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Approval of biosimilar medicines


Whether they are referred to as biosimilars, follow-on biologics or subsequent-entry biologics, these products present particular challenges to industry and regulatory authorities

Ken Seamon

Senior Associate

Institute of Biotechnology
University of Cambridge

Biosimilar medicinal products represent a new and challenging approach for developing versions of biopharmaceutical products that are no longer protected by patent. The regulatory approval of generic chemical drugs is based on the premise that is possible to determine that two drugs are chemically equivalent based on standard analytical methods and bioequivalence studies. This determination of chemical identity and bioequivalence then allows one to conclude that the generic product would have the same safety and efficacy profile as the original product.

However, biological and biotechnology products represented principally by therapeutic proteins are significantly more complicated and it is generally recognised that it is not possible to unambiguously determine that two protein therapeutic products are identical based only on analytical methodologies. The regulatory and scientific standards developed by the EMEA for evaluating biosimilar products resulted from extensive scientific discussions and consultations resulting in a number of significant guidelines.[1] The review of biosimilar medicines utilises clinical data in addition to analytical and bioequivalence data to support the safety and efficacy comparison with a reference product. The type and extent of data depend on the specific product and its use in a given patient population. In addition, due to the complexity of biological products and the potential for differences in the occurrence of rare safety events, it is also important that programmes be in place for accurate pharmacovigilance and unique identification of the products on the market.[2,3]

Current status
The EMEA has reviewed a number of biosimilar products since establishing the regulatory standards and approach for review. It is useful to examine the recent examples as they exemplify the complexity that is inherent in biological products as well as the process established by the EMEA.

Table 1 summarises the status of biosimilar products that have been reviewed by the EMEA. Ten medicinal products have been evaluated, representing five different product classes and five different active substances. The biosimilar active substances include two somatropins, one epoetin alfa, one epoetin zeta, one filgrastim and one interferon alfa 2a.

Human growth hormone
Human growth hormone was one of the first products reviewed and approved by the EMEA. Omnitrope® was compared with the reference product, Genotrope®, by analytical data and clinical data to assess efficacy and safety. During development, an early version of the Omnitrope product was found to have a slightly different impurity profile and immunogenicity profile from the reference product; however, the final Omnitrope product demonstrated the same clinical profile as Genotrope. Based on these data Omnitrope was approved. The FDA also subsequently approved Omnitrope, but not as a generic product.

The biosimilar growth hormone Valtropin® is manufactured using a yeast expression system which is different from the Escherichia coli expression system used to manufacture the reference product Humatrope®. The quality and clinical data were supportive for approval.

This demonstrates that the evaluation of a biosimilar medicine will clearly depend on the strength of the quality and clinical data which can allow for differences in the production process.

Interferon alfa 2a
Interferon alfa 2a is used for the treatment of hepatitis C. Alpheon, a biosimilar interferon alfa 2a, was reviewed by the EMEA and was not recommended for approval.[4]

The data submitted to the EMEA, which included both analytical data as well as clinical data for safety, efficacy and immunogenicity, did not demonstrate that the products were sufficiently similar to support approval. Differences were noted between the impurity profiles of the products and the data did not demonstrate sufficient equivalence of the clinical safety and efficacy parameters. There were also deficiencies noted in the manufacturing validation. This underscores the rigour of the EMEA review process and the importance of evaluating both chemical and clinical data for determination of approval for biosimilar products.

Erythropoietin is a complex glycoprotein therapeutic which is used for the treatment of anaemia. The largest markets are for the treatment of anaemia associated with renal disease and as a consequence of cancer chemotherapy.

There are five biosimilar erythropoietins approved by the EMEA derived from two different active substances, epoetin alfa and epoetin zeta. The reference product for each biosimilar was Eprex�, the currently marketed epoetin alfa. Each product was compared with Eprex through analytical testing and clinical testing to assess safety, efficacy, and immunogenicity.

The pivotal studies for comparison compared Eprex with the biosimilar products for the correction of anaemia for patients with renal disease on dialysis and not on dialysis.

Studies were carried out that compared the ability to correct and maintain haemoglobin levels and the data was found to be supportive. Additional data were provided for epoetin alfa and epoetin zeta to support an indication in oncology. The additional data were not designed to demonstrate equivalence but to confirm the expected results for the treatment of anaemia in these patients. The epoetin alfa biosimilars used a double-blind study with Eprex, and the epoetin zeta used an uncontrolled noncomparative trial. The data in both studies demonstrated that increases in haemoglobin were consistent with expected values and there were no significant differences in serious adverse events. Based on this supportive data in the oncology setting the products were approved for treatment of anaemia due to chemotherapy.

The immunogenicity of administered erythropoietins is of special concern due to the potential for pure red cell aplasia that has been observed as a result of the occurrence of anti-erythropoietin antibodies.[5] There were no treatment-associated increases in antibodies in the pivotal and supportive studies. However, the data are not supportive of subcutaneous use in immunocompetent patients and the biosimilar products have the same contraindications and warnings as the reference product.

The choice of reference product for a biosimilar is not absolutely defined by the international nonproprietary name (INN), as evidenced by epoetin zeta, which was approved based on a comparison with epoetin alfa.

The name “epoetin” indicates that the primary amino-acid sequence of the proteins is identical, while the Greek letter may denote an unquantified difference in the sugar structures on the protein backbone. Slight differences in the glycoform profiles of epoetin alfa and epoetin zeta were not considered by the EMEA to be significant enough to affect the safety and efficacy of the product.

The clinical data from the studies carried out in the renal population and the oncology setting did not demonstrate any significant differences between the two products.

The EMEA has recently offered a positive opinion on three biosimilar filgrastims, a biosimilar granulocyte-colony stimulating factor (G-CSF) based on a comparison with Neupogen®. The EMEA guidelines for a biosimilar G-CSF suggest that clinical data would be required to compare a biosimilar with the reference product in the setting of chemotherapy-induced neutropenia. However, there was also a reference to the use of pharmacodynamic data to support an approval.

There is no detailed information in the summaries of the recommendations and it will be interesting to see what data were evaluated. The data were considered robust enough to support the indications of treatment of neutropenia associated with chemotherapy, as well as for mobilisation of peripheral blood stem cells for transplant.

It will also be interesting to see if data were provided for both indications.


Biosimilar products in other regions
In the US, it is not possible to approve generic copies of most of the approved protein therapeutics using a generic approval process. It has been recognised by the FDA that a generic approval standard would not be scientifically justified.

The US Congress is considering legislation that would allow the approval of biosimilar medicines (usually referred to as follow-on protein products or follow-on biologics in the US). Even after legislation that would authorise follow-on protein products, it would then be up to the FDA to establish the appropriate standards for the approval of such products. However, the FDA will probably take advantage of the extensive discussions that have taken place over the past years with regard to protein therapeutics, and the approach will probably be similar to that taken by the EMEA with regard to product class specific requirements for quality, safety, efficacy and immunogenicity.

Actions taken in April 2008 by the FDA suggest that there will continue to be a rigorous evaluation of the product, which will include both analytical and clinical data determined by the product and its intended use.

Recently, the FDA announced that Myozyme® (alglucosidase alfa), manufactured by Genzyme, which was manufactured at a different scale from the approved product, could not be approved because of differences in glycan structures and indicated that this would be viewed as a different product.[6]

This does not really represent a new, more rigorous position by FDA. There have been many examples where changes in manufacturing have resulted in changes in the product, resulting in requests for more data to support approval or modifications to the new process.

However, this recent example supports the fact that the FDA will continue to be very rigorous in its evaluation of any differences in the physical parameters of proteins. The FDA also refused to approve a generic version of conjugated oestrogens due to the lack of immunogenicity data, again underscoring the concerns relating to immunogenicity of biological products.[7]

The approval of Omnitrope in the US, although not a generic approval, is consistent with the FDA’s approach in that clinical data along with analytical data was required to support approval.

Canada has recently published a draft guideline on biosimilar medicines, which are referred to as subsequent-entry biologics (SEBs). This guideline also underscores the importance of evaluating analytical data along with clinical data to support the safety and efficacy comparison.[8] The Canadian draft guideline, which is currently receiving comments, indicates that the standards will be determined based on the specific product and indication and reiterates a number of important points consistent with the EMEA approach:

  • SEBs are not evaluated as generic products.
  • Data should be submitted to demonstrate comparability based on analytical data, pharmacokinetic data, and clinical data for safety and efficacy.
  • Approval of an SEB does not imply that the SEB is substitutable with the reference product. A determination of substitutability will require separate justification and potentially additional data.
  • Immunogenicity should be evaluated and compared with the reference product.

The EMEA guidelines establish a process and standards for evaluating biosimilar medicines to assure prescribers that they have a safety and efficacy profile comparable to that of the reference product. So far, this has been established through an extensive comparison of physical and biochemical attributes and clinical studies to assess safety and efficacy. The extent of the clinical trials has differed for each biosimilar; however, clinical data have been required in the major indications.

For example, studies assessing clinical safety and efficacy were required for both the renal and oncology settings for the epoetin alfa and epoetin zeta submissions. Comparative clinical data were also required in the biosimilar epoetin studies to look for development of anti-erythropoietin antibodies. The importance of the clinical data was highlighted by the evaluation of the biosimilar interferon alfa 2a. This biosimilar interferon alfa showed differences with regard to quality, pharmacokinetics, and clinical safety and efficacy parameters. Based on these differences the product was not recommended for approval.

There has been a significant amount of discussion regarding the international non-proprietary names (INN) for biosimilar medicines. Some have argued that the biosimilar medicine should have the same INN name as the original product, while others have proposed that the products should be distinguished by unique INN names due to the complexity of the products and the potential for confusion with regard to pharamacovigilance. This discussion is still active at the World Health Organization, and the recent approvals by the EMEA have not resolved the issue.

Two biosimilar epoetins have been approved by comparison with the same epoetin alfa reference, and each biosimilar epoetin has differences in glycan structure compared to the reference product. It is still not clear what criteria should be used in discriminating such complex glycoproteins. This discussion will be important as INN names are frequently used in decisions regarding substitution as well as for monitoring phramacovigilance.

The EMEA does not make recommendations with regard to substitution of products. This is an area of considerable discussion as the products enter the market.

However, it is recognised that biological products and thus biosimilar products do have unique characteristics that suggest a higher degree of caution is needed with substitution. This has been a topic of considerable discussion and although decisions regarding substitution are made by national authorities, the EMEA has stated that any decision to substitute a reference product with a biosimilar should be done in consultation with a qualified healthcare professional.[9]

In addition, some national authorities have taken actions to limit any automatic substitution of biological products. However, as pointed out by others, the issue of generic substitution may not be relevant for many of the biosimilar products as most of the products are hospital-dispensed and are not covered by substitution practices and laws for retail pharmacies.[9]

The past five years has seen significant activity with regard to biosimilar medicines, with the EMEA providing a number of documents and guidelines. This has resulted in at least five biosimilar active substances entering the market.

It is still premature to make any statement about the impact of biosimilars on the overall healthcare landscape. Certainly, biosimilars have the potential to affect the pricing dynamics for biological products; however, it is not expected that they will have the impact of conventional chemical generic products.

The cost and expertise required to manufacture and develop a biosimilar medicine is quite different from that required to produce a conventional generic drug and potential discounts for biosimiliars are only in the range of 20% to 30%.[10]

However, it will certainly be an active area of investigation and development, and in fact a number of larger pharmaceutical companies are considering investments in this area. â–

European Medicines Agency. Scientific Guidelines for Human Medicinal Products. London: EMEA; 2008. Available online at:
2. Krämer, I. The future of biosimilars. Hospital Pharmacy Europe 2008;36:24-7.
3. Tredree, R. A current perspective on biopharmaceuticals. Hospital Pharmacy Europe 2008;37:47-9.
4. European Medicines Agency. EMEA. Refusal assessment report for Alpheon. Procedure no. EMEA/H/C/000585. London: EMEA; 2007.
5. Casadevall N, et al. Epoetin-induced autoimmune pure red cell aplasia. Am Soc Nephrol 2005;16:67-9.
6. Genzyme website.
7. Momenta Pharmaceuticals. Momenta Pharmaceuticals announces receipt of FDA letter: M-enoxaparin ANDA not approvable in current form. Cambridge (MA): Momenta; press release, 6 November 2007.
8. Health Canada. Notice: draft guidance for sponsors. Information and submission requirements for subsequent entry biologics (SEBs). Ottawa: Health Canada; 27 February 2008.
9. European Medicines Agency. Questions and answers on biosimilar medicines (similar biological medicinal products). EMEA/74562/2006. London: EMEA; 2007.
10. Moran N. Fractured European market undermines biosimilar launches. Nat Biotechnol 2008;26(1):5-6.

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