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European Biopharmaceutical Review

Spot the Difference

The obstacles and challenges arising from the assessment of biosimilars continue to complicate new drug applications. One answer is the development of a robust clinical methodology for the evaluation of biosimilarity and interchangeability.

In the US, when an innovative drug product is going off patent, generic companies may file an abbreviated new drug application (ANDA) for approval of the generic copies (with identical active ingredient) of the innovative drug product under the Drug Price Competition and Patent Term Restoration Act (known as Hatch- Waxman Act) of 1984. For the approval of generic drug products, the US Food and Drug Administration (FDA) requires that evidence in average bioavailability (in terms of the rate and extent of drug absorption) be provided through the conduct of bioequivalence studies.The assessment of bioequivalence as a surrogate endpoint for the evaluation of drug safety and efficacy is based on the fundamental bioequivalence assumption that if two drug products are shown to be bioequivalent in average bioavailability, it is assumed that they are therapeutically equivalent and hence can be used interchangeably.Under this assumption, criteria, study design and statistical methods for the assessment of bioequivalence for the generic approval of small molecule (chemical) drug products are well established both in the EU, the US and the Asian Pacific region (1-2).

Unlike generic chemical drug products which contain identical active ingredient(s), the generic versions of biologic products are made of living cells.The generic versions of biologic products are referred to as biosimilars by the European Medicines Agency (EMA), follow-on biologics (FOB) by the US FDA, or subsequently entered biologics (SEB) by the Public Health Agency of Canada.



There are fundamental differences between biosimilars and generic chemical drugs (see Table 1). For example, biosimilars are known to be variable and very sensitive to the environmental conditions such as light and temperature. A small variation may translate to a drastic change in clinical outcomes, such as safety and efficacy. In addition to differences in the size and complexity of the active substance, important differences also include the nature of the manufacturing process. Since biologic products are often recombinant protein molecules manufactured in living cells, manufacturing processes for biologic products are highly complex and require hundreds of specific isolation and purification steps (3).Thus, in practice, it is impossible to produce an identical copy of a biologic product, as changes to the structure of the molecule can occur with changes in the production process. Since a protein can be modified during the process (for example, a side chain may be added, the structure may have changed due to protein misfolding, and so on), different manufacturing processes may lead to structural differences in the final product, which result in differences in efficacy and safety, and may have a negative impact on the immune responses of patients. It should be noted that these issues also occur during the post-approval changes of the innovator’s biological products.

In practice, the question of particular interest to pharmaceutical scientists and regulators is whether the wellestablished bioequivalence assessment, review and approval process can be applied to the assessment, review and approval of biosimilarity of biosimilars.

European Regulations

For approval of biosimilars in Europe, the EMA has issued a new guideline describing general principles for the approval of similar biological medicinal products, or biosimilars.The guideline is accompanied by six concept papers that outline areas in which the agency intends to provide more targeted guidance (4-11). Specifically, the concept papers discuss approval requirements for four classes of human recombinant products containing erythropoietin, human growth hormone, granulocytecolony stimulating factor and insulin. The guideline consists of a checklist of documents published to date which are relevant to data requirements for biological pharmaceuticals. It is not clear what specific scientific requirements will be applied to biosimilar applications. In addition, it is not clear how the agency will treat innovator data contained in the reference product dossiers.While the guideline provides a useful summary of the biosimilar legislation and previous EU publications, it provides few answers to the issues.

US Regulations

In the US, current approval pathway for follow-on biologics depends on whether the biologic product is approved under the United States Food,Drug and Cosmetic Act (US FD&C) or is licensed under the United States Public Health Service Act (US PHS). For products approved under an NDA (US FD&C Act), generic versions of the products can be approved under an ANDA, for example under Section 505(b) (2) of the FD&C Act. For products that are licensed under a BLA (under the US PHS Act), there exists no abbreviated BLA. For the assessment of similarity of follow-on biologics, the FDA would consider the following factors:
  • The robustness of the manufacturing process
  • The degree to which structural similarity could be assessed
  • The extent to which the mechanism of action was understood
  • The existence of valid, mechanistically related pharmacodynamic assays
  • The comparative pharmacokinetics (PK)
  • The comparative immunogenicity
  • The amount of clinical data available
  • The extent of experience with the original product (12-14)
Scientific Factors for Assessing Biosimilars

As stated in the BPCI Act, a biosimilar product is a biological product that is highly similar to the reference product notwithstanding minor differences in clinically inactive components and there are no clinically meaningful differences in terms of safety, purity and potency. Thus, an interesting question to clinical researchers is whether the wellestablished criteria, study design and statistical methods for the assessment of bioequivalence for chemical drug products can be applied to assess biosimilarity of follow-on biologics. In practice, it is a concern that the standard methodology for bioequivalence assessment may not be appropriate for assessing biosimilars due to fundamental differences between small molecule drug products and biological products. For example, criteria and statistical methods for assessment of bioequivalence of chemical drug products are developed for drug products with identical active ingredient(s). For biosimilars, they are not identical but similar. Besides, bioequivalence studies are often conducted on healthy volunteers (more homogenous and less variable) for characterising drug absorption profiles in terms of some primary PK parameters. For biologic products, it may not be appropriate to conduct biosimilarity studies on healthy volunteers, but instead on the patient population (which is less homogenous and more variable). Thus, the selection of similarity limit is critical to ensure that the biosimilar under investigation is at least as effective as the innovative biologic product and it is superior to the placebo control.

Interchangeability

For the biological product to be interchangeable with the reference product, the BPCI Act indicates that there must be sufficient evidence to show that the biological product is biosimilar to the reference product and it can be expected to produce the same clinical result in any given patient. Also, it needs to show that for a biological product that is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch. Although similar ideas for assessing drug interchangeability for chemical drug products may be applied to biosimilars if independent estimates of intra-subject variabilities, inter-subject variabilities, and the variability due to subjectby- drug interaction can be obtained under a valid study design, the US FDA has slightly perception of drug interchangeability for biosimilars. From the FDA’s perspectives, interchangeability includes the concept of switching and alternating between an innovative biologic product (R) and its follow-on biologics (T).The concept of switching is referred to as not only the switch from R to T or T to R (in the narrow sense of switchability), but also T to T and R to R (broader sense of switchability). As a result, biosimilarity for R to T, T to R, T to T, and R to R need to be assessed based on some biosimilarity criteria under a valid study design. In order to assess biosimilarity for R to T,T to R, T to T, and R to R, the Balaam’s 4x2 crossover design (TT, RR, TR, RT) may be useful.

On the other hand, the concept of alternating is referred to as either the switch from T to R and then switch back to T (T to R to T) or the switch from R to T and then switch back to R (R to T to R). Thus, the difference between the switch from T to R or the switch from R to T and the switch from R to T or the switch from T to R needs to be assessed for addressing the concept of alternating. For addressing the concept of alternating, a two-sequence, threeperiod dual design (TRT, RTR) may be useful. For addressing both concepts of switching and alternating for drug interchangeability of biosimilars, a modified Balaam’s crossover design (TT, RR,TRT, RTR) is then recommended.

Obstacles and Challenges

For assessment of biosimilars, intuitively we may modify the established process for bioequivalence assessment for chemical drug products.However, bioequivalence assessment is done in terms of PK responses for drug absorption under the fundamental bioequivalence assumption, which constitutes the legal basis for bioequivalence assessment. For biosimilars, there does not exist a widely accepted fundamental biosimilarity assumption except for the one proposed by the SSAB in 2009.The SSAB proposed assumption states “When a follow-on biologic product is claimed to be biosimilar to an innovator product in some well-defined study endpoints, it is assumed that they will reach similar therapeutic effect or they are therapeutically equivalent” (15). In practice, however, this assumption is difficult, if it is not impossible, to be verified.

Biosimilarity Criteria
It is claimed that a test drug product is bioequivalent to a reference (innovative) drug product if the 90 per cent confidence interval for the ratio of means of the primary PK parameter is totally within the bioequivalence limits of 80 to 125 per cent.This one-size-fitsall criterion only focuses on average bioavailability and ignores heterogeneity of variability.Thus, it is neither scientifically nor statistically justifiable for assessment of biosimilarity of followon biologics. In practice, it is therefore suggested that appropriate criteria, which can take the heterogeneity of variability into consideration, should be developed, since biosimilars are known to be variable and sensitive to small variations in environmental conditions (16-17).

The Degree of Similarity
At the FDA public hearing, questions that are commonly asked are ‘How similar is considered similar?’ and ‘How should the degree of similarity be measured and translated to clinical outcomes (such as safety and efficacy)?’ These questions closely related to drug interchangeability of biosimilars or follow-on biologics which have been shown to be biosimilar to the innovative product (18-19).

Study Design
For assessment of bioequivalence for chemical drug products, a crossover design is often considered, except for drug products with relatively long halflives. Since most biosimilar products have relatively long half-lives, it is suggested that a parallel group design should be considered.However, parallel group design does not provide independent estimates of variance components such as inter- and intrasubject variabilities and variability due to subject-by-product interaction.Thus, it is a major challenge for assessing biosimilars under parallel group designs.

Regulatory Standards
Although EMA of EU has published several product-specific guidance documents (based on the concept papers), it has been criticised that there are no objective standards for assessment of biosimilars because it depends upon the nature of the products. Product-specific standards seem to suggest that a flexible biosimilarity criterion should be considered and it should be adjusted for variability and/or the therapeutic index of the innovative (or reference) product.

Major Challenges
As described above, there are many uncertainties for the assessment of biosimilarity and interchangeability of biosimilars. As a result, it is a major challenge to both clinical scientists and biostatisticians to develop valid and robust clinical/statistical methodologies for assessment of biosimilarity and interchangeability under the uncertainties. In addition, the question of how to address the issues of quality and comparability in manufacturing process is another challenge to both the pharmaceutical scientists and biostatisticians.

Conclusion

Biosimilars and reference biological medicines are not identical but similar. Biosimilars are not generic products but follow-on (or subsequent entered) biologic products. Biosimilarity indicates similarity but not the degree of similarity, and hence biosimilarity does not generally imply interchangeability.

For small molecule chemical drug products, bioequivalence generally reflects therapeutic equivalence under the fundamental bioequivalence assumption.Thus, drug interchangeability in terms of prescribability, switching and/or alternating is generally reasonable. For biological products where variations are higher, biosimilarity does not generally reflect therapeutic comparability. In addition, parallel-group designs rather than crossover kinetic studies are often performed.Therefore, switching and alternating should be pursued only with substantial caution.

References
  1. Guidance on Bioavailability and Bioequivalence Studies for Orally Administrated Drug Products – General Considerations, Center for Drug Evaluation and Research, the United States Food and Drug Administration, Rockville, Maryland, US, 2003
  2. Note for Guidance on the Investigation of Bioavailability and Bioequivalence, The European Medicines Agency Evaluation of Medicines for Human Use, EMEA/EWP/QWP/1401/98, London, 2001
  3. Kuhlmann M and Covic A, The protein science of biosimilars, Nephrol Dial Transplant 21(5): pp4-8, 2006
  4. Note for Guidance on Comparability of Medicinal Products Containing Biotechnology-derived Proteins as Drug Substance – Non Clinical and Clinical Issues, the European Medicines Agency Evaluation of Medicines for Human Use, EMEA/CHMP/3097/02, London, 2003
  5. Guideline on Comparability of Medicinal Products Containing Biotechnologyderived Proteins as Drug Substance – Quality Issues, the European Medicines Agency Evaluation of Medicines for Human Use, EMEA/CHMP/ BWP/3207/00/Rev 1, London, 2003
  6. Guideline on Similar Biological Medicinal Products, the European Medicines Agency Evaluation of Medicines for Human Use, EMEA/CHMP/437/04, London, 2005
  7. Draft Guideline on Similar Biological Medicinal Products Containing Biotechnology-derived Proteins as Drug Substance: Quality Issues, the European Medicines Agency Evaluation of Medicines for Human Use, EMEA/CHMP/49348/05, London, 2005
  8. Draft Annex Guideline on Similar Biological Medicinal Products Containing Biotechnology-derived Proteins as Drug Substance – Non Clinical and Clinical Issues – Guidance on Biosimilar Medicinal Products containing Recombinant Erythropoietins, the European Medicines Agency Evaluation of Medicines for Human Use, EMEA/CHMP/94526/05, London 2005
  9. Draft Annex Guideline on Similar Biological Medicinal Products Containing Biotechnology-derived Proteins as Drug Substance – Non Clinical and Clinical Issues – Guidance on Biosimilar Medicinal Products containing Recombinant Granulocyte- Colony Stimulating Factor, the European Medicines Agency Evaluation of Medicines for Human Use, EMEA/CHMP/31329 /05, London 2005
  10. Draft Annex Guideline on Similar Biological Medicinal Products Containing Biotechnology-derived Proteins as Drug Substance – Non- Clinical and Clinical Issues – Guidance on Biosimilar Medicinal Products containing Somatropin, the European Medicines Agency Evaluation of Medicines for Human Use, EMEA/CHMP/94528/05, London, 2005
  11. Draft Annex Guideline on Similar Biological Medicinal Products Containing Biotechnology-derived Proteins as Drug Substance – Non Clinical and Clinical Issues – Guidance on Biosimilar Medicinal Products Containing Recombinant Human Insulin, the European Medicines Agency Evaluation of Medicines for Human Use, EMEA/CHMP/32775/05, London, 2005
  12. International Conference on Harmonization Q5C Guideline on Quality of Biotechnological Products: Stability Testing of Biotechnological/Biological Products, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, the US Food and Drug Administration, Rockville, Maryland, 1996
  13. International Conference on Harmonization Q6B Guideline on Test Procedures and Acceptance Criteria for Biotechnological/Biological Products, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, the US Food and Drug Administration, Rockville, Maryland, 1999
  14. International Conference on Harmonization Q5E Guideline on Comparability of Biotechnological/Biological Products Subject to Changes in Their Manufacturing Process, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, the US Food and Drug Administration, Rockville, Maryland, 2005
  15. Chow SC, Endrenyi L and Lachenbruch PA, Yang LY, and Chi E, Scientific factors for assessing biosimilarity and drug interchangeability of follow on biologics, Biosimilars 1: Inpress, 2011
  16. Chow SC, Hsieh TC, Chi E and Yang J, A comparison of moment-based and probability-based criteria for assessment of follow-on biologics, Journal of Biopharmaceutical Statistics 20: pp31-45, 2010
  17. Hsieh TC, Chow SC, Liu JP, Hsiao CF and Chi E, Statistical test for evaluation of biosimilarity of follow-on biologics, Journal of Biopharmaceutical Statistics 20: pp75-89, 2010
  18. Roger SD, Biosimilars: How similar or dissimilar are they? Nephrology 11: pp341-346, 2006
  19. Roger SD and Mikhail A, Biosimilars: opportunity or cause for concern? Journal of Pharmaceutical Science 10: pp405-410, 2007

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Shein-Chung Chow is a Professor at the Department of Biostatistics and Bioinformatics at Duke University School of Medicine, US. Shein-Chung is currently the Editor in Chief of the Journal of Biopharmaceutical Statistics and Biostatistics Book Series of Chapman and Hall/CRC Press. He is a Fellow of the American Statistical Association and has authored/coauthored over 200 methodology papers and 19 books, which include Design and Analysis of Clinical Trials and Controversial Statistical Issues in Clinical Trials. Shein-Chung received his PhD in statistics from the University of Wisconsin, US. Email: sheinchung.chow@duke.edu
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