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Biosimilarity: The FDA Perspective

treatments. (http://www.worldipreview.com/article/biosimilar-biologics -is-the-us-being-left-behind)

Bigmoleculewatch.com (2015, October 27) FDA rejects Hospira’s epogen biosimilar. http://www.bigmoleculewatch.com/2015/10/27/fda-rejects-hospiras-epogen -biosimilar/. Calvo, P. (2013, November 1). Biosimilar biologics: Is the US being left behind? World IP Review. http://www.worldipreview.com/article/biosimilar-biologics -is-the-us-being-left-behind. FDA—Review of Biosimilar Biologic Product Applications. http://www.fda.gov /downloads/forindustry/userfees/biosimilaruserfeeactbsufa/ucm459686.pdf, 2015. FDA—Postmarket Drug Safety Information for Patients and Providers. http:// www.fda.gov/Drugs/DrugSafety/Postmarketdrugsafetyinformationfor patientsandproviders/ucm220037.htm, 2011. FDA—Biosimilar User Fee Act (BsUFA). http://www.fda.gov/ForIndustry/UserFees /BiosimilarUserFeeActBsUFA/default.htm, 2015.

372

Index

Page numbers followed by f and t indicate figures and tables, respectively.

A

Abatacept, 43t AbbVie, 39, 176 Abciximab, 42t Abseamed, 41t Acid dissociation, 193 Actemra, 43t Actimmune, 44t ADA (adenosine deaminase) assays controls, 190–191 development, 190 immunogenicity assay challenges, 190 on PK assessment, 189–190 positive control, 190, 276 response, 265 specificity and characterization of, 191–192 Adalimumab, 37, 38, 103t, 159, 176, 183t Ado-trastuzumab emtansine, 45t Advate, 43t Affordable Care Act, 31, 50, 88, 128–129 Afrezza, 43t Age of the lots product and testing, 316–317 Aggregates, target protein derivatives, 236 Aggregation, 305 about, 293 in chemical degradation, 272–273 models, 294 protein, 135 requiring bimolecular collision, 305 Agitation of protein solutions, 294 Albiglutide, 44t Albumin stabilizer, 303 Aldesleukin, 42t Aldurazyme, 43t Alemtuzumab, 42t Alglucosidase alfa, 44t Alternating, concept of, 195–196 Amgen, 104 Amino acid analysis (AAA), 225 Amino acids, 270 Amplification technique, 230 Anakinra, 44t Analytical quality, assumptions, 91–93 Analytical similarity; see also Biosimilar(s)/biosimilarity assessment, 80–88, 150–151, 172 critical factors, 150–151 expression system, 80–81 finished drug product, 86–87 functional activities, 83–84 impurities, 84–85 manufacturing process, 81–82 physicochemical evaluation, 82–83 quality attributes, 172–173 receptor-binding and immunochemical properties, 84 reference product and reference standards, 85–86 stability profile, 87 assumptions, 91–93 data about, 150 FDA and, 150 generating, 150 generation of, 150 373

Index

374

stages of, 157–160, 158f, 159–160 analytical and functional similarity, 159 clinical pharmacology, 159–160 clinical trials in patients, 160 postmarket surveillance, 160 preclinical or nonclinical safety, 159 stepwise approach to establishing, 326f Analytical similarity, statistical approach to, 313–359 background, 313–314 general principles for evaluating analytical similarity, 316–328 analytical similarity assessment plan, 316–320 design and conduct of similarity testing, 326–328 statistical methods for evaluation, 320–325 managing tiers, 328–335 tier determination, 329–335 reference and biosimilar products, 315–316 setting acceptance criteria, 335–342 fingerprint-like similarity, 338–342 specific analytical topics, 342–346 HCP and residual DNA, 344–346 stability profile, 343–344 Analytical similarity assessment criteria and tier assignments for bevacizumab, 341t–342t for filgrastim, 337t–338t for insulin products, 339t–340t Analytical similarity assessment plan, 320 Analytical tools for biosimilars, 151, 151f Analytical ultracentrifugation (AUC), 171 Analytics, choice of, 151 Anaphylaxis, 264 Animal data demonstrating biosimilarity, 60–62 safety of proposed product, 152 Animal toxicity data, 152 Anion-exchange chromatography (AIEC), 219 Antibody-dependent cell-mediated cytotoxicity (ADCC), 37, 171t, 183 Antibody detection, assays for, 278–279 Antibody positive samples, confirmation of, 282–284, 283t Antioxidant, 289 Apidra, 44t Aranesp, 45t, 167 Arcalyst, 43t Aspartate, 177 Assay(s) for antibody detection, 278–279 bioanalytical considerations controls, 190–191 development, 190 ELISA, 179, 181, 192 immunogenicity, 192–193 specificity and characterization, 191–192 cell-based, 181 concentration and activity, 94 controls, 190–191 development, 190 disposition kinetics profiling, 186–188, 187f functional analytical similarity assessments, 83–84 demonstrating biosimilarity, 59–60 ligand-binding, 93–94

PD and PK, 93–95 receptor-binding, 181–183, 183t Assay performance, 317 Assays used for assessing the attribute, 318 Assay variability, defined, 352 Assessment analytical similarity, 80–88 critical factors, 150–151 expression system, 80–81 finished drug product, 86–87 functional activities, 83–84 impurities, 84–85 manufacturing process, 81–82 physicochemical properties, 82–83

quality attributes, 172–173 receptor-binding and immunochemical properties, 84 reference product and reference standards, 85–86 stability profile, 87 exposure and response, 89–91 immunogenicity, 65–67 clinical, 63–65 Assumptions, about analytical quality and similarity, 91–93 Attributes

CQAs, see Critical quality attributes (CQAs) declared, 351 fingerprint-like similarity, 165, 166f, 167f impurity vs., 40 inherent and legacy, 356

QAs, see Quality attributes (QAs) Authorized biological drugs, licensed vs., 35 Autocrine or intracrine signaling, 2 Autologous-cultured chondrocytes, 45t Avastin, 43t Avonex, 37

B

Basaglar®, 106 Basiliximab, 44t Batch-to-batch reference similarity, 185 Belatacept, 44t Belimumab, 45t Benlysta, 45t Betaferon, 284 Bevacizumab, 43t analytical similarity assessment criteria and tier assignments for, 341t–342t pharmacokinetic parameter evaluation of, 345t Bexxar, 42t Biacore, 192, 281 Binding antibodies, 265 Bioactivity, 180–181, 229 Bioanalytical considerations, 186–193

ADA on PK assessment, 189–190 assay controls, 190–191

assay development, 190 disposition kinetics profiling assay, 186–188, 187f immunogenicity assays, 192–193 potency, 188 specificity and characterization of ADA, 191–192 testing limits, 189 Bioanalytical methods, integrity of, 93–95 Bioequivalence, of generic drug, 102, 156 Bioferon product, 37 Biological drugs authorized vs. licensed, 36 chemical vs., 157t size and complexity of, 131–132 Biological product development (BPD), biosimilar type 1 meeting, 52 type 2 meeting, 52 type 3 meeting, 52–53 type 4 meeting, 53 Biological products

BLA for, 126–129 antibody–drug conjugates, 129 chemically synthesized polypeptide, 126–128 “product class” as protein product, 128–129

BPCI Act for, 74, 88–89 reference products and, 32–33 50–51, 53 reserve samples of, 115–116 specific properties of, 131 strength of, 117–118 Biologics Control Act, 29 Biologics license application (BLA) action package for, 118–119 for biological product, 126–129 antibody–drug conjugates, 129 chemically synthesized polypeptide, 126–128 product class as protein product, 128–129 filings, 103–104 for marketing products, 73 Biologics Price Competition and Innovation (BPCI) Act, 39, 131, 46 amended definition of “biological product,” 126–128 for biological products, 74, 88–89 Index

375

Index

376

defined, 31, 153 for extrapolating pediatric information, 121–122

FDA guidance, 50–51 history of developments, 31, 32 interchangeability, determination, 119 interchangeable biosimilars, 39 objectives, 50

PREA and, 120

U.S. Biosimilar candidates through 2024, potential, 42t–45t Biopharmaceutical tools background orthogonal approach, 212 tools, 211–212 choice of effectiveness, 229 higher-order structure (HOS), 228 identity, 223–228 protein purity, 229–237 chromatography high-performance IEXC (HP-IEXC), 219–220 high-performance reversephase chromatography (HP-RPC), 220 high-performance size exclusion chromatography (HP-SEC), 220 ion-exchange chromatography (IEXC), 218–219 reverse-phase chromatography (RPC), 219 electrophoresis 2D-SDS PAGE, 221 native electrofocusing, 221–222 SDS-PAGE, 221 Western blot (WB), 222–223 mass spectrometry (MS), 212–217, 213t–214t, 215f peculiarities and attributes, 213t–214t spectroscopy techniques, 217–218 testing method, 237–238, 238f Biosensor-based immunoassays, 281–282 Biosimilar developer, 291 Biosimilar(s)/biosimilarity, 29–46 analytical similarity, stages of, 157–160, 158f, 159–160 approved by FDA by 2017, 41t background, 29–31, 145–146 bioanalytical considerations, 186–193; see also Bioanalytical considerations ADA on PK assessment, impact of, 189–190 assay controls, 190–191 assay development, 190 disposition kinetics profiling assay, 186–98, 187f immunogenicity assays, 192–193 potency, 188 specificity and characterization of ADA, 191–192 testing limits, 189 biosimilarity tetrahedron, 169–170, 170f

BPD, see Biological product development (BPD), biosimilar clinical pharmacology studies, see Clinical pharmacology studies clinical similarity, 183–186 about, 183–184 clinical study challenges, 184 statistical understanding, 184–186 study challenges, 184 types, 183–184 comparability versus similarity, 165–169, 166f, 167f, 168f critical attributes, relationship, 197f definitions, 53, 89, 145–146, 313, 366 by EMA, 145–146 by FDA, 145 demonstration of, see Demonstration of biosimilarity dependency of effectiveness and safety, 366, 367f developing, 3–4 establishing, 53 explicit views on development, 130–135

FDA analytical similarity data, 150–151 analytical tools, 151, 151f analytics, choice of, 151 animal toxicity data, 152

BPCI Act and, 146 clinical data, type of, 152 clinical studies, 152 comparative clinical study, 153 comparative human PK and PD data, 152 defining biosimilars or biosimilarity, 147 development concepts, 149 extrapolation, 154–155 guidance, 149 human PK and PD study considerations, 153 interchangeability, 147 351(k) application content, 147–148 351(k) information on biosimilarity, 148 licensure, 148 nonlicensed product, 149 reference product, 147 reference product by PHSA, 148–149 stepwise approach for data generation, 149–150 totality of evidence, 150, 153–154, 154f FDA mind-set, 146–155; see also Food and Drug Administration (FDA) FDA Q&As, 109–126 fingerprint similarity, 163–165, 164f, 166f, 167f future of, 41, 42t–45t, 369, 371–382 in India, 41 interchangeability, 193–196, 195f in Japan, 40, 44t landscape, see Landscape, biosimilar products leadership, 365, 366f levels of similarity, 160–163; see also Levels, of similarity meeting, initial advisory, 51–53, 368–369, 369t, 370t, 371t phase 3-type trials, 367–368 potency, 179–183 bioactivity, 180–181 cell-based assays, 181 protein content, 180 receptor-binding assays, 181–183, 183t potency of biosimilar products about, 179–180 bioactivity, 180–181 cell-based assays, 181 protein content, 180 receptor-binding assays, 181–183, 183t proposed products, see Proposed biosimilar products purity, 175–179 about, 175–176, 176f contributors, 176f process-related impurities, 178–179 product-related impurities, 176–178, 178t quality attributes, 170–175, 171t, 172t rise of, 31–40 similarity, levels of about, 160–161, 160f highly similar (level 3), 162 highly similar with fingerprintlike similarity (level 4), 162–163 not highly similar (level 2), 161–162 not similar (level 1), 161 similarity concept, 155–157, 157t, 158f statistical modeling, see Statistical modeling tetrahedron, 169–170, 170f understanding, 145–197 in use, 40–46, 41t Biosimilar User Fee Act (BsUFA), of 2012, 32, 52, 109–110, 368–369, 369t Biotherapeutic product, 146 Blinatumomab, 45t Blincyto, 45t Blinding, defined, 355 Botox, 43t Bovine spongiform encephalopathy (BSE), 233 BPCI, see Biologics Price Competition and Innovation (BPCI) Act Index

377

Index

378

Bridging-format electrochemiluminescence, 278 Buffer, 289 Buffering agents, 302, 303

C

Calcitonin-salmon, 107 Calmodulin, 11 Canakinumab, 45t Capillary electrophoresis (CE), 171 Capillary zone electrophoresis (CZE), 212 Carbamylated forms, target protein derivatives, 236 Case-by-case basis, one-size-fits-all vs., 37 Cation exchange (CEX), 171 Cation-exchange chromatography (CIEC), 219, 230 Catridecacog, 44t Cell-based assays, 181 potency of biological product, 181 Cell-based neutralization assays, 279–281 Center for Biologics Evaluation and Research (CBER), 30, 33, 109, 156, 230 Center for Drug Evaluation and Research (CDER), 30, 33, 109, 129, 156 Certolizumab pegol, 44t Cervarix, 43t Cetuximab, 42t Channel-linked receptors, 182 Characterization of ADAs, 191–192

HOS of proteins, 54 proposed biosimilar products, 56, 58 structural, protein products, 59 Chelating agents, 302 Chemical degradation, 296–300, 298t, 299t; see also Formulation similarity; Immunogenicity of biosimilars aggregation, 272–273 formulation changes, 274–275 impurities and production contaminants, 273–274 manufacturing and processing factors, 273 Chemical drugs, biological vs., 157t Chemical instability, 296 Chemical ionization, 216 Chemically synthesized polypeptide, 31, 126–128 Chemical stresses, 273 Chemistry, manufacturing, and controls (CMC) information data submission, 76 detailed guidance for, 75 non-U.S.-licensed comparator product, 124–125 Chinese hamster ovary (CHO) cells, 16 ChondroCelect, 45t Choriogonadotropin alfa, 42t Chromatography; see also Biopharmaceutical tools high-performance IEXC (HP-IEXC), 219–220 high-performance reverse-phase chromatography (HP-RPC), 220 high-performance size exclusion chromatography (HP-SEC), 220 ion-exchange chromatography (IEXC), 218–219 reverse-phase chromatography (RPC), 219 Cimzia, 44t Circular dichroism (CD), 211 Citrate, 290 Cleaved forms, target protein derivatives, 237 Clinical data, type of, 152 Clinical pharmacology, 159 Clinical pharmacology studies, 88–101 background, 88 critical considerations, 89–93 analytical quality and similarity, 91–93 exposure and response assessment, 89–91 residual uncertainty, evaluation, 91 integrity of bioanalytical methods, 93–95 concentration and activity assays, 94 ligand-binding assays, 93–94

PD assays, 94–95 safety and immunogenicity, 95

PK/PD studies, 159–160 role, 88–89 supporting demonstration of biosimilarity, 95–101 appropriate PD time profile, 100 crossover design, 96 dose selection, 97–98 parallel design, 96 PD measures, 99–100 PK and PD results, statistical comparison, 100 PK measures, 98–99 reference product, 96–97 route of administration, 98 study design, 96 study population, 97 utility of simulation tools, 100–101 Clinical similarity, 183–186; see also Biosimilar(s)/biosimilarity about, 183–184 clinical study challenges, 184 statistical understanding, 184–186 study challenges, 184 types, 183–184 Clinical studies comparative considerations, 153 demonstrating biosimilarity, 62–71 comparative, 68–69 design and analysis, 69–70 end points, 69 extrapolation of clinical data across indications, 70–71 human pharmacology data, 64–65 immunogenicity assessment, 65–67 nature and scope, 63 noninferiority clinical trials, 70 PK and PD studies, 63–65 sample size and duration of study, 69 study population, 69 nature and scope of, 152 pharmacology studies, see Clinical pharmacology studies Clinical trials in patients, 160 Coherence, 218 Combining lots, in statistical modeling, 359 Comparability, similarity vs., 36, 165, 167–169, 168f Comparability protocol, 167, 174 changes, by originator, 169 defined, 167, 174 glycosylated biopharmaceuticals under, 168f Comparability versus similarity, 165–169, 166f, 167f, 168f Comparative clinical studies considerations, 153 demonstrating biosimilarity, 68–69 Comparative EMA and FDA mindset, 135–140 Comparative human PK and PD data, 152 Compendia specifications, 356–357 Complement-dependent cytotoxicity (CDC), 171 Complexity, 252 of biological drugs, 131–132 Compton scatterings, 218 Concentration and activity assays, 94 Confidence level defined, 346–347 tier testing, 353 Consultation, with FDA, 72 Container closure system, with proposed biosimilar product, 110–111 Coomassie staining, 222 Copaxone, 137 Corifollitropin alfa, 43t Covalent aggregation, 272, 293 CQA, see Critical quality attributes (CQA) Critical attributes, relationship, 197f; see also Biosimilar(s)/ biosimilarity Critical process parameter (CPP), 246 Critical quality attributes (CQA), 324, 325, 331, 335; see also Quality attributes (QAs) analytical similarity demonstration for filgrastim, 171, 172t establishing, 335 background, 243–245, 244f, 245f Index

379

Index

380

development exercise CQA assessments, 255–261, 256t–260t equivalence testing for, 353 for functional similarity demonstration for filgrastim, 171, 172t identifying, 137, 150 impact, definition of, 257 product-related/process-related, 347 risk assessment process and iterative process, 254–255 overview, 246–248, 247f risk question definition and target linkages, 248–251, 249f, 250f tailored risk assessment tool development, 251–253, 252t threshold definition for, 253–254, 254t severity score, 256t tier testing, 324, 328, 329 tier 0, 355 tier 1, 355 tier 2, 355 workflow, 245, 246f Crossover design, 96 Crystallography, 218 C-terminal lysine, 176 Cyanate, 236 Cyramza, 44t Cytokines, 1

D

Darbepoetin alfa, 45t Data analytical similarity, 150 animal, 60–62, 152 clinical pharmacology, see Clinical pharmacology studies type, 152 comparative human PK and PD, 152 demonstrating biosimilarity, 58–71; see also Demonstration of biosimilarity Data fishing, defined, 351 Deamidation, 177, 296 Declared attributes, defined, 351 Degree of similarity, defined, 355 Degree of uncertainty around quality attribute, 318 Delivery device, with proposed biosimilar product, 110–111 Demonstration of biosimilarity animal data, 60–62 approaches to developing and assessing evidence, 56–58 stepwise approach, 56–57 totality-of-the-evidence approach, 57–58 clinical studies, general considerations, 62–71 comparative, 68–69 end points, 69 extrapolation of clinical data across indications, 70–71 human pharmacology data, 64–65 immunogenicity assessment, 65–67 nature and scope, 63 noninferiority clinical trials, 70 PK and PD studies, 63–65 sample size and duration of study, 69 study design and analyses, 69–70 study population, 69 exposure and response assessment for, 89–93 functional assays, 59–60 inclusion of animal PK and PD measures, 62 interpreting animal immunogenicity results, 62 quality considerations in, 73–80 background, 73–74 general principles, 75–80 scope, 75 structural analysis, 58–59 totality of the evidence, 34, 57–58, 67, 70, 72, 153–154, 154f Denosumab, 45t Des-amido forms, target protein derivatives, 235–236 Development exercise

CQA assessments, 255–261, 256t–260t Deviation, 248, 251 Diabetes, insulin glargine for, 106

Direct-format binding assays, 278 Disposition kinetics profiling assay, 186–188, 187f Disulfide aggregates, 236 Disulfide bond, 298 Disulfide link, 226 Docetaxel, 185 Dosage form, 123–124 Dose selection, clinical pharmacology studies, 97–98 Doxorubicin, 185 Draft Guidance for Industry Assay Development for Immunogenicity Testing of Therapeutic Proteins, 268 Drug Price Competition and Patent Term Restoration Act (1984), 50, 101–102

Drug(s) antibody–drug conjugates, 129 biological authorized vs. licensed, 36 chemical vs., 157t size and complexity of, 131–132 chemical vs. biological, 157t development, 149

FDA, see Food and Drug Administration (FDA) finished drug product, 86–87 generic, bioequivalence of, 102, 156 for human/animal use, categories of, 155–156 hypersensitivity, 267 medicines vs., 36 Drug substance/drug product stability, 291–293, 292t; see also Formulation similarity

DTP, 42t Dulaglutide, 45t Dynamic light scattering (DLS), 283

E

Ecallantide, 45t Eculizumab, 44t Edman degradation reaction, 224 Effectiveness, efficacy vs., 36, 146 Efficacy, effectiveness vs., 36, 146 Elaprase, 43t Elastic scattering, 218 Electrochemiluminescence, 192, 276, 278 Electromagnetic radiation, 217 Electronic excitations, 218 Electron ionization, 216 Electrophoresis, 226; see also Biopharmaceutical tools 2D-SDS PAGE, 221 native electrofocusing, 221–222

SDS-PAGE, 221

Western blot (WB), 222–223 Electrospray ionization (ESI), 171, 216 Elelyso, 45t ELISA method, 276, 277 Elonva, 43t Emission, radiative energy, 217–218 Enbrel, 167 End-of-Phase 2 (EOP2) meeting, 122–123 Endotoxins, 230 End points, demonstrating biosimilarity, 69 Enhanced chemiluminescent, 279 Enoxaparin, 36, 163–165, 164f Entyvio, 44t Enzymatic hydrolysis, 178 Enzyme-linked immunosorbent assay (ELISA), 171t, 179, 181, 192 Enzyme-linked receptors, 182 EP2006, equivalence interval analysis of, 332t, 349, 350 Epoetin alfa, 45t Eprex®, 141, 179 Eprex immunogenicity, 267 Epstein–Barr virus, 232 Equal number side by side, defined, 349 Equivalence acceptance criteria (EAC), lots for, 351 Equivalence demonstration, risks in, 346t Equivalence of formulations, demonstrating overview, 305–306, 306t standard studies preclinical and clinical studies, 308 process development, 307 storage stability study, 306–307, 307f transportation, handling, and delivery study, 307–308 Index

381

Index

382

Equivalence interval, defined, 348 Equivalence interval analysis of EP2006 by the FDA, 332t Equivalence testing (Tier 1), 318 Erbitux, 42t Erythropoietin (EPO), 40, 265, 274, 303 Establishment inspection reports (EIRs), 169 Etanercept, 41t, 103t European Economic Area (EEA), 139, 140 European Medicines Agency (EMA), 39 biosimilar comparability, 35 biosimilar product, defined, 145–146

FDA vs., 135–140 guidelines, 35 for LMWH products, 163–165 European Union (EU), biosimilars in, 40, 41t Euthyroidism, clinical symptoms of, 65 Evaluation

CBER, 30, 33, 109

CDER, 30, 33, 109, 129 physicochemical, analytical similarity assessment, 82–83 of residual uncertainty, 91 Exception excipients, 289 Exclusivities interchangeable, 104 reference product, 129–130 regulatory, 101–105, 103t Explicit views, on development of biosimilars, 130–135 improved analytical methods, 132–133 measurement standards, 134 size and complexity of biological drugs, 131–132 therapeutic proteins, 131–132 three properties of, 134–135 Exposure and response assessment, 89–91 Expression system, 80–81 Extinction coefficient method, 224–225 Extrapolation of clinical data across indications, 70–71 considerations, 154–155 defined, 39 FDA mind-set, 154–155 proposed biosimilar product and, 120–122

F

Fabrazyme, 42t Factor VIII (procoagulant), 43t FDA, see Food and Drug Administration (FDA) Federal Food, Drug, and Cosmetic (FD&C) Act, 29–30, 50, 115, 117, 119–124, 128 Fermentation, 235 Filgrastim, 7, 9f, 35 analytical similarity assessment criteria and tier assignments for, 337t–338t

Filgrastim-sndz, 41t

Granix, 104 innovator vs. originator, 35

Neupogen, 104, 162 norleucine in, 37 pegylated, 35 product-related impurities of, 178t tbo-filgrastim, 103–104 Filtration, 233, 235 Fingerprinting and enoxaparin, 164f Fingerprint-like similarity, 38–39, 338–342; see also 351(k) terminology attributes, 165, 166f, 167f criteria, 164, 164f defined, 38–39 highly similar with, 162–163 regulatory guidance, FDA, 163–165, 164f, 166f, 167f requirements, 165, 166f statistical modeling, 338–342 use of, 165 Finished drug product, 86–87 Fixed structure ingredients (FSIs), 155–157, 157t Fluorescence emission, 238 Fluorescence resonance energy transfer (FRET), 177 Fluorophore, 177 Follitropin alfa, 42t, 43t Follitropin beta, 42t Food and Drug Administration (FDA); see also Biosimilar(s)/biosimilarity analytical similarity data, 150–151

analytical tools, 151, 151f analytics, choice of, 151 animal toxicity data, 152 in approving complex products, 35 biosimilar landscape, see Landscape, biosimilar products BPCI Act, see Biologics Price Competition and Innovation (BPCI) Act BsUFA, 32, 52, 109, 110 clinical data, type of, 152 clinical studies, 152 comparative clinical study, 153 comparative human PK and PD data, 152 consultation with, 72 defining biosimilars or biosimilarity, 147 development concepts, 149 EMA vs., 135–140 extrapolation, 154–155 FDCA, 29, 30 guidance, 33t, 149 human PK and PD study considerations, 153 interchangeability, 147 interchangeable biological product, 34 351(k) application content, 147–148 351(k) information on biosimilarity, 148 mind-set, biosimilars/ biosimilarity, 146–155 analytical similarity, assessment, 150–151 analytical similarity, data, 150 analytical tools, 151, 151f animal data, 152 choice of analytics, 151 clinical data, type, 152 clinical studies, 152 comparative clinical study considerations, 153 comparative human PK and PD data, 152 defined, 145, 147 expectations, 157, 158f extrapolation, 154 extrapolation considerations, 154–155 guidance, 149

human PK and PD study considerations, 153 interchangeable/ interchangeability, defined, 147 351(k), application, 147–148 351(k), information on biosimilarity, 148 key development concepts, 149 licensure pathway for biological products, 146–148 nonlicensed product, 149 reference products, 147–149 stepwise approach, 149–150 summary of key concepts, 155 totality of the evidence, 150, 153–154, 154f nonlicensed product, 149 phase 3-type trials, 367–368

PHSA, see Public Health Service Act (PHSA) protein, definition of, 30–31

Purple Book, 32–33, 107–108 reference product, 147 reference product by PHSA, 148–149 regulatory guidance, see Regulatory guidance, FDA stance, 35 stepwise approach, 149–150 totality of evidence, 150, 153–154, 154f Food and Drugs Act (1906), 29 Formal meetings, FDA guidance, 51–53 biosimilar initial advisory, 51–53

BPD type 1, 52

BPD type 2, 52

BPD type 3, 52–53

BPD type 4, 53 Formulations about, 301–304 aggregation, 305 components of, 302t higher-concentration, 300–301 lyophilization, 305 lyoprotectants, 304 surfactants, 304 Formulation similarity background, 289–291 chemical degradation, 296–300, 298t, 299t drug substance/drug product stability, 291–293, 292t Index

383

Index

384

equivalence of formulations, demonstrating overview, 305–306, 306t standard studies, 306–308, 307f formulation considerations, 301–305, 302t, 303f higher-concentration formulations, 300–301 physical degradation, 293–296 Forteo, 43t Fortical®, 107 Freedom of Information Act, 169 Fucosylated type–glycans, 261 Functional assays analytical similarity assessments, 83–84 demonstrating biosimilarity, 59–60 Functional similarity, 159

G

Galactosylation, 249f Ganirelix acetate, 42t GCSF reference standard, 183 Gel electrophoresis, 221 Genentech, 106 Genotropin, 106 Glatiramer acetate, 137 Global mind-set, 45 GlucaGen®, 107 Glucagon injection, 107 Glucarpidase, 43t Glutamine, 177 Glycans, 270, 271 high mannose–type, 260 Glycan testing, 227 Glycoproteins, 23 Glycosylation, 15, 226–228, 270–271 Golimumab, 44t Gonal-F, 42t Good manufacturing practices (GMP), 235 G-protein–coupled receptors, 182 Gram-negative bacteria, 230 Granix, 104 Granulocyte colony–stimulating factor (GCSF), 47

H

Hamburg, Margaret, Dr., 371–382 Hard ionization techniques, 216 Hatch–Waxman Act, 50, 101–102 HCP, see Host cell protein (HCP) Helixate, 42t Hemophilus influenza type b, 44t Hepatitis B vaccine, 43t Herceptin, 43t Heteronuclear single quantum coherence, 228 Higher-order structure (HOS) biosimilars, 228 of proteins, characterization, 7 High mannose–type glycans, 260 High-performance anion-exchange chromatography with pulsed amperometric detection (HPAEC-PAD), 227 High-performance chromatographic methods, 229 High-performance ion-exchange chromatography (HP-IEXC), 219–220 High-performance liquid chromatography (HPLC), 171 High-performance size exclusion chromatography (HP-SEC), 220 Hormones, 2 protein, 2–3 Hospira, 367 Host cell protein (HCP), 178–179, 231–232, 344 Human epidermal growth factor receptor 2 (HER2) inhibitor, 183 Human insulin, 298 Human papillomavirus vaccine, 43t Human pharmacology data, 64–65 Human PK/PD study considerations data analysis plan, 153 study design, 153 Humira, 42t HUMIRA (example), 290 Humoral immune system, 1 Hyaluronidase human injection, 106 Hydrolysis, 296 Hydrophobic chromatography, 219 Hydrophobic interaction chromatography (HIC), 223 Hydrophobic proteins, 237 Hylenex®, 106 Hypervariable region, 2

I

Ibritumomab tiuxetan, 43t ICH guidelines, 40 ICH Quality Guidelines, 325 Identity, biosimilars; see also Biopharmaceutical tools amino acid analysis (AAA), 225 disulfide link, 226 extinction coefficient, 224–225 glycosylation, 226–228 peptide mapping, 225 primary structure, 223–224 sequencing, 224 terminal sequence, 226 Idursulfase, 43t IEXC, see Ion-exchange chromatography (IEXC)

Ilaris, 45t Immune tolerance breakdown, 270 Immunoassays, 231 biosensor-based, 281–282 Immunoblotting procedure, 282 Immunochemical properties, 84 Immunogenicity (IM) assays, 190, 192–193 assessment animal, 62 clinical, 65–67 defined, 95 testing, 190 Immunogenicity of biosimilars chemical degradation aggregation, 272–273 formulation changes, 274–275 impurities and production contaminants, 273–274 manufacturing and processing factors, 273 factors influencing expression-related factors, 271–272 intrinsic immunomodulatory effects, 270 molecule-specific factors, 269 structural factors, 270–271 overview, 265–268, 267t of recombinant drugs, 268t Immunogenicity testing assays for antibody detection, 278–279 biosensor-based immunoassays, 281–282

cell-based neutralization assays, 279–281 confirmation of antibody positive samples, 282–284, 283t single assay, 276–277 stability, 284 testing protocols, 275–276 testing strategy, 277–278 two-assay approach, 277 Immunoglobulin, 1 Immunoglobulin E (IgE) antibodies, 264 Immunoglobulin M (IgM), 268 Immunological tests, 211 Immunomodulatory effects, 270 Immunoreactivity, 188 Impact, definition of, 257t; see also Critical quality attributes (CQA) Impedance spectroscopy, 218 Improved analytical methods, potential benefits, 132–133 Impurities attributes vs., 40 biosimilarity tetrahedron, element, 175–179 contributors, 176f process-related, 178–179 and production contaminants, 273–274 product-related, 176–178, 178t proposed and reference products, 84–85 Imvamune, 44t Increlex, 42t Index of refraction, 218 Indirect-format binding assays, 278 Inelastic scattering, 218 Inflectra, 41t Infliximab (Remsima), 41t, 42t, 103t, 141, 183t Information on biosimilarity, 351(k), 148

CMC data submission, 76 detailed guidance for, 75 non-U.S.-licensed comparator product, 124–125 demonstrating biosimilarity, 58–71; see also Demonstration of biosimilarity Index

385

Index

386

pediatric, BPCI Act for extrapolating, 121–122 publicly-available, FDA and, 118–119 Inherent attributes, 356 Innovator, originator vs., 35 Insulin aspart recombinant, 42t detemir recombinant, 43t glargine, 42t, 106, 128 glulisine recombinant, 44t Integrity, of bioanalytical methods, 93–95 concentration and activity assays, 94 ligand-binding assays, 93–94

PD assays, 94–95 safety and immunogenicity, 95 Intercenter agreement (ICA), 30 Interchangeability; see also Biosimilar(s)/biosimilarity about, 193–196, 195f defined, 147 Interchangeable biosimilars/ interchangeability biological product, 193–196 defined, 34, 39 determination of, 119 exclusivity, 104

FDA Q&As, 109–126 Interchangeable product, 34–35, 147 Interferon alfa-2b, 42t, 44t Interferon beta-1a, 268 Interferon gamma-1b, 44t International Conference on Harmonisation (ICH), 113 risk assessment process defined by, 246 International Union of Pure and Applied Chemistry, 19 Intracellular receptors, 182 Intrachain bonds, 226 Intron A, 44t Investigator brochure (IB), study protocols and, 126 Ion exchange (IE), 171 Ion-exchange chromatography (IEXC), 218–219 Ionizer, 216 Ipilimumab, 45t Irreversible aggregation, 302 Ishikawa diagrams, 247–251, 249f Isoaspartate, 177 Isoelectric focusing (IEF), 171 Isomerization, 296 Isotonicity, 305 Ixiaro, 44t

J

Japan, biosimilars in, 40 Japanese encephalitis vaccine, 44t Jetrea, 44t

K

Kadcyla, 45t Kalbitor, 45t Kepivance, 42t Kineret, 44t Kjeldahl analysis, 229 Kozlowski, Steven, Dr., 130–131

L

Label copy, 39 Labeling, for reference product, 121–122 Landscape, biosimilar products, 29–46 authorized vs. licensed, 36 background, 29–31 biosimilars in use, 40–46, 41t effectiveness vs. efficacy, 36 extrapolation, 39

FDA stance, 35 fingerprint-like similarity, 38–39 future of, 41–45, 42t–45t global mind-set, 45 impurity vs. attributes, 40

India, biosimilars in, 40–41 innovator vs. originator, 35 interchangeable biosimilars, 39

Japan, biosimilars in, 40, 44t 351(k) route, 33–35 label copy, 39 legislative history, 31–33 medicines vs. drugs, 36 no clinically meaningful difference, 37–38 one-size-fits-all vs. case-by-case, 37 pediatric waiver, 39 rise of, 31–40 similarity vs. comparability, 36 totality of the evidence, 37 Lantus, 42t

Laronidase, 43t Leachables, 291 Leadership, 365, 366f Legacy attributes, 351 Legacy values, 356 Lemtrada, 42t Levels, of similarity, 160–163 confidence-based, 160–161, 160f highly similar, 162 highly similar with fingerprintlike similarity, 162–163 not highly similar, 161–162 not similar, 161 Levemir, 43t Licensed biological drugs, authorized vs., 36

Licensure pathway for biological products, FDA, 146–148 of proposed biosimilar product, 55, 111–112, 114–117 Ligand-binding assays, 93–94 Ligand-gated ion channels, 182 Lipids, 234–235 Liquid aqueous formulation, 290 Liquid chromatography–mass spectroscopy (LC-MS), 171 Liraglutide (rDNA origin), 44t, 45t Lots multiple, 59, 77–79 originator, number of, 37 proposed products, 77, 78, 173

QAs and, 173–174 reference, 77, 78, 173, 180, 315, 319, 320, 322, 325, 327, 332

U.S.-licensed comparator, 114 Lovenox, 163, 165 Lower limit of quantification (LLOQ), 189 Low–molecular weight heparin (LMWH), 163–165 Lucentis, 43t Lutropin alfa, 42t Luveris, 42t Lyophilization, 305; see also Formulations Lyoprotectants, 304; see also Formulations

M

Macromolecular protein, 293 Macugen, 42t Manufacturing process, for proposed product, 81–82 Margin determination, 321–322 Margins and ranges, defined, 352 Marketing Authorisation Application (MAA), 36 Mass accuracy, 217 Mass spectrometry (MS), 177, 212–217, 213t–214t, 215f; see also Biopharmaceutical tools Matrix-assisted laser desorption/ ionization time of flight mass spectrometry (MALDI-TOF), 171 m-cresol, 294 Measurement standards, potential benefits, 134 Mecasermin (rDNA origin), 42t Mechanical stresses of agitation, 293 Medicines, drugs vs., 36 Meetings, FDA regulatory guidance, 51–53 biosimilar initial advisory, 51–53

BPD type 1, 52

BPD type 2, 52

BPD type 3, 52–53

BPD type 4, 53

BsUFA fee structure, 368–369, 369t estimated hours and full-time equivalents, 371t program submissions and applications, volume of, 370t sponsor, meeting with FDA, 109–110 Messenger ribonucleic acid (mRNA) transcripts, 2–3 Metal ion–catalyzed oxidation, 297 Metreleptin, 44t Miacalcin®, 107 Microbial agents, 235 Microflow imaging (MFI), 273 Milk fat removal, 234 Mircera, 44t Mixed graphic and numerical data, 357 Mode of action (MoA), 211 Molecular spectra, 218 Monoclonal antibodies (mAb), 228, 260t, 297 characterization techniques, 215f Index

387

Index

388

Monograph standards, 173 Motifs and domains, 9–11 Multimeric proteins, 299 Multiple testing, 317 Myalept, 44t Mycoplasmas, 235 Myozyme, 44t

N

N-acetyl acid (NANA), 20 Nanofiltration, 233 Nano intelligent detection system (NIDS)®, 193 Natalizumab, 43t Native electrofocusing, 221–222 Native-to-unfolded-to-aggregate model, 294 Natpara, 44t Nature Reviews: Drug Discovery, 37 Neulasta, 42t Neupogen, 104, 162, 358, 359 Neutralization assays, cell-based, 279–281 Neutralization of therapeutic protein, 271 Neutralizing antibodies, 265 Neutropenia, 7 New England Journal of Medicine Nature Reviews, 37 New measurement standards, potential benefits, 134 N-glycolyl acid (NGNA), 20 N-linked glycans, 227 NMR spectroscopy, 228 No clinically meaningful difference, 37 Nonclinical safety, 159 Nondisclosure agreement (NDA), 29, 156 approval, 105, 156 categories, 156 filing, 102 investigational NDA (IND), 73 requirement, 29, 30 Nonenzymatic fragmentation, 299 Nonglycosylated proteins, 224 Noninferiority (NI), 184 clinical trials, 70 testing, 357–358 Nonlicensed products

FDA and, 149 non-U.S.-licensed comparator, 112–114, 124–126 Nonnative aggregation, 272 Nonparametric tolerance interval, defined, 353 Norditropin SimpleXx, 42t Norleucine, 37 Novartis, 107 NovoMix 30, 42t Novo Nordisk, 107 NovoThirteen, 44t Nplate, 44t Nuclear magnetic resonance (NMR), 211 Nucleic acid, 230 Nulojix, 44t Number of selected lots, defined, 353–355

O

Obama, Barack, 31, 32, 146 Obizur, 44t Ocriplasmin, 44t Octocog alfa, 44t Office of Communication, Outreach and Development (OCOD), 109 Oligosaccharides, defined, 132 Omalizumab, 43t Omnitrope, 106 Onabotulinumtoxina, 43t O-N-acetylgalactosamine, 227 One-dimensional SDS-PAGE, 221 One sample, defined, 348–349 One-size-fits-all, case-by-case vs., 37 Opalescence, 300 Orange Book, 107 Orbitrap mass spectrometry, use of, 38–39 Orencia, 43t Orgalutran/Antagon, 42t Originator, innovator vs., 35 Orthogonal testing, in statistical modeling, 349 Ovidrel, 42t Oxidation, 272, 297–298 of proteins, 177 Oxidized forms, target protein derivatives, 236

P

Palifermin, 42t Palivizumab, 42t

Panitumumab, 43t Paracrine signaling, 2 Parallel design, 96 Parathyroid hormone, 44t Patient Protection and Affordable Care Act, 31, 88 Pediarix, 42t Pediatric Research Equity Act (PREA), 51, 119–122 Pediatric study plan (PSP), 122–123 Pediatric study waiver, 39; see also 351(k) terminology Pegaptanib sodium, 42t Pegasys, 43t Pegfilgrastim, 42t Peginterferon alfa-2a, 43t Peginterferon alfa-2b, 42t PEGIntron, 42t Pegvisomant, 42t PEGylation, 271 Peptide bonds, 7–8, 299 Peptide mapping, 225–226 Peracetic acid, 235 Peroxide, 298 Pfizer, 106, 367 pH, optimization of, 302 Pharmaceutical development, aim of, 243 Pharmacodynamics (PD) assays considerations, 93–95 clinical immunogenicity assessment, 63–65 clinical pharmacology studies, 89–91 data, comparative human, 152 human, study considerations, 153 measures, 99–100 animal, inclusion of, 62 results, statistical comparison, 100 studies, integrity of bioanalytical methods in, 93–95 time profile, appropriate, 100 Pharmacokinetics (PK) assay considerations, 93–95 assessment, ADA on, 189–190 clinical immunogenicity assessment, 63–65 clinical pharmacology studies, 89–91 data, comparative human, 152 human, study considerations, 153 measures, 98–99 animal, inclusion of, 62

results, statistical comparison, 100 studies, integrity of bioanalytical methods in, 93–95 Pharmacokinetic parameter evaluation of bevacizumab, 345t Pharmacopoeial Convention, US, 173 Pharmacovigilance, 141 Pharmacovigilance program, 282 Phase 3-type trials, FDA and, 367–368 Phenol, 294 Phenylalanine, 224 Photooxidation, 297 PHS Act, 313 Physical degradation, 293–296; see also Formulation similarity Physicochemical properties, assessment of, 82–83 Polio vaccine, 42t, 44t Polyacrylamide gel electrophoresis (PAGE), 178–179 Polyethylene glycol (PEG), 271 Polymerase chain reaction (PCR), 230 Polypeptide, chemically synthesized, 31, 126–128 Polysorbate, 302, 303 Population, sample vs., 347 Postmarketing safety monitoring considerations, 71–72 surveillance, 160 Postmarket surveillance, in EU, 160 Posttranslational modifications (PTM), 177, 191, 222, 223, 228, 329 therapeutic proteins, 134 Potency, of biosimilar products, 179–183 bioactivity, 180–181 bioanalytical considerations, 188 cell-based assays, 181 protein content, 180 receptor-binding assays, 181–183, 183t Potency testing, 188 Preclinical safety, 159 Preprohormones, 3 Preservative, 289, 304 Prions, 233–234 Process-related impurities, 178–179 Process-specific assays, 232 Index

389

Index

390

Prochymal, 43t Product-related impurities, 176–178, 178t; see also Biosimilar(s)/ biosimilarity about, 176–177 deamidation, 177 oxidation of proteins, 177 proteases, 177–178 Prohormones, 3 Proleukin, 42t Prolia, 42t Properties of biological products, 131 immunochemical, 84 physicochemical, 82–83 receptor-binding, 84 therapeutic proteins, 134–135 Proposed biosimilar products characterization, 56, 58 clinical pharmacology studies, see Clinical pharmacology studies delivery device/container closure system, 110–111 demonstration of biosimilarity, see Demonstration of biosimilarity development program, sponsor and, 109–110 dosage form, 123–124 expression system, 81 finished drug product, 86–87 formulation of, 110 impurities in, 84–85 licensure of, 55, 111–112, 114–117 manufacturing process, 81–82 physicochemical evaluation of, 82–83 postmarketing safety monitoring for, 72

PREA for, 119–122

PSP, 122–123 stability profile, 87 Proteases, 177–178 Protein aggregates, 293 aggregation, 11–14 association, 11–14 content, 180, 229 defined, 30, 31 expression variability, 22–24 formulations, see Formulations hormones, 2–3

immunoblot, 222 interferences, 193 oxidation, 297 pharmaceuticals, stability problem, 292t sequencing, 224 stability, 291 Protein Data Bank, 11 Protein products aggregation, 135 amended definition of “biological product,” 126–128 complexities, 53–55 content, potency testing, 180 3D conformation, 77–78

HCP, 178–179 heterogeneity, 77 human PK and PD profiles, 64–65 manufacturing process considerations, 54–55 nature of, 54 oxidation, 177 pharmacologic activity of, 59–60 physicochemical characteristics, 82 product class as, 128–129 receptor-binding and immunochemical properties, 84 structural characterization, 59 therapeutics, 131–132 three properties, 134–135 Protein–protein interaction, 300 Proteins, posttranslational modification, 14–22 glycosylation, 19–22 Protein structure building elements, 4, 5f–6f peptide bond, 7, 8f translation, 7 Proteolytic enzymes, 234 Protocols comparability, see Comparability protocol testing, 275–276 Provenge, 42t Pseudovaccination effect, 274 Public domains, defined, 358 Public Health Service Act (PHSA), 29–30, 33, 148 abbreviated licensure pathway, 31

FDA Purple Book, 32–33, 107–108

NDA requirement, 29, 30 section 351(a), 32, 50, 76, 96, 108, 124, 126, 147 section 351(i), 53, 126–128 section 351(k), 32–33, 50–52, 55, 129–130, 147, 148 section 351(k)(2)(A)(i)(IV) of, 117–118, 123–124 Publicly-available information, FDA and, 118–119 Puregon/Follistim, 42t Purity, 175–179; see also Biosimilar(s)/biosimilarity about, 175–176, 176f impurities, contributors, 176f process-related impurities, 178–179 product-related impurities, 176–178, 178t Purity, protein about, 229 aggregates, 236–237 carbamylated forms, 236 cleaved forms, 237 des-amido forms, 235–236 endotoxins, 230

HCP, 231–232 lipids, 234–235 microbial agents, 235 mycoplasmas, 235 nucleic acid, 230 oxidized forms, 236 prions, 233–234 proteolytic enzymes, 234 scrambled forms, 237 virus contamination, 232–233 Purple Book, 32–33, 107–108

Q

QbD, see Quality-by-design (QbD) Quality attributes (QAs), 170–175, 171t, 172t; see also Biosimilar(s)/biosimilarity

CQAs, see Critical quality attributes (CQAs) with immunogenicity and safety, 255 for mAb, 260t with MoA, 255 overview, 170–175, 171t, 172t similarity assessment of filgrastim, 258–259 Quality-by-design (QbD), 243, 244f, 245 Quality by Design and Process Analytical Technology, 170 Quality considerations, in demonstrating biosimilarity, 73–80 background, 73–74 general principles, 75–80 scope, 75 Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a Reference Product, 314 Quality range, defined, 348 Quality range approach (Tier 2), 322–323 Quality target product profile (QTPP); see also Critical quality attributes (CQA) defined, 243 workflow and, 245 Quantum mechanical systems, 217 Quarter-over-quarter (Q/Q) formula, 180 Quencher, 177, 178 Questions and answers (Q&As), FDA, 108–130 background, 108–109 biosimilarity/interchangeability, 109–126 delivery device/container closure system, 110–111 dosage form, 123–124 formulation of proposed and reference products, 110 interchangeability, determination, 119 licensure of proposed biosimilar product, 111–112, 114–117 non-U.S.-licensed comparator product, 112–114, 124–126 PREA, 119–122 proposed biosimilar development program, 109 PSP, 122–123 publicly-available information, 118–119 QT/QTC study, 114–115 Index

391

Index

392

reserve samples of biological products, 115–116 sponsors, meeting with FDA, 109–110 strength of biological products, 117–118 BLA for biological product, 126–129 antibody–drug conjugates, 129 chemically synthesized polypeptide, 126–128 product class as protein product, 128–129 exclusivity, 129–130

R

Radioimmuneprecipitation (RIPA), 277, 278 Raleigh scattering, 301 Ramachandran plot, 7 Raman scatterings, 218 Ramucirumab, 44t Random lots, in statistical modeling, 353 Ranges, in statistical modeling, 352 Ranibizumab, 43t Receptor-binding assays, 181–183, 183t Receptor-binding properties, 84 Recombinant human EPO (rHuEPO), 274 Recombivax HB, 43t Recothrom, 42t Reference medicine, 145 Reference products; see also Biosimilar(s)/biosimilarity biological products and, 32, 50–51, 53

BPCI Act, 96–97 clinical pharmacology studies, see Clinical pharmacology studies defined, 33, 147 demonstration of biosimilarity, see Demonstration of biosimilarity dosage form as, 123–124 exclusivity, 129–130 expression system, 81

FDA mind-set, 148–149 finished drug product, 86–87 formulation of, 110 impurities in, 84–85 interchangeability, 193–194 351(k) application, 33–34 manufacturing process for, 55 by PHSA, 148–149 physicochemical evaluation of, 82–83 postmarketing safety monitoring for, 72 reference standards and, 85–86 stability profile, 87

U.S.-licensed, 55, 112–114, 126 variability, 351, 359 Reference standards, reference product and, 85–86 Regulatory guidance, FDA, 47–141 analytical similarity assessment, 80–88 expression system, 80–81 finished drug product, 86–87 functional activities, 83–84 impurities, 84–85 manufacturing process, 81–82 physicochemical evaluation, 82–83 receptor-binding and immunochemical properties, 84 reference product and reference standards, 85–86 stability profile, 87 background, 47–50, 48t, 49t for biological products, 48t 505(b)(2) vs. 351(k) pathways, 105–107, 106t clinical pharmacology studies, 88–101; see also Clinical pharmacology studies background, 88 concentration and activity assays, 94 critical considerations, 89–93 developing, for supporting demonstration of biosimilarity, 95–101 integrity of bioanalytical methods, in PK and PD studies, 93–95 ligand-binding assays, 93–94 PD assays, 94–95 role, 88–89 safety and immunogenicity, 95

comparative EMA and FDA mind-set, 135–140 consultation with FDA, 72 exclusivities, 101–105, 103t explicit views on development, 130–135 improved analytical methods, 132–133 new measurement standards, 134 size and complexity of biological drugs, 131–132 therapeutic proteins, 131–132 therapeutic proteins, three properties of, 134–135 formal meetings, 51–53 biosimilar initial advisory meeting, 51–53

BPD type 1 meeting, 52

BPD type 2 meeting, 52

BPD type 3 meeting, 52–53

BPD type 4 meeting, 53 ICH guidance, 49t overview, 50–51 pharmacovigilance, 141 postmarketing safety monitoring considerations, 71–72 Purple Book, 107–108 Q&As, 108–130; see also Questions and answers (Q&As) background, 108–109 biosimilarity/ interchangeability, 109–126

BLA for biological product, 126–129 exclusivity, 129–130 quality considerations, in demonstrating biosimilarity, 73–80 background, 73–74 general principles, 75–80 scope, 75 relevant to biosimilars, 48t–49t scientific considerations, 53–71; see also Scientific considerations background, 53 demonstrating biosimilarity, see Demonstration of biosimilarity manufacturing process considerations, 54–55 nature of protein products, 54 protein products, complexities, 53–55 U.S.-licensed reference product, 55 Release criteria, statistical modeling, 359 Remestemcel-L, 43t Remicade, 42t Remsima (infliximab), 41t, 42t, 103t, 141, 183t ReoPro, 42t Replagal, 42t Replicates, 349 Reserve samples, of biological products, 115–116 Residual DNA, 344–346 Residual uncertainty, evaluation, 91 Resonance spectroscopy, 218 Retacrit, 367 Retroviruses, 232 Reverse-phase chromatography (RPC), 219 Rilonacept, 43t Risk assessment process; see also Critical quality attributes (CQA) and iterative process, 254–255 overview, 246–248, 247f risk question definition and target linkages, 248–251, 249f, 250f tailored risk assessment tool development, 251–253, 252t threshold definition for, 253–254, 254t Risk assessment tools, 251 Risk number (RN), 251, 254 Risk ranking, 318 Risk ranking of attributes, 317–318 Rituxan, 43t, 167 Rituximab, 43t, 103t, 169, 183t Romiplostim, 44t RotaTeq, 43t Rotavirus vaccine, 43t Route of administration, clinical pharmacology studies, 98

S

Safety clinical/preclinical, 159 monitoring considerations, 71–72 Index

393

Index

394

Safety similarity background, 263–265 immunogenicity chemical degradation, 272–275 factors influencing immunogenicity of biosimilars, 269–272 overview, 265–268, 267t regulatory guidance, 268–269 immunogenicity testing assays for antibody detection, 278–279 biosensor-based immunoassays, 281–282 cell-based neutralization assays, 279–281 confirmation of antibody positive samples, 282–284, 283t single assay, 276–277 stability, 284 testing protocols, 275–276 testing strategy, 277–278 two-assay approach, 277 nonclinical testing, 284–286 Salting out effect, 295 Sample(s) population vs., 347 reserve, of biological products, 115–116

size for comparative clinical study, 69 unbalanced, 350 Saxenda, 45t Scatter plots of proliferation bioassay, 334f Scientific Considerations in Demonstrating Biosimilarity to a Reference Product, 313–314 Scientific considerations, FDA guidance, 53–71 background, 53 demonstration of biosimilarity, 56–71; see also Demonstration of biosimilarity animal data, 60–62 clinical studies, general considerations, 62–71

developing and assessing evidence, approaches, 56–58 functional assays, 59–60 inclusion of animal PK and PD measures, 62 interpreting animal immunogenicity results, 62 structural analysis, 58–59 manufacturing process considerations, 54–55 protein products complexities, 53–55 nature of, 54

U.S.-licensed reference product, 55 Scrambled forms, target protein derivatives, 237 SDS-PAGE, see Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) Search engines, 223 Section 505(b)(2), 351(k) vs., 105–107, 106t Section 351(k) application, 50–51 information on biosimilarity, 148 interchangeability, determination, 119 351(k)(2)(A)(i)(IV) of PHSA, 117–118, 123–124 pathways, 505(b)(2) vs., 105–107, 106t of PHSA, 32–33, 50–52, 55, 129–130 publicly-available information, 118–119 route, 33–34 SEDFIT program, 38 Sendai virus, 232 Sephadex, 234 Sialic acids, 227 Side-by-side testing, 349–350 Significance level, defined, 346 Silver staining, 222 Similarity, 155–157, 157t; see also Biosimilar(s)/biosimilarity clinical, 183–186 statistical understanding, 184–186 study challenges, 184 types, 183–184

comparability vs., 36, 165, 167–169, 168f concept, 155–157, 157t, 158f degree of, 356 fingerprint-like, see Fingerprintlike similarity Similarity, levels of; see also Biosimilar(s)/biosimilarity about, 160–161, 160f highly similar (level 3), 162 highly similar with fingerprintlike similarity (level 4), 162–163 not highly similar (level 2), 161–162 not similar (level 1), 161 Simponi, 44t Simulation tools, utility, 100–101 Simulect, 44t Single assay, 276–277 Sipuleucel-T, 42t Size of biological drugs, 131–132 sample for comparative clinical study, 69 Size exclusion (SE), 171 Size of a test, defined, 346 Smallpox vaccine, 44t Sodium dodecyl sulfate (SDS), 176 Sodium dodecyl sulfatepolyacrylamide gel electrophoresis (SDSPAGE), 178, 221 Soft ionization, 216 Soliris, 44t Solubility, 300 Somatropin, 42t, 106 Somavert, 42t Specificity, of ADAs, 191–192 Spectroscopy techniques, 217–218; see also Biopharmaceutical tools

Sponsors demonstration of biosimilarity, see Demonstration of biosimilarity

FDA Q&As meeting with FDA, 109–110 non-U.S.-licensed comparator product, 112–114, 124–126

proposed biosimilar development program, 109–110 reserve samples of biological products, 115–116 finished drug product, 86–87 formal meetings, FDA staff and, see Formal meetings, FDA guidance general PK and PD assay considerations, 93 global mind-set, 45 manufacturing changes, 81–82 pediatric study waiver, 39 product-related impurities, 40 U.S.-licensed reference product, 55, 112–114, 126

Stability profile, statistical modeling, 343–344, 343f of proposed and reference products, 87 Stabilizers, 303 Statistical analysis plan, development of, 319–320 Statistical power, defined, 347 Statistical tier testing, 334f Stelara, 44t Strength, of biological products, 117–118 Stress testing proteins, 237 Structural analysis, demonstrating biosimilarity, 58–59 Study considerations comparative clinical, 153 human PK and PD, 153 Study population clinical pharmacology studies, 97 demonstrating biosimilarity, 69 Surface plasmon resonance (SPR), 192, 260t Surfactants, 304; see also Formulations Surveillance, postmarket, 160 Susoctocog alfa, 44t Switchability, 195, 196 Synagis, 42t

T

Taliglucerase alfa, 45t Tandem mass spectrometry, 171 Tangential flow filtration (TFF), 301 Index

395

Index

396

Tanzeum, 44t Tbo-filgrastim, 103–104 T cells, 263 Teriparatide, 43t Terminal sequence, 226 Testing limits, bioanalytical consideration, 189 Testing lots, defined, 358–359 Tetrahedron, biosimilarity, 169–170, 170f Teva Pharmaceuticals, Inc., 104 Therapeutic Biologics and Biosimilars Team (TBBT), 109 Therapeutic protein immunogenicity, 269 Therapeutic proteins, 4, 131–132 three properties, 134–135 3D structure, 135 posttranslation modifications, 134 protein aggregation, 135 Therapeutic Proteins International, 237 3D structure, therapeutic proteins, 135 351(k) route, 33–34 351(k) terminology, 35–40 authorized versus licensed, 36 effectiveness versus efficacy, 36 extrapolation, 39 fingerprint-like similarity, 38–39 impurity versus attributes, 40 innovator versus originator, 35 interchangeable biosimilars, 39 label copy, 39 medicines versus drugs, 36 no clinically meaningful difference, 37–38 one-size-fits-all versus case-bycase, 37 pediatric waiver, 39 similarity versus comparability, 36 totality of the evidence, 37 Thrombin alfa, 42t Thyrogen, 42t Thyroid-stimulating hormone, 65 Thyrotropin alfa, 42t Tier 1 testing method, 333f Tier testing plan, 329 Tocilizumab, 43t Tolerance interval approach, 322 Tositumomab, 42t Totality of the evidence approach demonstration of biosimilarity, 34, 57–58, 67, 70, 72, 153–154, 154f

FDA and, 35, 150 351(k) application, 35 Toxicity studies, animal, 61–62 Toxicokinetics, 285 Trans-membrane proteins, 274 Trastuzumab, 41t, 43t, 45t, 103t, 183t Trulicity, 45t Two-assay approach, 277 Two-dimensional SDS-PAGE, 221 Types of attributes/assays, 318 Tyrosine photooxidation, 297 Tysabri, 43t

U

Ultraviolet (UV)-absorbance measurements, 225 method, 224 Ultraviolet (UV) A272 methods, 212 Unbalanced samples, in statistical modeling, 350 Unigene, 107 United States biosimilars in, 40 licensed reference product, 55, 112–114, 126 Upper limit of quantification (ULOQ), 189 U.S.-licensed reference product, 315–316 Ustekinumab, 44t

V

V419, 44t Variable structure entities (VSEs), 155–157, 157t Vectibix, 43t Vedolizumab, 44t Velaglucerase alfa, 44t Vibrations, 218 Victoza, 44t VigiBase, 141 Virus contamination, 232–233 Viscosity, 301 Visual displays (Tier 3), 323 Vitrase, 106 Voraxaze, 43t Vpriv, 44t

W

Waxman, Henry, 31 Western blot (WB), 222–223 Whole protein man spectroscopy, 223 World Health Organization (WHO) biosimilar product, defined, 146

X

Xgeva, 45t Xolair, 43t

Y

Yervoy, 45t

Z

Zaltrap, 44t Zarxio, 41t, 140, 162 Zevalin, 43t Ziv-aflibercept, 44t Index

397