To Label or Not to Label

Landmark Study Supports Industry Position

Frederick J. Balboni, Jr., Executive Director, Consortium for the Advancement of Patient Safety (CAPS)

For decades, pharmaceutical companies have printed messages on the ferrules and cap overseals of injectable-drug vials to help ensure safe delivery and administration. Messages include dosing and storage instructions as well as brand names and logos aimed at combating drug counterfeiting.

Frederick J. Balboni, Jr.

These labels will have to change on Dec. 1, 2013, when the revised US Pharmacopeia (USP) General Chapter <1> Injections, Labeling of Ferrules and Cap Overseals takes effect. The revised chapter limits printing on ferrules and cap overseals to cautionary statements.

USP released its most recent proposed revision to General Chapter <1> on Aug. 4, 2010. The text will be published in USP 34–National Formulary (NF) 29 in November, with the implementation date set for December 2013. The most recent USP revision replaces the chapter revision published in the Pharmacopeial Forum's January–February 2011 issue, which had an implementation date of May 2011. USP's first proposed revision of General Chapter <1> was published in early 2005.

The new standard classifies printing on ferrules and cap overseals as labeling for the first time. The new chapter also requires pharmaceutical companies to provide justification to the US Food and Drug Administration for printing a cautionary statement on a vial ferrule or cap overseal. If no cautionary statement is necessary, the top of the ferrule and cap overseal must remain blank.

Members of the Consortium for the Advancement of Patient Safety (CAPS) are disappointed with USP's proposed revision. Since the revision to USP <1> was first proposed five years ago, industry has sent written comments and made presentations to USP in support of a less restrictive standard, emphasizing the crucial role of printed information in minimizing administrative errors and improving patient safety. USP contends that most vial-cap messages create a "billboard effect" and that healthcare practitioners should rely on package inserts and drug-vial labels.

CAPS representatives met with FDA in 2009 to discuss the issue. During the meeting, an FDA representative stated that no factual, independent data supported either position (i.e., that of CAPS or USP) and recommended a human factors engineering (HFE) study to examine the use of vial labels. CAPS commissioned such a study and the findings (described below) indicate that USP's revision has the potential to threaten patient safety. CAPS presented the data to USP's Nomenclature Expert Committee on May 25, 2010, to assist the organization in creating an acceptable, viable standard.

The study was led by Anthony Andre, PhD, founding principal of Interface Analysis Associates and adjunct professor of human factors and ergonomics at San Jose State University in California. Andre is a certified ergonomist and the president-elect of the Human Factors and Ergonomics Society, an international organization with chapters in the US, Canada, and Europe.

The study consisted of three phases carried out between January and March 2010: a literature review, a web-based survey of more than 300 healthcare practitioners across the United States, and an HFE analysis. The data points to these overall conclusions:

• No medication-error data could be found that pointed to the ferrule or cap overseal as a source or cause of incidents or accidents.

• When presented with the idea of certain ferrule or cap overseal messages being prohibited, an overwhelming majority of respondents (74%) stated that "it would be harmful to eliminate most of these messages."

• Less information is not necessarily more effective, meaning that limiting messages to crucial information does not make such information more visible.

The survey showed that the majority of respondents value cap messages that would be prohibited by the USP revision. Eighty percent of survey respondents said they foresee an increase in medication errors if many of the currently allowed cap messages are prohibited, and 69% disagree with USP's approach to making crucial warnings more salient to those who handle drug vials.

The HFE analysis studied 20 healthcare practitioners, all of whom handle drug vials and are responsible for cross-checking against prescriptions and drug-delivery orders. Participants were asked to select the correct drug among a group of vials, using realistic patient-prescription scenarios. Some of the vials had cap labels that would be prohibited by the USP proposal. During the test, practitioners were able to find and select drug products with cap labels with greater speed and more accuracy than those that did not have labels. In addition, participants rated more positively the ease-of-use and confidence they felt when working with cap labels.

For example, one registered nurse initially selected a drug with a 100 U potency, thinking she had obtained the drug with a potency of 10 U. She noticed her mistake only when the message "100 U" printed on the cap caught her attention. In a post-task interview, she confirmed that without this printing, she would have left the 100-U vial on the drug cart for administration. CAPS considers the study findings a conservative perspective on the value of cap messages because many healthcare practitioners are not trained to notice or use cap messages in drug selection.

The results of all three phases of the study (see the full results at www.caps-edu.org) suggest that the current standard proposed by USP for General Chapter <1> will not achieve the stated objective of increased patient safety. CAPS maintains that strategically placed messages on drug vial caps can provide an additional layer of protection for healthcare practitioners when they determine dosage before administering injectable drugs. In addition, sophisticated technologies may prove effective to help prevent counterfeit drugs from infiltrating the nation's drug supply.

In a commentary released on August 4, USP stated, "The Expert Committee was not persuaded that the results of the HFE evaluation were in opposition of the proposed standard, as the experimental scenarios did not test the proposed standard" (1). The release from USP also stated that the committee "determined there was not sufficient reason to conduct or await any studies prior to the release of the standard (1)."

USP will accept comments on the new standard for 90 days after its November 2010 publication. In light of the CAPS study and potential impact on patient safety, CAPS encourages industry, caregivers, and patients to contact USP regarding this important issue.

Revised Standard Designed to Reduce Patient Death and Disability from Misadministration of Injectables

Shawn C. Becker, Director, Healthcare Quality Standards, US Pharmacopeia

The US Pharmacopeia's (USP) revised standard to USP General Chapter <1> Injections, Labeling of Ferrules and Cap Overseals section is designed to address medication errors that may be linked to misadministration of injectable products at the time of use. Such errors have been implicated in episodes of patient death and disability. As an indicator of the importance of reducing medication errors from all sources, not just injectables, the Institute of Medicine (IOM) has estimated that as many as 98,000 people die in any given year from medical errors that occur in hospitals. Of these, IOM estimates the intensive-care unit (ICU) medication error rate to be as high as 6% (2). In direct-observation studies assessing medication errors with injectables, the rate is even higher, according to IOM. Some studies demonstrate medication-error rates as high as 49%.

Shawn C. Becker

Although USP's goal in revising this standard is to assist healthcare practitioners to protect their patients from harm, the organization recognizes the significant impact the revision will have on industry and is addressing this concern through an extended implementation period of more than three years.

In developing this standard, the USP Nomenclature Expert Committee recognized that the situations in which injectable products are often administered can be extremely busy, including in emergency rooms or in ICUs. Reports—including the aforementioned from IOM—as well as from the National Coordinating Council for Medication Error Reporting and Prevention and the Institute for Safe Medication Practices have indicated that labeling of injectable products may be linked to medication errors in the administration of these products. Patient-safety data from US hospitals collected through the USP MEDMARX program (1998–2006) indicated that the most severe medication errors for injectable products were predominantly related to human performance deficits, occurring most often at the time of administration, with environmental distractions as the major contributing factor. The goal of the standard is to minimize opportunities for this type of error.

The new standard

Changes to USP General Chapter <1> have been considered by four USP expert committees during the past decade. These committees are made up of independent, outside experts. The committees evaluated evolving scientific literature, reviewed data from medication-error reporting databases, facilitated stakeholder meetings, and routinely consulted with the US Food and Drug Administration regarding the labeling of injectable products.

Over the years, expert committees have implemented changes to many labeling standards to reduce the likelihood of serious medication errors arising from misadministration of medicines. These changes affected potassium chloride for injection concentrate, neuromuscular blocking agents, and vincristine-sulfate injectable products. Although these medication-specific revisions were needed to address dangerous situations, the USP Nomenclature Expert Committee decided it was also necessary to address the problem of misadministration systematically across all injectable pharmaceuticals. In June 2010, USP's 2005–2010 Nomenclature Expert Committee voted to adopt changes to the ferrules and cap overseals section of the chapter in the interest of patient safety.

The revised section of the standard states that only cautionary statements may appear on the top (circle) surface of the ferrule or cap overseal of a vial containing an injectable product. The cautionary statement should appear on both the ferrule and cap overseal but may appear solely on the ferrule if the cap overseal is transparent and the cautionary statement beneath the cap is readily legible. Products that do not require cautionary statements should be free of information on this surface, so continued from page 97

that those with cautionary statements are immediately apparent. This systematic approach to the labeling of injectable products will help ensure that cautionary statements can be easily seen by practitioners, thereby reducing the opportunity for errors from misadministration of these products.

The standard defines a cautionary statement as one intended to prevent an imminent life-threatening situation and may include instructional statements that may provide potency or other safety-related instructions if warranted. Cautionary statements must be simple, concise, and devoid of inessential information. Inessential information includes company names, logos, and product tradenames.

The decision

The standard was revised under the direction of USP's Nomenclature Expert Committee. USP Expert Committees are composed of outside experts that operate under strict conflict-of-interest rules to establish public standards. These volunteers have diverse healthcare backgrounds such as pharmacy, nursing, and fields of medicine, or experience in academia, health plans, consumer organizations, or the pharmaceutical industry. Under USP's public review process, expert committees publish proposed new or revised standards. Comments by any party are considered by the committee for scientific merit, and standards are adjusted based on this feedback. Standards are adopted by USP expert volunteers by a majority vote.

The CAPS position reflected alongside this column was first presented to the USP Nomenclature Expert Committee in May 2010, as part of the public comment period. The committee considered this information along with all other comments submitted in making its final decision on the standard.

Concerns about the proposed standard fell into two categories: first, whether important information that could affect the safety of the patient would be restricted under the standard; and second, whether anticounterfeiting measures on product caps would be considered usable. The Nomenclature Committee took these issues seriously. Addressing the first matter, the Expert Committee determined that the standard is designed to help ensure the visibility of the most critical safety messages. It is important to note that the standard will not restrict messages contained elsewhere on the injectable vial (e.g., vial skirt or label), but only on the ferrule and cap overseal areas. With regard to the second matter, the Expert Committee recognized the importance of anticounterfeiting activities, and concluded that there are many mechanisms for ensuring product accountability that involve technologies and approaches other than labeling ferrules and cap overseals.

Implementation

According to FDA, if manufacturers believe they need to include a cautionary statement about an imminent life-threatening situation on the ferrule or cap overseal of their product, they must provide a rationale to FDA regarding why the situation addressed in the statement is considered to be life-threatening. FDA will expect manufacturers to provide data to support the assertion that the statement is safe, unambiguous, and provides the best message to minimize the life-threatening situation. Given the effects this change could have on manufacturers, the USP Nomenclature Expert Committee established a delayed official date for the revised standard. The standard will be published formally on Nov. 1, 2010, in USP 34–NF 29 and will become official Dec. 1, 2013, thereby giving industry three years to implement the change.

USP appreciates the input of all parties regarding this revised standard, and recognizes the changes the standard will require of manufacturers in the coming years. USP believes this activity will support healthcare professionals in their work and help protect patients from serious medication errors that could result in death and disability.

Reference

1. USP, Commentary–General Chapter <1>, Aug. 4, 2010, www.usp.org/pdf/EN/USPNF/genChapter1Commentary.pdf, accessed Aug. 31, 2010.

2. IOM, To Err is Human: Building a Safer Health System (National Academy Press, Washington, DC, 2000).