SEB submissions in Canada


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SEB submissions in Canada

  1. 1. Presented by Neha GandhiYogender Arya 1
  2. 2. Bio-therapeutic products also known as biologic drugs have asuccessful record in treating many life-threatening and chronicdiseases.The recent expiration of patents and/or data protection for the firstmajor group of originator biologics and the anticipation of additionalexpirations has led to the development of products that are designedto be “similar” to a licensed originator product.In Canada, they are referred to as Subsequent Entry Biologics (SEBs),copies of previously approved biological products. By Yogendra Arya and Neha Gandhi 2
  3. 3. Biologics SEBsBiologics are drug products derived SEB is defined by Health Canada asfrom biological sources and include “a biologic drug that enters thegene therapies, vaccines, antibodies market subsequent to a versionand other therapeutic products previously authorized in Canada, andderived through biotechnology with demonstrated similarity to a reference biologic drug.In order for a product to be considered an SEB it should have the sametherapeutic effects as the originally approved biologic, a similar safety profileand the same guarantees to be free of contaminating viruses or otherinfectious agents.SEB manufacturers may make reference to the information contained in aninnovator’s biologic drug submission – that is, the reference biologic drugsubmission – in order to reduce the amount of clinical data required to obtain marketing approval for its product. By Yogendra Arya and Neha Gandhi 3
  4. 4. The Biologics and Genetic Therapies Directorate (BGTD) regulates biologicsunder Divisions 1, 1A, 2, 4, 5, and 8 of Part C of the Food and DrugRegulations.Information provided by manufacturers is evaluated to verify that thebiologic meets quality, safety and efficacy requirements, and that the benefitsof the biologic outweigh the risks for its intended use.A Notice of Compliance (NOC) and Drug Identification Number (DIN) areissued to sponsors when their products are authorized for sale (distribution)in Canada.After a biologic has received an NOC, the manufacturer must adhere toBGTDs Lot Release Program, which sets out risk-based criteria for testing ofthe product prior to its release onto the Canadian market. By Yogendra Arya and Neha Gandhi 4
  5. 5. EXAMPLES OF BIOLOGIC DRUGS AND THEIR USES DRUG THERAPEUTIC FOCUSHormone Product, Growth Hormone, Growth Hormone Disorder, Anemia Associated With Kidney Disease,Erythropoietin, Insulin DiabetesImmuno modulator Interferon-Beta-1b Multiple SclerosisMonoclonal Antibodies: Infliximab, Inflammatory Disorders: Rheumatoid Arthritis, Cancer, MacularAdalimumab, Trastazumab Ranzibizumab, Degeneration, Non-Hodgkin’s Lymphoma, Lumphocytic, Leukemia,Rituximab Rheumatoid ArthritisEnzymes Imiglucerase Gaucher DiseaseAnti-coagulant therapy low molecular weight By Yogendra Arya and Neha Gandhi 5heparin Clotting Disorders
  6. 6. The concept of an SEB applies to all biologic drug submissions where thesponsor seeks authorization for sale based on demonstrated similarity to apreviously approved biologic drug.Existence of Reference Biological Drug  authorized for sale  sufficient efficacy and safety dataThe product (i.e., SEB) can be well characterized by a set of modern analyticalmethodsThe SEB, through extensive characterization and analysis, can be judgedsimilar to the reference biologic drug by meeting an appropriate set of pre-determined criteria.It applies to biologic drugs that contain, as their active substances, wellcharacterized proteins derived through modern biotechnological methodssuch as use of recombinant DNA and/or cell culture. By Yogendra Arya and Neha Gandhi 6
  7. 7.  The responsibility of sponsor to provide the necessary evidence to support the application The Food and Drugs Act and Regulations within the existing regulatory frameworks for biologic, pharmaceutical, and generic pharmaceutical drugs Similarity between the SEB and Reference Authorization of an SEB is not a declaration of pharmaceutical or therapeutic equivalence to the reference biologic drug. All SEBs are subject to the laws, and patent and intellectual property principles outlined within the Food and Drug Regulations (Data Protection), Patented Medicines (Notice of Compliance) Regulations, and the Patent Act. Once a Notice of Compliance (NOC) is issued, the SEB is a new biologic drug and regulated accordingly. However, an SEB should not be used as a reference biologic drug for another SEB submission. By Yogendra Arya and Neha Gandhi 7
  8. 8. Applicable Regulations: Subject to the Food and DrugRegulations for authorization and oversight for the following:C.08.002 (1)(a): No person shall sell or advertise a new drugunless the manufacturer has filed with the Minister a NewDrug Submission (NDS) relating to the new drug that issatisfactory to the Minister.C.08.002 (2): A New Drug Submission shall contain sufficientinformation and material to enable the Minister to assess thesafety and efficacy of a new drug. By Yogendra Arya and Neha Gandhi 8
  9. 9. Reference Biologic Drug  Suitable to support the submission;  Authorized for sale and should be marketed in Canada;  The same reference biologic drug should be used throughout the studies supporting the safety, quality, and efficacy of the product  Same dosage form, strength, and route of administration  The active substance must be shown similar;  An SEB should not be used as a reference biologic drug; and  Should have adequate safety, efficacy, and effectiveness data By Yogendra Arya and Neha Gandhi 9
  10. 10. Regulated by Part C, Division 8 of the Food and Drug.Submission requirements for SEBs will be determined on a case by case basis, and mayinclude, but not be limited to: A complete chemistry and manufacturing data package A rationale for the choice of the innovator biologic and extensive published information on its safety and efficacy. Sufficient characterization information to demonstrate both chemical and biological comparability to the innovator product. Sufficient comparative animal toxicity and toxicological data, where appropriate. By Yogendra Arya and Neha Gandhi 10
  11. 11.  Pharmacodynamic data to demonstrate comparable bioactivity based on parameters or surrogate markers that are clinically relevant and validated. Pharmacokinetic data to demonstrate comparable bioavailability of the SEB to the innovator product based on suitable validated pharmacokinetic parameters. Data characterizing the immunogenic profile of the SEB in humans and its potential impact on safety and efficacy. A clinical package which demonstrates the safety and efficacy of the SEB including comparative studies between the SEB and innovator products By Yogendra Arya and Neha Gandhi 11
  12. 12. Clinical trials conducted in Canada involving SEBs are subjectto Part C, Division 5 of the Food and Drug Regulations, whichoutlines the requirements applicable to the sale and importationof drugs for use in human clinical trials in Canada.Sponsors need to include all information identified in C.05.005of the Food and Drug Regulations in their application forauthorization.If a non-Canadian reference biologic drug is used in clinicalstudies in Canada, data must be provided to support its safetyand to satisfy the intent of the regulatory requirements forchemistry and manufacturing information. . By Yogendra Arya and Neha Gandhi 12
  13. 13. The target time for review of an SEB will be thesame as that for an NDS.Sponsors of SEBs are encouraged to consult withBGTD for regulatory guidance at any stage of thedevelopment of an SEB. By Yogendra Arya and Neha Gandhi 13
  14. 14. In addition to a full chemistry and manufacturing (C&M)data package that is expected for a standard new biologicdrug, the SEB package should provide extensive data onthe demonstration of similarity with the referencebiologic drug, including characterization Studiesconducted in a side-by-side format. By Yogendra Arya and Neha Gandhi 14
  15. 15. The assessment of similarity should be organized inthe Common Technical Document (CTD) as a distinctcollection of data in module 3 with an associatedsection in the Quality Overall Summary containingappropriate cross-references.However, the reorganization of modules 2 and 3 of aCTD submission already prepared for anotherregulatory jurisdiction should not be necessary By Yogendra Arya and Neha Gandhi 15
  16. 16. Once granted an NOC, an SEB is considered to be a new(“stand-alone”) product with all of the associatedregulatory requirements.For any changes to the manufacturing process thatwarrant a demonstration of comparability, the products tobe compared will be the pre-change and post-changeversions of the SEB.Comparisons with the original reference biologic drug arenot required. By Yogendra Arya and Neha Gandhi 16
  17. 17. An SEB product sponsor is eligible to apply for one or more clinicalindications granted to the reference biologic drug in Canada.Where a clinical indication being sought is not held by the referencebiological drug, full clinical trial data shall be provided in support ofthat indication.Non-clinical studies:In vitro studiesIn vivo studiesClinical studies:Pharmacokinetic studiesPharmacodynamic studiesClinical efficacy and safety trials By Yogendra Arya and Neha Gandhi 17
  18. 18. An SEB is not the first in its class to be brought tomarket; it is therefore important that an RMP bepresented prior to issuance of marketingauthorization.The RMP should be designed to monitor and detectboth known inherent safety concerns and potentiallyunknown safety signals that may result from theimpurity profile and other characteristics of the SEB. By Yogendra Arya and Neha Gandhi 18
  19. 19. A PvP should be provided and should include thesubmission of periodic safety update reports(PSURs).The PSURs for an SEB should include adiscussion of the benefit-risk balance of theSEB post-market. By Yogendra Arya and Neha Gandhi 19
  20. 20. ADR reporting is required post-market under section C.01.016of the Food and Drug Regulations: Any serious ADR that is reported requires the manufacturer of that drug to submit all information with respect to that report within 15 days after receiving the information. Furthermore, on an annual basis or as requested by the Director, the manufacturer will conduct a concise, critical analysis of the adverse drug reactions and serious adverse drug reactions after such an occurrence. After an analysis, the Director may request written summary reports where safety is questionable. By Yogendra Arya and Neha Gandhi 20
  21. 21. Unlike generic pharmaceutical drugs, the sponsor of an SEB will not be able to utilize the PMof the reference biologic drug in its entirety as that of its own product.The contents of the PM for SEBs will include following information: A statement indicating that the product is an SEB Key data on which the decision for market authorization was made Tables showing the results of the comparisons between the SEB and reference biologic Drug Information on the indications approved for use There should be no claims for bioequivalence between the SEB and reference biologic Drug There should be no claims for clinical equivalence between the SEB and the reference biologic drug By Yogendra Arya and Neha Gandhi 21
  22. 22. It is Health Canada’s intention to harmonize as much aspossible with other competent regulators and internationalorganizations such as the World Health Organization. Hence,Health Canada may be adapting suitable definitions,terminology, and applicable guidance documents.Health Canada recommends that sponsors refer to the productclass specific guidance documents developed by the SimilarBiological (Biosimilar) Medicinal Products Working Party,European Medicines Agency as the scientific principles areconsistent with those of Health Canada. By Yogendra Arya and Neha Gandhi 22
  23. 23.  Guidance for Sponsors: Information and Submission Requirements forSubsequent Entry Biologics (SEBs) mps/alt_formats/pdf/brgtherap/ applic-demande/guides/seb-pbu/seb-pbu-2010-eng.pdf By Yogendra Arya and Neha Gandhi 23