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Drug Labeling

Labeling is a general term encompassing many things about a drug. Labeling is divided for pharmacovigilance purposes into several different documents. For drugs that are not yet on the market (approved for sale), labeling used for adverse events (AE) reporting and all other “official” considerations is the “Investigator Brochure” as prepared by the sponsor and submitted to the health authorities (e.g., U.S. Food and Drug Administration, Health Canada). After a drug is approved for marketing (e.g., New Drug Application or Marketing Authorization granted), the labeling that is used for regulatory reporting of AEs now changes to that document prepared by the sponsor and submitted to, negotiated with, and approved by the health authority for that jurisdiction: the “Package Insert” (PI) in the United States, and the Summary of Product Characteristics (SPC or SmPC) in the European Union. The other key labeling document is the Clinical Core Safety Information (CCSI). All are discussed below.

The requirements for the IB are listed in ICH E6 Guidance on Good Clinical Practices (Web Resource 34-1), which has been adopted in most jurisdictions. It is a compilation of clinical and nonclinical data on the study product that is relevant to the investigators performing the trial, allowing them to understand the rationale and key features of the drug. It is the sponsor’s responsibility to prepare the IB and keep it up to date. It summarizes the chemical, physical, and pharmacologic properties of the drug; nonclinical studies; effects in humans; including absorption, distribution, metabolism, and excretion (ADME) data, as well as clinical studies in volunteers and patients covering both efficacy and safety. Marketing experience, if available, is also included.

The IB should contain summaries of safety across multiple trials with indications in subgroups using tabular summaries of ADRs. Important differences in ADR patterns/incidences across indications or subgroups should be noted if present. The IB should provide a description of the possible risks and ADRs to be anticipated on the basis of prior experiences with the product and with related products. Any precautions or special monitoring to be done should also be noted. The IB can be dozens of pages long and should be more inclusive rather than less inclusive. It is not a marketing document and will be reviewed by investigators, Investigational Review Boards/Ethics Committees and data safety management committees.

The IB should be updated yearly or more often if new information, particularly about safety, becomes available. This document is used in the preparation of 7- and 15-day expedited (alert) reports to the health authorities and for investigational new drug annual reports (e.g., Development Safety Update Reports, or DSURs).

After a drug is approved for marketing and if it is also in clinical trials, it will have both an IB and postmarketing labeling (e.g., SPC, U.S. PI).

The “Core Safety Information” (CSI), or “Company Core Safety Information” (CCSI), which is part of the larger “Company Core Data Sheet” (CCDS), contains the key safety data for the marketed product. This document was defined originally by the CIOMS III and CIOMS V documents (Web Resource 34-2). The CCSI contains (only) basic safety information that should appear in the safety labeling for the product in all countries where the product is used. It should not contain speculation or safety information that might appear in only one country’s labeling for some local reason. Thus, the information in the CCSI represents the minimal safety data that should appear globally in all local or national labeling. Additions may be made in local labeling beyond what is in the CCSI if the local health authority or company so chooses. Marketing considerations should not play a role in preparing the CCSI. AEs due to excipients should be included, but those that have no well-established relationship to the drug should not be included. The CCSI is used to determine which AEs are considered “listed” when preparing the Periodic Safety Update Reports (PSURs). It is not used for expedited reporting expectedness (the approved, postmarketing label is used).

Other safety documents used in various countries include the Development Core Safety Information, Development Core Data Sheets, and Target Product Profiles. They all are similar to the CCSI and contain key safety information used for clinical trials, periodic reporting, and so forth. It is likely that the DSUR—the parallel to the PSUR used for marketed drugs—will formalize the safety reference document to be used.

The U.S. requirements for labeling are summarized in 21CFR1. The official definition of labeling for a marketed product is 21CFR1.3(a) (see Web Resource 34-3):

Thus, it includes the FDA-approved written material describing a drug, such as the Package Insert and the packaging and box that a drug is shipped or sold in. Synonyms for labeling include “Package Insert,” “professional labeling,” “direction circular,” “approved labeling,” and “package circular.” It also includes the FDA-approved patient labeling (called “Medication Guides”) where this exists (see Web Resource 34-4 for approved patient medication labeling).

In 2003, the FDA introduced the new requirements for the electronic formatting of labels, called the “Structured Product Labeling” (SPL), using a document markup standard approved by HL7 (see Chapters 8, 19, and 20). See FDA’s website for further information on this labeling initiative (Web Resource 34-5).

The specific requirements for drug labeling are found in 21CFR201.57 (Web Resource 34-6). These labeling requirements, which were revised in 2006, include:

Note that the highlights section, is a short summary (1/2 to 2 pages) of the rest of the labeling. Labels before 2006 have largely the same sections, though there is no highlights section, and the safety sections are much shorter in many cases.

FDA issued a guidance covering the new requirements in more detail, entitled “Labeling for Human Prescription Drug and Biological Products—Implementing the New Content and Format Requirements” (Web Resource 34-7). Several other guidances covering the various sections of the labeling were also issued and are available at Web Resource 34-8.

The guidance covering the adverse reaction section will be discussed briefly here (Web Resource 34-9).

• The goal is to include only information useful to practitioners making treatment decisions and monitoring patients. Exhaustive lists of AEs should be avoided.
  
• The Adverse Reactions (ARs) section should contain those that occur with the drug itself and ARs from the class if appropriate. Clinical trial and spontaneous reports must be listed separately.
  
• All serious and otherwise important ARs should be listed and cross-referenced (e.g., Boxed Warning, Warnings and Precautions).
  
• ARs that resulted in a significant rate of discontinuation or other clinical intervention, such as dose change in clinical trials.
  
• ARs from clinical trials is the major component of the AR section and should include the most commonly occurring ARs (e.g., all ARs >10% and 2 × placebo rate). This section should describe the clinical trial database in terms of exposure, number of patients, demographics, types of studies, doses, and so forth. Data should be presented in a table to allow side-by-side comparisons. The best available data should be used—placebo-controlled and dose response studies.
  
• Less common ARs should be presented if there is a basis to feel that a causal relationship to the drug exists.
  
• Additional information should be given for the most clinically significant ARs (i.e., most common, cause discontinuation, or dose change or require monitoring).
  
• Dose response, demographic, and subgroup information should be included if important.
  
• If there are multiple indications and/or multiple formulations, a discussion about these issues in regard to safety should be included.
  
• A separate listing of spontaneous ARs should be included, particularly those that are serious, frequent, or seem to be causally related ARs.
  
• When reporting rates are included, all cases of that AE should be used rather than just those the reporter feels are related.
  
• Comparative safety claims (frequency, severity, or character of the AR) must be based on data from adequate and well-controlled studies.
  
• Negative findings, if convincingly demonstrated in an adequate trial, may be included.
  
• Data may be pooled from studies when the studies are appropriate to pool (similar design, populations, etc.).
  
• Data should be coded meaningfully and grouped as appropriate (e.g., sedation, somnolence, and drowsiness should be grouped as a single AR). Syndromes should be used where appropriate (e.g.. hypersensitivity).
  
• ARs should be categorized by body system, by severity (in decreasing frequency), or by a combination of both. An appropriate frequency cutoff may be specified.
  
• Quantitative data (e.g., labs, vital signs, ECGs) should be presented as rates of abnormal values, with a cutoff for inclusion (e.g., five times the upper limit of normal) rather than a grading system.
  
• If the AR rate is less than it is for the placebo, this information should not be included unless there is a compelling reason to do so.
  
• Statistical significance should not be included unless based on an adequately designed and powered study.
  
• The label should be reviewed at least annually to be sure all appropriate data are included.

For an example of this labeling, see the Zyprexa (olanzpine) label (May 2010) at Web Resources 34-10 and 34-11. The label is 32 pages long, and the Warnings and Precautions section runs about 7 pages and includes 7 tables. The AR section runs 9 pages and contains 14 tables, and the Interactions section runs 2 pages. From a practical point of view, if a practitioner has a question, such as “Does this drug cause headache?” and if it is not listed in the summary, the most expedient way to find this is to load the document onto a computer or handheld device as a PDF file and search for that term. Multiple hits may occur, leading to listings in several tables from which the practitioner can draw his or her conclusions. One might observe that this is not necessarily a quick or practical way to find out whether a specific AE or problem has occurred with the product in question.

Many drug labels and patient information for specific drugs can be found at the FDA website (Web Resource 34-12). In addition, most pharmaceutical companies have posted their product labeling on their websites. If the drug is sold in multiple countries, each local company website usually posts the local labeling.

In the United States, many, but not all, prescription drug labels are printed in the reference book known as the Physicians’ Desk Reference (PDR), published yearly by Thomson. It is about 3000 pages long and has photos of many of the products as well as the product information. There are other editions for over-the-counter (OTC) products, veterinary products, and so on. See Web Resource 34-13. An electronic version is available free to medical professionals at Web Resource 34-14. Other countries have the equivalent publications with drug labeling.

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