Generics and Known Drug Substances

Regulatory Context

A generic medicinal product has the same qualitative and quantitative composition in active substances 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 appropriate bioavailability studies. An authorised generic medicinal product cannot be placed on the market until ten years have elapsed from the initial authorisation of the reference product.

Known active substances are also utilised for new formulations, new indications or new fixed combinations which will need further development work to bridge to the original development work performed. For example, new fixed combinations will require new pre-clinical tests or new clinical trials relating to that combination but it may be sufficient to refer to the original development data and provide bibliographic references relating to each individual active substance. When known active substances are successfully developed for new indications with significant pre-clinical or clinical studies, one year of data exclusivity can be granted.

real regulatory flowchart- generics-and-known-drug-substances

Key issues in this Sector

Transparency Directive
The European Commission released a proposal in 2012 for a directive relating to the transparency of measures regulating the prices of medicinal products for human use and their inclusion in the scope of public health insurance systems. The new directive represents an important simplification measure and will replace the directive from 1989. It will help to reduce key hurdles that delay generic medicines. In early 2013 MEPs supported the proposal. The proposal includes a shorter 30 day price and reimbursement approval for generic medicines, a ban of patent linkage, which links the approval of the price and reimbursement of generic medicines to the patent status of the originator reference product and a decision that pricing and reimbursement assessment will not include reassessment of the elements on which the marketing authorisation has been granted.

Better Patent Regulation
Pharmaceutical products are covered by a number of patents. A patent can be approved for a new indication, formulation, salt or ester which can block the registration or marketing of a generic medicine for treatments where the base patent has already expired. This is a strategy known as ‘evergreening’. The Commission acknowledged that the increase in patents was partly due to ‘defensive patent strategies’ with the objective of ‘delaying or blocking entry of generic medicines’.

Data exclusivity for Fixed Combinations
A European court case is currently on-going between a pharmaceutical company and the European Medicines Agency (EMA). The proceedings concern EMA’s refusal to grant a generic marketing authorisation for a fixed dose combination medicinal product. The applicant in the proceedings alleges that the refusal to validate their application for an authorisation on the basis that the reference product is protected by a ten year period of exclusivity is contrary to the relevant harmonised European Union (EU) law properly interpreted.  The company argues that the marketing authorisation holder for the product was not entitled to enjoy a ten year period of data exclusivity, as the product was a fixed dose combination, combining two active substances, which had been supplied and used within the EU as components of a number of different medicinal products for some years. Notably, the Notice to Applicants, Volume 2A, Chapter 1 Marketing Authorisation states that fixed combination medicines within the meaning of Article 10b of Directive 2001/83/EC are regarded as new and unique products which do not fall within the scope of the global marketing authorisations for the individual active substances and therefore they should benefit from an independent period of data and market exclusivity. Until the case is resolved, many companies that invest in research and development of combination products will likely now wait before proceeding with any further product development, because, if the applicant succeeds, these companies would be clearly disadvantaged.

Difficulties to be avoided

Unexpected questions cause delays
Questions can be received from authorities during any review procedure. Questions 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 responses to questions can be prepared in advance before receipt to reduce the clock stop time to a minimum. Extended delays to market for generics after patent expiry can have a large impact on margins.

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. In an application for generic medicinal products 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

The most efficient route for your regulatory approval
Real Regulatory has up-to-date knowledge in key therapeutic areas throughout the product lifecycle and can assist you in dealing with current 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 regulatory strategy from formulation and analytical development to ensure the quickest entry to market for your product.

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