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U.S. Department of Health and Human Services

Animal & Veterinary

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VICH Working Group Making Progress on Agreement on Pharmacovigilance

by Margarita Brown, DVM, Office of Surveillance and Compliance
FDA Veterinarian Newsletter 2006 Volume XXI, No II

When a drug is marketed in different countries, the statement is sometimes made that it has been used for years in Country X without problems. But what does that statement really mean? In the past, little thought was given to how other countries manage veterinary pharmacovigilance, or monitoring drug adverse experiences. The assumption tends to be that all countries do things the same way. However, in today’s global society, this assumption takes on new importance.

The regulatory agencies of the member nations of the International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Medicinal Products (VICH), which are the United States, the European Union, and Japan, as well as the pharmaceutical companies that market their products internationally, all have staff dedicated to veterinary pharmacovigilance. However, there may be marked regional differences not only in the criteria defining an adverse event report, but also in when and how these reports are submitted to various regulatory agencies.

The pharmaceutical companies have had to navigate the regulatory shoals of many nations, sending adverse event reports at varying intervals and containing varying information, resulting in tedious and expensive duplication of reports and subsets of reports. Yet, with all this carefully collected data being sent around the world, there has been little or no sharing of adverse event information. Regulators in Japan may have no knowledge of label changes made by regulators in the United States. Regulators in the United States may be completely unaware of a cluster of adverse events in Germany.

VICH is an initiative concerned with developing harmonized technical requirements for the approval of veterinary medicinal products in the European Union, Japan, and the United States, and includes input from regulatory and industry representatives. In 1996, VICH was organized after the success of a similar harmonization effort involving human medicines—the International Conference on Harmonisation of Technical Requirements for Approval of Pharmaceuticals for Human Use (ICH).

Since 1997, the VICH Pharmacovigilance Expert Working Group has been meeting with the purpose of standardizing the collection of adverse event information and the timely sharing of that information with member and observer nations. Standardizing serves the dual purpose of vastly expanding the information available for regulators, and decreasing the burden and expense to the pharmaceutical companies of meeting multiple and diverse regulatory requirements.

Challenges

Several challenges become apparent when trying to meet the needs of different regulatory agencies. One of the biggest is how to negotiate around existing regulations. Different countries have varying degrees of flexibility to change a standing regulation, and the representatives’ authority to make such changes might be even more variable. Some regulations might be approved for change, but the timeline for implementation might extend into the distant future. The crafting of guidelines that allow circumnavigation of such impediments requires close attention to the use of language and a great deal of patience.

Definitions become extremely important when standards are being set. One country might require notification of a “serious” adverse event within a certain time frame, while another might require notification of a “serious and unexpected” adverse event within that time. But what, exactly, is meant by “serious” in each of those countries? Some countries might market a product that is not exactly the same as the product sold in another country, but the products might be similar. Sharing information for a similar product could expand the knowledge of the active ingredients, or provide adverse event information for a species approved for use on the label for one country, but not in another. Again, the definition of “same” or “similar” seems intuitive, but these concepts are actually nebulous and require exact delineation for international standards. Factor in the need for precise translation into languages other than English, and the inclusion of a single word can make all the difference between agreement and stalemate.

Although the required grasp of detail and structure can make negotiations seem frustrating and slow, the benefits will be well worth the effort and expense. Considerable time can elapse from the marketing of a new drug to the detection of a serious adverse event that was not identified in the few hundred animals participating in the pre-approval studies. A drug that quickly gains widespread use in hundreds of thousands of animals can provide the necessary basis for recognition of as yet unrecognized serious adverse events. Sharing of adverse event information under different conditions of use will benefit the international recognition of such events. Access to the more than 30,000 reports received annually in the United States will increase the strength of the emerging safety signals from the several thousand anticipated adverse events reported annually across the EU and the approximately 300 adverse events reported annually in Japan.

Crucial ingredients in the sharing of information include not only the standardization of the information collected but also its rapid transmission. The regulatory agencies of the EU and Japan already have systems in place for electronic submission of veterinary adverse drug events, while the Center for Veterinary Medicine is currently in the pilot phase of receiving adverse events electronically from industry. All of these in-house systems are different. The challenge is to establish the means by which manufacturers can send the same reports to their international branches, as well as to all the regulatory agencies. To this purpose, the Pharmacovigilance Expert Working Group is now standardizing the electronic data elements of the adverse event report and evaluating existing systems for widespread distribution so that the information can be received by the member nations, regardless of their internal processing system.

After four years of persistent dedication to negotiation, the members of the Pharmacovigilance Expert Working Group have succeeded in signing four of the five VICH Guidelines in their jurisdiction:

  • Management of Adverse Event Reports (GL24 Draft -Guidance), which is CVM’s Guidance for Industry #117: Pharmacovigilance of Veterinary Medicinal Products: Management of Adverse Event Reports (AER’s)
  • Periodic Safety/Summary Updates (GL29 Draft -Guidance), which is CVM’s Guidance for Industry #142: Pharmacovigilance Of Veterinary Medicinal Products: Management Of Periodic Summary Update Reports (PSUs)
  • Controlled List of Terms (GL30 Draft -Guidance), which is CVM Guidance for Industry #143: Pharmacovigilance of Veterinary Medicinal Products: Controlled List of Terms
  • Data Elements for Submission of Adverse Event Reports (GL42 Draft -Guidance), which is CVM’s Guidance for Industry #182, Pharmacovigilance of Veterinary Medicinal Products: Data Elements for Submission of Adverse Event Reports

All members of the Pharmacovigilance Expert Working Group have a strong commitment to reaching agreement on the Electronic Standards for Transfer of Data (GL35). With this remarkable achievement so close at hand, electronic submission and automatic population of the databases of the regulatory agencies will be a very big step towards even more rapid recognition of adverse events and the appropriate actions needed to maximize the safe and effective use of veterinary drugs.