Biosimilars: Is Close Enough Good Enough?

Biosimilars have sparked the interest of the general public and the pharmaceuticals industry. Now, scientists pause to question whether biosimilars are as effective as biotherapeutics in treating disease. Biosimilars are proteins which are similar but not identical to the proteins used to treat chronic diseases.1 One drawcard is that biosimilars may improve the accessibility of biotherapeutic treatments to those in developing nations.1 However, issues regarding the quality and the effectiveness of treatments remain, along with concerns about the legal implications.

Are biosimilars as effective as biotherapeutics at treating chronic diseases?  The World Health Organisation (WHO) has posed this question amidst the hype surrounding this new form drug.¹ Biotherapeutics are proteins that are used as an active ingredient in some therapies to treat chronic diseases such as diabetes.¹ In contrast, biosimilars are proteins which are similar to but not identical to therapeutic proteins.^2,3 Biosimilars could make biotherapeutics more accessible to people in developing nations as biotherapeutics are often expensive.¹ Issues of effectiveness and quality arise as biosimilars are not identical to the original innovator product.²

Proteins are complex molecules and as methods used to manufacture biotherapeutic proteins are not disclosed, variations in the manufacturing process are likely to occur.² These, in turn, could cause slight variations in the biosimilar’s structure, making it similar but not identical to the original therapeutic protein.² Variations in a protein’s structure will strongly influence its stability and bioactivity.^2,3  This could influence in-vivo activity and half-life by altering the rate of degradation.^2,3 Consequently variations in both shelf-life and the severity of the immune reaction will occur.²
 
Manufacturing methods may be altered at many different stages in the process.^2,4 In particular, variations in the cell-line or the cell culture can alter the structure of the final protein.² For example, a major biotherapeutic in use is recombinant human (rh)-erythropoietin (EPO), which is used to treat renal conditions.² The presence of four particular chemical groups on the protein EPO will causes the EPO protein to increase.² This is due to a decrease in the clearance and an increased level of activity.² This has clinical implications and alters the amount of substance which would be used to individuals. In fact, recent analyses of biosimilar EPO products found that the composition of different batches varied greatly.²

Biotherapeutics can elicit an immune response when given over a long period of time.^2,5 The ability of a drug to promote an immune reaction  varies and is called the immunogenecity of the protein.⁶ Variations in the ability to elicit an immune response exist between biosimilar and their innovator products. One theory relating to the increased immunogenic capability of biosimilar products is that there are increased levels of immunogenic proteins.^2,7 Increased levels may result from reduced purity of the biosimilar product leading to more toxic proteins and can result in the faster development of an immune reaction.² Reduced effectiveness of the protein may negate the benefit of obtaining a cheaper biotherapeutic.

A recent WHO conference outlined the regulatory implications of biosimilars.¹ They are now in the process for developing overarching guidelines to aid the control of these controversial substances.¹ Some countries have started to develop their own regulatory guidelines. In Europe, the European Medicines Agency (EMEA)  developed a specific set of guidelines to register biosimilar products.^2,8 This has been both costly and time consuming for companies resulting in some sponsors listing the biosimilars as a new chemical as opposed to a biosimilar.^2,8 In Australia, the first biosimilar to be approved was Omnitrope.⁹ Biosimilars are not classified as generic drugs and it is acknowledged that guidelines for generic drugs would not be adequate.⁹ At the moment the Therapeutic Goods Council (TGA) has chosen to adopt the EMEA guidelines to evaluate biosimilars.⁹

Biosimilars are controversial and need to be monitored to prevent misuse.  It is important that appropriate legal guidelines are used to regulate their use. When considering biosimilar products one must ask, “Is close enough, good enough?”

References:

1. Juong J, Robertson JS et al. WHO informal consultation on regulatory evaluation of therapeutic medicinal products held at WHO Headquarters, Geneva, 19-20 April 2007. Biologicals. 2008; 1-8
2. Covic A, Kuhlmann M. Biosimilars: recent developments. Int Urol Nephrol. 2007; 39:261-266
3. Kuhlmann M, Covic A. The protein science of biosimilars. Nephrol Dial Transplant. 2006; 21 (5): 4-8
4. Roger SD, Mikhail A. Biosimilars: Opportunity or cause for concern? J Pharm Pharmaceut Sci. 2007; 10 (3): 405-410
5. Kessler M, Goldsmith D, Schellekens H. Immunogenicity of biopharmaceuticals. Nephrol Dial Transplant 2006; 21 (5): 9-12
6. "immunogenicity n."  Concise Medical Dictionary. Oxford University Press, 2007. Oxford Reference Online. Oxford University Press.  University of Western Australia.  19 February 2008 http://www.oxfordreference.com/views/ENTRY.html?subview=Main&entry=t60.e4916
7. Locatelli F, Roger S. Comparative testing and pharmacovigilance of biosimilars. Nephrol Dial Transplant. 2006; 21 (5): 13-16
8. Wiecek A, Mikhail A. European regulatory guidelines for biosimilars. Nephrol Dial Transplant. 2006; 21 (5): 17-20.
9. 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