Inside the Science: The journey of clinical trials and off-label treatments

To understand how a new treatment reaches someone with ALS, we need to explore the rigorous scientific journey behind it. From early-stage research in laboratories, through the complex phases of clinical trials, to the cautious use of off-label therapies, each step is carefully designed to ensure a treatment’s safety and efficacy. In this edition of Inside the Science, we explore how potential treatments are tested, why the process takes time, and how to navigate off-label therapies.

For ALS, discoveries often start in a fundamental research lab, where potential new treatments are first tested in cellular and animal models that mimic aspects of the disease. If a therapeutic compound (a substance with the potential to be a drug) shows promising results in these models, testing may then move on to humans through clinical trials. The presentation of ALS in people is significantly more complex than in animals and cells in the lab, so a rigorous process is needed to test the compound’s efficacy and safety.  

Because of that complexity, a compound with promising data in lab models is not guaranteed to show the same results in humans. This is a major challenge in developing treatments, as many of these compounds were studied because they had a strong scientific rationale for why they could be helpful for people with ALS. It is impossible to say if a new compound will stop or slow the disease based solely on scientific basis or data collected in the lab. Therefore, how a compound interacts in the human body needs to be studied in clinical trials. 

Ultimately, developing new treatments for ALS is challenging because scientists are still aiming to fully understand what exactly is causing the disease. Some cases, such as those linked to known genetic variants, offer hope for new ways to approach therapies. A recently approved drug for SOD1-ALS (Qalsody), for example, targets a root cause of ALS in people living with the SOD1 genetic variant. This offers promise that ALS is a curable disease, but treatments need to be identified correctly. We know that for most ALS cases, there is likely no single cause, but rather a complex interaction of factors that contribute to the disease. Understanding these interactions is key to developing broader, more effective treatments. 

Trials are conducted in multiple phases, usually three main ones. As a result, the clinical trial process will often take several years. In an urgent disease like ALS, there can be frustration over the long process, which doesn’t consider the limited time people living with the disease have. Within the research community, there are also increasing discussions about how the trial journey could be reassessed for ALS, including the optimization of phases, biomarkers, outcome measures, trial duration, and how the results are interpreted and communicated (which is a discussion for another Inside the Science…). 

Ultimately, all drugs undergo this journey, with each phase of a trial purposely designed to test a specific aspect of the drug.  

• Phase 1 trials assess ideal dosing, safety, and tolerability (how well an individual can tolerate a drug without significant side effects) in a small group of participants.  

• • As these trials are focused on safety, only a small number of participants are included to protect patients and healthy volunteers from potential harm.  

• • Testing different doses is important because at low levels, a potential therapy might not show an effect, but at higher levels, it might be toxic.  

• • Often, therapies already approved for other conditions can move straight to Phase 2 because safety and dosage information already exists. 

• • Additionally, Phase 1 trials are increasingly being used for getting a better understanding of the biological activity of a treatment through an exploration of biomarkers. Biomarkers are biological measures that tell us information about a person’s health status. As an example, the level of cholesterol in the blood can serve as a biomarker for the risk of heart disease. 

• Phase 2 trials involve testing on a larger number of individuals for safety, tolerability, and biomarker engagement, using the optimal dose regimen identified in Phase 1. These trials often don’t have enough participants to truly determine if a therapy is effective, but some signals are used to justify investment in a Phase 3 study. 

• • Some drugs may appear to show promising results in this phase; however, Phase 2 trials cannot confirm a benefit. A larger number of participants is needed to ensure that positive results are not due to random chance or bias. The right number of participants are determined by statistical calculations. 

• Phase 3 trials are larger and longer studies that confirm efficacy and continue to monitor side effects and biomarkers in an even bigger group. These trials should have enough participants to determine if the drug has a benefit to that specific population.  

A real-world example of the need for Phase 3 trials is the case of Albrioza. This drug was approved with conditions by Health Canada for ALS, based on results from a Phase 2 trial that were thought to indicate some benefit. Final approval was conditional on results from a confirmatory Phase 3 trial. When those results were released, the trial showed no benefit to people living with ALS and the drug was pulled from the market. If a larger, confirmatory Phase 3 trial had not been conducted, people with ALS would still be taking a drug that didn’t help them and carried side effects for many people. 

• • Some compounds can seem to show promise in a Phase 2 trial but fail in Phase 3 due to overinterpretation of early data signals. A drug may also demonstrate biological activity early on but fail to lead to meaningful clinical improvements that take longer to manifest. Because of this, there have been many false positives Phase 2 ALS trials. Thus, it is difficult to make efficacy claims without a powered Phase 3 trial.  

• Some drugs also undergo a Phase 4 trial, which occurs after regulatory approval to gather additional information on the drug’s long-term risks, benefits, and optimal use in real-world settings. 

This structured process ensures that drugs are not only effective but also safe for the intended population. Without clinical trials, we would lack the scientific evidence needed to make informed decisions about treatment. 

Without testing a drug in a controlled environment, the perceived effectiveness of the treatment is prone to bias. If a physician knows a patient is receiving a new drug and expects it to work, they might unconsciously observe, interpret, and record symptoms more positively, a phenomenon known as observer bias. Similarly, a patient may perceive improvements based on expectation alone.  

This can lead to a placebo effect. This effect happens when a person thinks their health is improving, or shows actual improvement, after receiving a treatment that has no active medical ingredient (a placebo), simply because they believe it will help. While the improvement may feel real, it is not due to the drug’s action in the body. Interestingly, sometimes a placebo effect is generated even with the experimental treatment, as it is based on the participant’s expectations of the therapy. Clinical trials are purposely designed to minimize biases and placebo effects through rigorous protocols, including blinding and control groups. You can watch a short TED-Ed video on placebo effect here.  

Apparent temporary improvements in trials can sometimes occur for reasons other than the placebo effect. ALS is a heterogeneous disease, meaning symptoms and progression will vary from person to person. Some people with ALS may even experience periods where the disease seems to slow down or temporarily stabilize (and even improve). However, ALS is progressive, and symptoms will ultimately worsen over time. This variability can explain why some treatments appear beneficial in small, early-phase trials but fail to show the same effect in a larger, longer-term study.  

To share the promise of a new treatment or pathway, researchers publish their findings in peer-reviewed articles and present them at scientific conferences. The global ALS research community is highly collaborative, with multiple international meetings each year. If a treatment has a strong scientific rationale or promising data, it is actively discussed and investigated further.  

Researchers are motivated to share their work with others in the field, as this increases their visibility, reputation, funding opportunities, and collaborations. Many are also personally connected to ALS and deeply committed to advancing the work.  

Peer-reviewed articles are especially important because they usually ensure the quality, credibility, and transparency of scientific research. Before publication, studies are evaluated by experts in the field who assess whether the methods and data are valid, if the results are interpreted correctly, and if the findings are not exaggerated or misleading. Because of this process, peer-reviewed articles are considered the most trustworthy form of scientific communication.  

ALS Canada has a guide to reading research papers that can be useful when trying to find evidence of ALS treatments on your own.  

Alternative treatments refer to therapies or practices used instead of standard, evidence-based medical treatments. They may include herbal supplements, vitamins, dietary protocols, stem cell injections, and more.  

Off-label use refers to the prescription of an approved drug for a purpose, dosage, or patient group not included in its original regulatory approval. While legal, this approach bypasses the rigorous testing required for drug approval in that specific context.  

With limited treatment options and no known cure, there is an urgency to find effective therapies for ALS. It’s understandable that people with ALS might turn to alternative or off-label therapies. 

However, before pursuing alternative or off-label treatment, it’s important to ask whether it has been studied and whether there is evidence for any benefit in ALS specifically. Strong evidence can come from peer-reviewed publications and discussion within the global research community.  

To combat misinformation and to help people navigate the research, renowned global ALS researchers review existing evidence for alternative and off-label treatments through a program called ALSUntangled. One of their resources, ALSUntangled 56: “ten red flags”-things to be wary of in alternative or off-label products, highlights warning signs to watch for in unproven therapies. 

Most of all, it is important to be seen at a specialized ALS clinic, where an ALS physician will have the experience and knowledge to discuss alternative treatments based on clinical judgment. The Canadian ALS Research Network (CALS) also meets regularly to discuss emerging therapies and evolving standards of care. The network’s position on off-label therapies is as follows: 

Using drugs off-label without sufficient evidence or oversight by an ALS physician can lead to: 

• Increased adverse events: Without clinical trial data, side effects may be unknown or underestimated. These side effects can not only affect quality of life by causing discomfort or pain, but also negatively impact overall health and, even in some cases, worsen ALS progression. ALSUntangled assesses risk factors in some of their reviews.  

Another real-world ALS example: Minocycline, an antibiotic, was once considered a potential treatment for ALS based on promising results in animal models. Since minocycline is already an approved antibiotic (commonly used for bacterial infections and acne), it began to be seen as a potential off-label treatment for ALS. However, a Phase 3 clinical trial later showed that minocycline accelerated ALS progression, making symptoms worse. Without this trial, it may have taken longer for clinicians and patients to notice the harm.  

• This highlights why it’s so important to have evidence in the ALS population specifically, even if the drug is already approved or has shown benefit for other diseases.  

• Ineffective treatment: Patients may receive therapies that don’t work for their condition, losing valuable time and money pursuing the therapy.  

Putting it all together, clinical trials protect people living with ALS, guide physicians, and ensure treatments are both safe and effective. While off-label drug use can offer hope in the unknown of “what if?”, it must be approached with caution, transparency, and a commitment to evidence-based care. It is important to remember that researchers around the world are working together toward a world free of ALS, with deep commitment and global collaboration.  

Disclaimer: The information on this page is provided for general information purposes only. It is not intended to replace personalized medical assessment and management of ALS. The ALS Society of Canada does not intend to disseminate either medical or legal advice. 

ALS RESEARCH AND CLINICAL TRIALS 101 Q&A DROP-IN 

Have any questions about ALS research or clinical trials? Stop by our monthly ALS Research and Clinical Trials 101 Q&A Drop-In session so ALS Canada’s Research Team can answer them. 

Register for free today. 

Inside the Science 

In our blog series, Inside the Science, we break down and discuss trending topics in ALS research, making complex science accessible to anyone affected by ALS.