To understand how ALS research studies work, it’s important to understand what a “study” entails. That can be confusing. Sometimes, “clinical study” or “research study” and “clinical trial” are used synonymously. Sometimes they aren’t.

For example, Good Clinical Practice ICH E6 guidelines consider the terms clinical trial and clinical study as synonymous.”1 In contrast, the National Institutes of Health makes a nuanced distinction, identifying clinical trials as a type of clinical study. “There are two main types of clinical studies: clinical trials (also called interventional studies) and observational studies.”2 Moreover, according to the FDA and the EU Clinical Trials Regulation, an observational study is not considered a clinical trial.3,4

So what’s the difference? By this definition, a clinical trial involves testing a novel treatment or intervention. Participants may receive an experimental treatment they couldn’t access otherwise. (Of course, they could also receive a placebo.) In contrast, in an observational clinical study, no intervention occurs. Researchers may evaluate a treatment a patient is already using, but there’s no new therapy involved.5,6

In previous posts, we’ve described what clinical trials entail, what to expect from a clinical trial and even how a research idea turns into a clinical trial, so let’s begin with the observational study.

What happens in an observational study?

In observational studies, the goal is to gather information and compare changes over time. So in terms of a medication, researchers observe and record the effects of a person’s current treatment without changing it.7

Observational studies help advance the research and understanding of the disease. Participants not only provide important data for researchers, but they also benefit from the insights into their own progression.8

Compared to clinical trials, observational studies tend to be less involved for participants. A person with ALS might be asked to complete a detailed questionnaire, have their vital signs taken, and provide blood and urine samples.

One important observational study, funded by Target ALS and the Muscular Dystrophy Association, involved patients with ALS. It found that serum NfL (neurofilament light chain) “may be considered a clinically validated prognostic biomarker for ALS and potentially as a pharmacodynamic biomarker of treatment effect.”9,10

Observational clinical studies can also be useful for assessing the role of external factors, including environmental contaminants (e.g., pollution and lead).11 These are often cohort studies — a type of observational study that looks at a group of people who are connected in some way, perhaps they are the same age or the same profession. (One of the biggest ongoing cohort studies involves female nurses.) One example of this is a 2021 study that looked at the incidence and mortality rates of ALS among NFL players compared to the U.S. male population.12

ALS research studies: Clinical trials

Typically, in clinical trials, a therapy is tested in one group of participants, who are compared to a control group that does not receive the intervention. These studies have several phases:13,14,15,16

  • Phase 0 trials are not common. They look at pharmacodynamics and pharmacokinetics in a few people.
  • Phase I trials usually include around 20 to 80 healthy people and focus on safety.
  • Phase II trials determine dosage and efficacy in people with ALS. These can include several hundred people.
  • Phase III trials can include 1,000 to 3,000 people and focus on safety and effectiveness. These trials typically take one to three years.
  • Phase IV involves continuous monitoring through real-world observation. Although not all products go through a Phase IV, the FDA often requires these post-marketing studies as a condition of approval.

So what does this mean for a person with ALS? If you decide to join a trial, you can expect:17,18,19,20

  • To provide informed consent, stating that you understand what the trial entails, including any risks.
  • Initial tests and assessments to establish a baseline.
  • Periodic check-ins to receive treatment and evaluation. Some trials will require a heavy time investment. Increasingly, however, some of this is being managed remotely.
  • To report your own experiences (aka, self-assessment): Patient-reported outcomes are critical to all studies, but especially for central nervous system (CNS) trials.

Each trial has eligibility restrictions. Inclusion criteria can include age range, disease duration or subtype of ALS. Exclusion criteria are factors that could make you ineligible for enrollment. These could involve certain medications or other illnesses.

ALS research studies: Where we are today

The overwhelming majority of human clinical trials fail to demonstrate clinical efficacy.21 CNS therapies, including those for ALS, typically have higher failure rates than other therapies.22 Moreover, CNS drugs take 20% longer to develop and 38% longer to approve than other therapies.23,24,25

Why the high failure rate? There are many possibilities, including wrong target, flawed trial design, mistakes in patient selection or insufficient exposure to the drug.26 But there are other challenges: barriers to research itself. Target ALS has identified several, all of which we’ve worked to address. Among them is a lack of funding, a lack of collaboration and a lack of access to scientific tools and resources.27

We continue to move closer to a cure. To learn more, visit the Target ALS website. It includes a wealth of information about our approach to supporting clinical studies and the research we fund.





1ICH E6 guidelines

3Framework for FDA’s Real-World Evidence Program – Dec 2018

4Regulation EU/536/2014



7 Cologne, Germany: Institute for Quality and Efficiency in Health Care (IQWiG); 2006-. What types of studies are there? 2016 Jun 15


9 Benatar M, et al. Validation of serum neurofilaments as prognostic and potential pharmacodynamic biomarkers for ALS. Neurology. 2020 Jul 7;95(1): e59-e69.


11 Environmental factors, such as lead Wang MD, Gomes J, Cashman NR, Little J, Krewski D. A meta-analysis of observational studies of the association between chronic occupational exposure to lead and amyotrophic lateral sclerosis. J Occup Environ Med. 2014;56(12):1235-1242. doi:10.1097/JOM.0000000000000323

12 Daneshvar DH, Mez J, Alosco ML, et al. Incidence of and Mortality From Amyotrophic Lateral Sclerosis in National Football League Athletes. JAMA Netw Open. 2021;4(12): e2138801. doi:10.1001/jamanetworkopen.2021.38801

13 NIH Clinical Trials and You, National Institutes of Health

14 The Drug Development Process  FDA. 2018


16 The Drug Development Process  FDA. 2018


18 Merck Manual

19 Thinking about joining a clinical trial? Here’s what you need to know. Harvard Health Blog

20 NIH Clinical Trials and You, NIH,

21 Petrov D, Mansfield C, Moussy A, Hermine O. ALS Clinical Trials Review: 20 Years of Failure. Are We Any Closer to Registering a New Treatment? Front Aging Neurosci. 2017; 9:68. Published 2017 Mar 22. doi:10.3389/fnagi.2017.00068

22 Gribkoff, V. K. and Kaczmarek, L. K.: The need for new approaches in CNS drug discovery: Why drugs have failed, and what can be done to improve outcomes. Neuropharmacology 120 (2017)

23 Tufts Center for the Study of Drug Development

24 Lansdowne, L. E.: Exploring the Drug Development Process. Drug Discovery from Technology Networks (2020)

25 Pascoe, E. M. et al.: Explainer: how do drugs get from the point of discovery to the pharmacy shelf? Conversation (2017)

26 Wobst HJ, Mack KL, Brown DG, Brandon NJ, Shorter J. The clinical trial landscape in amyotrophic lateral sclerosis-Past, present, and future. Med Res Rev. 2020;40(4):1352-1384. doi:10.1002/med.21661



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