Before an experimental drug can be tested in humans, there must be strong evidence that it is unlikely to cause harm. Throughout a treatment’s preclinical development, researchers perform studies in disease models, such as cells or mice, to look for adverse effects. For most drugs in the United States, the final steps in this process are called Investigational New Drug (IND)-enabling studies.

The primary goal of IND-enabling studies is to demonstrate that a drug will be safe for use in humans with as much certainty as possible before asking volunteers in a clinical trial to take it. The results of these studies are essential parts of an IND application, which a drug sponsor must submit to the Food and Drug Administration (FDA) for approval before they can begin conducting a clinical trial.

What are IND-Enabling Studies?

An IND application must contain data from multiple types of studies that examine the behavior of a drug in a living animal. These include two main types of IND-enabling studies, called toxicology studies and Absorption, Distribution, Metabolism, and Excretion (ADME) pharmacology studies.

  • ADME Pharmacology studies examine how a drug behaves in the body. To satisfy regulators, researchers must demonstrate that a drug is reaching the parts of the body it is intended to reach and affecting the target it is meant to. To accomplish this, they conduct studies that look at aspects of a drug’s behavior in the body, including:
    • Absorption: How the drug travels from the site of its administration into the body (such as the stomach for an oral drug or a vein for an intravenous drug).
    • Distribution: How the drug’s ingredients move around the body after it has been administered.
    • Metabolism: How a drug behaves as it is broken down by the body.
    • Excretion: How the drug eventually passes through the body.
  • Toxicology studies look at whether a drug is causing harm to any part of the body. Researchers will carefully examine how the drug affects the body at a variety of different doses—information that may later help determine the safe dose range for a human trial. An investigational drug will undergo several different kinds of toxicology studies, which may include:
    • Acute toxicity studies, which look for adverse events from a single dose of the drug.
    • Chronic toxicity studies, which look at whether the drug may cause harm when taken over longer periods.
    • Studies that examine the drug’s effects on certain organs or groups of organs, such as the central nervous or respiratory systems.
    • Studies that look at how a drug could affect the reproductive system in both males and females, as well as how the drug affects a developing fetus when given during pregnancy.
    • Genotoxicity studies, which examine whether a drug could cause genetic mutations in some cells.
    • Carcinogenicity studies, which look at whether a drug is associated with the development of cancer over time.

These studies must be conducted in animal models of at least two species, both of which must be mammals. This could include mouse models of the disease, as well as larger animals such as pigs or non-human primates that more closely mimic human biology.

Good Laboratory Practices

Generating reliable data from IND-enabling studies is essential to ensuring the relative safety of participants in any following human clinical trial. Therefore, these studies are governed by a special set of regulations known as Good Laboratory Practices (GLP), established by the FDA. GLP regulations outline specific requirements about staffing, quality assurance, facilities, equipment, and standard operating procedures for any lab conducting IND-enabling studies. These regulations aim to make sure that any institution carrying out these critically important studies will produce consistent and reliable results.

The Other Components of an IND Application

In addition to the data from ADME pharmacology and toxicology studies, a drug sponsor must provide additional information about the how they are going to manufacture, prepare, and validate the performance of the drug they are going to produce. These are referred to as chemistry, manufacture, and control (CMC) studies, and include:

  • Information about the physical, chemical, and biological characteristics of the drug.
  • How the drug is made, including the sponsor’s detailed plans to manufacture the drug for a potential clinical trial.
  • How the drug will be tested to ensure consistent strength, quality, and purity.

The sponsor must also provide detailed plans for how they are going to approach the first human trials for the treatment, including:

  • Detailed plans for the first clinical study in humans if the IND application is approved.
  • Information about the clinicians who will serve as the clinical investigators for the potential trial.

These IND-enabling details and results, along with any previous preclinical studies demonstrating potential for efficacy, are then reviewed by the FDA or regulatory agencies. The reviewers will look to see if the sponsor has presented sound evidence for the drug’s safety, potential for efficacy, and that the sponsor has an adequate plan for carrying out a trial. If this application is approved, human trials can begin.

IND-enabling at ALS TDI

The ALS Therapy Development Institute (ALS TDI) is the most comprehensive preclinical research institute dedicated solely to ALS. Because it will take many treatments to end ALS, ALS TDI acts as a “Drug Discovery Engine”, discovering and advancing a wide range of potential therapies for the disease. When we identify a drug that shows promise, we find partners that have the capacity to advance these candidates into human trials. This allows us to maximize our impact by filling the ALS pipeline with diverse treatment options.

ALS TDI researchers engage in every aspect of preclinical drug development, including basic research, drug discovery, and lead optimization. When a potential treatment shows promise after going through many rigorous studies in our cellular and animal models of ALS, we will undertake IND-enabling studies to ensure that it has the best chance of reaching a human trial. IND-enabling studies conducted by ALS TDI have resulted in one drug, tegoprubart, reaching human trials. Another potential treatment, a copper complex molecule known as TDI1831, is currently being advanced through IND-enabling studies.

To learn more about ALS TDI’s preclinical research to end ALS and how you can support it, visit https://www.als.net/als-research/.

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