Regulatory Context

A typical generic medicinal product is essentially similar to a reference product (Directive 2001/83/EC Article 10(1)). Thus, it has the same qualitative and quantitative composition in terms of drug substance(s) and the same pharmaceutical form as a reference medicinal product which has been previously authorised. Bioequivalence between the two has also normally been demonstrated by an appropriate bioavailability study or studies. An authorised generic medicinal product cannot normally be placed on the market until ten years have elapsed from the initial authorisation of the reference product.

Known drug substances are also utilised for new formulations, modified release formulations, new indications or new fixed combinations which will need further development work to bridge to the original development work performed (Directive 2001/83/EC Articles 10(3) and 10(b)). For example, new fixed combinations will require new pre-clinical tests or new clinical trials relating to that combination, while for the individual drug substances it may be sufficient to refer to the original development data and provide bibliographic references only. When significant pre-clinical or clinical studies are performed to support these so-called hybrid applications, the authorised product can benefit from data exclusivity.

For more well-established active substances which meet the specified criteria, an alternative application based solely on a literature review to complete the non-clinical and clinical sections of the dossier may also be an option – a so-called bibliographic or well-established use application (Directive 2001/83/EC Article 10(a)).

Issues in this Sector

Generic Product Profile

In the coming years to 2020, the profile of the majority of products coming off-patent is due to change from small molecule in the main towards more speciality products and biologics. These are more difficult to develop and make, and may require more clinical trial work to support. Whist the margins on the product will be greater, so too will the time to get through development, approval and commercialisation.

Cost Erosion

In these times of austerity, payers are putting enormous pressure on the pricing of generic products, with margins increasingly squeezed. Companies need to be imaginative in dealing with this reality. Strategies include ensuring maximum efficiency of production, sourcing cost-effective providers and targeting niche product types.

Limitations on Pre-Empting Patent Expiry

The introduction of the Bolar provision in Europe has enabled European manufacturers to handle and develop generic medicines prior to patent expiry. Previously, this could only happen in certain countries where different patent positions or non-observance or non-existence of patents made it possible.

However, certain barriers to such development still remain, for instance the manufacture of commercial batches within the EU prior to patent expiry. As a result, products developed and manufactured in those ‘non-patent’ position countries can be on the market earlier than product manufactured within Europe. This is achieved by importing finished product on the day of patent expiry.


There has been a recent growth in the number of companies looking to provide slightly more innovative products to the market, for instance by introducing fixed-dose combination products and modified-release formulations, to allow less frequent dosing and offer an improved safety profile.

Speed to Market

Since the introduction of the so-called 8+2+1 rule, generic companies know precisely the potential target timing for submission. However, IP protection also needs to be considered. Therefore, clever planning and experience with the EU systems of approval is key to ensuring approvals are in place at the right time.

Unexpected Questions Cause Delays

Questions from authorities during assessment of a generic application can cause delays to approval timelines. It is important that areas of weakness in an application are identified in advance so questions can be anticipated and tackled before receipt to reduce the clock stop time to a minimum. With increasing public demand for generic pharmaceuticals, there is great pressure on the development timelines for generic companies and there are huge benefits to being the first to market. Extended delays to market for generics after patent expiry can have a large impact on profit margins.


In an application for a generic medicinal product, the concept of bioequivalence is fundamental. This can be particularly difficult for drugs with high variability, poor absorption or for endogenous substances with their own baseline concentrations.


The Most Efficient Route for your Regulatory Approval

Real Generics can assist you in dealing with issues in drug development and in anticipating costly delays your application might encounter.

We can assemble a dedicated team to support you throughout the development process and provide expert advice on regulatory strategy starting from formulation and analytical development, to make sure that development progresses rapidly and ensure the quickest possible market entry for your product.