A Brief Guide to Small-Molecule Compounds and FDA Regulations

Pharmaceutical companies have a renewed interest in developing small-molecule compounds in recent years.

Small molecules have shown promise in fighting cancer, polyomaviruses, and major depressive disorder.

Therefore, pharmaceutical executives should understand common issues that can occur during the development process.


What Are Small-Molecule Compounds?

Small-molecule compounds are typically given orally, work within and outside of cells, and are distributed to the organs and tissues.

An identical copy can be easily made through replicable processes that involve chemical synthesis. They have a predictable chemical process and are mostly not immunogenic. Small molecules can be easily analyzed after they are made to determine their quality, safety, and efficacy. They can generally be shipped at room temperature in blister packs that are easy to use and store.

Small-molecule compounds are active in multiple species and their action is through a specific mechanism. Toxicity can occur from the primary drug or its metabolites.

They are broken down into active and inactive metabolites. Their clearance is generally linear, and they have a relatively short half-life. Their potential for interaction with other drugs is moderate to high.

The Regulatory Process for Small-Molecule Compounds

Although the development process has traditionally been different for small-molecule compounds, it has converged with that of other compounds in recent years.

As such, the regulatory strategies for small-molecule compounds resemble those for large-molecule compounds, and small-molecule compounds go through similar stages of discovery and development.

During the discovery stage, a target molecule is identified through bench research. Preclinical, phase 1, phase 2, and phase 3 trials are conducted during the development stage.

Common Issues With Small-Molecule Compounds

Issues can arise during both the discovery and development phases. Because the process to identify a target compound can be lengthy, assays must be capable of screening large numbers of small-molecule compounds within compound libraries over a short time period to determine those that interact with their respective targets.

As such, the type of assay to use can present a challenge. Both physiochemical methods and functional methods of testing should be used to identify the components of the compound.

Selection of tests may depend upon the type of compound. For instance, if the compound is an antibody drug conjugate, enzyme-linked immunosorbent assays and cell-based assays may be used during the early stages to determine the potency.

However, enzyme-linked immunosorbent assays may be omitted during the later stages, in some cases. Determining the appropriate animal model may also present an issue. As such, several models may be tested before one is chosen.

A small-molecule drug may require at least thirty studies during the discovery phase, and determining which studies to conduct can pose a challenge. Both single- and multiple-dose pharmacokinetic and pharmacodynamic studies are needed.

Studies of bioequivalence; bioavailability; absorption, metabolism, and distribution; and drug interactions should be executed. In addition, QTc studies and studies in special populations should be conducted. Unlike drugs for other studies, crossover studies are usually permissible. Immunogenicity usually does not need to be assessed. Healthy subjects are enrolled.

Issues such as chemistry, manufacturing, and control requirements can arise during the review by the Food and Drug Administration. In general, however, all approaches should be based on valid and reliable scientific methods.

Marketing Small-Molecule Compounds

Small-molecule compounds must be approved by the appropriate regulatory authority before they can be marketed. Companies looking to market these compounds in Europe can use either the centralized pathway or the mutual recognition pathway.

Companies looking to market small-molecule compounds in the United States must submit a New Drug Application to CBER. All processes consist of minimizing danger to the patient and assuring the quality, purity, and consistency of the product.

In general, it is important for companies to have formal meetings with the appropriate regulatory agencies during the development of these products. They should also involve the quality control department early during a product’s development. Taking these steps will increase a compound’s chances of being approved.

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Topics: Process, Small Molecules, Regulations, FDA regulatory consultants, Compliance Consulting