Investigational Drugs: Product-Related Issues Pose Significant Challenges (Part I)

April 19, 2018

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).

**Figure 1.** One of 24 unlabeled vials of a lyophilized injectable investigational product, sitting on top of the labeled bulk box shipped to a clinical site.

unlabeled syringes — **Figure 2.** Although the syringes, which contain two different study medications, were provided in labeled cartons, once removed, the syringes are unlabeled and look alike.

box of unlabeled vials — **Figure 3.** Unlabeled oral investigational drug shipped to a clinical site in two strengths - 200 mg in the larger bottles containing 60 tablets each, and 80 mg in the smaller bottles containing 30 tablets each. When the clinical site complained, the study sponsor insisted there is no problem since the contract between the drug company and the third-party supplier of the drugs did not state that the bottles must be labeled.

Bulky unlabeled boxes. Some injectable investigational drugs are individually packaged and shipped to clinical sites in bulky plain white boxes (Figure 4) that all look the same. These unlabeled boxes often contain only one vial of medication (with a vial of diluent, if required) despite their large size. The inner vials may be labeled, but the outer boxes are not. The clinical site must label the boxes prior to storage in the refrigerator or other storage area, which often takes up significant space. While most vials must remain in the boxes during storage to protect the medication from light, some clinical sites remove the vials and place them in amber bags, which also must be labeled prior to storage.

unlabeld box — **Figure 4.** Some injectable investigational drugs that are light sensitive are packaged individually in bulky unlabeled white boxes that must be labeled by the clinical site prior to storage.

Missing, confusing, or unnoticeable drug name. The labels on investigational drugs often contain various numbers in nonstandard locations. For example, the label may include the license plate-type number, a study or protocol number, a lot number, and a kit number, making it hard to discern the meaning of each set of numbers (Figure 5). Some container labels associate various numbers (and dates) with a key or legend that is referenced in the protocol, under a peel-off label, or in some other associated document (Figure 6). But the product license plate-type number may not be prominent or discernable from the other numbers on the label. In some cases, the predominant feature on the label is the sponsor’s name. Sometimes the product is identified by a protocol or study number only (Figure 7) or is only identified under the peel-off label. A few investigational drug labels do not include the product name or license plate-type number at all.

cc-292 vial — **Figure 5.** This container contains investigational drug CC-292, which is listed at the top of the label. Another arm of the study uses investigational drug CC-122. The study comparing these two treatments is named CC-122-DLBCL-001. Listing the study name, which begins with CC-122, directly below CC-292, could lead to misidentifying this product as the drug used in the second arm of the study, CC-122.

label with legend — **Figure 6.** Investigational drug labels may associate various numbers and dates with a key or legend (I, II, III, IV) that is referenced in the protocol, under a peel-off label, or in some other associated document, making it hard to discern the meaning of each set of numbers and dates on the immediate label.

drug strength label — **Figure 7.** This investigational drug is identified by the protocol number only, although it has been assigned a generic name (tipifarnib). Also, the strength of the product (100 mg) can only be found below the peel-off label, although the drug is available in multiple strengths.

Missing or hard to find strength. The product strength or concentration may also be missing or not prominent on investigational drug labels, even if there are multiple drug strengths in use for open label protocols. In some cases, the strength of the drug is included only below the peel-off label (Figure 7). If the concentration is not listed on the product label, it may be linked to a lot number, which must be checked to verify the concentration. If the concentration of a parenteral medication is listed on the label, it is often expressed as a per mL strength, not the strength per total volume (e.g., vial labeled as 25 mg/mL but contains 1.67 mL of medication). While blinding of the dose may be necessary for some studies, practitioners must be able to select and dispense the correct product strength.

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.

multiple languages on label — **Figure 8.** Two languages on the same label.

dozens of labels on vial — **Figure 9.** Investigational drug with dozens of international labels in different languages behind a peel-off label.

Small font size and no differentiation of text. Many investigational drugs are labeled using a very small font size. Some labels are as small as a thumb nail, requiring a magnifying glass to read the many lines of text. The same font size is often used throughout the label, and there is little use of differentiation strategies such as boldfaced type, color, or other means to help distinguish the products. Thus, drug packages look remarkably similar, which can lead to confirmation bias when products are selected from the shelf. For example, it is very difficult to observe the differences between drugs and their diluents due to the small text size, lack of prominence of “diluent,” and appearance of the license plate-type number or generic name on both the drug and diluent vials.

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.

three dates on one label — **Figure 10.** The three dates on this investigational drug package may cause confusion. The date next to legend item II (08 2014) is the initial expiration date; the date (01 2012) next to the legend item V is the manufacture date; the date next to legend item II (12 2016) on the sticker below the label is the updated expiration date.

Protocol variability. The template and requirements for investigational drug protocols, pharmacy manuals, drug information sheets, and investigator brochures are not standardized; protocol content varies between studies and sponsors, and important information is difficult to locate since there are no standardized sections. For example, the protocol may be missing information about stability, dose reduction strategies, or how to store and prepare the drug, which can sometimes be found by searching numerous other study-related documents. Inconsistencies in the information presented in protocols and pharmacy manuals have also been reported, and errors in pharmacy manuals, which are often not reviewed by an institutional review board, are common. Protocol updates, which are frequently needed as the drug moves through various phases of clinical trials, are sometimes disorganized or unavailable.

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.

Look for Part II in our May 3 newsletter as we consider recommendations to improve the nomenclature, labeling, and packaging of investigational drugs for safe use.

Part II - Investigational Drugs: Strategies for Sponsors, FDA, and Clinical Sit…