What is an Investigational Product (IP)? Understanding Investigational Drug Management in Clinical Trials

Definition of investigational product in clinical trials

In the realm of clinical research, an investigational product (IP) refers to a therapeutic drug or biologic, medical device, vaccine, diagnostic, or placebo being studied or used as a reference in a clinical trial.[1] This includes investigational drugs (also referred to as “study drugs” or “experimental drugs”) – those that are not yet approved for marketing – as well as drugs that already have a marketing authorization, when they are being used for an unapproved/novel indication, when they are formulated differently from the approved version, or when they are being studied to gain further information about an approved use. When the IP is considered to be a medicinal product, it may be referred to as an investigational medicinal product (IMP).

Investigational product (IP) vs investigational medicinal product (IMP)

The terms investigational product (IP) and investigational medicinal product (IMP) might seem interchangeable, but they have distinct meanings within the context of a clinical trial.

Investigational products (IPs) include therapeutic drugs/biologics, vaccines, placebos, as well as medical devices or non-medicinal products being tested in a trial, such as health supplements.

In contrast, investigational medicinal products (IMPs) are a specific subset of IPs that are considered medicines. While this still includes placebos and various types of therapeutics, it does not include medical devices or other non-medicinal IPs being investigated in a clinical trial. Thus, all IMP are IPs, but not all IPs are necessarily IMPs.

Investigational product management in clinical trials

The process of managing investigational products in clinical trials involves oversight at several critical stages. This includes the design/development, manufacturing, packaging, labeling, shipping, and distribution to trial sites (or patients’ homes or local dispensaries, in the case of direct-to-patient (DTP) trials). Sponsors must ensure compliance with regulations along the whole supply chain of the study drug, which differ from step to step. Robust quality assurance and quality control systems are essential for maintaining strict control and providing a clear audit trail to demonstrate adherence to quality and regulatory standards.

Who has ultimate responsibility for an investigational product?

The investigational product may pass through many actors before it reaches the patient. However, the clinical trial sponsor bears the ultimate responsibility for the handling and management of the investigational product. Thus, it is the sponsor’s job to establish strong quality control procedures and/or partner with trustworthy providers, for manufacturing through to distribution.

Investigational product handling

Investigational product handling encompasses a series of steps, through which the quality and integrity of the study drug must be strictly upheld, while also maintaining traceability.

Beginning with development and manufacturing, the synthesis, formulation, packaging, and labeling of the drug must be carried out in compliance with current good manufacturing practices (cGMP). As drug manufacturing is quite a different skill set from the core operations of conducting a clinical trial, many sponsors opt to outsource the manufacturing of the study drug. A contract manufacturing organization (CMO) or contract development and manufacturing organization (CDMO) would be the typical go-to, although some CROs also offer these pre-trial services.

Distribution may involve specific requirements, such as cold storage or expedited shipping to get the drug to patients before expiry. Instructions for the delivery and handling of the IP should be detailed and clear. In most cases, the distributor will also need to comply with specific regulations, which may include aspects of cGMP, and thus specific carriers with expertise in handling unapproved investigational products may be used. All movements of the study drug must be recorded to ensure traceability and be able to demonstrate compliance.

Clear instructions should also be provided for trial sites and staff and/or the patients (when applicable, i.e., if they administer the drug themselves) regarding dosage, administration, handling, storage, and appropriate disposal.

Where is information on storage requirements for the investigational product usually found?

Details related to storage and handling requirements for IPs should be outlined by the study sponsor, and can usually be found directly on labeling materials affixed to the packaging of the IP, indicating possible temperature range restrictions or other important guidelines like protection from exposure to light. These guidelines should be followed closely, as they are intentionally designed to preserve drug potency (and prevent its breakdown) and ensure patient safety.

Storage and handling requirements will be based on stability studies conducted during the development phase of the IP (by the sponsor or the CMO/CDMO developing or manufacturing the IP), and are compiled in the investigator’s brochure (IB).

Regulations and guidelines governing the manufacturing, packaging, and labeling of investigational drugs

Investigational drug products must comply with strict regulations and guidelines set forth to ensure patient safety and drug quality and consistency. Manufacturing processes must adhere to rigorous standards known as good manufacturing practices (GMP, or cGMP – current GMP), which are defined and enforced by regulatory authorities. In the US, the Food and Drug Administration (FDA) oversees GMP compliance, while in the EU the European Medicines Agency (EMA) assumes this responsibility (there are slight variations in how GMP is implemented between the US and the EU; see this article).[2] These guidelines cover all aspects of production, from raw materials to facilities and equipment and staff training.

It is essential that investigational drugs are packaged in a manner that ensures product integrity until they reach the end user. Labeling on investigational drugs also needs to be both informative and clear, to comply with laws regarding the handling of unapproved investigational products. Investigators must follow specific local regulations regarding investigational product packaging and labeling to include all of the necessary information, which could include things like the trial title, sponsor ID, protocol number, expiration dates, safety precautions, storage requirements, etc. For blinded studies, a randomization code may be used, which would allow emergency unblinding if necessary while maintaining the integrity of blinding amongst study personnel.

For international or multicenter trials, the complexity of packaging, labeling, and distribution regulations can increase dramatically as different jurisdictions have different laws regarding investigational products. Similarly, for decentralized clinical trials (DCTs) that might use direct-to-patient (DTP) drug distribution, the shipment of investigational products to regular people who aren’t licensed researchers or healthcare providers comes with its own unique set of challenges.

Regulations also mandate certain aspects of quality control and quality assurance, which could include monitoring, inspections, audits, and quality checks. These are usually to be conducted by the sponsor, who must ensure precise record-keeping of all aspects of investigational product management in order to provide a strong audit trail and demonstrate compliance throughout the supply chain. This oversight is designed to maintain high levels of transparency and accountability within clinical trials, ultimately safeguarding patients' health and rights.

Conclusion

In clinical research, the terms investigational product (IP), investigational medicinal product (IMP), study drug, and experimental drug all refer to the product that is being investigated in a clinical trial, to test either its safety or efficacy (or both) in humans. While a study drug, by definition, either has not yet received approval for marketing and use, or is being studied in a context that differs from that for which it was priorly approved, there are rigorous regulations in place that hold sponsors to strict standards meant to ensure purity, quality, and consistency of the study drug, as well as its appropriate handling and storage, with the ultimate goal of maximizing patient safety through the course of clinical investigations.