Biosimilars

What are biosimilars?
How are biosimilars different?
Safety profile of biosimilars
Legal Implications

What are biosimilars?

Biosimilar is the term coined for protein drugs that are similar, but not identical to, an existing product. Unlike the situation with non-protein drugs it is not possible to create an identical copy or ‘generic’ of a biological drug; this is mainly due to the complex nature of protein molecules. The fact that biosimilars are not perfect copies of the originator drugs they are created to resemble has raised a series of questions concerning their regulation, quality and safety.

How are biosimilars different?

It is possible for a single protein molecule to exist in many forms due to the different ways it can ‘fold’ in on itself. Although these different forms are almost indistinguishable, it is known that they can display differences in their interactions within the body. Biosimilar drugs have been known to show less, the same, or more activity then the original drug. Changes to protein shape can be brought about by the manufacturing process itself and also by the inclusion of certain ingredients within a product. Differences in protein shape can also result in faster product degradation, leading to a decreased level of safety.

The manufacturing process used to create biological drugs involves a complicated series of events which are all known to influence the final shape of the drug. As pharmaceutical companies do not disclose information about how they manufacture biological drugs it is almost impossible for a generic drug producer to use the exact same process as that used to create the original drug. It is proposed that a difference in critical production steps is the main contributor to variations between the originator and biosimilar drugs.

Safety profile of biosimilars

All protein drugs when used over a long period of time will lose their effectiveness; due to inactivation by the body’s normal immune response. Although the immune response normally results in decreased drug activity, in rare cases autoimmune reactions have been reported. Currently the largest concern is that biosimilars may provoke a faster immune response than the original drug. This could mean that patients would have a much shorter period of time to benefit from a drug or that they might suffer some serious side effects.

Legal Implications

Australia
The first biosimilar to be approved in Australia was Omnitrope, which has been on the market since late 2005. Biosimilars pose a regulatory issue because they are not considered to be 'generic' drugs. It is clear that the approval processes for generic small molecule drugs are not adequate for biosimilars. In the recent National Health Act Amendment (Pharmaceutical Benefits Scheme) Act 2007, a definition of the word 'biosimilars' was omitted. Consequently, its meaning is still poorly understood. The registration of biosimilars in Australia is regulated by the Therapeutic Goods Administration (TGA), which determines whether a biosimilar is safe and effective. To evaluate biosimilars, the TGA has adopted the EMEA guidelines.
Europe
As biopharmaceuticals continue to come off patent there has been an increasing push by generic drug companies for the right to register their own product versions. The problems surrounding the registration of biosimilars, centre around the fact that they are not biologically identical to the products already on the market. In 2005 the European Medicines Agency (EMEA) issued a statement declaring that biosimilars are not generic drugs and should therefore be subject to different protocols prior to marketing approval. The EMEA has developed a specific set of guidelines for registration of biosimilar drugs, which promises to be both costly and time consuming for sponsors. In some cases the large expenses involved have prompted drug companies to opt for listing of their product as a new drug rather than a biosimilar.
United States
In addition to the usual requirements for generic drug trials, the EMEA requires crossover trials against the innovator product, randomised clinical trials, safety monitoring and submission of a post marketing surveillance plan. It is expected that the cost savings from biosimilar products may not be to the same level as that seen with traditional generics. Since the decision by the EMEA, there has been much lobbying in the US to have an ‘abbreviated’ listing process similar to the European model. Despite continued lobbying, the FDA is yet to release its own formalised guidelines.

It is clear that there is still much work to be done to assuage the concerns that have surrounded the introduction of biosimilars. Until these issues are addressed by appropriate legal framework and enquiry, the question ‘is close enough good enough?’ remains hanging.

Reference

Covic A, Kuhlmann M. Biosimilars: recent developments. Int Urol Nephrol. 2007; 39:261–266.
Kuhlmann M, Covic A. The protein science of biosimilars. Nephrol Dial Transplant. 2006; 21(5): 4–8.
Locatelli F, Roger S. Comparative testing and pharmacovigilance of biosimilars. Nephrol Dial Transplant. 2006; 21 (5): 13–16.
Kessler M, Goldsmith D, Schellekens H. Immunogenicity of biopharmaceuticals. Nephrol Dial Transplant 2006; 21(5): 9–12.
Wiecek A, Mikhail A. European regulatory guidelines for biosimilars. Nephrol Dial Transplant. 2006; 21 (5):17–20.
Submission to the Senate Standing Committee for Community Affairs Inquiry into the National Health Amendment (Pharmaceutical Benefits Scheme) Bill 2007 by Amgen Australia, June 14 2007