the way current research is done and are unlikely to change in any demonstrable way in the near future because changing those processes would expose patients, doctors, and scientists to far more risk. Eliminating or significantly reducing that framework would not benefit patients and could in fact lead to more harm, since accelerating therapeutics from the lab to humans might mean cutting corners with animal research, which is where dosing ranges are usually determined, thus meaning clinical researchers would not have a strong understanding of where to begin. Without knowing where to begin with dosing, clinical researchers could unintentionally begin at a high, toxic dose. Instead, since therapeutics go through animal research, dosing ranges are found, including sub-perceptible ranges, therapeutic ranges, and toxic ranges. Once a drug has been found to be safe and effective in animals, then clinical researchers start with a lower therapeutic dose than expected in humans so as to verify its safety before focusing on efficacy.
The cause is unknown
There are a lot of factors that go into how medicine defines conditions. Some conditions are so defined based on a cause that is clearly understood; some conditions are defined based on a group of symptoms that commonly appear together with or without a known cause. Most conditions are not very basic. Even conditions with clearly understood risk factors, such as lung cancer, are not always attributed to a specific cause. You’ve likely heard of people who smoke a pack of cigarettes a day for decades never developing lung cancer, and people who shockingly develop lung cancer even though they avoided all behavioral and environmental risk factors and don’t have any known genetic factors that predispose them to lung cancer. The key point here is that for conditions that are not entirely genetic, we really just don’t have a perfect picture of all existing factors that can result in a given condition.
So why is knowing the cause important for treating a condition? This is a sort of multi-faceted question. Understanding the cause of a condition — medically termed “etiology” — is personally relevant to patients, medically relevant to doctors, and scientifically relevant to scientists and epidemiologists. For some conditions, especially those that adversely affect the immune system, knowing the cause could be the difference between relapsing or not. For other conditions, it might not be a question of relapsing but actually related to how the cause, which may be genetic, environmental or behavioral, is perpetuating the clinical presentation. If a cause can be found, then the patient can do their best to reduce exposure which may have a positive impact on their short- and long-term health. Conditions can have somewhat homogeneous clinical presentation, meaning patients present with similar symptoms, despite being caused by different factors. With a known or strongly suspected cause, the doctor can better treat the patient. Even having a general idea of what the cause is instead of simply calling it idiopathic (meaning no known cause can be found or differentially determined) can provide the doctor useful information that can influence treatment plans. Patients can also gain a sense of comfort or peace when they have a known cause for their complex condition, especially those that affect the nervous system.
Teasing out etiology also has scientific implications; the better condition etiologies are understood, the better researchers can develop their diagnostic, measurement, and therapeutic research priorities. Having fewer uncertainties should have the benefit of accelerating scientific research. Of course, scientific research also informs how etiology is discovered. It is not necessarily possible to perfectly identify and understand how an amalgam of different factors come together to give rise to a person’s specific development of a condition. Epidemiology, the study of population dynamics related to public health, is another critical component of the research realm. Epidemiologists seek to better understand the incidence and prevalence of conditions across the population and the varying subpopulations; these researchers look to find where disproportionate rates of a condition show up. If researchers notice a condition is more likely to develop in a more humid climate, they can then develop a list of hypotheses for which factors might contribute to this. With a better understanding of etiology, every step in the process of prevention, diagnosis, treatment, and curing a condition will be better tailored and conveyed to the patients and general population.
This challenge is of particular significance in neurological conditions. Alzheimer’s, Parkinson’s, treatment-resistant depression, epilepsy, multiple sclerosis, and amyotrophic lateral sclerosis (ALS) are all neurological conditions without known etiologies, leaving patients and their family members with uncertainty in addition to dealing with the condition. While it might not be possible to get exact answers, providing some degree of clarity or understanding will likely benefit those who are affected by a diagnosis, either mentally or even therapeutically. For therapeutic development, knowing the cause gives researchers a better starting point — instead of many, many places — to work from in terms of treating and resolving a condition.
There’s also another component: If the medical and scientific systems can work out a condition’s etiology, it strengthens the legitimacy and credibility of these systems. It will give patients confidence that these systems are working towards a better future, which also improves patient, doctor, and scientist morale, which is certainly not for nothing.
Disease mechanism is poorly understood
Sometimes, a possible cause with a low-to-moderate degree of certainty is found for a patient with a mostly usual clinical presentation. For many conditions, there are many theories for etiology, but knowing what causes a condition is unfortunately not enough. Researchers must also mechanistically explain how a cause and pathology give rise to a clinical presentation. For a condition to be determined to be entirely genetic, researchers must have a very strong understanding of what the specific gene or genes that are dysfunctional in a patient should do if they aren’t disrupted. This might sound relatively simple but it is unfortunately not; genes do not exist in a vacuum and affect other genes just as other genes affect the specific gene of interest. Not all disrupted genes are considered equal or the same, either. For example, cystic fibrosis, a genetic disease that affects the cystic fibrosis transmembrane conductance regulator gene, has more than two thousand known mutations that give rise to many different phenotypes of clinical presentation. When a condition’s mechanism of action is relatively well-understood, researchers have a much better starting place for therapeutic development since they can begin to target specific processes within the body.
To understand how this is a challenge — and how a much stronger understanding of the mechanism of action would accelerate therapeutic development — consider Alzheimer’s for a moment. There are many risk factors correlated with an increased likelihood to develop Alzheimer’s, but there is not a consensus on how much any given risk factor contributes to the development of Alzheimer’s. In terms of neuropathological clinical presentation, Alzheimer’s is associated with the presence of neurofibrillary tangles and beta-amyloid plaques, but in people who died in advanced age, it’s hard to distinguish between the brains of people with Alzheimer’s and without. While it has been shown that these lesions and the loss of synaptic components are strongly and significantly correlated with cognitive dysfunction, there remains uncertainty about how these specific abnormalities develop, which is partially related to cause, but also related to both the underlying mechanism of Alzheimer’s and how synaptic loss directly contributes to cognitive decline. With a better understanding of how a condition’s pathology gives rise to its clinical presentation, drug developers can target those pathways and mechanisms, which would suggest a better likelihood of success. Neurological conditions would stand to gain a benefit in particular since there remains a lot to be learned about the nervous system. Which brings us to the next challenge…
Remaining uncertainty or unknowns about the nervous system and the interconnectivity/interdependence of human bodily systems
The human body is very, very complex. The nervous system, comprising the brain, the spinal cord, and our nerves, is itself a complex bodily system, but our body systems are interconnected, interdependent, and bidirectionally influential. Conditions don’t have to directly affect multiple organ systems for them to indirectly affect multiple systems. Much remains to be learned about the brain and other parts of the nervous system. Our brains give rise to our minds and our minds have a pronounced effect on our bodies, as evidenced by the placebo effect. The lack of clarity on many aspects of how the nervous system works and how different parts of our brain contribute to different functions makes developing therapeutics additionally challenging. Medications must be deemed safe and effective before they will become available to the general patient population, but many steps go into the drug development pipeline before then, including figuring out what a therapeutic agent should target. With the complexity of the nervous system and its relationship to the rest of the body, researchers must navigate not understanding the cause of a condition, how its pathology gives rise to the condition, and the complexity of the nervous system. As the nervous system and the profoundly complex brain become better understood, this will have important, positive downstream implications for those affected by neurological conditions.
Lack of strong biomarkers
Biomarkers are measurements used in medicine and research to diagnose and monitor conditions. They are incredibly important in clinical research as biomarkers are usually the very outcome measures by which therapeutics are determined to be safe and effective. Biomarkers are used in the management of every condition, but validated biomarkers — those that have been determined to be reproducible and accurate as a specific measure of a biological process — do not. Without validated biomarkers, a host of measurements are used to diagnose and monitor a condition. To effectively monitor a condition, validated biomarkers are not necessary; it’s possible to effectively monitor and treat a condition with a set of biomarkers that are individually good metrics for individual biological processes. Often, though, that then means the biomarkers are lagging indicators — they rely on downstream disease processes which might be irreversible — to discern decline if clinical presentation hasn’t worsened already.
Good, validated biomarkers are beneficial for a few reasons. One, they can increase diagnostic accuracy and precision, which means earlier treatment which can often improve outcomes. Improved diagnostic ability for conditions like Alzheimer’s would also improve clinical research since eligibility criteria and outcome measures could be better tailored by biomarkers which would make clinical trial dollars go further. Validated biomarkers can also provide clinicians better insight into the incremental variations in patients which would allow them the opportunity to intervene sooner and more effectively. Strong biomarkers provide support for proposed disease mechanisms and processes, so from the perspective of drug development, biomarkers act as both an indicator for targeted disease processes and as a metric for which therapeutic agents can be measured as effective or not in those specific processes.
Lack of funding and/or research
For conditions to become better understood and for therapeutics to be successfully developed, a lot of research and funding is required. Unfortunately, this can be a major barrier; in one report, it was found that 22% of late-stage clinical trials failed due to commercial reasons. The reasons why lack of funding and research are barriers to therapeutic development are obvious, and they underscore why it’s critically important to resolve the other existing challenges. Much like disease causes can often be multifactorial, therapeutic development too is stifled by a host of challenges.
Most of the challenges that limit therapeutic progress are not condition-specific, but certain conditions or types of conditions can be more acutely affected by these challenges. Neurological conditions are unfortunately frequently in that category; etiology around many neurological conditions is not highly understood; confusion around mechanisms and disease processes obscure prioritization of research goals; the inherent complexity of the nervous system; and without better biomarkers, more funding, and more research, improving uncertainty will take even more time.
While these challenges can seem Herculean, it’s important to remember that as challenges exist, there are thousands of researchers and doctors across the world trying to resolve every single one of them all the time.
- Joint, Ankle, External Brace [Product Classification]. (n.d.). Retrieved July 1, 2022, from https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpcd/classification.cfm?ID=5414
- Health, C. for D. and R. (2018). Learn if a Medical Device Has Been Cleared by FDA for Marketing. FDA. https://www.fda.gov/medical-devices/consumers-medical-devices/learn-if-medical-device-has-been-cleared-fda-marketing
- Shen, J., Swift, B., Mamelok, R., Pine, S., Sinclair, J., & Attar, M. (2019). Design and Conduct Considerations for First‐in‐Human Trials. Clinical and Translational Science, 12(1), 6–19. https://doi.org/10.1111/cts.12582
- U.S. Department of Health and Human Services Food and Drug Administration & Center for Drug Evaluation and Research (CDER). (n.d.). Guidance for Industry (p. 30).
- Perl, D. P. (2010). Neuropathology of Alzheimer’s Disease. The Mount Sinai Journal of Medicine, New York, 77(1), 32–42. https://doi.org/10.1002/msj.20157
- Types of CFTR Mutations | Cystic Fibrosis Foundation. (n.d.). Retrieved July 2, 2022, from https://www.cff.org/research-clinical-trials/types-cftr-mutations
- Kocahan, S., & Doğan, Z. (2017). Mechanisms of Alzheimer’s Disease Pathogenesis and Prevention: The Brain, Neural Pathology, N-methyl-D-aspartate Receptors, Tau Protein and Other Risk Factors. Clinical Psychopharmacology and Neuroscience, 15(1), 1–8. https://doi.org/10.9758/cpn.2017.15.1.1
- What are the parts of the nervous system? (n.d.). Https://Www.Nichd.Nih.Gov/. Retrieved July 2, 2022, from https://www.nichd.nih.gov/health/topics/neuro/conditioninfo/parts
- Hunter, D. J., Losina, E., Guermazi, A., Burstein, D., Lassere, M. N., & Kraus, V. (2010). A Pathway and Approach to Biomarker Validation and Qualification for Osteoarthritis Clinical Trials. Current Drug Targets, 11(5), 536–545.
- Fogel, D. B. (2018). Factors associated with clinical trials that fail and opportunities for improving the likelihood of success: A review. Contemporary Clinical Trials Communications, 11, 156–164. https://doi.org/10.1016/j.conctc.2018.08.001
- Hwang, T. J., Carpenter, D., Lauffenburger, J. C., Wang, B., Franklin, J. M., & Kesselheim, A. S. (2016). Failure of Investigational Drugs in Late-Stage Clinical Development and Publication of Trial Results. JAMA Internal Medicine, 176(12), 1826–1833. https://doi.org/10.1001/jamainternmed.2016.6008