
An investigational drug is a chemical or biological substance that has been tested in the laboratory and approved by the US Food and Drug Administration (FDA) for testing in people during clinical trials. Investigational drugs can include both prescription and nonprescription medications, but some fall into the category of high-alert medications and have a narrow therapeutic index that requires careful testing to determine the most effective and safe doses. While the sponsoring company’s attention is highly focused on the safety profile of the drug and its clinical effects on patients, those working on new drug development, product manufacturing, and protocols for clinical trials are rarely well versed in medication error-prevention principles. Additionally, limited regulatory oversight exists to guide, standardize, and govern investigational drug labeling, packaging, and nomenclature, making this a lower priority for many sponsoring companies compared to the efficacy and safety profile of the drug. These conditions can create a perfect storm for errors with investigational drugs that may cause serious harm to patients and lead to inaccurate outcome data about the drug.
According to healthcare practitioners who have reported hazards and errors with investigational drugs to ISMP, there are many troubling product-related safety concerns that currently exist. In Part I, we explore the risks associated with investigational drug nomenclature, labeling, and packaging in detail. In Part II, which will be published in our May 3, 2018 newsletter, we will recommend strategies for clinical sites that participate in investigational drug studies, as well as manufacturers and FDA, to improve the safety of investigational drug nomenclature, labeling, and packaging.
Drug Nomenclature
Look-alike product identification. In the early phase of research, investigational drugs are most often identified using a number preceded by an abbreviation of the sponsoring company’s name (e.g., AMG-123456 for a drug sponsored by Amgen Oncology)—much like a vehicle license plate. Many clinical sites that participate in investigational drug studies are involved in multiple studies by the same sponsor; thus, the sponsor’s abbreviation preceding the identification number adds to investigational drug name similarity. After the sponsor’s abbreviation, the numbers that are used to identify the different drugs may vary by just the last digit (e.g., BMS-123456, BMS-123457, BMS-123458), further contributing to name similarities. Some letter/number designations can be up to 25 characters long, or are described using multiple words. These longer identifiers are often truncated on computer screens. The license plate-type numbers may also overlap with an existing protocol number.
Product name changes are not reflected on labels and protocols. As the investigational drug moves into different phases of clinical trials, a product with a license plate-type number may be assigned a generic name. While the research team, packing slips, and other shipping documentation may refer to the drug by its new generic name, product labels may continue to reflect an older license plate-type number. It is even possible for the license plate-type number to change during the life of the study, particularly if the sponsor is part of a merger or the company or product is sold. Nevertheless, stockpiled drug labeled with the original license plate-type number may still be distributed to clinical sites. When a generic name is assigned, or the license plate-type number has been changed, updates in the associated protocol and pharmacy manual may also lag behind or may be updated with just a statement about the name change, making it difficult to find information about the various names used for the specific investigational drug. Changing drug names that may not be reflected on the product labels or in protocols causes significant challenges with proper drug identification when prescribing, dispensing, and administering investigational drugs.
Drug Labeling
Unlabeled products. Some investigational drugs are shipped by the company or a third-party supplier to a clinical site without any labels at all. While the outer carton and shipping slip may identify the drugs, the individual product containers are without a label (Figures 1, 2, and 3).







Missing formulation. For studies in which different formulations of the drug are being tested (e.g., with and without a salt), the formulation may be missing from the container label. Different dosages may be the only differentiating factor to determine the correct formulation. Also, investigational drugs for which changes in the formulation were made between clinical trials are often labeled the same. Only the lot numbers can help differentiate the prior phase and current phase formulations, not the labels or product appearances.
Missing barcodes. Most investigational drugs do not include barcodes on labels that can be used by practitioners to verify dispensing and administration accuracy. Clinical sites can add a barcode to the label, which some sponsors have requested, but the process is time consuming and error-prone.
International labels. Many investigational drugs are involved in international studies. Thus, information may be presented in two or more languages on the same label (Figure 8). Otherwise, paper labels and protocol information in up to 15 different languages may be included behind a peel-off label on the container (Figure 9). With these paper labels, practitioners at clinical sites have complained about how hard it is to access the necessary information, first because the adhesive on the peel-off label is often strong, and then because they must browse through many pages of labels to find the desired language. The label information is not presented in a standard format, so it is difficult to find even basic information like the drug name, strength, dosage form, and bottle count. Clinical sites have also noted difficulty working with these vials in a sterile environment while compounding when multiple labels are attached to the product.


Unsafe abbreviations and dose expressions. Labels on investigational drugs sometimes include error-prone abbreviations or dose designations (e.g., U for units, trailing zeros [1.0 mg]). Protocols, pharmacy manuals, and other related product information also use known error-prone abbreviations and terminology that should be avoided.
Missing lot numbers. Investigational drug labels do not consistently include lot numbers, which impedes the tracking of drug identity, expired products, recalls, and adverse drug reactions.
Missing expiration dates. Because “beyond use” dates of investigational drugs may be updated during a trial based on ongoing testing, some sponsors do not list an expiration date on the product label, or even on the packing slip, certificate of analysis, or drug accountability form. Instead, sponsors require clinical sites to call an interactive voice response system (IVRS) or access an interactive web response system (IWRS) to check expiration dates—a process that is time consuming and disruptive to workflow. Or sponsors may send broadcasts or letters to the clinical sites to notify them about updated expiration dates. However, missed broadcasts or letters have resulted in dispensing expired drugs, and lag time with the IVRS or the IWRS has resulted in cases where expired drugs have not been replaced in time to dispense to patients, or intervention with the sponsor was needed to avoid dispensing a drug that would reach expiration during outpatient use. If a sponsor chooses not to relabel an oral product with an updated expiration date based on retesting, the product dispensed to a patient may appear to be expired when it is not. When expiration dates are included on product labels, their placement and format is not consistent, and there may be confusion (Figure 10) between the manufacture date, the initial expiration date, and an updated expiration date.

Drug Packaging
Few unit-dose packages. Many oral investigational drugs are not supplied in unit-dose packages. They are shipped in bulk packages that often require repackaging to avoid contamination of the bulk supply. Additionally, vial sizes of parenteral drugs are sometimes inappropriate for the dose being studied and may require dozens of vials to prepare a single dose. This sensitizes practitioners to expect to use many vials when preparing a dose of the medication. Thus, recognition of a possible overdose is less apparent during the preparation of investigational drugs than it would be during preparation of other drugs, where the use of dozens of vials for a single dose would clearly signal an error. Some investigational drugs are packaged in such small vials that the label covers the entire vial making it difficult to inspect the product prior to use. Conversely, serial dilution or aliquots may be required to prepare a low dose of the investigational drug for a low-dose cohort.
Packaging not appropriate for the route. Some investigational drugs are packaged in ways that could lead to administration by the wrong route. For example, liquid medications intended for oral administration have been packaged in vials, and products like granules or pellets that are intended to be sprinkled on or mixed with food have been packaged in capsules that patients may inadvertently swallow.
Tablet appearance. Multiple strengths of tablets often look identical in color, shape, and size, and they have no markings to help differentiate the strengths. While this may be essential for blinded studies (in which the strength is not known to the patient, provider, and at times, the research team), the same batches of look-alike tablets may be used for open label studies as well (where the tablet strength is known to all).
Quantity in containers. Practitioners have reported that sealed bottles of oral investigational drugs have contained different quantities than stated on the label or packing slip, which requires repackaging of the product to ensure patient compliance with the protocol.
Suggested citation:
Institute for Safe Medication Practices (ISMP). Investigational drugs: product-related issues pose significant challenges (part 1). ISMP Medication Safety Alert! Acute Care. 2018;23(8):1-5.