Investigational Drugs: Strategies for Sponsors, FDA, and Clinical Sites to Prevent Product-Related Errors (Part II)
Limited regulatory guidance exists for investigational drug labeling, packaging, and nomenclature, exposing sites that participate in clinical trials to many troubling product-related safety risks. Many of these risks are unique to investigational drugs and are less likely to be encountered with US Food and Drug Administration (FDA)-approved medications used outside the research setting. Some of these safety concerns, which were described in detail in Part I in our April 19, 2018 newsletter, include:
- Look-alike license plate-type identification names during the early phase of research
- Generic name assigned in later phases not included on the label or in the protocol
- Unlabeled containers or bulky outer cartons
- Labels without a discernable drug name or identified by only a protocol number
- Labels without strength/concentration, formulation, lot number, expiration/retest date, and/or barcode
- Inaccurate expiration/retest dates
- Look-alike labels in small black and white font, sometimes with unsafe abbreviations and dose expressions
- Critical product information (e.g., name and strength) hidden below a peel-off label
- Labels expressed in multiple languages, each often found behind a peel-off label
- Products packaged in inappropriate sizes (e.g., single doses require many vials or serial dilutions/aliquots) or in containers typically not used for the intended route of administration (e.g., oral medications in vials)
- Identical tablet/capsule appearance for different strengths of the same drug
- Different quantities of capsules/tablets in sealed bottles than is stated on the label
- Variable or missing content in protocols, pharmacy manuals, drug information sheets, and investigator brochures
These conditions increase the risk of potentially harmful errors that may elude detection and lead to inaccurate data about the safety and effectiveness of investigational drugs.
Regulatory Standards and Professional Guidelines
The US Code of Federal Regulations (CFR) requires the following warning on the immediate package of any investigational drug: “Caution: New Drug—Limited by Federal (or United States) law to investigational use.”1 The CFR also includes requirements for the handling of investigational controlled substances, informed consent, investigational new drug applications, responsibilities of sponsors and investigators, and institutional review board (IRB) involvement.1,2 However, unlike commercially available FDA-approved medications, there is scant FDA guidance in place related to investigational drug labeling, packaging, and nomenclature to promote safety.
The American Society of Health-System Pharmacists (ASHP)3 and the Hematology/Oncology Pharmacy Association (HOPA)4 have both published best practices associated with investigational drugs. Among the many practice recommendations, these guidelines call upon clinical sites to establish storage, dispensing, and labeling requirements for investigational drugs; track expiration dates; employ barcode scanning; and implement many other strategies critical to the safe use of investigational drugs. For example, the ASHP guidelines recommend that pharmaceutical sponsors leave ample space on the product container to allow further labeling of the product by the pharmacist,3 and the HOPA guidelines recommend following all applicable state and federal labeling guidelines, including USP <797>, when labeling pharmacy-prepared parenteral investigational drugs.4
The Joint Commission’s (TJC) Medication Management Standards5 require accredited hospitals to manage investigational drugs safely by addressing the review, approval, supervision, and monitoring of these drugs. The standards also require pharmacy to control the storage, dispensing, labeling, and distribution of all investigational drugs.
Despite the current CFR requirements, professional guidelines, TJC standards, and other published literature, there are very few recommendations specific to the sponsors’ responsibilities for safe investigational drug labeling, packaging, and nomenclature. Most of the guidelines and recommendations currently focus on what clinical sites should do to prevent errors, placing the onus for error prevention largely on practitioners, with no consistent standards for drug sponsors to help with this burden. Thus, in Part II, we recommend error mitigation strategies primarily for sponsors, along with FDA to help standardize and enforce these strategies, that are responsive to the labeling, packaging, and nomenclature risks identified in Part I. We have also provided key recommendations for clinical sites to help support safe investigational drug labeling, packaging, and nomenclature.
Error Mitigation Strategies
Prior to Clinical Trials
- Select and approve a standardized identifier for a new investigational drug that is unique and distinctive from other investigational drugs and the protocol number.
- Assign a generic drug name as early as possible, preferably before the investigational drug begins Phase II trials.
- Perform a risk assessment on the new investigational drug’s name, labeling, and packaging to identify any potential risks that might result in medication errors. Use this information to improve the safety of product naming, packaging, and labeling prior to submission to FDA for approval for testing in humans.
- During IRB review, assess the potential for medication errors with each new protocol. If labeling and packaging information has not been provided with the protocol, request it from the sponsor. Make the principal investigator aware of any safety concerns so they can address them with the sponsor.
- When the investigational drug is assigned a generic name, or if the standardized identifier changes, initiate a timely and coordinated name change in the protocol, pharmacy manual, product labeling and packaging (including stockpiled drug), and other product-related information after communicating the name change and timeline to all participating clinical sites. Whenever possible, list both the generic name and standardized identifier on all product-related materials, including labels.
- Never refer to an investigational drug solely by its protocol number, IRB number, study acronym or title, investigator’s name, or other common name. Use the official sponsor-assigned, standardized identifier early in the research phase, and then the approved generic name if assigned later during subsequent clinical trials.
- Establish a standard process for coordinating and communicating product name changes.
- Store investigational drugs in a designated, secure area in the pharmacy, in bins or shelves labeled with their protocol names and IRB numbers (which is how they are often prescribed). Separate the product strengths by protocol name, number, or other identifier (e.g., Protocol A, Placebo A; Protocol B, Placebo B; Drug A or B (blinded); Drug A + Drug B; Drug A x mg, Drug A 2x mg) in labeled bins or shelves.
- Package oral investigational drugs in patient-ready unit-of-use packaging (e.g., no large bulk bottles of 1,000 capsules that need to be repackaged for multiple patients, but rather patient-specific bottles of capsules containing exactly a 1-month supply).
- Package parenteral investigational medications in vials/containers in the size and volume that best corresponds to the dosing, so that dozens of vials/containers or serial dilutions/aliquots are not required for single doses.
- Package products in forms typically associated with the intended route of administration (e.g., products for oral administration should not be packaged in vials).
- When appropriate, package parenteral products in vials or containers large enough to accommodate a readable label while still allowing visual inspection of the medication through the container. Be sure the vials/containers are compatible for use with a closed system transfer device (CSTD) if necessary. If use of a specific CSTD is required, the sponsor should provide it with the drug.
- Establish good manufacturing practices and quality control testing standards to ensure the intended number of oral tablets or capsules are packaged in each container (which should match the quantity listed on the product label).
- For open label studies, use color, size, shape, and/or unique imprint codes to help differentiate various strengths of the same oral investigational product.
- Include the storage directions and site-specific protocol number on the shipping box to facilitate proper storage immediately upon arrival at the clinical site.
- Standardize investigational drug shipping invoices/packing lists to include all information required on the product labels, including expiration/retest dates and site- specific protocol number, along with the investigator’s name.
Sponsors (and Third-Party Suppliers)/FDA
- Label all investigational drugs before providing them to clinical sites.
- Label the immediate container (see Figure 1 for an example) with the following required elements:
- Protocol/clinical trial number
- Name of the product, including the salt, if applicable
- Generic name followed by the standardized identifier in parentheses if both are available
- For small volume parenterals, total dose per total volume should be the prominent expression of strength, followed by the per mL strength in parentheses
- Units on the label should match the units per dosing instructions in the protocol
- Formulation (e.g., lyophilized powder, solution, suspension, capsule, tablet)
- Quantity per container
- Lot/batch number
- Expiration/retest date
- Medication number (only required for blinded studies)
- Storage requirements
- CFR statement: Caution: New Drug—Limited by Federal (or US) law to investigational use
- Name and address of sponsor
- The following optional information may also appear on the label, if space permits:
- Investigator name
- Patient number
- Special warnings
- If expiration/retest dates are not on the immediate container labels, the packing slips must contain the expiration/retest dates with each shipment.
- For label text on product containers, use a font size of 8 or larger, and make the drug name and strength most prominent. If possible, use a larger bold font for the drug name. Use tall man letters to help distinguish look-alike names. Avoid extraneous information and known error-prone abbreviations and dose expressions.
- Label the outer cartons (white bulky boxes) of investigational drugs with a minimum of the product name, dosage strength/concentration, formulation, protocol number, quantity, lot/batch number, and storage requirements.
- As expiration dates are extended, product relabeling should be the sponsor’s responsibility. Relabeling should occur before dispensing a medication to a patient.
- Display the primary (e.g., peel-off) label in English only for studies conducted in the US. Or, make the last peel-off label in English and affix it to the container.
- Standardize the format and content of labels provided in international languages under the peel-off label, and limit the number of labels under a peel-off label.
- Include a barcode on all investigational drug containers that will identify the product if scanned.
- Label investigational drugs intended for single patient compassionate use in a manner that differentiates them from the main study supplies.
- Label commercially available drugs used in investigational studies in a manner that helps differentiate them from the main pharmacy supplies.
- Sponsors should consider following USP standards (e.g., USP <7>) and FDA guidances (e.g., www.ismp.org/ext/10, www.ismp.org/sc?id=2975) that pertain to labeling to prevent medication errors with commercially marketed products.
- Do not accept any investigational drugs without labels. Return any unlabeled products to the sponsor or third-party supplier, or destroy the products onsite per organizational policies.
- If expiration/retest dates are not on the immediate container labels or packing slips, quarantine the product until such information is provided for suitability of use.
- Affix a pharmacy-generated label to individual investigational drugs or a bag that holds a supply of vials/containers of the same drug/strength/concentration to provide any information that is poorly visible or missing on the product label (e.g., strength, concentration, lot numbers). Or use highlighters or markers to draw attention to key information on the label or rewrite important information on an empty portion of the label. Auxiliary labels and highlights should be applied before the drugs are added to stock or dispensed to patient care areas.
- To prevent mix-ups, separate investigational drugs for single patient compassionate use from the main study supplies, and separate commercially available products used in clinical trials from the main pharmacy supplies.
- Employ barcode scanning when dispensing and administering investigational drugs.
- When dispensing an investigational drug to a patient for home use, affix a pharmacy-generated auxiliary label to the investigational drug container (or an outer bag) to provide dosing and other important information that may be poorly visible, confusing, or missing on the product label. Follow up with the patient within a week (or timeframe specified in the protocol) to assess proper use and tolerance of the drug. Also, provide the patient with contact information, including both daytime and emergency telephone numbers, for any questions or issues that arise.
- Track investigational drugs by lot/batch numbers, which correspond to inventory with specific expiration/retest dates. Do not mix the physical inventory of products with different lot/batch numbers to ensure drug accountability tracking and documentation. Monitor expiration/retest dates, and follow the sponsor/organizational guidelines for returning or discarding expired medications.
Protocols, Pharmacy Manuals, and Investigator Brochures
- Provide study specific pharmacy manuals and ensure all pharmacy forms and accountability logs align with the requirements of the protocol.
- Standardize the sections and format of protocols, pharmacy manuals, and investigator brochures so clinical sites can find the required information. Avoid known error-prone abbreviations and dose expressions in these references.
- Create a reference sheet (study fact sheet) to summarize the most important protocol information, which should be compiled by an investigational drug service pharmacist prior to implementation. Establish a process to update and maintain these as the protocol changes with amendments, and a system for version control.
- Provide real-time access to current study protocols, reference sheets, pharmacy manuals, and investigator brochures to practitioners involved in prescribing, preparing, dispensing, or administering investigational drugs.
- Along with the protocol, require the IRB to review and approve supplemental material including the pharmacy manual and drug/study information for the patient.
- Clinical sites should report errors and potential hazards with investigational drugs to the IRB and sponsor. ISMP also urges clinical sites to report errors with investigational drugs to the ISMP National Medication Errors Reporting Program. Reports will be shared with FDA. Sponsors should investigate all errors and take action to mitigate contributing factors that led to the errors.
- US Code of Federal Regulations, Title 21, Chapter I, Subchapter D, Part 312. 2018.
- Brown JN, Britnell SR, Stivers AP, Cruz JL. Medication safety in clinical trials: role of the pharmacist in optimizing practice, collaboration, and education to reduce errors. Yale J Biol Med. 2017;90(1):125-33.
- Kay SC, Luke DG, Tamer HR. ASHP guidelines for the management of investigational drug products. Am J Health-Syst Pharm. 2018;75(8):561-73.
- Amin SR, Lee JS, Avila JG, Boron MJ, Conley S, Enos R, et al. HOPA investigational drug service best practice standards. Hematology/Oncology Pharmacy Association. 2014.
- The Joint Commission E-dition. Accreditation requirements for hospitals: medication management [Internet].