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Licensing Guidelines and Regulations Posted 14/12/2012

First posted: 12 August 2011 

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The Dutch healthcare system is characterised by continuous debate and discussion about its structure and reform. Some reforms have helped to prepare the way for the new basic health insurance scheme, which was implemented on 1 January 2006 [1].

Under the new Health Insurance Act, all patients are covered by health insurance and all insurance funds must provide the obligatory basic insurance package, but they also have the option of offering supplementary insurance [2].

In The Netherlands, as with other medicinal products, marketing authorisation must be obtained for all generic medicines before they can be marketed. This may be done as soon as dossier protection for a medicinal product has expired after 10 years [3].

The Dutch Medicines Evaluation Board (MEB) – College ter Beoordeling van Geneesmiddelen (CBG) – is responsible for the approval, i.e. marketing authorisation, of medicinal products in The Netherlands. A dossier for a generic medicine does not have to contain preclinical or clinical test results, as long as the applicant can show that the medicinal product is a ‘generic’ version of a reference medicinal product. The reference medicinal product itself must have been granted marketing authorisation in the EU at least eight years previously.

The generic medicinal product must contain the same active substances at the same concentration as the original medicinal product. It must also have the same pharmaceutical form, e.g. tablet, capsule or injection fluid. The generic medicinal product must also have the same therapeutic efficacy and safety as the original medicinal product.

Biological medicinal products also have generic variants, so-called biosimilars. In the case of biosimilars, comparative research must also be conducted with both the reference and the biosimilar medicinal product. These studies must demonstrate that there is no significant difference between the safety and efficacy of the biosimilar medicinal product and the biological reference medicinal product.

The way the CBG-MEB approves generics is based on assessment of the quality of the medicine and bioequivalence testing according to strict European guidelines. Registration of generic medicines in The Netherlands will only take place (in most cases) when appropriate bioequivalence studies have been demonstrated. Once bioequivalence has been demonstrated, and the CBG is convinced that the generic has the same efficacy and safety as the branded medicine, it may be authorised. Consequently, the CBG-MEB is of the opinion that branded medicines can be safely exchanged with generic medicines.

There are, however, some exceptions to the bioequivalence requirements. The Dutch CBG-MEB has a list of substances, for example amoxicillin and paracetamol, for which it is generally accepted that these do not cause bioavailability problems when incorporated in conventional pharmaceutical forms for oral use [4].

For an innovator product, a complete dossier including pharmacological, toxicological and clinical data must be submitted with a marketing authorisation application. However, a complete dossier is not required when applying for generic medicinal products, in order to prevent unnecessary repetition of pharmacological, toxicological, and clinical human and animal trials. The applicant may refer to the complete dossier belonging to another product, the reference medicinal product, as long as the requirements for the accelerated procedure are met.

The reference medicinal product’s dossier must contain the pharmacological, toxicological and clinical data; thus, the issuing of the marketing authorisation for the reference product must have been based on a complete file. The CBG-MEB is not required to have access to this data. That is, the reference product need not have obtained marketing authorisation in The Netherlands. When evaluating requests submitted via the accelerate procedure, the CBG-MEB must verify that the submitted product is generic with respect to a reference medicinal product.

The term ‘generic medicinal product’ and the legal basis for the accelerated procedure is described in article 10, paragraph 2 under b) of Directive 2001/83/EG: ‘generic medicinal product’ shall mean a medicinal product that has the same qualitative and quantitative composition in active substances and the same pharmaceutical form as the reference medicinal product, and whose bioequivalence with the reference medicinal product has been demonstrated by appropriate bioavailability studies. The ‘reference medicinal product’ is a medicinal product authorised under Article 6, in accordance with the provisions of Article 8.

Article 10 of Directive 2001/83/EG not only governs the contents of the generic medicinal product’s file, but also lays out rules for the protection of data in the reference medicinal product’s dossier (data exclusivity). The accelerated procedure is described in Article 42 of the Dutch Medicines Act (Geneesmiddelenwet).

References

1. Österreichisches Bundesinstitut für Gesundheitswesen (ÖBIG). Surveying, Assessing and Analysing the Pharmaceutical Sector in the 25 EU Member States. July 2006.

2. Wet van 16 juni 2005, houdende regeling van een sociale verzekering voor geneeskundige zorg ten behoeve van de gehele bevolking (Zorgverzekeringswet). Available from: www.st-ab.nl/1-05358-zvw.htm

3. Dutch Medicines Evaluation Board – College ter Beoordeling van Geneesmiddelen (CBG-MEB), Legislation & guidelines [page on the Internet]. The Hague, The Netherlands, CBG-MEB [cited 2011 May 13]. Available from: www.cbg-meb.nl/CBG/en/human-medicines/regulatory-affairs/legislation-guidelines

4. Dutch Medicines Evaluation Board – College ter Beoordeling van Geneesmiddelen (CBG-MEB), Allergy information, Exemptions to the bioequivalence investigation list [page on the Internet]. The Hague, The Netherlands, CBG-MEB [cited 2011 May 13]. Available from: www.cbg-meb.nl/CBG/en/human-medicines/medicinal+products/Allergy-information/

Useful information sources

EMA, Committee for Proprietary Medicinal Products (CPMP), Guideline on the investigation of bioequivalence (CPMP/EWP/QWP/1401/98 Rev.1) 24 July 2008 [monograph on the Internet] London, UK, EMA [cited 2011 May 13]. Available from: www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003011.pdf

EMA, Committee for Medicinal Products for Human Use (CHMP), EMEA Procedural Advice for Users of the Centralised Procedure for Generic/Hybrid Applications (EMEA/CHMP/ 225411/2006) 2 July 2008 [monograph on the Internet] London, UK, EMA [cited 2011 May 13]. Available from: www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2009/10/WC500004018.pdf

EMA, Committee for Proprietary Medicinal Products (CPMP), Note for guidance on modified release oral and trans-dermal dosage forms: Section II (pharmacokinetic and clinical evaluation) (CPMP/EWP/280/96) 1999 [monograph on the Internet] London, UK, EMA [cited 2011 May 13]. Available from: www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003126.pdf

EMA, Committee for Proprietary Medicinal Products (CPMP), Note for guidance on the clinical requirements for locally applied, locally acting products containing known constituents (CPMP/EWP/239/95) 1995 [monograph on the Internet] London, UK, EMA [cited 2011 May 13]. Available from: www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003687.pdf

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