Regulatory strategy: Regulatory strategy could be seen as the adaptations a company makes to move its product from the development state to achieving marketing approval. It incorporates the drug development plan, an outstanding issue or question, background information, regulations and/or guidance documents, strategic advice and recommendations on implementation.
Drug: Brimonidine Tartrate 0.2% w/v (2 mg/ml) Eye Drops
Example - Strategy for Generic Application in EU
Dosage form: Eye drops
Date of marketing authorization: 1997-03-18
MA Holder: Allergan Ltd.
Innovator: Alphagan®,0.2% w/v (2mg/ml) eye drops
Question: What would be the legal basis for my application?
Summary
Background and Definitions
Article 8(3) of Directive 2001/83/EC: Provides the information on full application so applicable to new drugs
Article 10 - Generic, hybrid or similar biological applications:
a. Generic applications: According to Article 10(1) of Directive 2001/83/EC, the applicant is not required to provide the results of pre-clinical tests and clinical trials if he can demonstrate that the medicinal product is a generic medicinal product of a reference medicinal product which is or has been authorised under Article 6 of Directive 2001/83/EC for not less than 8 years in a Member State or in the Community.
- Same qualitative and quantitative composition in active substances as the reference product,
- same pharmaceutical form as the reference medicinal product,
- Whose bioequivalence with the reference medicinal product has been demonstrated by appropriate bioavailability studies.
- strict definition of a ‘generic medicinal product’ is not met;
- bioavailability studies cannot be used to demonstrate bioequivalence;
- changes in the active substance(s), therapeutic indications, strength, pharmaceutical form or
- route of administration of the generic product compared to the reference medicinal product
c. Similar biological application: In Article 10(4) of Directive 2001/83/EC
Article 10a - Well-established use application
Article 10b - Fixed combination application
Article 10c - Informed consent application
Assumptions:Put in assumption about hybrid application Article 10(3) of Directive 2001/83/EC (Because eye drops - bioavailability studies cannot be used to demonstrate bioequivalence)
Strategic advice: As per the note for guidance on the clinical requirements for locally applied, locally acting products containing constituents (CPMP/EWP/239/5) defines the clinical requirements for locally acting products with a known active substance.
Locally acting products are products which are applied locally and are assumed to exert their effect at the site of the application.
Examples are dermatological products (e.g. creams, ointments), inhalatory products like powders or aerosols for inhalation, eye drops, ear drops, nasal products, but also other products which act locally.
It is necessary to show for locally acting products that the product to be approved (either a generic or reformulated product) is therapeutically equivalent to the product already approved (based on a full dossier).
What would be the route of procedure?
a. centralized procedure: If SmPC is harmonized in all countries, applicant can choose centralized procedure.
b. Mutual Recognized procedure (MRP): If the product is already registered in a member state. The MRP starts with a National procedure with the chosen RMS. To run a MRP you need at least a RMS and one CMS. The amount of CMSs can be as big as 26. In an ideal world the MRP will take 420 days: 210 days for the National Procedure (license granted by the RMS) + 90 days for the assessment report from the RMS + 90 days for the MRP + 30 days for the national steps (translation of the SmPC, packaging materials and providing the license). The Marketing Authorization is issued by the national agency. The MRP can be repeated if you want to add additional member states at later dates - this is called repeat MRP second wave and so on. The RMS remains the same and the member states where the product was already registered through the MRP remain involved.
c. Decentralized procedure (DCP): If the product is not registered yet in any member state. You need at least RMS and one CMS. The procedure starts without a National Procedure. The dossier will be submitted to all the involved Member States at the same time. It is possible to end the procedure at Day 105 if consensus is reached, at Day 120, at Day 150 and at Day 210 (followed in each case by 30 days for the national steps). The assessment report will be send from the RMS to the involved CMS at Day 70. The standard clock stop is 90 days. The Marketing Authorization is issued by the national agency.
d. National procedure: If the product is not registered in any member state and if the application is restricted to one member state. The official time for granting a license is 210 days (without the clock stop) but in real life the average is about one year. The MA is then issued by the national agency.
Criteria for selecting a RMS
- Size of market within the EU
- Patents/Data Exclusivity & Market Exclusivity
- Registration cost (Strength specific)
- Consideration of future variations
- Potential for specific up-front agreements
- Long-term partnership
- Reference product availability
- Availability of slots (For DCP)
Date of first marketing authorization is 1997-03-18, so while selecting RMS and CMS Data
exclusivity has to consider as the important factor. Because data exclusivity is differs from county to country if the date of marketing authorization is before 31 October 2005.
10 years: Belgium, Germany, France, Italy, the Netherlands, Sweden, United Kingdom,
Luxemburg;
6 years: Austria, Denmark, Finland, Ireland, Portugal, Spain, Greece, Poland, Czech Republic, Hungary, Lithuania, Latvia, Slovenia, Slovakia, Malta, Estonia, Cyprus and also Norway, Liechtenstein and Iceland.
The “8+2 +1” formula applies to all new medicinal products where the application was submitted after 31 October 2005. In these cases generic medicines companies can apply for a marketing authorisation based on bioequivalence only after the 8-year data exclusivity period has expired, and can only market their products two or three years after that. The effective period of marketing exclusivity is therefore 10 or 11 years. The extra year applies when new indications (which have significant clinical benefit) are added by the originator during the first eight years of marketing the product.
Two options:
1. If DCP slots are available better to go for DCP, because applicant can get MA in more countries with single filling.
2. If Applicant having potential for specific up-front agreements with local parties better to go for national procedure, because applicant can get MA in short period of time, later can extend to Remaining countries through MRP.
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