FDA's New Labeling Requirements: The Importance of XML for SPL Compliance

Motivated by internal government recommendations, initiatives, and legal mandates, the US Food and Drug Administration released structured product labeling (SPL)–related regulations for 21 CFR Parts 314 and 601. On Feb. 5, 2004, the agency provided an SPL draft guidance for industry entitled, Providing Regulatory Submissions in Electronic Format—Content of Labeling as recorded in the Federal Register (1) and announced acceptance of SPL applications on Sept. 24, 2004, in public docket number 92S-02512. The challenge was to build an effective regulatory guidance system using more-flexible application tools than portable document format (PDF) or Microsoft Word for the electronic maintenance of market applications such as human drugs and biologic content. At the forefront of the research was Health Level Seven (HL7), a volunteer American National Standards Institute–accredited standards developing organization that focuses on the development of specifications for the standardized maintenance of clinical and administrative healthcare data. HL7 has defined a new data file definition called SPL, which is based on the Web standard extensible markup language (XML). As of this month, FDA requires that all labeling content information for human prescription drugs be submitted in SPL XML format. PDF format will no longer be accepted. So, what is XML and why is it important for SPL compliance?

XML and SPL applications

XML, an electronic file format supported by numerous software manufacturers and endorsed by the World Wide Web Consortium (W3C) as an industry standard, enables practical solutions for electronic business transactions. Because it can be read by multiple source applications and disseminated in a variety of formats, XML delivers the promise of "one version of the truth." For example, the boxed warning information in an FDA-approved submission can be repurposed immediately as the content in the next print run of an accordion-style printed insert that accompanies a physical product. The printing system can be readily updated by the approved structured content in the SPL file.

Designed for large-scale electronic publishing and exchanging information on the Web, XML is a subset of standard generalized markup language (SGML). XML development began in 1996 and was formally recommended by W3C in 1998 (3). XML is much like HTML in its coding structure. They differ, however, in that XML was created to define and describe specific pieces of information using user-defined custom tags and attributes, while HTML is limited by the use of predefined tags for visual representation of information.

The XML standard provides a wide-open platform to create data structures and related data-storage elements. Custom designed data definitions, data types, attributes, hierarchal relationships, and general taxonomy are collected in XML schemas. Once created, XML tag elements defined in the schema can be used, as needed, to record the actual data values in the XML file.

FDA provides a large set of elements in a predefined SPL schema for representing labeling data. This SPL schema set is dedicated to recording drug product information and has embedded coding values to support efficient computability for search and retrieval. The SPL schema structure ensures that a uniform representation of the product data is maintained across all labels.

SPL XML applications can maintain all of the textual-based information, data elements, and images needed for drug approval, including drug listing information. XML also can efficiently handle multimedia such as tables, images, and complex documents. Pharmaceutical companies can expand the XML format into almost every branch of their businesses.

XML can integrate dissimilar operations by consistently exchanging standardized data. Because the content is kept separate from the format, multiple application databases using XML can be distributed across many servers while maintaining the integrity of the data. Likewise, documents can be viewed on various media with extensible stylesheet language (XSL) style sheets, which allows different ways of presenting the labeling information, in accordance with the preferences of the targeted audience without the need to reprogram or manipulate the information. XML supports both unicode and multilingual documents, thereby facilitating the internationalization of complex data.

SPL compliance

SPL is the introductory XML-based standard for medical and biological labels. Interestingly, XML is quickly becoming the standard in the healthcare industry. In fact, pharmaceutical and medical markets are planning to extend the appliation of XML to clinical trials and patient medical histories. HL7 is developing XML data definitions for stability data and protocols. Before SPL, PDF files were used for human drug biological content submissions throughout all process stages. The format's inability to allow queries and the reuse of specific data, however, made it impractical for labeling. We project XML eventually will be the defacto file format for the electronic submissions of all medical products information. XML enables real-time changes as well as the submission of changes or additions in sections, thereby eliminating the need to resubmit the entire label for approval. This capability may significantly reduce the labeling-content negotiation phase of the FDA approval process.

Components. Three major components comprise the SPL XML format: header, body sections, and data elements. The header, or classification, contains general information about the label and product. It sets the context for the remainder of the document. Header elements are primarily data-field items such as identification, version, name, and address.

Human readable content, multimedia, and encoded computer processing content are included within the SPL body sections, which are primarily text-based information but can include tables, images of molecular structures, lists, and chart diagrams. The body sections contain product content divided into units of text such as drug interactions, dosage and administration, and warnings.

The drug listing information is defined by many data elements organized according to packaging, active ingredient, inactive ingredient, observation (e.g., color), and route of administration sections. Storing the information and exchanging it across and within institutions requires that the structure be identical throughout all documents; the SPL format accomplishes this conversion.

Detailed SPL specifications can be found on the FDA structured product labeling resources Web site entitled, "SPL Implementation Guide for FDA Content Labeling Submissions" (4). FDA's required format is defined in the SPL version 2a.

Benefits of XML-based SPL compliance

Executing SPL compliance using XML can provide several advantages not only to pharmaceutical and medical products manufacturers, but also prescribers and consumers. Coordinating data collection and storage makes the evaluation of labeling changes more efficient and the dissemination of labeling to improve risk management faster. Therefore, higher quality prescribing and safety information can be delivered to a medical practitioner faster than it is delivered today.

Minimizing redundant data collection also improves patient safety and quality assurance. Revisions can be made to existing legacy data elements or sections for original or subsequent submissions. As a result, companies no longer need to resubmit an entire product label from scratch because XML markups can call up data buried in the body section or narrative block. Moreover, interoperability with other systems and human-readable labeling content compatible with other systems promotes more coordinated efforts across regulatory agencies.

One of the most compelling benefits of XML related to product labeling is its potential to facilitate global harmonization of labeling content. The same content used for an SPL submission can be repurposed for use in a European Union product information management (PIM) submission. Europe will begin voluntary implementation of the PIM standard for centrally registered products on Nov. 20, 2005. The evolving nature of XML technology and data definition standards offers the opportunity for the internationalization of a whole host of medical, pharmaceutical, and biological products applications and services. XML is redefining the database infrastructure with a standardized product for the international community.

Ron Celeste* is the president of ThinSpring, 991 US Highway 22, Suite 200, Bridgewater, NJ 08807, tel. 908.595.2145, fax 908.231.0444, ron.celeste@thinspring.comwww.thinspring.com. Gary Saner is the manager of Structured Content Services for Reed Tech (Horsham, PA), www.reedtech.com

*To whom all correspondence should be addressed.

References

1. US Food and Drug Administration, "Providing Regulatory Submissions in Electronic Format: Content of Labeling," Fed. Regist. 69 (24) (Feb. 5, 2004), http://a257.g.akamaitech.net/7/57/2422/14mar20010800/edocket.access.gpo.gov/2004/pdf/04-2536.pdf.

2. FDA, "Content Labeling," public docket 92S-0251 (Sept. 2004), http://www.fda.gov/ohrms/dockets/dockets/92s0251/92s-0251m000031.pdf.

3. World Wide Web Consortium (W3C), "XML Recommendation" (Mar. 27, 1999), http://www.w3.org/XML/1999/XML-in-10-points.

4. FDA, "SPL Implementation Guide for FDA Content of Labeling Submissions: Version 2a" (Mar. 2005), http://www.fda.gov/oc/datacouncil/spl.html.

Additional information

• D.Obasanjo,"Understanding XML"(July 2003), http://msdn.microsoft.com/XML/Understanding/default.aspx?pull=/library/en-us/dnxml/html/understxml.asp.

• S.Powell and G.Kalten,"The Future of Labeling," Pharm. Exec. 25 (1), 60–64 (2005).

• Guidance for Industry Providing Regulatory Submissions in Electronic Format—Content of Labeling (FDA, Rockville, MD, Apr.2005), http://www.fda.gov/cder/guidance/6719fnl.htm.

• Structured Product Labeling Resources (FDA, Rockville, MD, Mar.2005), http://www.fda.gov/oc/datacouncil/spl.html.

• N.Walsh, A Technical Introduction to XML (1998), http://www.xml.com/pub/a/98/10/guide0.html?page=2#AEN58.

• World Wide Web Consortium (W3C),Extensible Markup Language (XML) 1.0 Cambridge, MA, Feb. 2004), http://www.w3.org/TR/2004/REC-xml-20040204.