Biosimilars Drugs poised to penetrate market Prof. Ibrahim A. Alsarra Professor of Pharmaceutics and Pharmaceutical Biotechnology Dept. of Pharmaceutics, College of Pharmacy King Saud University Saudi Arabia

Key facts to know about biosimilars Total market value of over $50 billion Development of biogenerics costs $20-80M By 2016, 10 of the 20 top-selling drugs globally are expected to be biologicals Biologics or Therapeutic products sales exceeded 100 Billion US Dollar last year There are 150 marketed biologic products worldwide Brandy Sargent, Recent Legislation a Boost for Biosimilars? The Cell Culture Dish. April 22, 2011. http://thecellculturedish.com/2011/04/recent-legislation-a-boost-for-biosimilars/#comments Key facts to know about biosimilars

Overview What are Biosimilars? Recent Legislation Safety Approval Processes US FDA Approved Biosimilar Products Important take-aways

Biosimilars (Europe and USA) or “Follow-on biologics (Japan)” or “Me too biologics (China)” or “Non-innovator biologics” or “Subsequent entry biologic (Canada)”. It includes: insulin, human growth hormone, monoclonal antibodies and other therapies for such difficult-to-treat illnesses as rheumatoid arthritis, cancer and Crohn’s. Martina Weise, Marie-Christine Bielsky, et al. Biosimilars-why terminology matters. Nature Biotechnology. 29, Pages: 690-693, August 2011.

Will science rule the day? What is a biosimilar, follow-on biologic, etc.?  Definitions Remain Unclear?  Will science rule the day? Martina Weise, Marie-Christine Bielsky, et al. Biosimilars-why terminology matters. Nature Biotechnology. 29, Pages: 690-693, August 2011.

Biosimilars, also known as “follow-on biologics,” are copies of currently marketed biopharmaceuticals. The goal of the biosimilar industry is to provide a similar product to the original and to make these products available at a reduced cost. Biopharmaceutical drugs are much more complex and difficult to manufacture, so there is no way to make an exact copy, only a similar. Brandy Sargent, Recent Legislation a Boost for Biosimilars? The Cell Culture Dish. April 22, 2011. http://thecellculturedish.com/2011/04/recent-legislation-a-boost-for-biosimilars/#comments

Unlike generics, there is no way to analyze what these differences may mean once administered to a patient. Due to these concerns, critics argue that there must be full clinical trials for these drugs to ensure patient safety. The question remains: whether patients and physicians will accept drugs that are similar but not exact? Brandy Sargent, Recent Legislation a Boost for Biosimilars? The Cell Culture Dish. April 22, 2011. http://thecellculturedish.com/2011/04/recent-legislation-a-boost-for-biosimilars/#comments

Supporters of biosimilars argue that biosimilars can provide a significant cost savings over existing biopharmaceuticals. For example, Omnitrope, a biosimilar human growth hormone that was approved in Europe in 2006, is offered at a 25% price reduction. Khadijah M. Britton, JD, Chief Communications Officer, US health and Science Policy, Massachusetts Institution of Technology, USA. Biosimilars are back… Or are they? Scientific American, August 2011.

Recent Legislation a Boost for Biosimilars?

On March 23, 2010, President Obama signed the Patient Protection and Affordable Care Act (PPACA). There is also a provision that provides exclusivity for the first biosimilar product that is deemed interchangeable with the innovator product. Approval and provide protection in the form of exclusivity, which is critical for companies investing hundreds of millions of dollars to create biosimilars.

This pathway is provided in the part of the law known as the Biologics Price Competition and Innovation Act (BPCI Act). Under the BPCI Act, a biological product may be demonstrated to be “biosimilar” if data show that, among other things, the product is “highly similar” to an already-approved biological product.   FDA Guidance for Industry: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM345649.pdf Locatelli F, Roger S. Comparative testing and pharmacovigilance of biosimilars. Nephrol Dial Transplant 2006;21(Suppl 5):v13-v16.

Unlike the process for approval of a generic chemical drug, the FDA has stated that the approval process will include Clinical Trials.  It is impossible to produce an exact copy of biopharmaceuticals, so manufacturers of biogenerics will attempt to make a similar product with the same function. Why?

Safety

Biosimilars Compared to Generic Drugs

A biologic is manufactured in a living system such as a microorganism, or plant or animal cells. Most biologics are very large, complex molecules or mixtures of molecules.  Drugs generally have well-defined chemical structures, and a finished drug can usually be analyzed to determine all its various components. Therefore, for biologics, "the product is the process." Because the finished product cannot be fully characterized in the laboratory, manufacturers must ensure product consistency, quality, and purity by ensuring that the manufacturing process remains substantially the same over time.

A biologic is manufactured in a living system such as a microorganism, or plant or animal cells. Most biologics are very large, complex molecules or mixtures of molecules.  Drugs generally have well-defined chemical structures, and a finished drug can usually be analyzed to determine all its various components. Therefore, for biologics, "the product is the process." Because the finished product cannot be fully characterized in the laboratory, manufacturers must ensure product consistency, quality, and purity by ensuring that the manufacturing process remains substantially the same over time.

The living systems used to produce biologics can be sensitive to very minor changes in the manufacturing process. Small process differences can significantly affect the nature of the finished biologic and, most importantly, the way it functions in the body. Process controls for biologics are established separately for each unique manufacturing process/product, and are not applicable to a manufacturing process/product created by another manufacturer.

To be approved as a generic, a drug must have the same active ingredient, strength, dosage form, and route of administration “bioequivalent” as the reference drug. FDA has stated that it has not determined how interchangeability can be established for complex proteins. Historically, FDA has permitted interchangeability only when two products are "therapeutic equivalents." However, when the follow-on manufacturer establishes a new manufacturing process, beginning with new starting materials, it will produce a product that is different from and not therapeutically equivalent with that of the innovator. (http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/App rovalApplications/TherapeuticBiologicApplications/Biosimilars/default.htm, November 2010)

Generic Originator

Drug vs. Biologics Follow-on Generics Safety is a priority for the development of all medicines, but biologics raise safety considerations above and beyond those of chemical drugs Safety Evidence from clinical trials is not necessary, and cannot be submitted in an application for a generic product Clinical Trials A follow-on biologic manufacturer that uses different starting materials and a different process will produce a product that is different from the innovative product Reproducibility Complexity of biologics currently makes it impossible to show in the laboratory that one biological product will work the same as another in patients Functionality Unlike chemical drugs, all biologics have the potential to stimulate antibody production in patients and such responses are highly unpredictable. Sometimes the antibodies produced in response to a biologic have no effect Immunogenicity

Worldwide experience with biosimilar development

Summary of approval process for small-molecule generics, new biologic agents, and biosimilars New biologic agent (full dossier) Biosimilar (reduced dossier) Quality • Individual quality assessment • Comparison with reference product • Individual quality assessment • Comprehensive comparison with reference product Pre-clinical • No data required • Full pre-clinical program • Abbreviated pre- clinical program (tolerance, PK/PD) Clinical • Bioequivalence study • Phase I • Phase II • Phase III in all indications • Risk-management plan • Phase I PK/PD study • Phase III study in a sensitive, representative indication

EMEA Policy on Automatic Substitution Since Biosimilar and biological reference medicines are similar but not identical, the decision to treat a patient with a reference or a biosimilar medicine should be taken following the opinion of a qualified healthcare professional. European Agency for the Evaluation of Medicinal Product. Questions and answers on biosimilar medicines (similar biological product) (EMEA/7456/2006). http://www.mhra.gov.uk/home/groups/es-policy/documents/websiteresources/con2030475.pdf

French Parliament Adopts New Law On February 2007: French Parliament adopted a new law on human medicinal product. This Law recognizes the unique nature of biosimilars and does not allow automatic substitution of biological medicines at the pharmacy level without the consent of the treating physician. Physicians must be able to monitor their patients for adverse reactions, therefore it is essential that they retain control over the treatment. Medicinal products for human use. Pharmacovigilance - Major developments. European Commission. http://ec.europa.eu/health/human-use/pharmacovigilance/developments/index_en.htm

According to the FDA, “biosimilarity” means: “That the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components and that there is no clinically meaningful differences between the biological product and the reference product in term of the safety, purity, and potency of the product”

FDA approach to determine “biosimilarity” requires the concept of “Totality of Evidence”, using a Stepwise Approach to demonstrate: Structure Function Animal toxicity Human pharmacokinetics Human pharmacodynamics Clinical immunogenicity Clinical Safety Clinical effectiveness

FDA Statement: Posted: Page Last Updated: 15/06/2016 Biosimilars are relatively new products in FDA’s landscape, so there is still a lot of work to do. For example, we are currently reviewing the comments received on our draft guidance on nonproprietary naming of biosimilar products, and we are committed to finalizing the naming and labeling guidance. FDA will continue to build upon its experience in reviewing and approving biosimilar products to ensure that new, safe and effective health care options become available for patients. http://www.fda.gov/Drugs/NewsEvents/ucm493240.htm

Shakespeare said it best: to be or not to be? It’s decision time for Big Pharma on entering the biosimilar space

List of USA Approved Biosimilar Products

List of Approved Biosimilar Products Zarxio (filgrastim-sndz) https://www.novartis.com/news/media-releases/fda-approves-first-biosimilar-zarxiotm- filgrastim-sndz-sandoz   Inflectra (infliximab-dyyb) http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm494227.htm Erelzi (etanercept-szzs) https://www.novartis.com/news/media-releases/fda-approves-sandoz-erelzitm-treat-multiple- inflammatory-diseases Amjevita (adalimumab-atto) https://www.amgen.com/media/news-releases/2016/09/fda-approves-amgens-amjevita- adalimumabatto-for-treatment-of-seven-inflammatory-diseases/

What is Filgrastim-sndz? Filgrastim-sndz is a biosimilar of the reference product Neupogen (fligrastim). Fligrastim (recombinant granulocyte-colony stimulating factor (G-CSF)), which stimulate the proliferation of white blood cells. It was first approved in EU in 2009 (under the tradename Zarzio), and subsequently developed for US marketing authorization. For indications, approval letter and description: http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2015/125553Orig1s000ltr.pdf

FDA approves Inflectra, a biosimilar to Remicade For indications, approval letter and description: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm494227.htm

Important take-aways

The future of biosimilars in the United States is yet to be determined The future of biosimilars in the United States is yet to be determined. The Food and Drug Administration (FDA) has not settled on a regulatory pathway for approval and are still working on it in the near future The FDA has stated similar concerns and implied that they would require detailed data for each indication. The largest companies with the highest revenue streams would be able to shoulder the costs and compete in the biosimilar space. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm436648.htm

Over the coming years, biosimilars will present opportunities for health care organizations to manage the growth of pharmaceutical expenditures. Pharmacists can play a key role in preparing health systems for projected rapid expansion in the use of biosimilars and associated medication-use policy challenges. Pharmacists will need to understand the differences in all of the approval pathways to work closely with physicians and other clinicians on the labeling associated with each medication and the manner in which it should be used.

Complex science of biologics makes each protein unique, not reproducible nor interchangeable Patients’ safety requires that standards for regulatory approval of biosimilars remain high Integrate patients and health experts in the decision-making process for policies and regulations of biosimilars