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BiosimilarsDr. Kunal Chitnis3rd Yr ResidentDept of PharmacologyT.N.M.C.2nd Feb 2013
 Biotechnology is in some ways as old as human history Our ancestors harnessed living organisms to make bread,curd, pane...
 Field soon expanded its focus to medical uses, led by the1940s introduction of penicillin made through a deepfermentatio...
A standard definition of biotechnology was not reacheduntil the United Nations & World Health Organizationaccepted the “19...
BiopharmaceuticalA drug created by means of biotechnology, especiallygenetic engineering:Primarily rDNA protein & Monoclon...
Biologic medicines are currently prescribed totreat a wide variety of conditions, including:• Blood conditions: leuko/neut...
 Represent a fast-growing segment of thepharmaceutical market constituting:• 32% of products in the development pipeline•...
Develop host cell Identify the human DNA sequence for the desired protein Isolate the DNA sequence Select a vector to c...
Modifying the selected cellGrowing a cell line from the original modified cellGrowing a large number of cells from the cel...
Differences in manufacture ofConventional drugs & Biologics Small Molecule Drugs Low molecular weight drugs→ Made by add...
 Biopharmaceuticals Strong relationship between manufacturing processesof biopharmaceuticals & characteristics of the fi...
Even small changes in production(Minor equipment/ Environmental variations)Significant changes inbehaviour of the cells & ...
 To assure high quality & consistency in final product,production process requires a high level of monitoring &testing th...
BiosimilarsWhat are biosimilars?Legally approved subsequent versions of innovatorbiopharmaceutical products made by a diff...
Definitions & Interpretations ofBiosimilar ProductsTerm By DefinitionSBP (SimilarBiologicProduct)WHO Similar to an already...
 Based on these different definitions, there are threedeterminants in the definition of the biosimilar product:• It shoul...
 High unit cost of biologics has resulted in patients’concerns about continued access to potentiallyeffective therapies ...
Global Scenario In 2010, sales of biologics reached $100 billionworldwide with the top 12 biologics generating $30 billio...
Indian Scenario India is one of the leading contributors in the worldbiosimilar market Over 50 biopharmaceutical brands ...
 India has inherited advantages of:• Cost effective manufacturing• Highly skilled, reasonably priced workforce• Huge mark...
Cost Effectiveness of BiosimilarsActiveSubstanceTrade Name Company Price(INR)Insulin Glargine(100 IU x 1 mL x10ml)Lantus S...
ActivesubstanceProductnameLaunch datein IndiaCompanyEpoetin alfa Epofit/Erykine Aug 2005 IntasBiopharma-ceuticalsDarbopoet...
Problem Statement Biosimilars are not biological generics Unique molecules which are supported by onlylimited clinical d...
Generic drugs Chemically & therapeutically equivalent to thebranded, original, low molecular weight chemical drugswhose p...
Approval of Generics In 1984, the US FDA was authorized to approve genericdrug products under the ‘Hatch-Waxman Act’ Whe...
Authorised on the basis of demonstrating that theyare the same in structure & bioequivalent toapproved product Requires ...
Differences between chemicalgenerics & biosimilarsI. Heavier Unlike structurally well-defined, low molecular weightchemic...
II. Larger Typical biologic drug is 100 to 1000 times larger thansmall molecule chemical drugs Possesses fragile three-d...
III. Difficult to define structure Small Molecule drugs → easy to reproduce & specifyby mass spectroscopy & other techniq...
IV. Complex manufacturing processes Manufacturers of biosimilar products will not haveaccess to manufacturing process of ...
 Versatile cell lines used to produce the proteins have animpact on the gross structure of the protein Such alterations ...
Issues of concern with use ofbiosimilarsI. Efficacy issues Differences between the bioactivity of the biosimilars &their ...
• 5 products failed to fulfill their own specification• Adequate hemoglobin monitoring→ variance in potencymay not be a cr...
Example 2:Study compared quality parameters (purity, content &efficacy) of several biosimilar brands taken from theIndian...
II. Safety issues Concerns regarding immunogenicityExample• ↑ in no. of cases of Pure Red Cell Aplasia associatedwith spe...
• Most of the cases in patients treated with Eprex→biosimilar of epoetin α produced outside of the US• Cause→ subtle chang...
III. Pharmacovigilance Due to limited clinical database at the time of approval→Vigorous pharmacovigilance required Immu...
IV.Substitution Allows dispensing of generic drugs in place of prescribed IP Rationale for generics→ Original drugs & th...
Same substitution rules should not be applied: Decrease the safety of therapy or cause therapeuticfailure Uncontrolled s...
V. Naming and labeling Generic adaptation of chemical medicines is assignedthe same name→ identical copies of the referen...
Status of Regulations for BiosimilarsGlobally Strong need for regulations governing biosimilars Implementation of an abb...
 WHO GuidelinesScientific basis for the evaluation & regulation ofbiosimilars was discussed & agreement fordeveloping WH...
 Regulatory framework in EU Guidelines on similar biological productscontaining biotechnology-derived proteins as active...
 Regulatory framework in US US FDA issued three draft guidance documents asrecent as 9th Feb 2012 on biosimilar productd...
Regulatory framework in IndiaSimilar biologics are regulated as per:• The Drugs and Cosmetics Act, 1940• The Drugs Cosmeti...
Apart from Central Drugs Standard Control Organization(CDSCO), the office of Drug Controller General of India(DCGI) two ot...
2. Genetic Engineering Approval Committee (GEAC) Functions under the Department of Environment (DoE)Statutory body for r...
Department of Biotechnology (DBT)definition“Biologics”Substances produced by living cells used in thetreatment, diagnosis ...
Principles for development of SimilarBiologics Developed through sequential process To demonstrate the similarity by ext...
 In case Reference biologic used for more than oneindication→ efficacy & safety of similar biologic has to bejustified or...
Selection of Reference Biologic (RB)RB→ Authorized using complete dossier Rationale for the choice of RB provided by the...
 Following factors should be considered for selection ofthe reference biologic:• Licensed in India & should be Innovator ...
• In case RB not marketed in India:Licensed & marketed for 4 years post approval ininnovator jurisdiction→ Country with we...
Manufacturing Process Should be highly consistent & robust If host cell line used for production of RB is disclosed,use ...
Prerequisites before ConductingPreclinical Studies At preclinical submission stage include a completedescription of:1. Mo...
2. Fermentation Process Development & ProteinPurification details should be provided• A well-defined manufacturing process...
3. Product Characterization• Physicochemical properties, biological activity,immunochemical properties, purity (process & ...
ii. Biological Activity:Appropriate biological assays to characterize the activity &establish the product’s mechanism of a...
 Apply more than one analytical procedure to evaluate thesame quality attribute Reference to acceptance limits for each ...
Preclinical Studies Comparative in nature & designed to detect differences Study design depends on:Therapeutic index, ty...
The following studies are required for preclinicalevaluation:1. Pharmacodynamic Studiesi. In vitro studies: Comparability...
2. Toxicological Studies At least one repeat dose toxicity study in a relevantspecies is required to be conducted Other ...
Animal models to be used:Scientific justification for the choice of animal model Relevant animal species is not availabl...
3. Immune Responses in Animals Test serum samples tested for reaction to host cell proteins Immune complexes in targeted...
Clinical StudiesData Requirements for Clinical Trial ApplicationApplicant has to submit application for conduct of clinica...
 Standards to demonstrate bioequivalence should meetthe CDSCO Guideline for Bioavailability andBioequivalence studies Co...
Appropriate design considerations can be combinedwith adequate justification:A. Single Dose Comparative PK Studies Dosage...
B. Multiple Dose Comparative PK Studies Biologic used in a multiple dose regimenMarkedly higher or lower concentrations ...
II. Pharmacodynamic (PD) Studies Done in patients or healthy volunteersIf PD marker is available in healthy volunteers→P...
III. Confirmatory Safety & Efficacy Study Based on the comparability established during preclinical& PK / PD studies Cli...
 To demonstrate the similarity in safety & efficacyprofiles, Equivalence trials with equivalence designs →Require lower &...
 Confirmatory clinical safety & efficacy study can bewaived if all the below mentioned conditions are met:i. Structural &...
iv. Comprehensive post-marketing risk management plan→Gather additional safety data →Specific emphasis on gathering immuno...
IV.Safety & Immunogenicity Data Comparative safety data based on adequate patientexposure (numbers & time) with published...
V. Extrapolation of Efficacy & Safety Data toOther IndicationsIf following conditions are met:• Similarity with respect to...
 New indication not mentioned by innovator will becovered by a separate applicationVI. Market Authorization Application ...
Post-Market Data for Similar BiologicsThe risk management plan should consist of the following:A. Pharmacovigilance Plan ...
 Periodic safety update reports (PSURs) submittedevery six months for the first two years after approval For subsequent ...
C. Post Marketing Studies (PMS) Plan of PMS should be captured in Pharmacovigilanceplan & update on the studies should be...
 Assay methods should be validated & be able tocharacterize antibody content & type (neutralizing/cross reactivity) of an...
Conclusion Biotechnological medicines shall become an importantpart of future healthcare landscape With patent expiratio...
Biosimilars
Biosimilars
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Biosimilars

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Biosimilars

  1. 1. BiosimilarsDr. Kunal Chitnis3rd Yr ResidentDept of PharmacologyT.N.M.C.2nd Feb 2013
  2. 2.  Biotechnology is in some ways as old as human history Our ancestors harnessed living organisms to make bread,curd, paneer & wine It was just during the early 20th century when the termbiotechnology came into use The term was coined in 1917 by Karl Ereky, a Hungarianengineer & professor who described a technology basedon converting raw materials into a more useful product At that time, the newly categorized field was focused onfood production, addressing such issues as malnutrition& famineHistory of Biotechnology
  3. 3.  Field soon expanded its focus to medical uses, led by the1940s introduction of penicillin made through a deepfermentation process→ Greatly impacted countless livesover a half-century ago Today, Biologic medicines are making significant impacton the lives of patients with serious illnesses throughoutthe world Hold promise to cure diseases like Cancers, Alzheimer’s,Multiple sclerosis, Arthritis & Cardiovascular disorders
  4. 4. A standard definition of biotechnology was not reacheduntil the United Nations & World Health Organizationaccepted the “1992 Convention on Biological Diversity”& defined biotechnology as:“Any technological application that uses biologicalsystems, living organisms or derivatives thereof, to makeor modify products & processes for specific use”
  5. 5. BiopharmaceuticalA drug created by means of biotechnology, especiallygenetic engineering:Primarily rDNA protein & Monoclonal antibody Typically derived from living organisms(animal cells, bacteria, viruses & yeast) Include:• Therapeutic proteins (cytokines, hormones & clottingfactors), Insulin, DNA vaccines, monoclonal antibodies• New experimental modalities such as gene therapy,stem cell therapy & RNA viruses
  6. 6. Biologic medicines are currently prescribed totreat a wide variety of conditions, including:• Blood conditions: leuko/neutro/pancytopenias• Cancers: Colon & Breast Ca or NHL• Immune system disorders: Rheumatoid arthritis,Psoriasis & Crohn’s disease• Neurological disorders: Multiple Sclerosis More than 400 biologics are in clinical trials These include therapies for cancers, Alzheimer’sdisease, heart disease, diabetes, HIV/AIDS &Autoimmune disorders
  7. 7.  Represent a fast-growing segment of thepharmaceutical market constituting:• 32% of products in the development pipeline• 7.5% of marketed products• Expected to grow exponentially at more than 20% per year• By 2016, seven of top ten pharma products worldwide willbe biologics• Potential to reach up to 50% share in globalpharmaceutical market in the next few years
  8. 8. Develop host cell Identify the human DNA sequence for the desired protein Isolate the DNA sequence Select a vector to carry the geneInsert the gene into the genome of a host Modification of cells→ “recombinant” technology The exact DNA sequence & type of host cell used willsignificantly influence the characteristics of the productManufacturing of Biopharmaceuticals
  9. 9. Modifying the selected cellGrowing a cell line from the original modified cellGrowing a large number of cells from the cell lineCultivating them to produce the desired proteinSeparating the protein from the cellsPurifying the collected proteinMajor steps involved
  10. 10. Differences in manufacture ofConventional drugs & Biologics Small Molecule Drugs Low molecular weight drugs→ Made by adding &mixing together known chemicals & reagents, in a series ofcontrolled & predictable chemical reactions Production techniques usually same as for InnovatorProduct Production process is highly standardised Contaminants are consistent & quantifiable
  11. 11.  Biopharmaceuticals Strong relationship between manufacturing processesof biopharmaceuticals & characteristics of the final product Manufacturing biologics is more complex A high level of precision is required → produce aconsistent product time after time
  12. 12. Even small changes in production(Minor equipment/ Environmental variations)Significant changes inbehaviour of the cells & changes in the proteinAlterations in the three-dimensional structure of theProteinQuantity of Acid–base variants & GlycosylationImpact Safety & Effectiveness of biologic
  13. 13.  To assure high quality & consistency in final product,production process requires a high level of monitoring &testing throughout the process A biologic drug typically has around 250 in-processtests during manufacturing, compared to around 50 testsfor small molecule drugs
  14. 14. BiosimilarsWhat are biosimilars?Legally approved subsequent versions of innovatorbiopharmaceutical products made by a different sponsorfollowing patent & exclusivity expiry of the innovator product• Because of structural & manufacturing complexities,these biological products are considered as similar,but not generic equivalents of innovator biopharmaceuticals
  15. 15. Definitions & Interpretations ofBiosimilar ProductsTerm By DefinitionSBP (SimilarBiologicProduct)WHO Similar to an already licensedreference biotherapeutic product interms of quality, safety & efficacyFOB(Follow-OnBiologic)US-FDA Highly similar to the referenceproduct without clinically meaningfuldifferences in safety, purity andpotencySEB(SubsequentEntryBiologic)Canada Drug that enters the marketsubsequent to a version previouslyauthorized in Canada withdemonstrated similarity to areference biologic drug
  16. 16.  Based on these different definitions, there are threedeterminants in the definition of the biosimilar product:• It should be a biologic product• the reference product should be an already licensedbiologic product• the demonstration of high similarity in safety, quality &efficacy is necessary Similarity should be demonstrated using a set ofcomprehensive comparability exercises at the quality,non-clinical & clinical level
  17. 17.  High unit cost of biologics has resulted in patients’concerns about continued access to potentiallyeffective therapies Recently, the expiration of patents for a number ofblockbuster biologics has ushered in an era of thesubsequent production of biosimilar products Contribute to ↑ access to these products at anaffordable price
  18. 18. Global Scenario In 2010, sales of biologics reached $100 billionworldwide with the top 12 biologics generating $30 billion By 2015, biologics responsible for $20 billion in annualsales will go off patent Global market for biosimilars was $311 million in 2010 &expected to increase to $2 billion-$2.5 billion in 2015
  19. 19. Indian Scenario India is one of the leading contributors in the worldbiosimilar market Over 50 biopharmaceutical brands have got marketingapproval Potential to replicate success of Indian Generic Industry Imported Innovators market is estimated aroundUS$ 220 million
  20. 20.  India has inherited advantages of:• Cost effective manufacturing• Highly skilled, reasonably priced workforce• Huge market Key benefit→ Reduce cost by 20-25%For instance, European Generic Medicines Agencyestimated that biosimilars generated annual savings of∼€ 1.4 billion in EU in 2009 Owing to affordability and easy accessibility, establishedgood reputation among healthcare professionals
  21. 21. Cost Effectiveness of BiosimilarsActiveSubstanceTrade Name Company Price(INR)Insulin Glargine(100 IU x 1 mL x10ml)Lantus Sanofi Aventis 2530Basalog Biocon 1475
  22. 22. ActivesubstanceProductnameLaunch datein IndiaCompanyEpoetin alfa Epofit/Erykine Aug 2005 IntasBiopharma-ceuticalsDarbopoetinalfaCresp Aug 2010 Dr Reddy’sLaboratoriesInsulinglargineBasalog 2009 BioconReteplase Mirel 2009 Reliance LifeScienesRituximab Reditux Apr 2007 Dr Reddy’sLaboratoriesFew Biosimilars Approved in India
  23. 23. Problem Statement Biosimilars are not biological generics Unique molecules which are supported by onlylimited clinical data at the time of approval Concerns regarding their efficacy, long-term safety& immunogenicity
  24. 24. Generic drugs Chemically & therapeutically equivalent to thebranded, original, low molecular weight chemical drugswhose patents have expired Identical to the original productMost countries already have well-established scientificstandards & legal mechanisms for authorising generics
  25. 25. Approval of Generics In 1984, the US FDA was authorized to approve genericdrug products under the ‘Hatch-Waxman Act’ When an innovator product is going off patent,pharmaceutical companies file an abbreviated newdrug application (ANDA) for approval of generic copiesof Innovator Product (IP) According to FDA’s definition, the generic drug productsshould be comparable to the reference drug product in:dosage form, strength, route of administration, quality,performance characteristics & intended use
  26. 26. Authorised on the basis of demonstrating that theyare the same in structure & bioequivalent toapproved product Requires evidence of comparable bioavailability →Conduct of Bioequivalence studies Non-clinical & Clinical data are not usually required Recognised for some time that this paradigm will notwork for biologically derived drugs
  27. 27. Differences between chemicalgenerics & biosimilarsI. Heavier Unlike structurally well-defined, low molecular weightchemical drugs, biopharmaceuticals are:High molecular weight compounds with complex three-dimensional structure For example, the molecular weight of Aspirin is 180 Dawhereas Interferon-β is 19,000 Da
  28. 28. II. Larger Typical biologic drug is 100 to 1000 times larger thansmall molecule chemical drugs Possesses fragile three-dimensional structure ascompared to well-characterized one-dimensionalstructure of chemical drug
  29. 29. III. Difficult to define structure Small Molecule drugs → easy to reproduce & specifyby mass spectroscopy & other techniques Lack of appropriate investigative tools to definecomposite structure of large proteins
  30. 30. IV. Complex manufacturing processes Manufacturers of biosimilar products will not haveaccess to manufacturing process of innovator products→Proprietary knowledge Impossible to accurately duplicate any protein product Different manufacturing processes use different cell lines,protein sources & extraction & purification techniques→ heterogeneity of biopharmaceuticals
  31. 31.  Versatile cell lines used to produce the proteins have animpact on the gross structure of the protein Such alterations may significantly impact:Receptor binding, Stability, Pharmacokinetics & SafetyImmunogenic potential of therapeutic proteins→Unique safety issue→ Not observed withchemical generics
  32. 32. Issues of concern with use ofbiosimilarsI. Efficacy issues Differences between the bioactivity of the biosimilars &their innovator productsExample 1:• 11 epoetin alfa products from 4 different countries(Korea, Argentina, China, India)• Significant diversions from specification for in vivo bioactivity• Ranged from 71-226%
  33. 33. • 5 products failed to fulfill their own specification• Adequate hemoglobin monitoring→ variance in potencymay not be a critical issue• Monoclonal antibody therapy for treating a transplantrejection/cancer patient→ variability not acceptable
  34. 34. Example 2:Study compared quality parameters (purity, content &efficacy) of several biosimilar brands taken from theIndian market & with those of the innovator drug products Carried out on 16 commercial brands covering 3 differentbiopharmaceuticals:pegylated G-CSF, G-CSF & erythropoietin Marked lack of comparability between biosimilars &innovator products Significant difference in the level of purity was observedamong various brands of biosimilars as per European &Indian Pharmacopoeia standards
  35. 35. II. Safety issues Concerns regarding immunogenicityExample• ↑ in no. of cases of Pure Red Cell Aplasia associatedwith specific formulation of epoetin α• Caused by the production of neutralizing antibodiesagainst endogenous epoetin
  36. 36. • Most of the cases in patients treated with Eprex→biosimilar of epoetin α produced outside of the US• Cause→ subtle changes in manufacturing process Eprex,human albumin stabilizer was replaced bypolysorbate 80→ ↑ immunogenicity → formation ofepoetin-containing micelles by interacting with leachatesreleased by the uncoated rubber stoppers of prefilledsyringes
  37. 37. III. Pharmacovigilance Due to limited clinical database at the time of approval→Vigorous pharmacovigilance required Immunogenicity is a unique safety issue Adverse drugs reactions monitoring data should beexhaustive Type of adverse event & data about drug such as:Proprietary name, International nonproprietary name(INN) & dosage
  38. 38. IV.Substitution Allows dispensing of generic drugs in place of prescribed IP Rationale for generics→ Original drugs & their genericsare identical & have the same therapeutic effect Produce cost savings
  39. 39. Same substitution rules should not be applied: Decrease the safety of therapy or cause therapeuticfailure Uncontrolled substitution → confounds accuratepharmacovigilance Adverse event emerges after switching from IP to itsbiosimilar without documentation → event will notbe associated to a specific product or it will be ascribed toa wrong product
  40. 40. V. Naming and labeling Generic adaptation of chemical medicines is assignedthe same name→ identical copies of the referenceproducts Biosimilars require unique INNs, as this would facilitate:• Prescribing & dispensing of biopharmaceuticals• Precise pharmacovigilance Need for Comprehensive labeling of biosimilars includingdeviations from IP & unique safety & efficacy data Assist the physician & pharmacist in making informeddecisions
  41. 41. Status of Regulations for BiosimilarsGlobally Strong need for regulations governing biosimilars Implementation of an abbreviated licensure pathwayfor biological products presents challenges, given theassociated scientific & technical complexities European Union has regulations in place for quite sometime for approving biosimilars US & India have recently covered these under theirrespective Acts by bringing in applicable guidelines fortheir evaluation & overall regulation
  42. 42.  WHO GuidelinesScientific basis for the evaluation & regulation ofbiosimilars was discussed & agreement fordeveloping WHO Guidelines was reached at the first‘WHO informal consultation on Regulatory evaluationof Therapeutic Biological Medicinal Products’ held inGeneva, 2007 Published guidelines on Evaluation of Similar BiologicalProducts with detailed recommendations on clinicaldevelopment in October 2009
  43. 43.  Regulatory framework in EU Guidelines on similar biological productscontaining biotechnology-derived proteins as activesubstance were adopted by European Medicines Agency(EMEA) in June 2006 Issued product specific biosimilar guidelinesIn European Union, the first patent onbiopharmaceuticals expired in 2001 & first biosimilarmedicine was approved by EMEA in 2006 In 2010, the European biosimilars market generatedrevenues of approximately $172 million
  44. 44.  Regulatory framework in US US FDA issued three draft guidance documents asrecent as 9th Feb 2012 on biosimilar productdevelopment under Biologics Price Competition &Innovation Act of 2009 (BPCI Act) Based on sponsors proving structural, composition &clinical similarities with an approved Biologic Includes importance of extensive analytical, physico-chemical & biological characterization in demonstratingthat proposed biosimilar product is highly similar to thereference product not withstanding minor differences inclinically inactive components
  45. 45. Regulatory framework in IndiaSimilar biologics are regulated as per:• The Drugs and Cosmetics Act, 1940• The Drugs Cosmetics Rules, 1945• Rules for the manufacture, use, import, export & storageof hazardous microorganisms/genetically engineeredorganisms or cells, 1989. Notified under the EnvironmentProtection Act
  46. 46. Apart from Central Drugs Standard Control Organization(CDSCO), the office of Drug Controller General of India(DCGI) two other competent authorities are involved in theapproval process1. Review Committee on Genetic Manipulation(RCGM) Works under Department of Biotechnology (DBT)Regulates import, export, carrying out research, preclinicalpermission, No objection certificate for clinical trial (CT)
  47. 47. 2. Genetic Engineering Approval Committee (GEAC) Functions under the Department of Environment (DoE)Statutory body for review & approval of activitiesinvolving large scale use of genetically engineeredorganisms & their products
  48. 48. Department of Biotechnology (DBT)definition“Biologics”Substances produced by living cells used in thetreatment, diagnosis or prevention of diseases“Similar Biological Product”Biological product produced by genetic engineeringtechniques & claimed to be similar in terms of quality,safety & efficacy to a reference innovator product, whichhas been granted a marketing authorization in India
  49. 49. Principles for development of SimilarBiologics Developed through sequential process To demonstrate the similarity by extensivecharacterization studies revealing molecular & qualityattributes with regard to Reference Biologic (RB) The extent of testing of the Similar Biologic (SB)is less than RB Ensure that the product meets acceptable levels ofsafety, efficacy & quality to ensure public health
  50. 50.  In case Reference biologic used for more than oneindication→ efficacy & safety of similar biologic has to bejustified or if necessary demonstrated separately for eachof the claimed indications Justification will depend on:• Clinical experience• Available literature data• Whether or not the same mechanism of action is involvedin specific indication
  51. 51. Selection of Reference Biologic (RB)RB→ Authorized using complete dossier Rationale for the choice of RB provided by themanufacturer in the submissions to the DBT & CDSCO Used in all the comparability exercise with respect toquality, preclinical & clinical considerations.
  52. 52.  Following factors should be considered for selection ofthe reference biologic:• Licensed in India & should be Innovator Product• Licensed based on a full safety, efficacy & quality data• Another SB cannot be considered as RB
  53. 53. • In case RB not marketed in India:Licensed & marketed for 4 years post approval ininnovator jurisdiction→ Country with well establishedregulatory framework• Period of 4 years may be reduced or waived→- No medicine/ palliative therapy is available- In national healthcare emergency• Active substance, dosage form, strength & route ofadministration of the SB→ same as that of RB
  54. 54. Manufacturing Process Should be highly consistent & robust If host cell line used for production of RB is disclosed,use the same cell line Alternatively any cell line that is adequately characterized& appropriate for intended use Applicant should submit a full quality dossier
  55. 55. Prerequisites before ConductingPreclinical Studies At preclinical submission stage include a completedescription of:1. Molecular Biology Considerations• Details regarding host cell cultures, vectors, genesequences, promoters etc. used in the production• Details of post‐translational modifications:Glycosylation, oxidation, deamidation, phosphorylation
  56. 56. 2. Fermentation Process Development & ProteinPurification details should be provided• A well-defined manufacturing process with its associatedprocess controls in accordance with Good ManufacturingPractice (GMP)
  57. 57. 3. Product Characterization• Physicochemical properties, biological activity,immunochemical properties, purity (process & productrelated impurities), contamination, strength & contenti. Structural and Physicochemical Properties:Includes determination of primary & higher orderstructure of the product
  58. 58. ii. Biological Activity:Appropriate biological assays to characterize the activity &establish the product’s mechanism of actioniii. Purity & Impurities:Differences observed in the purity & impurity profiles →Assess potential impact on safety & efficacy by conduct ofPreclinical & Clinical studies
  59. 59.  Apply more than one analytical procedure to evaluate thesame quality attribute Reference to acceptance limits for each test parametershould be provided & justified based on the data fromsufficient lots of similar biologics.Differences between SBP & RBP evaluated fortheir potential impact on safety & efficacy→Additional characterization studies may be necessary Submit the data generated along with the following toRCGM for obtaining permission
  60. 60. Preclinical Studies Comparative in nature & designed to detect differences Study design depends on:Therapeutic index, type & number of indications applied Conducted with the final formulation Dosage form, strength & route of administration shouldbe same as that of RB Approval:• Prior to conduct of the studies statutory approvals fromrespective Institutional Biosafety Committee (IBSC) &Institutional Animal Ethics Committee (IAEC) be submitted
  61. 61. The following studies are required for preclinicalevaluation:1. Pharmacodynamic Studiesi. In vitro studies: Comparability established by in vitro cell based bioassay(e.g. cell proliferation assays or receptor binding assays)ii. In vivo studies: Cases where in-vitro assays do not reflect thepharmacodynamics, In vivo studies should be performed
  62. 62. 2. Toxicological Studies At least one repeat dose toxicity study in a relevantspecies is required to be conducted Other toxicological (mutagenicity, carcinogenicity) studiesnot generally required
  63. 63. Animal models to be used:Scientific justification for the choice of animal model Relevant animal species is not available→ undertaken intwo species i.e. one rodent & other non rodent species Route of administration→ include only intended route Dose→ Calculated based on the therapeutic dose RB Three levels of doses (low, medium and high) →Corresponding to 1X, 2X & 5X of human equivalent dose Schedule of administration→ therapeutic schedules
  64. 64. 3. Immune Responses in Animals Test serum samples tested for reaction to host cell proteins Immune complexes in targeted tissues by histopathology→evaluating immune toxicity Clearance:• Study reports cleared by respective IBSC before beingpresented & cleared by RCGM for conducting appropriatephase of clinical trial
  65. 65. Clinical StudiesData Requirements for Clinical Trial ApplicationApplicant has to submit application for conduct of clinicaltrial as per the CDSCO guidance for industry, 2008I. Pharmacokinetic Studies Design should take following factors into consideration:Half life, Linearity of PK parameters, Endogenous levels &diurnal variations of SB, Conditions & diseases to be treated,Route(s) of administration & Indications
  66. 66.  Standards to demonstrate bioequivalence should meetthe CDSCO Guideline for Bioavailability andBioequivalence studies Comparative pharmacokinetic (PK) studies →Healthy volunteers or patients to demonstratesimilarities in pharmacokinetic characteristics If patient population is used for PK studies,Phase III / PD study can be coupled in one study design
  67. 67. Appropriate design considerations can be combinedwith adequate justification:A. Single Dose Comparative PK Studies Dosage within the therapeutic dose range of RB Appropriate rationale for dose selection Parallel arm design→• Biologics with a long half life or• Proteins for which formation of antibodies is likely or• Study is done in patients Cross over design→ Drugs with short half life
  68. 68. B. Multiple Dose Comparative PK Studies Biologic used in a multiple dose regimenMarkedly higher or lower concentrations are expected atsteady state than that expected from single dose data PKmeasurements Time-dependence & dose-dependence of PK parameterscannot be ruled out
  69. 69. II. Pharmacodynamic (PD) Studies Done in patients or healthy volunteersIf PD marker is available in healthy volunteers→PD in healthy volunteers can be done At least one PD marker→ linked to efficacy of molecule Surrogate markers should be clinically validated PD studies combined with PK studies→PK/PD relationship have to be characterized PD study can also be a part of Phase III clinical trialwherever applicable
  70. 70. III. Confirmatory Safety & Efficacy Study Based on the comparability established during preclinical& PK / PD studies Clinical trialsComparative, parallel arm or cross-overSample sizes should have statistical rational
  71. 71.  To demonstrate the similarity in safety & efficacyprofiles, Equivalence trials with equivalence designs →Require lower & upper comparability margins In the case of a non-inferiority trial, only thelower margin is defined Nature, severity & frequency of Adverse events shouldbe compared
  72. 72.  Confirmatory clinical safety & efficacy study can bewaived if all the below mentioned conditions are met:i. Structural & functional comparability characterized to ahigh degree by physicochemical & in vitro techniquesii. The SB is comparable to RB in all preclinical evaluationsiii. PK / PD study has demonstrated comparability & done in:• in-patient setting• safety measurement (including immunogenicity)• for adequate period &• with efficacy measurements
  73. 73. iv. Comprehensive post-marketing risk management plan→Gather additional safety data →Specific emphasis on gathering immunogenicity data Cannot be waived if there is no reliable & validated PDmarker
  74. 74. IV.Safety & Immunogenicity Data Comparative safety data based on adequate patientexposure (numbers & time) with published data on RB Both pre-approval & post-approval assessment of safetyis desired Pre-approval safety assessment → Intended to provideassurance of absence of any unexpected safety concerns
  75. 75. V. Extrapolation of Efficacy & Safety Data toOther IndicationsIf following conditions are met:• Similarity with respect to quality has been proven to RB• Similarity with respect to preclinical assessment• Clinical safety & efficacy is proven in one indication• Mechanism of action is same for other clinicalindications• Involved receptors are same for other clinical indications
  76. 76.  New indication not mentioned by innovator will becovered by a separate applicationVI. Market Authorization Application Submit application for market authorization as perCDSCO guidance document for industry
  77. 77. Post-Market Data for Similar BiologicsThe risk management plan should consist of the following:A. Pharmacovigilance Plan Clinical studies done on SB prior to market authorizationare limited in nature→ Rare adverse events are unlikelyto be encountered Comprehensive Pharmacovigilance plan should beprepared by manufacturer
  78. 78.  Periodic safety update reports (PSURs) submittedevery six months for the first two years after approval For subsequent two years the PSURs to be submittedannually to DCGI officeB. Adverse Drug Reaction (ADR) Reporting All serious unexpected adverse reactions must bereported to the licensing authority within 15 days ofinitial receipt of the information by the applicant
  79. 79. C. Post Marketing Studies (PMS) Plan of PMS should be captured in Pharmacovigilanceplan & update on the studies should be submitted to theCDSCO At least one non-comparative post-marketing clinicalstudy with focus on safety & immunogenicity should beperformed If immunogenicity is evaluated in clinical studies→Not mandatory to carry out additional non-comparativeimmunogenicity studies in PMS
  80. 80.  Assay methods should be validated & be able tocharacterize antibody content & type (neutralizing/cross reactivity) of antibodies formed Neutralizing antibodies→ their impact on the PK/PDparameters, safety & efficacy assessedD. Archiving of Data Applicant should archive all the data for a period of atleast five years after marketing approval Site & Material of archiving should be indicated
  81. 81. Conclusion Biotechnological medicines shall become an importantpart of future healthcare landscape With patent expiration of innovator products,biosimilars will increasingly become available Awareness of the deviations between biosimilars &innovator products in terms of efficacy, safety &immunogenicity is essential for proper prescription &safety of the patients How similar is similar enough?

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