The Commission's Directorate-General for Enterprise and Industry has launched a public consultation on ideas for amending the regulatory framework governing the manufacture, trading and distribution of active substances and medicines for human use, amid "clear evidence that the risks to public health in the EU are set to increase still further if the Community does not act firmly" against counterfeit drugs. Responses to the consultation, as well as the findings of a study already launched by the Commission to assess various policy options for preventing the counterfeiting of medicines in the EU, will feed into the ongoing impact assessment of a legal proposal to combat counterfeiting. This could include changes to the core pharmaceutical Directive, 2001/83/EC, to Directive 2003/94/EC on Good Manufacturing Practice (GMP) for pharmaceuticals, and to the EU guidelines on GMP, Good Distribution Practice, inspections and exchange of information. The consultation document paints an unsettling picture of an environment in which a total of 2,711,410 counterfeit medicinal products were seized at EU customs borders in 2006, 384 per cent more than in 2005. It also notes a shift in counterfeiting strategies from 'lifestyle' medicines such as erectile dysfunction and weight-loss products towards life-saving drugs, including treatments for cancer, infectious diseases, psychiatric disorders and heart disease; and towards the licensed distribution chain, including authorised wholesalers, parallel traders and pharmacies, in addition to the internet. Moreover, the line between counterfeit and sub-standard active substances in medicines is blurring, raising further the risk of serious health consequences for patients, the Commission warns. A number of factors may have facilitated the rise of counterfeiting in the pharmaceutical market, the consultation document suggests: - Deficiencies in supply-chain integrity, "as there is uncertainty as to whether certain participants in the distribution chain are subject to pharmaceutical legislation (e.g., brokers, traders, business-to-business platforms)" - Lack of transparency for economic operators as to whether wholesalers and other actors in the distribution chain comply with GDP - Shortcomings in product integrity, "especially when packs are opened for repackaging and changed for relabeling purposes" - Difficulties in conducting targeted recalls, especially in the case of counterfeit products - Legal uncertainty and differing practices between EU member states over the application of pharmaceutical legislation to imports for the purpose of export - Active substances may not be manufactured in compliance with GMP, in declared sites or in accordance with declared procedures The proposed remedies to these flaws fall under the general headings of: - Subjecting all parties in the distribution chain to pharmaceutical legislation - Improving product integrity and traceability - Sharpening the technical requirements for GMP and GDP - Tightening inspections and supervision - Improving transparency The first of these measures would involve clarifying that the responsibilities and obligations of all players in the distribution chain, including brokers, traders and agents, were the same as those of wholesalers under pharmaceutical legislation. The Commission is also considering making audits of GMP/GDP compliance by qualified auditors (these might include third-party audits by accredited companies) mandatory. This would apply not only to dealings between manufacturers and contract manufacturers but to the relationship between manufacturers and supplying/purchasing wholesalers, where there were grounds for suspicion of non-compliance. Ideas for improving product integrity include requiring a unique seal for the outer packaging of a medicinal product in its journey from the manufacturer to the retailer or wholesaler. The right to open the seal would be restricted to the market authorisation holder and the end-user of the product (i.e., hospital, healthcare professional, patient). This rule would not apply to all medicines but to certain categories of product identified through a risk-based approach, taking into account the potential public health impact of counterfeiting and the profit strategies of counterfeiters. The move would be backed up by a ban on repackaging. In terms of traceability, the consultation document suggests introducing an obligatory product pedigree, comprising a "unique and centrally accessible record of all past ownerships and transactions". The supplied retailer/pharmacy would be the final traceable point in the distribution chain. As the Commission notes, a pedigree of this kind is currently under discussion for recommendation by the World Health Organization in its revised Good Distribution Practices. As things stand, Directive 2001/83/EC refers to batch numbers as the obligatory identification tool on pharmaceutical packaging. If counterfeit drugs are to be effectively traced, though, identifying who has handled a specific pack in the supply chain may be crucial, the consultation document says. This would call for mass-serialisation based on a code on the outer product packaging that would 'individualise' the pack and could be checked with a reading device. The requirement could be restricted to certain categories of product according to a cost-benefit analysis, the Commission proposes. It also notes that various tamper-proof technologies for implementing this concept (e.g., datamatrix/2D bar-coding) are under discussion in the pharmaceutical industry. The European Federation of Pharmaceutical Industries and Associations (EFPIA) says it plans to launch a pilot project on mass serialisation (2D bar-coding) towards the end of this year. Ideas for tightening up GMP and GDP include a mandatory requirement for regular audits of active substance suppliers by drug manufacturers and importers to verify compliance with Good Manufacturing Practice. Where scientifically feasible, this would need to involve sufficiently discriminating analytical techniques, such as fingerprinting technologies or Near Infrared Spectroscopy. The Commission also proposes turning GMP principles for active substances placed on the EU market into a legal act of Community law to ensure enforceability. At the moment, GMP for active substances is only established as a guideline. Among other GMP-related suggestions are allowing competent authorities, in cases of suspected non-compliance with Good Manufacturing Practice, to carry out either announced or unannounced inspections of active substance manufacturers. The competent authority would need to conduct repeated inspections in exporting countries if "the third country applies standards of good manufacturing practice not at least equivalent to those laid down by the Community or if mechanisms for supervision and inspections are not at least equivalent to those applied in the Community". Another suggestion is a mandatory notification procedure for manufacturers or importers of active substances, with information on notified parties available through a Community database (e.g., via extension of the EudraGMP database). In addition, distributors, agents, traders and brokers involved in placing active substances on the EU market would be subject to the relevant GMP standards. As the consultation document points out, the traditional focus of pharmaceutical legislation in the EU has been more on the manufacture, importation and marketing of finished drugs than on the manufacture and supply of active ingredients. The possibility that risks to patient health and safety may originate at an early stage of the production chain was highlighted in a declaration by the European Parliament in September 2006. Compliance with Good Distribution Practice could be more easily assessed by establishing a publicly accessible Community database containing information on the authorisations and GMP/GDP certificates of wholesalers or distributing manufacturers, the Commission proposes. This could again be achieved via an extension of the EudraGMP database. The consultation document also suggests making it a requirement to issue GDP certificates after each inspection of a wholesaler. One more line of defence against counterfeit drugs would be clarifying Directive 2001/83/EC to stress that imported medicinal products intended for export - even if they are not heading for the EU market - would be subject to same rules as other imported medicines (e.g., obligatory import authorisation, GMP, qualitative and quantitative analysis). Current uncertainties over the precise extent of the rules for medicines imported for export have led to divergent enforcement practices among the member states and to "blind spots" in the supervision of drugs entering the EU, the Commission notes, adding: "Moreover, there is a risk that these "blind spots" are being used to channel counterfeit products into the legal supply chain." The consultation on measures to combat counterfeit medicines, which runs until 9 May 2008, was welcomed by the EFPIA. The data and analysis outlined by the Commission "corroborates the evidence collected by EFPIA on prevalence of counterfeits, including the increasing penetration in the EU legitimate supply chain", the association said. Nor did it resist the opportunity to take a pot-shot at parallel importers. "As long as repackaging and breaking of seals in the distribution chain is allowed, patient safety will be highly at risk," the EFPIA claimed. The industry association has called for a ban on repackaging of pharmaceuticals, clearly defined liabilities for all players in the distribution chain (including brokers, traders and agents), stricter rules on auditing and controls on the supply chain, and the application of penalties for trafficking in counterfeits.