Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

The annex to Council Directive 75/318 and its consequences on new and existing marketing authorisations in the EC ***

Karen Frischke (Abschlußjahr: 2001)

To the present, no other disease apart from AIDS has attracted such an amount of public and political attention as the bovine spongiform encephalopathy (BSE) has. Recently, the media reported about new cases of BSE and Creutzfeldt-Jakob disease (CJD) in France, Great Britain and Germany. It seems, that the prion strain which causes BSE in cattle has overcome the species barrier and has infected human beings. People, especially in Europe, are worried about these facts and are afraid of this disease, that possibly has the potential to set off an epidemic.

The disastrous effect of BSE, commonly known as 'mad cow disease', on the meat-eating habits of the citizens of the European Union, is well known. As the implications for medicines are less obvious and certainly less publicised, the safety of medicinal products according to BSE was not really questioned by the consumers, although there are a lot of materials of bovine origin widely used in medicinal products, e. g. collagen, calf serum and trypsin. But also excipients such as wool fat, lactose, gelatine and talc can be bovine derived. It is estimated, that about 80 % of medicinal products contain bovine derived ingredients.

Several Commission Directives and emergency measures were implemented between 1994 and 1996 to protect against BSE, which were followed by a Commission decision on the 'prohibition of the use of material presenting risk as regards transmissible spongiform encephalopathy, published on July 30th 1997. The challenge thereafter was to introduce legislation, guidelines and procedures, that would minimise the risk of TSE and, at the same time, to ensure the continued availability of important medicinal products.

During 1992, the efforts of minimising the risk of transmitting animal spongiform encephalopathy agents via medicinal products resulted in the publication of a guideline. Responsible for this guideline was the Biotechnology Working Party (BWP) of the Committee for Proprietary Medicinal Products (CPMP). A new draft note for guidance was released for consultation in October 1998 and finally adopted in April 1999. In this document the potential sources of TSEs are defined, which are not only cattle but also ruminants like goats and sheep. Furthermore, the document applies current knowledge to reach conclusions about how the risks of TSE can be minimised. For each product an overall risk-benefit evaluation has to be carried out.

On September 8th the CPMP Note for Guidance was expanded into a Commission Directive (1999/82/EC), which amended the annex to Council Directive 75/318/EEC. The Commission Directive states that "the applicant must demonstrate that the medicinal product is manufactured in accordance with the Note for Guidance on minimising the risk of transmitting animal spongiform encephalopathy agents via medicinal products and its updates, published by the European Commission in Volume 3 of its publication 'The Rules Governing Medicinal Products in the European Union' ".

Article 2 of the above mentioned Directive 1999/82/EC has great consequences for pharmaceutical manufacturers and also for regulatory agencies throughout the EU. In accordance with this article, all existing marketing authorisations should meet the criteria of the Directive by March 1st 2001. New applications for marketing authorisation have to demonstrate compliance with the criteria by July 1st 2000. All this requires considerable effort by the industry to generate the necessary documentation, and where necessary, change raw materials and /or processes, and it will cause an enormous additional burden on regulators to review submissions in time for the deadline.

In order to achieve a more efficient route towards assessing the suitability of materials with a potential risk of transmitting agents of animal spongiform encephalopathies actions have been taken. Theoretically, regulators could be faced with reviewing the same material many times in several different product dossiers. This redundant work would waste a lot of time and would cause additional burden both for the regulators and for the marketing authorisation applicants. Instead, suppliers of such risk raw materials have the possibility to apply for a Certification of Suitability from the European Pharmacopoeia, as announced in Council of Europe Resolution AP-CSP (99), which was adopted on December 22nd 1999. With this certificate of suitability, marketing authorisation holders are able to demonstrate compliance with Directive 75/318 without submitting own documents. Another possibility for the marketing authorisation holder to show compliance to this directive is to provide specific scientific data about the risk material to the authorities.

With this thesis, the consequences of the annex to Council Directive 75/318/EEC, the impact of new and existing marketing authorisations in the EU and the workload involved will be shown.

Pages: 31