How to navigate the complex world of BIOSIMILARS

As the life sciences sector faces unprecedented challenges, the market for “generic” biopharmaceuticals is looking to be one of the few attractive targets. However, market entry poses significant challenges and will likely generate plenty of work for legal and regulatory teams. Here is how to go about it.

Biocon Biopharmaceuticals, India

By: Thomas Bjorn, Solicitor, , London and Alexander Denoon, Solicitor, Lawford DaviesDenoon, London

With the cost of treatment for a single patient often exceeding $100,000 a year, biopharmaceuticals are attractive targets for generics companies as the patents protecting the original products expire.

Even established pharmaceutical companies have expressed interest, as evidenced by Pfizer’s announcement in October 2010 of a joint venture with Biocon (India’s largest biotech company) to bring biosimilar insulintreatments to market.

Merck US moved into the sector in 2008, and also traditional generics firms (including Sandoz, Cipla, Teva and Desani Pharma) are pursuing opportunities in this field.

Market entry hurdles

There are, however, numerous barriers to market entry.

First, the scientific and technical challenges to manufacturing biosimilars are significant in comparison with conventional generics. Estimates included in a recent article in the Economist suggest that while “a typical generic drug may cost a few million dollars to develop … a biosimilar version could cost perhaps $100m-150m.1”

Second, many people are predicting that the elaborate process for the approval of biosimilars is likely to be a significant battleground between innovator and generic companies. Innovators will want to defend their market and protect patients from products with different characteristics even after expiry of the patents, while generic companies will need to recoup their investments in such complex systems.

It is, for these very reasons, difficult to convince a regulator to approve a biosimilar product.

Third, in most cases biosimilars will be prescriptiononly products, which will require a sophisticated sales force and experience in dealing with reimbursement and regulatory requirements.

Generic vs Biosimilar

Given the complexity of the products, a separate regulatory approval regime has been established for biosimilars. Here are the most important things you need to know, before entering the field:

While traditional generic medicines merely need to establish their bioequivalence to the original reference product and therefore do not usually need to undergo clinical trials in humans, biosimilars must undergo, at least abbreviated, trials.

In Europe the rules regarding the approval of generic medicines and biosimilars are set out in Article 10 of the Medicinal Products Directive 2001/83/EC, which provides that a generic medicinal product will be compared with a reference medicinal product (RMP), which already holds a marketing authorisation.

It is worth bearing in mind that a generic (or a biosimilar) can only be placed on the market after the expiry of the applicable data exclusivity period. In most cases, this will be ten years after the grant of the marketing authorisation for the RMP (see Article 10 of the Directive).

A generic medicinal product can be granted a marketing authorisation without the need for new clinical trials if:

  • It has the same qualitative and quantitative composition in active substances as the RMP
  • It has the same pharmaceutical form as the RMP
  • Bioequivalence of the generic and the RMP can be shown through bioavailability studies

However, if a biological does not meet the definition of a generic (e.g. differences regarding manufacturing processes, such as the use of a different expression system), the results of appropriate pre-clinical tests and clinical trials relating to these conditions must be provided. By way of example, this may require the manufacturer to conduct trials on 100 patients rather than on 1,000 patients for a conventional phase III clinical trial. The type and quantity of supplementary data must comply with relevant criteria in the Annex to the Directive and related detailed guidelines issued by the various competent authorities. These requirements will also extend to the exciting field of advanced therapy medicinal products (such as stem cell therapies).

A manufacturer wishing to develop a biosimilarproduct and having identified the relevant RMP must therefore carry out such studies as may be required to establish the necessary data to support the equivalence.

Applicants should ensure that there is a clear path to approval. The EMEA has issued guidelines and Q&A’s regarding biosimilars and the scientific data necessary to support a claim of biosimilarity. Competent authorities adopt a helpful approach to guidance on the requirements for biosimilar applications. Regulatory matters are no longer administrative issues. These are now considered strategic issues for biopharmaceutical companies. As a result, regulatory and intellectual property teams should devise coordinated strategies for market entry and prepare for market entry by competitors.


While competent authorities enjoy a high degreeof discretion in complex assessments2, given the enormous value at stake, there is significant prospect for challenging a decision by a competent authority to approve or reject an application for a biosimilar (whether on grounds related to quality, safety or efficacy). The most common basis for challenge is likely to be unreasonableness (including improper considerations and irrationality), but challenges based on procedural fairness and legitimate expectation will also be considered.

A biopharmaceutical is usually a protein (such as a monoclonal antibody) that has been manufactured using genetically engineered microbial, mammalian or plant cells. In contrast, small molecule pharmaceuticals are normally chemically synthesised. Due to the complexity of the biopharmaceutical protein and the fact that the protein may be extremely sensitive to minor changes in the manufacturing process, biopharmaceuticals are usually significantly more complicated and expensive to produce than conventional pharmaceuticals. Many of the current crop of “blockbuster” medicines are biopharmaceuticals. Biopharmaceuticals currentlymake up more than 20% of global medicine sales, and they are projected to grow at double-digit rates as sales of many conventional medicines decline.

The material contained in this article is provided for general purposes only and does not constitute legal or other professional advice. Appropriate legal advice should be sought for specific circumstances and before action is taken.

© , March 2012

Please contact:

Thomas Bjorn- Consultant Solicitor

DD +44 (0)20 7553 9930

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