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Standardization Challenges in Pharmaceutical Product Labeling

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Product labels can be viewed as a “clinical instruction manual”, providing a concise description of the benefits and risks for a consumer and relevant information to dispensers, patients, and their caregivers. The format and content of medicinal product labeling is defined by regulations which differ between jurisdictions. Regardless of the specific presentation, the purpose of labeling is to provide accurate, clear and actionable information to all users of the product, with a primary focus on the prescriber, whose relevant clinical knowledge and ability to understand the content is presumed.

After initial approval of a pharmaceutical drugs license, it is often the case that far more data from real-world clinical use accumulates, which sheds new light on the utility of a product. Routine pharmacovigilance (PV), non-registrational studies and clinical practice experience may identify important new uses, amplify, expand, refute or even contradict initial labeling information; and provide insights into and support for different indications, dose regimens, limitations of use, safety information and magnitude of risk.

The increasing availability of electronically accessible clinical “big data” and the advanced tools under development for its analysis presents unprecedented opportunities to re-evaluate the true effectiveness and safety of a medicine or combination of medicines under the conditions of actual clinical use. The effectiveness of medicines as assessed within patient populations can differ substantially from those included in clinical trials. This also provides an opportunity to assess long-term efficacy, safety and head-to-head comparisons of different treatments. Labeling needs new approaches to progress beyond today’s limited snapshots of small patient populations and short-term exposures to address these new capabilities.

Labeling compliance

For biopharmaceutical companies, product labeling is a highly regulated and complex process that is an integral part of their overall quality system. Critical compliance findings associated with labeling compliance reported from the
2016-2017 Medicines and Healthcare Products Regulatory Agency (MHRA) good PV practice inspections were as follows:

  • Failures and significant delays to submit safety variations required to update the safety sections of summaries of product characteristics (SPCs) and patient information leaflets (PILs)
  • Superseded versions of SPCs and PILs on the marketing authorization holders (MAH’s) website
  • Missing clinically important safety information (contraindications and special warning & precaution) for many products
  • Failure to maintain the authorized product information through submission of an appropriate variation application after The Pharmacovigilance Risk Assessment Committee (PRAC) recommendation and confirmed signals.

Similar findings were noted in an aggregate analysis of the comments made in the periodic aggregate safety assessment reports (PSUR) received from EU regulatory agencies.1 The most frequent comments from the health authorities were requests for labeling changes, which had a high or significant impact on patient safety, drug benefit-risk profile and the MAH’s PV system, featuring in ~30% of all comments reviewed.

Examples of labeling discrepancy and data request from health authorities included change to a warning of the core data sheets not implemented nationally, or information included in national labeling but not in the core data sheet, communication of a signal/risk (labeling change) or minimizing a risk (Risk Management Plan change).1 
In another report on analysis of PRAC conclusions, labeling change was one of the most common outcomes of PSUR assessment report (17% of PRAC conclusions on PSURs).2,3

Keeping product labels up-to date

In order to complete a safety-driven label change, an organization must have written practices in place to organize the different functional groups with the required expertise. There should be a clear feedback process, where interactions with local or regional health authorities are tracked and communicated back to the global labeling team to maintain the currency of the local labels and alignment with core labels. Companies must have a comprehensive strategy that identifies roles and responsibilities of different stakeholders and a clear communication plan that captures meaningful and relevant content to progress the signal to the label and beyond. The majority of biopharmaceutical companies establish a safety governance team to identify, adjudicate, communicate and mitigate product safety risks and support signal detection and management activities.

As a general rule, all MAH of innovator and generic drug products have an ongoing obligation to ensure their product labeling is accurate. When new information becomes available that causes the labeling to become inaccurate, false or misleading, the application holder must take steps to update labeling. Health authorities including
US Food and Drug Administration (FDA) recommend that MAHs should review labeling for outdated information annually as a minimum. A drug is considered misbranded if its labeling is false or misleading or does not provide adequate directions for use and appropriate warnings.4

Risks of noncompliance

The relevant health authority may withdraw approval of any generic drug if it finds that the labeling for the drug product is no longer consistent with the innovator product. Noncompliance can affect the ongoing operations of a company in several ways, including possible withdrawal of a drug from the market, increased scrutiny from regulators, delays to pending market application approvals and loss of revenue. The MAH violating requirements for safety labeling changes may be subject to civil monetary penalties and misbranding charges.

Updating the agency-approved label involves multiple challenges. There are no agreed standards or guidance available regarding modifications and updates to the core labeling documents. There are additional questions around how certain commonly but inconsistently used sections of a core data sheet, including how warnings, precautions, contraindications are defined and applied. For example, there may not be a standard nomenclature for "frequency" (rare, common, frequent, etc.) and other terms.

Often, the MAH is asked to resubmit the labeling due to incorrect presentation of information. Examples of such issues include:

  • Disorganized or unclear or unrelated information presented in the dosage and administration section
  • Inadequate description of warning or lack of information on steps to prevent, reduce, or monitor risk or adverse events in warnings and precautions section
  • Inclusion of a laundry list of events that are not likely related to the drugs or missing critical information about clinical implication
  • Lack of practical instruction for preventing or managing drug-drug interactions.

Progress towards standardization

There has been some movement towards standardizing the product labeling process internationally. Since January 2015, the
European Medicines Agency has been publishing an overview listing allsafety signals discussed during the PRAC meeting and the recommendations for updates of product information. The MAH can use these publications to update their product information and obtain label approval by filing the appropriate safety variation.  Similar to the EMA, the US FDA also disseminates new safety information about the product to new drug application, biologics license application or abbreviated new drug application holders using the safety labeling change (SLC) notification letter. They are expected to update their labeling accordingly.

During the lifecycle of the product, the core data sheet is reviewed at least annually and updated appropriately, or when a trigger event occurs. A trigger event could include a safety-related update, a product line extension, product quality changes or a change in the MAH’s position on core labeling based on feedback from the health authority. These updates to the core data sheet need to be accurately reflected in the product’s label within a set timeline to meet the global and local compliance requirements.


1. Jullian S, Jaskiewicz L, Pfannkuche HJ et al. Aggregate analysis of regulatory authority assessors' comments to improve the quality of periodic safety update reports. Pharmacoepidemiol Drug Saf. 2015;24(9):971-9.

2. Arlett P, Postigo R, Janssen H, Spooner A. Periodic benefit–risk evaluation report: a European Union regulatory perspective. Pharm Med. 2014 (a); 28: 309–15.

3. Arlett P, Portier G, de Lisa R, et al. Proactively managing the risk of marketed drugs: experience with the EMA Pharmacovigilance Risk Assessment Committee. Nature reviews Drug discovery 2014 (b); 13(5): 395–7.

4. US FDA 21 CFR Part 201. Content and Format of Labeling for Human Prescription Drug and Biological Products; Requirements for Pregnancy and Lactation Labeling. Final Rule, June 30, 2015.

About the author(s)

Dr. Rajendra Wable is Senior Domain Lead-Medical Writing and Regulatory Affairs at Covance. His experience includes regulatory writing, product safety assessment and management of global labeling documents. He has hands-on experience in authoring a variety of regulatory submission documents including protocols, clinical study reports, investigator’s brochure, CTD Summaries and Overviews required for marketing applications.  He is also experienced in developing strategies for regulatory submission and responding to health authority queries. He has worked as a Study Director/Study pathologist for various regulatory toxicity studies and managed several PK, PD and toxicology projects.

Bindu Narang is a seasoned pharmaceutical professional, and has over 25 years of experience working both with pharmaceutical companies and CROs. She has set-up regulatory, medical communications and regulatory operations teams and has worked closely with teams in Labeling, Medical Information Services and Safety and Risk Management. Bindu holds a Masters degree in Pharmaceutical Sciences (Medicinal Chemistry). Bindu currently heads Scientific Writing and Regulatory Affairs at Covance.