by ecancer reporter Janet Fricker

This year the patents of several oncology monoclonal antibodies are set to expire in Europe, including cetuximab (Erbitux) in June and trastuzumab (Herceptin) in July.

Such events open the way for pharmaceutical companies to ‘copy’ and market biosimilars, the regulatory term used to define medicines similar to biological medicines that have already been approved.

“Biosimilars ultimately mean more competition, and more competition should result in prices for oncology drugs going down,” said Matti Aapro, a medical oncologist from the Clinique de Genolier, Switzerland.

Pharmaceutical companies, including Amgen, Pfizer, Merck and Boehringer, are all jumping on the band wagon, reasoning that biosimilars offer the potential to deliver greater profits than developing novel agents from scratch.

While biosimilars in oncology are not new – biosimilars for supportive care drugs like epoetins (treatment of chemotherapy-induced anaemia) and filgrastim (prevention of chemotherapy induced neutropenia) are already available in Europe- those for actual cancer treatment are poised to enter the market.

Complex production

The reality for biosimilars is that they are not nearly as simple to produce as generic drugs.

While generic small molecule medicines are typically manufactured by chemical synthesis, most biopharmaceuticals are made in living organisms such as microorganisms or animal cells.

The desired proteins must then be isolated and purified from the cell culture medium using purification techniques that maintain the protein’s structural and functional integrity.

The result is that biologic drugs show some batch to batch variation, regardless of whether originators or biosimilars.

Additionally, expiring patents do not necessarily provide access to the precise manufacturing conditions used to produce the originator therapy, such as cell line clones and growth mediums, making it almost impossible for biotech companies to duplicate agents perfectly.

Even small structural alterations can have an impact on immunogenicity, and analytical or animal data cannot always predict human immune responses.
The upshot is that special regulatory pathways are being put in place to ensure biosimilars do not have reduced efficacy or different adverse reactions from originator drugs.

Regulatory pathways

The European Medicines Agency (EMA) has undoubtedly trail blazed the biosimilars regulatory pathway, setting out its approach as early as 2003.
As of January 2014 18 biosimilar drugs have been authorised for market in the nations comprising the EU (two have since been withdrawn), with a further two drugs now under review (one for follitropin alfa and the other for insulin glargine).

The EMA states that for biosimilar medicines, companies need to carry out studies showing that the medicine is similar to the reference medicine and does not have meaningful differences in terms of quality, safety, or efficacy.

Studies on quality include comprehensive comparisons of the structure and biological activity of their active substances, while studies on safety and effectiveness should demonstrate that there are no significant differences in their benefits and risks, including immune reactions.

In June 2013 further product specific guidance was established by the EMA for monoclonal antibodies, that added to existing general guidance.
New advice included use on clinically relevant endpoints, patient populations and surrogate endpoints in efficacy trials.

“Partly this is in recognition that for curative treatments detecting differences in overall survival between the biosimilar and originator becomes of paramount importance. Longer and larger studies are needed,” explained Aapro.

Lagging behind is the FDA, who is still in the process of debating draft guidelines produced in 2012, and considering issues such as how close copies should be to the originator drug and how biosimilars should be named and labelled.

One thorny subject is whether the FDA can approve biosimilars based on reference products that have been approved overseas, but not in the US.

“For the US the fact that a biosimilar regulatory pathway has not been established is limiting competition and causing delays in reducing the cost of drugs,” said Aapro.

Nations in Asia Pacific, Latin America and Eastern Europe are also in the process of establishing biosimilar regulatory pathways, providing sponsors with opportunities to select research sites strategically to optimise development timelines and achieve registration goals.

Oncologists using biosimilars or generic products need to be aware that switching patients from one agent to a similar but ‘not quite identical product’ could have important clinical consequences.

“Many of these drugs have narrow windows of efficacy versus toxicity, and switching from drug A to drug B could have a major effect,” cautioned Aapro.

It is vital, he added, that drugs dispensed to patients should be clearly labelled and not automatically substituted, so that the drugs responsible for any adverse effects can be traced. In 2012 the European Commission (EC) introduced a directive requiring EU member states to ensure that biological medicines are clearly identified by name of the product and batch number.

Doctors, the EMA maintains, should be in charge of the decision to switch between the reference product and generic or biosimilar or vice versa.

With generic medicines it can be common practice for pharmacists to undertake automatic substitution without the knowledge of the prescribing physician.

To safe guard against this practice, several European countries have introduced regulation to ban the automatic substitution of the often cheaper biosimilar treatments.

Cost effectiveness

One of the big hopes for biosimilar drugs is that they will enhance competition and increase access to cost effective biologic medicines.
But due to the complex manufacturing process and more stringent testing needed it is recognised that biosimilar drugs will undoubtedly cost more to produce than generics.

Estimates suggest that savings for biosimilars will reflect a 10 to 30% discount from the originator product compared to 90% currently achieved with generic chemical drugs.

Nevertheless, argued Aapro, the potential cost savings can still be substantial.

A study by the European Generic Medicines Association found that a 20% reduction in the price of six off-patent biopharmaceuticals would save € 160 billion each year in Europe ¹.

Biosimilars not only offer the potential to deliver cost savings, but also to produce ‘biobetters’, or ‘bio superiors’.

Such products, which result from modifications in protein or glycol engineering, have the potential to deliver new easier to administer forms, less side effects or longer half-lives in the body.

For pharmaceutical companies an undoubted benefit is that ‘biobetters’ are expected to warrant patent protection and to command higher prices rather than being sold at discounts. So the goal of cost savings may ultimately prove elusive.

Reference
1. European Generic medicines Association. The future of pharmaceuticals: generic medicines enhancing pharmaceutical competition and ensuring healthcare sustainability issues [homepage on the Internet]. 2007 [cited 2013 May 24]. Available from: http://198.170.119.137/doc/ega_FuturePharmaceuticals.pdf