Compounded Drugs in Research: Navigating IND Exemptions and Current Regulations 

Research involving compounded versions of lawfully marketed drugs may not automatically qualify for exemption from Investigational New Drug (IND) requirements. This is because compounded drugs differ from drugs approved by the Food and Drug Administration (FDA) in terms of regulatory oversight, quality control, and safety assurances. 

Drug compounding is a long-established practice in pharmacy that allows for the preparation of personalized medications tailored to meet specific patient needs. While this provides a crucial therapeutic alternative for patients with unique medical requirements or limited treatment options, compounded drugs do not undergo the same rigorous FDA oversight as FDA-approved drugs. This lack of oversight has significant implications for research involving compounded formulations, especially regarding IND exemptions. 

Definition of Compounded Drugs 

Compounded drugs are patient-specific medications prepared by licensed pharmacists or physicians. They often involve mixing, combining, or altering ingredients to create a formulation that addresses an individual’s unique medical needs. These drugs are essential when FDA-approved drugs are unavailable, unsuitable, or in short supply. However, it’s important to note that compounded drugs are not FDA-approved and lack the comprehensive safety, efficacy, and quality assurances associated with marketed drugs. Their labeling may also lack vital information, including directions for use and warnings, which underscore potential risks.¹ 

Regulatory Framework for Compounded Drugs 

The regulation of compounded drugs involves oversight from both federal and state authorities. The Drug Quality and Security Act (DQSA) of 2013 amended the Federal Food, Drug, and Cosmetic Act (FD&C Act) in response to severe adverse events, including fatalities, linked to substandard compounded drugs. The Compounding Quality Act, the first title of the DQSA, aimed to balance the public health need for compounded drugs with the associated risks. 

The DQSA established two categories of drug compounders: 

• Section 503A — Traditional Pharmacies: These pharmacies operate under state boards of pharmacy regulations and are generally permitted to compound drugs for individual patients based on valid prescriptions. 
• Section 503B — Outsourcing Facilities: These facilities are subject to stricter FDA oversight, including compliance with Current Good Manufacturing Practices (CGMPs), and can compound drugs in bulk without patient-specific prescriptions.² 

This dual regulatory system highlights the inherent variability in the quality and safety of compounded drugs, which is crucial to consider when using them in research. 

New Drug Approval Process 

In contrast to compounded drugs, new drugs intended for commercial distribution undergo a rigorous FDA approval process. This process includes preclinical studies, clinical trials, IND applications, and New Drug Applications (NDA). Before being granted market approval, the FDA evaluates the drug’s safety, efficacy, manufacturing processes, and labeling. Post-market surveillance continues even after approval to monitor drug safety. This comprehensive evaluation process ensures that approved drugs meet stringent standards for quality, safety, and effectiveness, which do not apply to compounded drugs. 

IND Exemptions and Compounded Drug Research 

For a clinical investigation to be exempt from IND requirements, the drug product must be lawfully marketed in the United States (US) and meet all conditions outlined in 21 CFR 312.2(b).  

Research involving modifications to the lawfully marketed drug may also be IND-exempt, provided they do not introduce risks exceeding those associated with the product’s standard, labeled use. This exemption would typically apply to low-risk modifications to the lawfully marketed dosage form, such as minor variations to solid oral dosage forms. For example, changes to the color, scoring, or capsule size of the marketed dosage form for blinding purposes would generally be considered low risk, if they do not involve significant manufacturing or formulation changes.³ 

While sponsors are primarily responsible for determining the need for an IND (21 CFR 312.2(a)), Institutional Review Boards (IRBs) play a critical role in ensuring study compliance with regulations, protecting the rights and welfare of participants, and assessing that the research does not introduce new risks (21 CFR 56.101). IRBs rely on sponsors and investigators to provide the documentation to support IND exemption claims. 

Compounded drugs present unique challenges. They lack FDA approval, possess an unknown safety and efficacy profile, and may have incomplete labeling. In addition, poor compounding practices can lead to serious drug quality issues, potentially resulting in patient harm or death. Consequently, compounded drugs in research studies are not in compliance with FDA regulations for IND exemption and IRBs cannot determine whether the research will not significantly increase risks associated with the use of the product (21 CFR 312.2(b)(1)(iii)). 

Ultimately, the FDA has the final authority to determine the requirements for investigating the compounded drug in the research. Sponsors and investigators should proactively consult the FDA when studying compounded versions of lawfully marketed drugs to determine IND requirements. 

Key Considerations for Researchers 

• Conduct a comprehensive assessment of the proposed study to identify any involvement of compounded drugs. 
• Engage with the FDA early in the research and development process to clarify regulatory requirements. 
• Collaborate closely with the IRB to ensure adherence to ethical and regulatory standards. 

Have more questions? Connect with a WCG expert. 

WCG’s IRB experts are here to answer your regulatory and compliance questions and to ensure quality, speed, and precision in your study’s protocol and document reviews. Partnering with WCG you gain access to unmatched expertise of nearly 200 IRB experts. Contact us today to learn more. 

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References 

1. Compounding and the FDA: Questions and Answers. https://www.fda.gov/drugs/human-drug-compounding/compounding-and-fda-questions-and-answers. 
2. Compounding Laws and Policies. https://www.fda.gov/drugs/human-drug-compounding/compounding-laws-and-policies. 
3. Investigational New Drug Applications (INDs) — Determining Whether Human Research Studies Can Be Conducted Without an IND. https://www.fda.gov/media/79386/download.