Fundamentals of EU Regulatory Affairs, Ninth Edition...Regulatory Affairs Professionals Society 645 Index preclinical study program for, 395 registration of, 397–399 safety reporting

643Regulatory Affairs Professionals Society

Index

Tables, figures, and case studies are indicated by appending “t”, “f”, or “c” to the page number. Contents of tables are not indexed separately.

Aabsorption, distribution, metabolism and excretion

(ADME)gene therapy products, 466, 468preclinical testing, 302–303

accelerated assessmentadditional pathways for, 538–539ATMPs, 452, 453tCAT request for human tissues, 480CHMP recommendation for, 35conditional authorisation, 475EMA advice meetings, 44tEMA initiatives, 101for orphan designation products, 538prepandemic influenza vaccines, 496procedures for, 475registration of medicinal products, 347regulatory mechanisms for, 3–4requests for, 283See also PRIME (PRIority MEdicines)

Active Implantable Medical Device Directive (AIMDD)repeal of, 184–185transition from, 178See also EU MDR and EU IVDR

active implantable/active medical devicesclassification change for, 146classification rules for, 191tlegal framework for, 165–170MDR rules

medical device legislation and classification, 191t

active pharmaceutical ingredients (API)EDQM inspection process, 369in generic products, 377

Active Substance Master File (ASMF)with combination products, 550generic medicinal products, 384IGDRP work on, 384MA dossier quality section, 280medicinal product registration, 350

acute/repeat dose toxicity studies, 303Ad Hoc Expert Group

MAA review, 54meeting of, 56

adaptive and alternative pathwaysaccelerated access initiatives by EMA, 295–296eligibility for, 295, 297f, 346HTA/EMA collaboration for, 88–89legal framework for, 296–298medicinal products, 296–298for orphan designation products, 539principles of, 296procedural guidance for, 298product eligibility for, 297f

Addition of Vitamins and Minerals and of Other Substances to Food Regulation, 504

Advanced Therapy Medicinal Products (ATMPs)authorised in EU, 455tborderline and criteria precluding from, 457–460certification of, 460characterisation and quality control, 462classification of, 456–457, 457t, 477–478classification procedures for, 456–460GTMP, 461–462, 464–465, 466legal framework, 480MA procedures for, 480pharmaceutical regulation evolution, 21–22

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Index

644 Regulatory Affairs Professionals Society

preclinical development, 465–466product characterisation, manufacturing and

quality control of, 462–463regulation, 451–470, 480risk management for, 466–467sCTMPs, 460–461, 462, 463–464, 465–466subcategories of, 452–453summary, 467–468supply without MA grant, 455–456TEPs, 461, 463, 465, 466

Adverse Drug Reactions (ADRs)/reportingfor biosimilar medicinal products, 401defined, 313Eudra Vigilance databases, 318, 401from healthcare professionals, 438human blood or plasma products, 525nonprescription medicinal products, 409for paediatric product development, 100PRAC activities for, 387requirements of Member States, 386–387See also pharmacovigilance

advertising and promotion, 103–114abbreviated ads as reminders, 106comparative advertisements, 110contents for HCPs, 105–106EFPIA goals and code, 104–105enforcement by competent authorities, 120to general public, 108general public content, 107–108generic medicinal products, 389HCPs, 105–106to healthcare professionals, 105healthcare professionals (HCPs), 105, 106–107Internet media, 109jurisdictions for, 111–112market surveillance, 110–111medical devices, 112nonauthorised products, 109–110nonprescription medicinal products, 408–409off-label information, 109–110OTCs, 108preapproval of material, 111–112press releases, 108–109regulatory framework, 103–104regulatory strategy for, 138sales representatives/sample distribution,

105–106scientific service by MAA, 111self-regulation, 104–105

affiliated countries and competent authorities, 161–163t

American Association of Tissue Banks (AATB), 473Anatomic, Therapeutic, Chemical Classification

(ATC) code, 282

animal modelsnonclinical testing, 235cpharmacodynamic testing, 395–396preclinical device testing, 235ctissue-engineered product, 495

Annual Safety Reports (ASRs), 311authorisation procedures for medicinal products

Centralised and Mutual Recognition Procedures for, 278–279

Centralised Procedure, 281–285Decentralised Procedure, 287–289, 290teCTD format and acceptability, 281legal framework for MAA, 278–279MA dossier quality section, 280MA system, 278–279Mutual Recognition Procedure, 285–287national authorizations, 289Notice to Applicants (NTA) for medicinal products,

278–279referrals, 292, 293

Authorised Representatives, 216, 255–256, 255t

BBelgium

advertising preapproval, 111BeNeLuxA, 23

bench testing for devices, 234–235cbibliographic applications/well-established use,

291–292biocompatibility testing

nonclinical studies, 234c, 235cpreclinical test plan, 229requirements from standards and risk

management, 230–231in tissue-engineered products, 465

bioequivalence, 378, 380–381Biologics Working Party (BWP), 21, 522biosimilar medicinal products

administration route and dosage parameters, 397authorised active substance in, 394clinical comparability demonstration for, 396–

397comparability to reference product, 394–395comparative development of, 399fdevelopment processes for, 395f, 396feffects of change to reference product, 399GLPs for, 396immunogenicity testing for, 397MAA data package for, 400tMAA submission for, 397–398pharmaceutical regulation evolution, 22pharmacovigilance and safety reporting, 400postapproval lifecycle management, 399–400


Index

preclinical study program for, 395registration of, 397–399safety reporting for, 400–401therapeutic interchangeability, 22, 399timeline for development of, 397ftypes of biological medicinal products, 393–394urgent safety restrictions for, 400

biotechnology-derived productsaccelerated assessment procedure, 415centralised procedure for, 415–416clinical information, 419conditional authorisation, 415development processes for, 394, 416developmental pharmaceutics, 416exceptional circumstances application procedure,

415GLP for preclinical testing, 418–419MA maintenance, 416manufacturing information for, 417pathways to marketing authorisation, 413–414pharmacovigilance and safety reporting, 419postapproval lifecycle comparability, 419postapproval variations, 419registration procedures for, 414–415release testing in Europe, 418TSE and viral clearance data for, 417–418

Blood Products Working Party (BPWP), 522borderline products classification, 200–201Brexit. See United Kingdom (UK)British Pharmacopoeia (BP)

quality systems and inspectorate process, 373

Ccarcinogenicity studies, 303CE Mark

compliance confirmation with, 155countries requiring, 272for IVDs, 213–214

central individual case study report (ICSR)electronic submissions, 449in PMSF, 440processing center performance, 441submission and processing requirements, 443,

445, 445fcentralised marketing authorisation

MAA review for, 53–60medicinal products, 278–279

Centralised Procedure (CP)advantages and disadvantages for biotechnology

products, 415, 419advantages/risk comparison for nonprescription

medicines, 406tapplication evaluation timetable for, 284t

ATMP MAA timetable, 481–483tauthorisation system, 20biosimilar medicinal product registration, 397,

401biosimilar medicinal products, 397biotechnology-derived product marketing

authorisation, 407–408, 413Brexit effects for UK, 10combination products, 544comparison of pathways for nonprescription

products, 406fDNA and therapeutic vaccines, 497dossier assessment procedures, 354dossier requirements, 433eligibility request for generic medicinal products,

386EMA committee evaluation of products, 7, 14EMA presubmission guidance, 414evaluation of products, 14generic medicines, 379human blood/plasma product registration, 523human blood/plasma product renewal and

pharmacovigilance, 525Information and Work Sharing projects, 386inspection process with, 366labelling and package leaflet (PL), 388MA issued under, 285MAA evaluation by EMA, 2MAA procedures, 281–283, 355fmedicinal product authorisation, 381medicinal product authorisation procedures,

281–285medicinal product clinical trials, 385national competent authorities medicine

authorisation, 561for nonprescription medications, 405orphan medicinal products, 525pan-European generic authorisation, 391pan-European registration system, 19postauthorisation assessment procedure, 426prepandemic influenza vaccines, 496prescription to nonprescription reclassification,

407–408product criteria for use, 19, 287, 293, 414product exclusivity under, 291registration of medicinal products, 341, 344regulatory dossier assessment, 354regulatory information resources for, 554, 557,

574scientific advice and parallel meeting for, 48vaccine licensure, 492variation assessment and notifications, 433–435

certificate of analysis, 369, 490

Index


Certificate(s) of Suitability (CEP)for APIs, 380EDQM issue of, 280, 352GMP inspections, 367–369registration of medicinal products, 352significance of, 369–370

Chemical Abstracts Service (CAS) number, 305Clinical Effectiveness (EFF) HTA model, 80clinical evaluation and clinical investigations

bench testing, 234c, 235cCE Mark requirements, 238Clinical Evaluation Report (CER), 238clinical pathway review, 241clinical strategy plan, 240clinical trial essentials, 241common mistakes in, 241–242elements of device evaluation, 238–239equivalence to existing device, 239GCP and quality in, 241objectives of clinical investigation, 239performing clinical investigation, 240–241planning the evaluation, 239–240report required, 238

Clinical Evaluation Report (CER), 238–240Clinical Investigation Protocol (CIP), 171, 241clinical investigations vs clinical trials

MDD, EU MDR definitions of, 116See also specific products

Clinical Trial Application (CTA)EU laws and regulations, 39vaccines, 490

clinical trial authorisation processapplication to national competent authority, 320Ethics Committee evaluation and Member State

competent authority, 319–320Ethics Committee opinion application, 320GMO-based products, 463, 497–498

Clinical Trials Directive (CTD), 310–312amendment of in-progress clinical trial, 323Annual Safety Reports (ASR) requirements of, 312application to IMPS, 315–317clinical trial end declaration, 323–324CTA process and authorisation process, 319–323declaring end of clinical trial, 323–324ECTR significant changes from, 314–315tEudraCT changes, 318–319EudraPharm function, 319objectives and transition to ECTR, 310, 312serious adverse reaction (SAR) reporting, 313

Clinical Trials Facilitation Group (CTFG), 313

clinical trials for medicinal products, 309–340amendment notifications, 320–323biological product guidance, 490clinical trial application scientific assessment,

327fclinical trial authorisation procedure, 326fclinical trial regulatory telematics structure

transitions, 317–318DSUR contents, 334tECTR and Clinical Trials Directive definitions,

316–317tECTR implementation

clinical trial application process, 324clinical trial authorisation, 324CTA dossier contents, 329f

EU Clinical Trials Register (EUCTR), 319EU Telematics, 317–318Part II CTA assessment, 328fserious adverse event reporting, 332f

Coding Directive, 485combination products, 543–552

borderline products, 545conformity assessment requirements, 549determination of registration pathway, 544directives and guidance documents, 547–548heparin and AIMD, 551cIVDs and CDx, 550labelling requirements, 551medicinal product/device delineation, 543–544pharmaceutical consultation procedure, 549–550postmarket surveillance requirements, 551product classification by PMOA, 544–547quality system requirements, 550–551regulatory classification determination, 548set for local anaesthesia with lidocaine, 551–552csunblock cream/embedded barrier for vitiligo,

552cin vitro fertilisation/transplant organs or tissue,

551ccombined ATMPs (cATMPs), 452, 456, 467Committee for Advanced Therapies (CAT)

ATMP classification and certification by, 457t, 460, 477, 533

ATMP Regulation and, 453–457combination products, 550, 557EMA responsibility for, 164feedback during MA review, 54, 55fMAA evaluation by, 480MAA review, 53–54, 54tPRAC advise to, 56PRIME rapporteur appointment from, 36–37rapporteur appointment from, 282, 430representation in, 54responsibilities of, 4, 8, 54t


Index

Committee for Medicinal Products for Human Use (CHMP)

ATMP marketing authorisation, 480conditional marketing authorisation grant, 35GCP adoption by, 330, 445human blood or plasma product regulation, 522,

531inspection requests from, 366MAA review, 53–54, 54tmeeting preparation timeline, 57fPDCO appointments, 95PRAC recommendation endorsements, 119responsibilities of, 7

Committee for Medicinal Products for Veterinary Use (CVMP), 8, 366, 555, 557

Committee for Orphan Medicinal Products (COMP), 343

orphan designation request review, 38rare disease designation review, 530responsibilities of, 8, 343, 532scientific advice from, 37, 48

Common European Submission Portal (CESP), 323–324

Common Specification (CS): GSPRs verifications, 225

Common Technical Document (CTD)biotechnology-derived product pharmaceutics,

416–417eCTD envelope, 351–352, 352teCTD format and acceptability for medicinal

products, 281MAA EU format and content, 280–281medicinal product registration, 351–352, 351tfor vaccines, 490

Common Technical Specifications (CTS) for IVDs, 214Communication and Tracking System (CTS) data

base, 288–289community interest referral, 293competent authorities. See national competent

authoritiesCompetent Authorities for Medical Devices (CAMD),

116, 164Complete/Full and Independent application, 289compliance and postmarket surveillance (devices)

clinical followup for AIMDs and MDs, 260–261Eudamed, 266–267feedback mechanisms for, 257–258Field Safety Corrective Action (FSCA), 258follow-up investigation, 264–265FSCAs and FSNs, 265GPSD, MDD, and EU MDR relationship, 258–259incidents and criteria for reporting, 262–264medical device global vigilance, 266PMS vs vigilance, 266–267

postmarket surveillance procedures, 259risk management in device industry, 260surveillance and control provisions, 267–268trend reporting, 265

Concerned Member States (CMS)application review timeline in, 322authorisation of clinical trials under ECTR,

324–325clinical trial acceptability, 324–325clinical trial management and notifications, 328clinical trial safety procedures, 323clinical trials for medicinal products, 311communications with Reference Member State,

355–356decentralised procedure applications, 345decentralised procedure referral, 293decentralised procedures, 288, 355–356dossier validation in, 354DSUR submission, 333IMPD cross-referencing, 330inspection report submission by sponsor, 330manufacture and importation, 388MRP, 356–357Mutual Recognition Procedure phase 2 timeline,

286national law application in, 337RMS evaluation for MA, 19scientific advice for IMPs, 324scientific advice from competent authority, 322sponsor selection of, 345vigilance procedures in, 478

conditional authorisationaccelerated assessment, 475biotechnology-derived products, 415by CHMP, 35for orphan designation products, 538registration of medicinal products, 346

conformity assessmentAIMDD documentation, 246AIMDD procedure, 250fAuthorised Representatives, 216, 255–256, 255tCE marking process, 244–245Class I device, self-declaration/self-certification,

250fClass IIa procedure, 249fClass III device options, 248fClass IIIb procedures, 249fconformity assessment in, 136documentation for, 247EC-type examination, 252, 254tfull quality assurance system, 253, 254thigh-risk IVD procedure, 253finternal production control, 252, 254tIVD procedure, 251f

Index


IVDD Annex II list b procedure, 252fIVDD documentation, 247tfor IVDs, 216MDD conformity assessment documentation,

247tNotified Bodies in, 255procedures for, 246tproduct quality assurance, 253, 254tproduct risk class and, 245, 248, 251–252product verification, 253, 254tproduction quality assurance, 252–253, 254tquality system requirements, 253, 255self-testing IVD procedure, 251f

Cost and Economic Evaluation (ECO), 80cost-based pricing (CbP model), 63–64custom-made devices

Essential Requirements for, 171EU MDR and EU IVDR, 170–171medical device legal system, 165–171

DDanish Centre for HTA (DACEHTA), 78Danish Promotion Code, 106Decentralised Procedure (DCP)

applications to other Member States, 286ATC code and, 282biosimilar medicinal product registration, 397biotechnology-derived product marketing

authorisation, 413CMDh, 8, 10EU regulatory bodies for, 341flow chart for, 290tgeneric medicinal products, 381, 382human blood/plasma postmarket requirements,

525human blood/plasma product registration, 523Information and Work Sharing projects, 386initial MAA, 356fmarket access mechanism, 19, 279, 285, 287–

289medicinal product authorisation procedures,

287–289medicinal product registration, 344–345, 355–

356nonprescription medicinal products, 405pathways for nonprescription products, 406fpostauthorisation requirements for

pharmaceuticals, 424referrals, 293regulatory dossier assessment, 355–356regulatory information resources for, 554variation assessment and notifications, 431,

433–434

Declaration of Conformity (DoC)authorised representative signature, 187CE Mark for conformity, 155Essential Requirements for, 213under EU IVDR, 216for placing on the market, 170responsible person for regulatory compliance,

145See also conformity assessment

Declaration of Helsinki, 311, 390delegated act definition, 366Description and Technical Characteristic of

Technology (TEC) HTA model, 80Design Traceability Matrix, 231Development International Birth Date (DIBD), 333Development Safety Update Report (DSUR)

contents of, 334tEVCTM for submission, 335format for, 443, 444tICH guideline for, 313, 332–333ICH replacement for annual report, 312

Directive defined, 184, 366Directorate- General for Health and Consumers (DG

SANCO), 522Directorate-General for Health and Food Safety (DG

SANTE), 522, 560divergent decision referral, 293dossier. See regulatory dossierDraft Assessment Report (DAR), 355drug and biologic regulatory pathways

MAA, 32product development, 31–32

drug product process validation scheme, 351–352drug-device combination products (DDCs)

classification, 193–194Drug-Eluting Stent (DES) and medicinal substance,

234–235c

Eelectrical magnetic disturbance testing, 233electrical safety, 233Electrotechnical Commission (CENELEC), 225EMA meeting preparation, MAA review

CHMP meeting preparation timeline, 57fcore briefing materials for, 57–58early preparation for, 57face-to-face meetings, 54–56Q&A preparation, 58rehearsals for, 59rehearsals in Amsterdam, 59representation and feedback from, 55fScientific committee role in, 53scripting/developing core presentation, 58


Index

slide development and management, 58–59Standard Assessment Review Timeline, 55fsteps for preparation, 56–57understand committee members, 57written briefing document, 58

EMA meetingsadvice meetings, 43–44tcommunications for MAA, 41–52general preparation for, 47–48for MAA, 41–52MAA procedural steps and, 42–47during MAA review, 53–60MAA review, 53–60scientific advice review, 48steps required for, 45ttimelines for, 46tSee also specific meeting types

enforcementCE marking errors, 117Eudamed communications, 118medicinal product advertising and promotion,

119–120medicinal product GMP compliance, 119medicinal product pharmacovigilance, 119medicinal products recalls, 119notified bodies, 118Safeguard Clause, 117

Enpr-EMA, 101, 559tEssential Requirements (ER)

clinical investigation vs clinical evaluation, 238–239

compared to GSPRs, 230conformity assessment for, 187consensus standards definition by, 225custom-made devices, 171GHRF Essential Principles concept, 222–224harmonised technical standards for, 177intended purpose and, 167for IVD manufacturer processes, 211legal documents, 18legislative harmonisation and compliance, 155,

213–214manufacturer GSPR demonstration, 238safety and performance vs technical

documentation, 23–24Ethical Analysis (ETH) HTA model, 80–81Ethics Committees (ECs)

application for opinion on clinical trial, 320contents of application to, 321t

EU Clinical Trials Register (EUCTR), 319EU In Vitro Diagnostic Medical Devices Regulation

(EU IVDR), 138EU laws and regulations

basic legislation for, 14

Clinical Trials Regulation (536/2014), 39codification/clarification of pharmaceutical

directives, 19CTA, 38–39current regulation evolution, 17–19Directive 2001/83/EC, 165, 184Directive 200427/EC, 165economic issues, 16–17falsification and counterfeiting, 17General Data Protection Regulation (GDPR), 138information availability and transparency, 16IVDD, 26medical device regulation evolution, 23–24medical product regulation development, 14–15orphan medicinal products (OMPs), 38paediatric development programs, 38Paediatric Regulation, 121patient advocacy and involvement, 16pharmaceuticals regulation, 20PRIME, 36–37product innovation, 15–16scientific advice and protocol assistance, 37–38traditional herbal medicinal products, 23unsafe product consequences, 15

EU MDR and EU IVDRATMPs, 480–484authorised representative, 173authorised representative agreement contract

forms, 179classification and conformity assessment, 146clinical evidence, trials, and regulatory

compliance, 144–145clinical investigation devices, 171Commission recommendation, 174, 174tcustom-made devices, 170–171delegated and implementing acts, 148EC working groups, 165, 166–167tEssential Requirements vs GSPRs, 238governance structure, 147–148, 147f, 176fhealthcare establishments, 164human tissues, cells and derivatives, 484implementation of MAID goods package, 142–143implications of, 148–149importers and distributors, 164improved elements, 173–174industry representation/trade associations, 165,

167tinstitutional cooperation and consensus

building, 164–165interpretation of device law

Commission as an arbitrator, 177Commission guidance, 175–176courts, 174guidance from Member States, 177

Index


guidance from other sources, 177key directives, 165legal system evolution, 178manufacturer, 171–173manufacturers and authorised representatives,

164market access mechanism, 144MDD and EU MDR device definitions, 168tMEDDEV guidance documents, 172–173tmedical devices and active implantable medical

devices, 142, 165–170national enforcement, 177–178NBOG Best Practice Guide, 175tnotified bodies changes with, 144overview, 180own-brand labelling and reprocessing, 146–147postmarket surveillance and vigilance, 145–146product liability, 178–179proposed IVDR classification rules, 145fscope of device directives, 165significance of technical standards, 177stakeholders, 159supply chain controls, 142fsupply chain vigilance obligations, 179–180timeline for adopting/transitional regime, 148traceability, 143–144

EU MDR and EU IVDRISO 13485 in transition to, 255QMS requirements and ISO 13485, 252–253

EU Medical Devices Regulation (EU MDR), 480–481EU regulatory affairs

adaptive and alternative pathways, 295–300advertising and promotion, 103–114ATMP regulatory framework, 451–470biosimilar medicinal products, 393–402clinical evaluation and clinical investigations,

237–242combination products, 543–552drug and biologic regulatory pathways, 31–40EMA and other regulatory bodies, 1–12enforcement and competent authorities, 115–120Falsified Medicines Directive (FMD), 121–134food for special medical purposes, 511–518food supplements, 501–510generic medicinal products, 377–392Health Technology Assessment (HTA), 77–92history of regulations, 13–30human blood or plasma products, 519–528human tissue regulation, 471–488MAA for biotechnology derived products, 413–

422Marketing Authorisation Application (MAA)

review, 53–60Marketing Authorisation Application (MAA)

submissions, 41–52medical device compliance/postmarket

requirements, 257–269medical device conformity assessment

procedure, 243–256medical device legislation and classification,

183–206medical device national particularities, 271–276medical device preclinical testing, 229–236medical devices legal system, 151–182medicinal product authorisation procedures,

277–294medicinal product clinical trials, 309–339medicinal product registration procedures,

341–362new MDR and IVDD regulation, 141–150nonprescription medicinal products, 403–412orphan medicinal products (OMPs), 529–542Paediatric Regulation, 93–102pharmaceutical postauthorisation requirements/

compliance, 423–436pharmaceutical quality systems and inspectorate

process, 363–376pharmacovigilance, 437–450preclinical testing and GLP, 301–308pricing and reimbursement, 61–76regulatory information resources, 553–573regulatory strategy, 135–140safety and performance requirements/technical

documentation, 221–228vaccines, 489–500in vitro diagnostic devices (IVDDs), 207–220

EU Tissue and Cell Directives (EUTCD), 471–473. See also specific tissue and cell products

EU Treaty, 14Eudamed

competent authority communications, 118market surveillance and vigilance, 267–268

Eudra Vigilance databases, 318, 566EudraCT paediatric clinical trial records, 319EudraGMDP inspection information in, 369EudraVigilance Clinical Trial Module (EVCTM), 332,

335EudraVigilance medicinal product dictionary

(xEVMPD), 440EudraVigilance Postauthorisation Module (EVPM),

493Eurasian Economic Union Member States, 374European Association of Tissue Banks (EATB), 473European Blood and Marrow Transplantation Group

(EBMT), 473European Clinical Trial Database (EudraCT)

clinical trial databases, 38, 100SUSAR reporting, 318


Index

European Clinical Trial Regulation (ECTR)adverse reactions in, 313application to IMPS, 315–317electronic reporting, 319EU Clinical Trials Register (EUCTR), 317–318EU Portal, 317EU portal and database, and associated legacy

systems, 311EU Telematics Strategy and Implementation

Roadmap, 317EudraVigilance Clinical Trial Module (EVCTM),

317–318evaluation for duplication, 318implementation guidance documents, 312–313Member States national laws and, 311significant changes from Clinical Trials Directive,

314–315tEuropean Commission (EC)

demonstration of GSPRs, 225initiatives and models for pricing, 63–64Notice to Applicants (NTA) for medicinal products,

278–279regulatory authorities, pharmaceutical quality,

365Task Force for Relations with the United Kingdom

(UKTF), 364, 366European community referral, 292European Directory for the Quality of Medicines

(EDQM)API assessment by, 380CEP issued by, 280

European Economic Area (EEA)CE marking requirements, 272

European Eye Banking Association (EEBA), 473European Federation of Pharmaceutical Industries

and Associations (EFPIACE marking requirements, 272codes of conduct, 104–105falsified medicines legislation, 123tproduct distribution, 106–107, 111regulatory information from, 564

European Food Safety Authority (EFSA)food supplement assessment by, 504–505foods for special medical purposes, 513–514scientific advice, 560

European Generics Medicines Association (EGA), 379

European Initiative for Paediatric Formulations (EuPFI), 100

European Medicines Agency (EMA)accelerated access initiatives, 295–300early access initiatives, 88–89EUnetHTA collaboration, 88–89, 88ffalsified medicine defined, 121

HTA parallel consultation, 88marketing recommendation for medicinal

products, 278–279regulatory authorities, pharmaceutical quality,

365European Medicines Verification Organisation

(EMVO), 131European Medicines Verification System (EMVS), 131European Network for HTA (EUnetHTA)

EMA collaboration, 88–89HTA assessments, 78–88MAA evaluation, 50, 65–67

European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP), 445–446

European Pharmacopoeia (Ph. Eur.), 373European Public Assessment Report (EPAR), 283,

398–399European Society of Human Reproduction and

Embryology (ESHRE), 473European Standardization Committee (CEN), 225European Transplant Coordinators Organisation,

473European Union (EU)

medical product regulatory bodies, 341–342pricing and reimbursement, 61–76

European Union Reference Dates (EURD)active substances, 388PSURs and PSUSAs scheduling, 360, 445

exceptional circumstancesmedicinal product registration, 346–347for orphan designation products, 538–539

expedited evaluation programsATMPs, 453tdecision tree for pathways, 454fSee also Adaptive Pathways; alternative

pathways; PRIME (PRIority MEdicines)External Reference Pricing (ERP)), 63, 64f. See also

pricing and reimbursement

Ffacility requirements

medicinal requirements, 305Falsified Medicines Directive (FMD), 121–134

active substance GMP, 128active substances and excipient definitions, 128tcombination therapies, 132companion diagnostics, 132defining, 122detection and management goals of, 132EMVS in, 131–132examples of SFFC medicines, 126falsified active substances in routes in supply

Index


chain, 125fharmonisation of regulation, 124implementation of, 124–125implementation process for, 128–129implications and challenges of, 129–131initiatives relevant to, 129tkey term definitions, 124tonline logo requirements, 128fproblem scope, 122stakeholder requirements, 124stakeholder requirements under FMD, 127tthird countries requirements under, 125, 128,

129tunique product identifiers and information flow,

131fField Safety Corrective Action (FSCA), 258Field Safety Notices (FSNs), 265first-in-human (FIH) trials guidance documents, 322fixed-combination application, 292follow-up referral, 292Food and Drug Administration (FDA)

collaboration on paediatric products, 100PSA for MAA/EMA meetings, 49

Food for Special Medical Purpose (FSMP) Regulation, 512–513

food for special medical purposes (FSMPs)communications and claims for, 516competent authority notification of marketing,

516compositional requirements for, 514–515definition of, 513food information and nutrition information,

515–516FSMP critical concepts, 513–514history of use, 511–512legal framework for regulation, 512–514reimbursement, 516single-use plastics directive for, 516

food supplements, 501–510competent authority notification of marketing,

504for food supplements, 505–507harmonisation of, 507health claims for, 505labelling (information to consumers), 503–504legal framework for regulation, 505–507, 512–513quality requirements, 503regulatory summary, 507–508safety assessment of ingredients, 504scope and definitions for regulation, 502–503vitamin/mineral content for safety, 504

Food Supplements Directive (FSD), 502–504foods for special medical purposes (FSMPs),

511–518

general principles of regulation, 512for specific groups, 512

Foods for Specific Groups (FSG) Regulation, 512–513, 516

Franceadvertising preapproval, 111HTA in, 82t, 83tHTA process in, 85fpricing/reimbursement procedures, 68–69pricing/reimbursement-HTA assessment

competent authorities, 68Universal Health Coverage Act (CMU), 67

Ggene therapy medicinal products (GTMPs)

clinical development, 466decision tree for classification, 459fintended use and manipulation criteria, 461manufacturing process, 461–463preclinical development, 464–465

General Electrical Safety Standard, 233General Product Safety Directive (GPSD), 259general safety and performance requirements

(GSPRs)applicable standards identification, 226checklist for, 223–224tdevice registration requirements, 216historical foundations for, 221–222IVDD revision by EU IVDR, 216–217manufacturer GSPR demonstration, 187, 238predicate device requirement, 227referencing applicable standards, 227regulatory status of European standards, 225requirements for, 222, 223standards and common specifications use for,

225technical documentation, 226–227terminology change, 238

generic medicinal products, 377–392advertising and promotion, 389biosimilar applications, 383biosimilar medicines, 380comparison with innovator medicines and

reference products, 377–378compendial monographs for, 380dossier requirements for, 383–386electronic submission of information for, 390GCP for, 390GDP for, 389, 390GLP for, 390GMP for, 389–390Good Pharmacovigilance Practices for, 386–387,

390


Index

GPMs for, 379–380international regulations for, 386labelling and package leaflet, 388–389legal basis for generic application for MA,

381–383, 381tmanufacture and importation for, 388postauthorisation surveillance of, 380PSURs for, 387–388RMP for, 387supervision and sanctions for, 390–391WHO definition of, 377wholesale distribution of, 389

generic/Abridged application, 289–290genetically modified organisms (GMO)

GTMPs, 463vector use in, 497–498

genotoxicity studies, 303Germany

competent authorities for pricing//reimbursement and HTA, 69

Gesetzliche Krankenversicherung (GKV), 69HTA in, 82t, 83tHTA process in, 86fmedicinal product pricing under AMNOG, 70fpricing/reimbursement procedures, 69–71Safeguard Clause action (catgut), 267

Global Harmonization Task Force (GHTF)Essential Principles concept, 222guidance document from, 240IMDRF succession to, 266IVD risk classification of IVDs, 212–213risk-based device classification, 206STED developed by, 226See also International Medical Device Regulators

ForumGood Clinical Practice (GCP)

biological product guidance, 490biosimilar clinical comparability demonstration

for, 396–397biotechnology-derived products, 416clinical investigation of devices, 240–241in drug life cycle, 364for generic medicinal products, 390legal framework and, 370–371

Good Distribution Practice (GDP)in drug life cycle, 364for generic medicinal products, 389, 390inspections for, 371

Good Laboratory Practice (GLP)ancillary quality system components, 306for biosimilar medicinal products, 396biotechnology-derived products, 416definition, 301in drug life cycle, 364

facility requirements, 305for generic medicinal products, 390inspections and compliance, 307medicinal product requirements, 302pharmacokinetic studies in vitro, 302–303pharmacology safety studies, 302preclinical studies required by, 302–303products covered, 304purpose and relevance guidance, 306–307Quality Assurance programme, 305regulations and guidelines for

toxicity studies, 302reporting study results

content of study plan, 306revisions for harmonisation, 307–308SOPs for test facility, 306study performance

study plan and content, 306test and reference items

characterization, 305–306receipt, handling, sampling and storage, 305

test facility organisationmanagement, 304principal investigator, 305study director, 304–305

test systems, 305in vivo feasibility and dose testing under, 303

Good Manufacturing Practice (GMP)biotechnology-derived products, 416certificate, 119, 369, 390–391in drug life cycle, 364foods for special medical purposes, 512for generic medicinal products, 389–390for herbal medicines, 410MAH compliance, 119

Good Pharmacovigilance Practices (GVPs)for biosimilar medicinal products, 400–401in drug life cycle, 364for generic medicinal products, 390GVP overview and modules, 439–449, 439tMA maintenance, 360Module I: PV systems and quality systems,

439–440Module II: PV system master file, 440Module III: PV inspections, 440–442Module IV: PV audits, 442–443Module IX: signal management, 446–447Module V: risk management systems (RMS), 443Module VI: adverse reaction management/

reporting, 443Module VII: PSURs, 443–445Module VIII: post authorisation safety studies,

445–446Module X: additional monitoring, 447–448

Index


Module XV: safety communications, 448Module XVI: risk minimisation measures, 448–

449nonprescription medicinal products, 409

Guidance documentsEuropean Commission Consensus Statements,

174tEuropean Commission documents, 174t, 175–176MDCG, 185MEDDEV Commission guidance, 172–173tNBOG Best Practice Guide, 175tTEAM-NB, 177

Hharmonisation

EURD in, 388of food supplements, 507GLP regulations, 307–308GSPR compliance demonstration, 225–226medical device regulation, 24–25of SmPC, 342, 345standards for IVDs, 213–216

Heads of Medicines Agencies (HMA), 311Health Claims (HCs)

food supplements, 505–506, 507foods for special medical purposes, 513, 516

health monitoring measuresactions against general threats to public health,

117comparison with Safeguard Clause, 267–268,

267tHealth Problem and Current use of Technology (CUR)

HTA model, 80Health Technology Assessment (HTA), 77–92

comparison in EU countries, 81–84, 83tdecision timeline, 87t, 88fEMA and EUnetHTA collaboration, 88harmonisation, 84–88HTA in Member States, 82tlegal framework, 77–78models used for: CUR, 80models used for: ECO, 80models used for: EFF, 80models used for: ETH, 80–81models used for: LEG, 81models used for: ORG, 81models used for: SAF, 80models used for: SOC, 81models used for: TEC, 80organisation and structure in EU, 81–84parallel advice for MAA, 49–51pricing and reimbursement, 65–66role in decision making, 84

role in product market, 78–80heated sleep apnea device, 234cherbal medicinal product MAA, 292human blood or plasma products, 519–528

batch-release requirements, 525CHMP working groups, 522Council of Europe publications on, 523DG SANTE, 522donation testing for, 523–524guidelines and documents for, 523–524legal framework, 522–523marketing authorisation dossier for, 524–525plasma master file, 525plasma-derived medicinal products, 520–521,

521tpostmarketing pharmacovigilance for, 525registration procedures for, 523Single European Code structure, 476ttransition to new regulations, 525–526TSE safety evaluation, 524virus safety evaluation, 524

Human Organ Transplantation Directive, 485human tissue products, 471–487

ATMP classification, 477classification of, 477–478contiguous legislation, 484–485distribution and import, 476donation of, 474donor selection and testing, 474–475, 475tEUTCD requirements, 473–474legislation on, 473–474licensing and inspections, 478MA authorisation for, 480MA procedure for, 480as medical device, 483pharmacovigilance (PV), 477–478processing and storage, 475–476procurement, 474quality system for establishment and responsible

person, 478–479regulation, 473, 480–484regulatory framework for, 484tresponsible person qualifications/

responsibilities, 479ttissue establishments and banks, 478traceability, 476–477

hybrid applications, 291

IIdentification of Medicinal Products (IDMP), 359immunogenicity data

advanced therapy medicinal products, 465biosimilar medicinal product development, 395


Index

biotechnology-derived products, 417–419comparability exercise for biosimilars, 396–397,

398pre-licensing product testing, 349vaccines, 494, 496

immunotoxicity studies, 303Impact on Clinical Research of European Legislation

(ICREL), 310Importing Directive, 485In Vitro Diagnostic Medical Devices Regulation (EU

IVDR), 141–149, 189–200in vitro diagnostic (IVD) medical device, 207–220

accessories, 210classification disputes, 203classification process, 201–203companion diagnostic (CoDx), 211–212device performance testing, 210essential requirements for, 213EU laws and regulations, 26in-house developed, 211IVD use, 209IVDD and IVDR classification rules, 204–205IVDD and IVDR scope, 208–209IVDD revision, 216–217laboratory use products and IVD devices, 210tmanufacturer process, 211medical device legislation and classification,

208–209pan-European requirements, 207regulations for safety, 217research-only, 210–211risk-based classification lists for, 212–213specimen receptacles, 209–210specimens examined, 209

In Vitro Diagnostic Medical Devices Directive (IVDD), 184–185

In Vitro Diagnostic Medical Devices Regulation (EU IVDR), 189, 544

influenza vaccines, 494–496, 495fInformation and Work Sharing projects, 386informed consent applications, 292in-house produced devices, 147innovator medicines (originator products), 378–379inspection process

in drug approval process, 367fEudraGMDP database entries, 369GLP regulations, 307pharmaceuticals, 366–369tissue establishment inspections, 478

installation qualification (IQ), 306Instructions for Use (IFU)

contents for IVDs, 215device evaluation and, 238

international birth date (IBD), 333

International Coalition of Medicines Regulatory Authorities (ICMRA), 374–375

International Conference on Harmonisation (ICH)coordination and cooperation enhancement, 117Development Safety Update Report, 312guidelines for biotechnology-derived products,

416–417harmonisation of preclinical testing, 302pharmaceutical quality systems, 365PSUR format revision and scheduling, 445

International Electrotechnical Commission (IEC)medical device standards, 230–231, 233–234standard use in EU, 164, 177

International Federation of Pharmaceutical Manufacturers Association (IFPMA)

code of ethics, 103, 105, 107promotional material approval, 111

International Generic Drug Regulators Pilot (IGDRP), 386

International Medical Device Regulators Forum (IMDRF)

consensus standards, 225–226coordination and cooperation enhancement, 117GHTF basis for, 266inspection guidelines, 374medical device global vigilance, 266

International Medical Products Anti-Counterfeiting Taskforce (IMPACT), 122, 123t

International Organization for Standardization (ISO)consensus standards definition by, 225standard harmonisation, 164, 561use in preclinical testing, 230See also specific standards

International Society of Pharmacoepidemiology (ISPE), 374, 445

invasive devices: classification rules for (MDR), 190tInvestigational Medicinal Product Dossier (IMPD)

biological product guidance, 490content requirements for, 490submission, 330–331

investigational medicinal products (IMPs), 317Clinical Trials Directive definition of, 315clinical trials for, 310CTD information in dossier, 330documentation requirements for, 490DSURs for, 332for FIH trials, 322GMP requirements for, 331manufacturing requirements for, 498risk-benefit amendment notification, 322SUSARs/DSURs for, 332

ISO 13485gap assessment for EU MDR and EU IVDR

transition, 255, 258

Index


harmonised quality system model, 214–215, 226production quality assurance model, 252–253QMS requirements, 215review of feedback, 259, 266, 268

ISO 14971FSCA warning methods, 265harmonised standards for risk management, 214postmarket surveillance and vigilance, 258risk management requirements, 226, 266, 268

Italian Farmaindustria Code, 106Italy

advertising preapproval, 111competent authorities for pricing//

reimbursement and HTA, 72HTA in, 82tpricing/reimbursement procedures, 72–73Servizio Sanitario Nazionale (SSN), 72

JJoint Action on Market Surveillance (JAMS), 3, 116Joint Immediate Action Plan, 118

Llabelling requirements

combination products, 551food for special medical purposes (FSMPs),

515–516for food for special medical purposes (FSMPs),

516food supplements, 503–504language for IVDs, 215–216

Legal Aspects (LEG) HTA model, 81legal framework/legislation

for adaptive and alternative pathways, 296–298Advanced Therapy Medicinal Products (ATMPs),

451–470, 480ATMP Regulation, 453–456clinical trial improvements, 312fclinical trials, 311Directive defined, 184for food supplements, 505–507foods for special medical purposes and special

groups, 512–514herbal medicinal products, 409–410human blood or plasma products, 522–523human tissue products, 473–474MAA, 32–34mechanism for medicinal products for human

use, 18–19medical devices, 141–149, 150–182, 183–206medical product, 18Opinion, 184orphan medicinal products, 530

pharmacovigilance (PV), 438–439product legislation, 17–18Recommendation, 184Regulation defined, 184

lifecycle of drugsregulations in, 364fresearch and development (R&D), 22–23

local tolerance studies, 303

MMarket Surveillance Operations Group (MSOG), 267Marketing Authorisation Application (MAA)

accelerated assessment for, 35approval types, 34, 36tfor biosimilar medicinal products, 397–398for biotechnology derived products, 292clarification and discussion meetings, 54–55communications to EMA, 41–52dossier quality section, 280EMA meetings during review, 53–60EU format and content of, 280human-veterinary variations, 20–21legal basis and dossier requirements, 32–34legal basis for generic application for MA,

381–383medicinal product application types, 289–292,

290t, 291–292for medicinal products, 279–284PIP requirements, 94–95, 98–100prior EMA meetings for, 41–52procedural steps and EMA meetings, 42–47procedure timelines for, 55f, 57fprocedures for, 34–35scientific advice and protocol assistance, 37–38Scientific Advice review, 54Scientific committee role in review, 53, 54t

Marketing Authorisation Holder (MAH)advertising to general public, 108advertising to healthcare professionals, 105definition of, 279EMVO, 119GMP compliance, 119MA maintenance, 359obligations for medicinal products, 282, 284,

289paediatric products, 99–100PIP preparation, 94–95product failure responsibility and liability, 342renewal date agreement with Reference Member

State, 424responsibilities and obligations for medicinal

products, 279–280role in various application types, 292


Index

scientific service implementation, 111submission of information for generic products,

390worksharing, 359

Marketing Authorisation (MA)adaptive and alternative pathways, 295–300food supplements, 504for generic medicinal products, 391human tissue products, 480regulatory strategy for, 138See also Centralised Procedure; Mutual

Recognition Procedure; National Proceduremaximum tolerated dose (MTD), 302MEDDEV guidance documents

authorised representatives, 143clinical evidence, trials, and regulatory

compliance, 144, 146revisions and updates, 118

Medical Device Coordination Group (MDCG)borderline combination products, 545centralised governance, 159, 165classification disputes, 203–205CTS adoption by implementing act, 214decisions on product qualification, 142device classification determination, 142enforcement and surveillance, 146–148, 159, 178regulatory classification determination, 545,

548–549, 551regulatory strategy development, 138regulatory strategy information, 138responsibilities of, 176–177revised guidance from, 230

Medical Devices Directiverepeal of, 184–185transition from, 178 (see also EU MDR and EU

IVDR)medical device legal system

adaptive and alternative pathways, 298clinical evaluation cycles, 159fCommission as an arbitrator, 177compliance verification, 155conformity assessment for AIMDs, 157fconformity assessment for IVD, 158fconformity assessment procedures, 156fcustom-made devices, 165–171development, 25–26EC working groups and activities, 166–167tEMA in, 164enforcement, 117enforcement and competent authorities, 117–118Essential Requirements and technical standards,

177essential requirements compliance, 155–159industrial trade associations, 167t

legislative process, 150 –152, 153fmanufacturer role in, 171market surveillance, 117–118MDD and EU MDR device definitions, 168tMEDDEV guidance documents, 171–172tmedical device laws, 165–170national enforcement, 177–178new approach regulatory philosophy, 153–154,

154tnew legislative framework (NLF), 157regulation evolution and harmonisation, 23–25See also EU MDR and EU IVDR; specific devices

medical device legislation and classification, 183–206

basic principles of application, 189–190classification disputes, 203classification matrix, 188tcomparison of EU MDR and MDD rules, 195–200tEU MDR and MDD rules, 200–201human tissue/cell products with, 483IVD classification process, 201–203, 202tIVDD and IVDR rule comparison, 204–205tkey concepts for classification, 191, 193MDR rules for invasive devices, 190tMDR rules: special, 192tmedical devices directives, 184–185medical devices definition and expansion of,

185–186non-invasive devices rules, 189tregulatory framework definitions, 184requirements, 186–187rule-based approach for, 187–189transition to EU MDR and EU IVDR, 185unclassified devices, 188in vitro diagnostic regulation, 189

medical device national particularitiesCE marking for, 271directives and regulations for, 272tEU outermost regions, 272tlanguage and labeling, 272–274national languages, 274tnotification requirements, 274–275translation requirements, 273tSee also pricing and reimbursement

Medical Device Vigilance System, 258, 261Medical Devices Coordination Group (MDCG), 159Medical Devices Regulation (EU MDR), 141–149Medicinal Product Directive (MPD), 18, 32, 506medicinal products for human use

adaptive and alternative pathways, 296–298bibliographic applications/well-established use,

291–292clinical trials for, 309–340Complete/Full and Independent, 289

Index


decentralised procedures, 290tenforcement, 119–120enforcement and competent authorities, 118–120factors affecting pricing, 62ffixed-combination application, 292generic/Abridged, 289–290herbal medicinal products, 292hybrid applications, 291informed consent applications, 292legislation in EU, 18–19Marketing Authorisation Application, 289–292mixed marketing, 292

medicinal products MAA applicationsbibliographic applications/well-established use,

291–292Complete/Full and Independent, 289decentralised procedures, 290tfixed-combination application, 292generic/Abridged, 289–290herbal medicinal products, 292hybrid applications, 291informed consent applications, 292mixed marketing, 292

Medicines and Healthcare products Regulatory Agency (MHRA)

joint inspection programs, 372–373Medicines for Europe, 379Member States

clinical trial authorisation procedures in, 324clinical trial safety procedures, 323competent authorities and affiliated countries,

161–163tcompetent authorities marketing guidelines,

278–279enforcement by competent authorities, 115–120EU MDR and ER IVDR significance for, 159–164GLP regulations in, 302interim device actions under Safeguard Clause,

267Marketing Authorisation Application in, 19See also Concerned Member States; national

competent authoritiesmixed marketing, 292Mutual Acceptance of Data (MAD) system, 302, 370Mutual Recognition Agreements (MRAs)

for generic product GMP inspections, 379–380for inspections, 371

Mutual Recognition Facilitation Group (MRFG), 286Mutual Recognition Procedure (MRP)

application format for, 281authorisation of medicinal products, 285–287biosimilar medicinal product registration, 381biotechnology-derived product marketing

authorisation, 413

comparison of pathways for nonprescription products, 406f

criteria for use of, 19, 285evaluation of products, 14flowchart for, 287ffor generic products, 381human blood/plasma postmarket

pharmacovigilance, 525MAA procedure with, 357fmedicinal product registration, 341for medicinal products, 287tmultiplication/duplication of applications, 289nonprescription products, 405phases and timeline for medicinal products,

285–287postauthorisation requirements for

biotechnology products, 424–425product registration, 356–357Reference Member State selection, 287–288registration for human blood/plasma products,

523registration for medicinal products, 289, 345,

356regulatory dossier assessment, 356–357regulatory information resources for, 554submissions and Reference Member State role

and timeline, 286–287Mutual Recognition Regulation, 502–503, 506mutual recognition/decentralised procedure

referral, 293

Nnational authorizations, medicinal products, 289national competent authorities, 115–120

action on medical device safety, 117–118application for clinical trial authorisation,

320–323clinical trial application, 321tcooperation and coordination for enforcement,

116–117coordination and cooperation enhancement, 117generic medicinal product safety, 390–391inspection process, 366listing of, 562–563tmedical devices, 117member states and affiliated countries, 161–163tnational regulatory bodies, 116pharmaceutical quality and inspections, 365–369pricing and reimbursement and HTA, 366tissue establishment inspections, 478

National Medicines Regulatory Authorities (NMRA), 130

National Medicines Verification Organisations


Index

(NMVOs), 132National Procedure

biosimilar medicinal product registration, 397comparison of pathways for nonprescription

products, 406fgeneric medicinal products, 381human blood/plasma products, 523MAA procedure with, 357fmarketing authorisation for medicinal products,

19medical product registration, 345–346medicinal product registration, 357nonprescription medicinal products, 405product registration, 345–346, 356–357regulatory dossier assessment, 357variability of, 285

new chemical entity (NCE): preclinical test plan, 302new legislative framework (NLF) for devices, 157nonclinical pharmacodynamics, 235cnonclinical studies. See Good Laboratory Practice;

preclinical testingnon-invasive devices: classification rules for (MDR),

189tnoninvestigational medicinal products (NIMPs)

defined, 315SUSARs for, 332

nonprescription medicinal products, 403–412advertising and promotion, 408–409advertising to general public, 409common uses of, 405tdefinition of, 404herbal medicinal products, 409–410legal basis of MAA, 405legislation of, 404marketing access pathways for, 404–405, 406tpharmacovigilance and safety reporting, 409product information and labelling, 405–407reclassification from prescription to, 407–408role in self-care, 404successful switch strategy for, 408warning statements and guidance for, 407

Notified Bodies: responsibilities of, 118Notified Body Operations Group (NBOG)

best practices guides, 175tguidance document from, 175, 185–186

Novel Foods Regulation, 504Nutrition and Health Claims Regulation (NHCR)

(Regulation (EC) No. 1924/2006), 505Nutrition Claims (NCs), 505

Ooffice based evaluation and risk assessment

(OBERA), 371

Official Control Authority Batch Release (OCABR)batch-release requirements, 493EDQM procedures for, 522plasma products, 525

Official Medicines Control Laboratories (OMCL)blood/plasma product testing, 522postmarketing lot release, 493vaccine testing by, 490

operational qualification (OQ), 306Opinion, defined, 184Oral Explanation (OE) meeting

purpose of, 55Organisation for Economic Co-operation and

Development (OECD)EMA collaboration, 10GLP guidelines, 327, 375, 390harmonisation of preclinical testing, 302–304mutual acceptance of data system, 370

Organisational Aspects (ORG) HTA model, 81Orphan Drug Act, 529Orphan Medicinal Products (OMP) Regulation

COMP established by, 531–532product designation procedure, 535significant benefit concept in, 536–537similar medicinal product and clinical superiority

in, 537orphan medicinal products (OMPs), 529–542

annual report requirement, 534application evaluation and timetable for, 533conditional marketing authorisation for, 538designation expiry, 535designation procedure application, 532–533designation request content, 535–536EU laws and regulations, 38European Commission decision, 533–534harmonisation efforts, 530incentives for development, 530–531legal framework, 530MAA for designation product, 536–537, 538medical plausibility for request and prevalence,

536orphan designation benefits, 342orphan designation benefits and criteria, 8, 38,

530, 534fparallel applications, 533pathways for expedited development and

approval, 538significant benefit concept in, 536–537similar medicinal product and clinical superiority

in, 537sponsorship transfer, 535

over-the-counter (OTC) medicines. See nonprescription medicinal products

advertising to general public, 108

Index


Own-Brand Labelling (OBL), 146–147

PPaediatric Committee (PDCO), 95, 343Paediatric Investigation Plan (PIP)

Marketing Authorisation Holder, 94–95submission procedures in, 97–99, 98f

paediatric product regulationapplication procedure, 97–99background and scope, 93–94compliance check, 99deferrals, 96–97Marketing Authorisation Holder, 99–100PDCO, 95PIPs, 94–95population and product definitions, 94product development under, 100–101research incentives, 99waivers, 95–96

Paediatric Regulation, 93–94Paediatric Use Marketing Authorisation (PUMA), 94Parallel Scientific Advice (PSA), 49particular nutritional uses (PARNUTs), 512Patients and Social Aspects (SOC) HTA model, 81performance qualification (PQ), 306Periodic Benefit-Risk Evaluation Report (PBRER)

EU format for, 445format for, 443, 444tICH guideline for, 445

Periodic Safety Update Report (PSUR)benefit-risk balance, 387–388, 401, 425–426,

449for biosimilar medicinal products, 401device technical documentation, 227frequency of, 416MAH submission of, 443PMCF in, 261postmarketing safety assessment, 425, 428, 429PSUR format revision and scheduling, 445renewal procedures and, 436requirements for, 440RMP update, 447sharing through Eudamed, 118submission and review process for, 360submission of, 443–445submission to EMA, 353synchronization with other reports, 333, 426, 445for technical documentation, 227validated signals in, 447

Periodic Safety Update Single Assessment (PSUSA)submission to EMA, 353

pharmaceutical directivesATMPs, 21–22

codification/clarification, 19development of regulatory system, 20human-veterinary MAA variations, 20

Pharmaceutical Inspection Convention (PIC), 117, 373

Pharmaceutical Inspection Co-operation Scheme (PIC/S)

for generic products, 379–380participants in (list), 373–375

pharmacodynamic (PD) testing: biosimilars, 395pharmacokinetic (PK) testing

for biosimilar medicinal products, 395with combination product, 235c

pharmacovigilance (PV)EC definition and development of, 438fees, 449GVP overview and modules, 439thuman tissue products, 477–478ICSR expedited submission requirements, 445flegal framework, 438–439notification of withdrawn products, 449risk management plan modules, 444tsignal management lifecycle, 447fsystem master file (PSMF) contents, 441fvaccines, 493

Pharmacovigilance Regulation, 493Pharmacovigilance Risk Assessment Committee

(PRAC)communications, 56coordination and cooperation enhancement, 117MA maintenance, 360MAA review, 53–54, 54t

photo-safety testing, 303Plasma Master File (PMF), 280plasma master file (PMF), 280, 525Post Market Clinical Follow-up (PMCF), 238postauthorisation requirements (pharmaceutical)

annual re-assessmentassessment procedures, 431dossier requirements for, 430–431

for biotechnology-derived products, 424–425centrally approved product renewal

assessment procedure, 429–430dossier requirements for, 426

legal framework for, 421, 424–425major changes/extension application, 435MRP/DCP product renewal, 424–425

assessment procedures, 426dossier requirements for, 425

other postauthorisation measures and enforcement, 431

re-examination, 430vaccines, 492–493variations


Index

assessment/notifications for, 433–435dossier requirements for, 431–433

postauthorisation safety studies (PASS), 324for biosimilar medicinal products, 401

postmarket clinical follow-up (PMCF)Class III and implantable devices, 238–239,

260–261for clinical efficacy evaluation, 298manufacturer’s obligations for, 157use in clinical strategy, 240

postmarket surveillance (PMS), 260device technical documentation, 227for generic medicinal products, 380manufacturer, 117–118

postmarket surveillance requirementscombination products, 551

Potential Serious Risk for Public Health (PSRPH)application withdrawal in DCP, 345

preclinical testingGLP regulations in, 301OECD GLP principles, 303–304See also Good Laboratory Practice; medical

device preclinical testingpreclinical testing of devices

biocompatibility testing, 231, 234c, 235cDesign Traceability Matrix for, 231electrical safety and magnetic disturbance

testing, 233nonclinical studies, 231, 235packaging validation, 232performance testing, 231preclinical test plan

regulatory requirements, 230standards requirements, 230user requirements, 230

risk management requirements, 230shelf life (aging) studies, 233software verification and validation, 233statistical methods, 234sterilisation validation, 232–233transport studies, 232usability (human factors) studies, 233

predicate deviceGSPRs requirements, 227

preliminary assessment report (PrAR)Reference Member State (RMS) authoring of,

355–356Prescription Medicines Code of Practice Authority

(PMCPA), 111pricing and reimbursement, 61–76

containment policies of Member States, 67fcurrent trends, 67economic evaluations, 66, 66ffactors affecting pricing for medicinal products,

61–62food for special medical purposes (FSMPs), 516legal framework, 62–63link between models and HTA, 67–74models and HTA case studies, 67–74models for, 64

cost-based pricing, 63–64reference-based, 63, 65tvalue-based pricing, 64

pricing factors for, 62freference pricing system for generic products,

377–378reimbursement, 65–67vaccines, 498

primary mode of action (PMOA), combination products, 544–545

PRIME (PRIority MEdicines)HTA/EMA collaboration for, 89laws and regulations, 36–37

promotion. See advertising and promotion

QQualified Person (QP/QPPV)

generic medicinal products, 389GMP certification, 331for human tissues/ATMPs, 479tpharmacovigilance (PV), 439pharmacovigilance for medicinal products, 280postmarket pharmaceutical compliance, 426–427PSMF and, 387in recall decisions, 119signal management, 446tissue establishment, 479vaccine development, 490vaccine release, 490See also responsible person (RP)

Quality Assurance (QA) programmeGLP requirements, 305

Quality Management System (QMS)assessors and inspector relationship in, 364–

365, 365ffor clinical evaluation procedures, 240in clinical investigation and evaluations, 240in clinical trial protocol, 330for combination products, 550–551in conformity assessment, 248conformity assessment in, 136EU IVDR requirements, 215human tissue products regulation, 473ICH QMS requirements, 365pharmacovigilance factors for, 440PMS requirements, 118postmarket surveillance in, 117–118, 259

Index


regulatory strategy for, 138technical documentation for, 226

quality review of documents (QRD)labelling templates, 407, 415medicinal product authorisation procedures, 281,

351, 358SmPC information requirements, 388, 448templates in Centralised Procedure, 415

quality systems and inspectorate processassessors and inspector relationship in, 365fBritish Pharmacopoeia (BP), 373EDQM inspection process, 369Eurasian Economic Union, 374European Pharmacopoeia (Ph. Eur.), 373GCP inspections, 370–371GDP inspections, 371for generic medicinal products, 390GLP inspections, 370GMP inspections, 367–369GMP/GDP Inspectors Working Group, 370ICMRA, 374industry associations, 374for IVDs, 214–215joint inspection program participants, 372–373legal framework for, 366, 366flist of other agency inspections, 371MRAs for inspections, 371OECD, 375pharmaceutical regulation evolution, 363–364pharmacopeial compendia, 373PIC/S, 373requirements for EU, 365Swiss Pharmacopoeia (Ph. Helv.), 373

Quality-Adjusted Life Years (QUALYs)in HTA assessment, 84in pricing and reimbursement, 66

Rreference medicine, 377

pharmacopoeial compendia for API, 380Reference Member State (RMS)

business validation and checklist for, 354DCP role of, 355–356Decentralised Procedure applications role and

timeline, 287–288decentralised procedure role, 344follow-up referral, 292initial product assessment, 342MAA evaluation, 19MAA presubmission meetings, 347mutual recognition and decentralised procedure

referrals, 293

Mutual Recognition Procedure (MRP), 345, 356–357

Mutual Recognition Procedure phase 2 timeline, 286

Mutual Recognition Procedure role, 286PrAP from, 355renewal date agreement with MAH, 424selection for MAA, 285selection of, 336worksharing for MA maintenance, 359

reference-based pricing model, 63, 65treferrals

community interest referral, 293divergent decision referral, 293European community referral, 292follow-up referral, 292generic medicinal product evaluation, 381mutual recognition/decentralised procedure

referral, 293registration of medicinal products, 341–362

accelerated assessment, 347adaptive pathway, 346ASMF for, 350bibliographic applications/well-established use,

349of biosimilar medicinal products, 397–399biosimilar medicinal products, 397–399for biotechnology-derived product, 414–415for biotechnology-derived products, 414–415Certificate(s) of Suitability, 352combination products, 544conditional approval, 346conditional authorisation, 346content of submissions, 351, 351teCTD envelope and CTD format, 351–352exceptional circumstances, 346–347fixed combination, 349full registration, 348generic products, 391generic registration, 348for human blood or plasma products, 523hybrid registration, 348informed consent, 349MA maintenance, 359–360MAA application types, 347–350MAH liability and, 342materials of human/animal origin, 352mixed marketing, 350orphan medicinal products, 342–343other documentation, 358–359paediatric investigations, 343–344presubmission meeting request, 347procedure types, 344–345PSURs and PSUSAs, 360


Index

questions on dossier, 358referrals, 360regulatory dossier changes/variations, 359regulatory dossier submission, 352–353regulatory dossier validation, 353–354routes for, 523scientific advice, 343scientific advice application, 350–351similar biological registration, 348–349urgent safety restrictions, 360

Regulation defined, 184, 366regulatory authorities

Council of Europe, 365EMA, 1–5, 7–10European Commission (EC), 365European Medicines Agency (EMA), 365European Medicines Regulatory Network, 5–7Task Force for Relations with the United Kingdom

(UKTF), 364, 366regulatory dossier

for blood/plasma products, 524–525Centralised Procedure, medicinal products, 354changes/variations for medicinal products, 359Decentralised Procedure (DCP), medicinal

products, 355–356for IVD design, 215Mutual Recognition Procedure (MRP), medicinal

products, 356–357National Procedure, medicinal products, 357submission for medicinal products, 352–353validation for medicinal products, 353–354

REgulatory FITness and performance programme (REFIT), 502, 506

regulatory information resources, 553–574agencies and committees, 557–561association electronic media, 569–570book publishers, 567–568commercial and government databases online,

565–567continued learning and associations, 570core SmPC guidance for vaccines, 496Council of Europe publications on blood/plasma

products, 523–524device regulation, 555–556EDQM databases, 567tEMA committees and working parties, 558–559tEU and international organisations, 561–564EU laws and regulations, 556–557framework for medicinal products, human use,

554global regulatory coverage databases, 567–568industry resources in electronic newsletters, 569industry stakeholder organisation, 565tinnovative medicines initiative (IMI), 564

medical product legislation in Eudralex, 554–555national competent authorities listing, 562–563tprofessional association/organisations, 564regulators outside the EU, 565regulatory system for medicines, 553–554social networking and mobile apps, 571–572

regulatory strategyconfirming strategy, 138–139developing and implementing, 136–138documentation of, 138–139information resources for development, 138key questions during development, 137tmarket considerations in, 135–136prescription to nonprescription strategy, 408review/update of, 139

reimbursement. See pricing and reimbursementReporting Member State

clinical trial authorisation process, 311, 324–326low-intervention clinical trial determination, 329

reprocessing, 147reproductive studies, 303responsible person (RP)

generic products, 386tissue quality systems, 478–479, 479tSee also Qualified Person (QP)

risk management plan (RMP), 425adaptive pathways and, 346for Advanced Therapy Medicinal Products

(ATMPs), 466–467for ATMPs, 466–467biocompatibility testing, 230–231in device industry, 260generic medicinal products, 387pharmacovigilance modules, 444tpreclinical device testing, 230requirements for, 440See also ISO 14971; pharmacovigilance

SSafeguard Clause

action by Member States, 267action on conforming devices, 117comparison of health monitoring measures,

267–268, 267tSafety (SAF) HTA model, 80safety measures in clinical trials, 323scientific advice and protocol assistance

for MAA, 37–38review before EMA meeting, 48

Scientific Advice Working Party (SAWP), 37Scientific Advisory Group (SAG) meeting, 55–56scientific committees (EMA)

MAA review, 53, 54t

Index


scientific service implementation, 111serious adverse events (SARs) for IMPs and NIMPs,

332Single European Code (SEC), 476t, 485single-use plastics directive, 516software

EU MDR and EU IVDR reclassification of, 142, 146, 167

GSPRs requirements, 222, 231with medical devices, 26, 186, 200–201, 208,

545preclinical device testing, 233verification and validation of, 233, 234cvigilance for, 261

somatic cell therapy medicinal products (sCTMPs)clinical development, 465–466intended use and manipulation criteria, 460–461manufacturing process, 462preclinical development, 463–464

Spaincompetent authorities for pricing//

reimbursement and HTA, 71HTA in, 82t, 83tNational Health Service (SNS), 71pricing/reimbursement procedures, 71–72

Spurious/Falsely-Labelled/Falsified/Counterfeit (SFFC) medicines, 121, 126, 129t, 132

Standard Assessment Review TimelineEMA meeting preparation, MAA review, 55f

Standard Operating Procedures (SOPs), 306Summary of Product Characteristics (SmPC)

advertising and promotion compliance, 104–107, 109

changes affecting safety, 360, 399–401, 424–425, 432 (see also pharmacovigilance)

generic and reference products, 33, 379, 382–383

human blood or plasma products, 522as IMPD, 331in MAA, 35medicinal product MA maintenance, 279–280,

286–289, 292national competent authority product

authorisation, 320product labelling, 388, 407, 427QRD review, 358–359for vaccines, 491, 492, 496See also specific application procedures

Summary of Safety and Clinical Performance (SSCP), 238

Summary Technical Documentation (STED), 226–227

Supplementary Protection Certificate (SPC)paediatric investigation incentives, 344

paediatric medicinal products, 94protection of innovator medicine by, 379

supply chain controls: new MDR and IVDD regulation, 142–143

suspected unexpected serious adverse reactions (SUSARs)

electronic reporting, 318reporting, 332–333

Swiss Pharmacopoeia (Ph. Helv.)quality systems and inspectorate process, 373

Ttechnical documentation

of Essential Requirements compliance, 215EU MDR and EU IVDR, 226–227for IVDs, 215

“the garlic case”, 506therapeutic interchangeability

biosimilar medicinal products, 22, 399tissue-engineered products (TEPS)

clinical development, 466decision tree for classification, 458fintended use and manipulation criteria, 461manufacturing process, 463preclinical development, 465

toxicity studiesfor biosimilar medicinal products, 395preclinical device testing, 235cpreclinical testing, 302

traceabilitynew regulations, 143–144SEC for tissues/ATMPs, 485

Traditional Herbal Medicinal Product Directive (THMPD), 409–410, 503, 506

traditional herbal medicinal products: regulation evolution, 23

Transmissible Spongiform Encephalopathy (TSE)biotechnology-derived products, 417–418blood and plasma evaluation for, 15, 524

Transparency Directive, 17, 62–63, 498, 560Treaty on the Functioning of the EU, 62trend reporting, 265

Uunique device identifiers (UDI), 138, 143, 215, 268,

485United Kingdom (UK)

advertising and promotion, 111–112assessors and inspector relationship in, 364–365Brexit effects for quality management, 364–365Brexit impact on medical devices, 272competent authorities for pricing/reimbursement

and HTA, 73


Index

HTA in, 82t, 83timplementation of ECTR in, 315National Health Service (NHS), 73pricing/reimbursement procedures, 73–74

United States (US): GLP regulations in, 302Urgent Safety Restriction (USR)

biosimilar medicinal products, 400dossier requirements for, 426timeframe for implementation, 432–433variation classification and, 436

usability testing, 234c

Vvaccine adverse event reporting system (VAERS),

493Vaccine Antigen Master File (VAMF)

development processes for, 491, 492EU regulations, 21veterinary vaccines, 23

vaccines, 489–500adjuvants in, 496–497classification and development pathway, 489–

490clinical studies, 492CTA for, 490–491DNA and therapeutic vaccines/GMO-based,

497–498GMO-based vaccines, 497–498guidance on, 496immunomodulators in, 497licensure, 492–498lot release, 492manufacturing process, 490–491nonclinical studies, 491–492overview, 498pandemic influenza, 496pharmacovigilance (PV), 493prepandemic influenza vaccines, 496pricing and reimbursement, 498seasonal influenza vaccines, 494–495, 495ffor special populations, 494vaccines, 492–493VAMF, 491VAMF certification, 491tVAMF certification and requirements, 21vector use in, 497

value-based pricing model, 64veterinary medicinal products

CMDv, 18CVMP role in authorisation, 8GMP inspections for, 373–374national competent authorities for, 6–7OMCLs testing, 522

pharmaceutical regulation evolution, 22–23regulatory agencies for, 2–3, 4–5, 365–366regulatory principles, 22–23scientific advice and protocol assistance, 48variations to MAAs, 20–21See also specific application procedures

vigilance procedures for IVDs, 214–215viral clearance, 418Voluntary Harmonisation Procedure (VHP)

CTFG and, 336implementation and guidance for, 313

Wworksharing in market authorisation maintenance,

359World Health Organization (WHO)

falsified medicine initiative/IMPACT, 122, 564generic medicinal product definition, 377Global Surveillance and Monitoring System

(GSMS), 130HTA definition by, 66International Clinical Trials Registry Platform

(WHO ICTRP), 335paediatric medicine initiative, 100pandemic vaccine development and, 496

wrongly affixed CE-marking, 117

Documents

Fundamentals of EU Regulatory Affairs, Ninth Edition...Regulatory Affairs Professionals Society 645 Index preclinical study program for, 395 registration of, 397–399 safety reporting