Guide For Medicinal Products and In Vitro Diagnostic (IVD) Medical Devices

Regulatory Framework

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This guide has been prepared to provide high-wing guidance on legal requirements for the registration/certification and maintenance of medicinal products and in vitro diagnostic medical devices (IVD) in Finland and generally in the European Union (EU).

The guide consists of two parts:

PART I: Medicinal products A substance or combination of substances that is intended to treat, prevent or diagnose a disease, or to restore, correct or modify physiological functions by exerting a pharmacological, immunological or metabolic action.

PART II: In vitro Diagnostic (IVD) Medical Devices An in vitro diagnostic (IVD) medical device is a reagent, instrument, software or system intended to be used in vitro for the examination of specimens for the purpose of providing information on:

• concerning a physiological or pathological process or state

• concerning congenital physical or mental impairment

• to determine the safety and compatibility with potential recipients

• to define or monitoring therapeutic measures

Also, IVDs medical devices like genetic tests and mobile applications are covered by this text part.

It should be noted that Medical Devices (MDs), which do not fall into the criteria of IVD, have their own regulation; MD Regulation (EU) 2017/745 (MDR). Such MDs are out of the scope of this guide.

Development of medicinal products or IVD medical devices is an inspiring yet challenging process. The purpose of this guide is to promote instructions on smoother and more effective product development and maintenance. Knowledge of and compliance with legal requirements is essential.

The main responsible party for fulfilling the legal requirements for a medicinal product/IVD medical device is the company registering/licensing the product on the market. For medicinal products, this party is called Marketing Authorisation Holder (MAH) and for IVD medical devices (and other MDs) it is called Legal Manufacturer. MAHs and Legal Manufactures have similar responsibilities to ensure the efficacy, safety and quality of their products, but there are separate regulations/guidance documents for these three product types.

Most, if not all, activities related to registering/licensing/maintaining of medicinal products and IVD medical devices can be outsourced to service provider(s) but the legal responsibility of having the required systems in place always remains at the MAH/Legal Manufacturer. In practice many MAHs/Legal Manufactures outsource at least some of the activities to optimize the use of resources and to maximize the expertise in areas requiring deep knowledge of requirements and wide experience.

This guide was prepared by DRA Consulting Oy, a Finnish consultancy company specialized in pharmaceutical industry and health technology. Key guidelines and source material are listed in each chapter of the guide.

We wish all new product developers the best of luck and success!

!

Introduction

Guide For Medicinal Products and In Vitro Diagnostic (IVD) Medical Devices

Regulatory Framework

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w

MEDICINAL PRODUCTS PART I

Part I Contents1. BASICS OF MEDICINAL PRODUCTS 8

1.1 Definition of a medicinal product 81.2 Categorisation of a medicinal product 81.3 Key operators around medicinal products 9

1.3.1 Pharmaceutical industry 91.3.3 Other operators 9

2. GOOD PRACTICES (GXP) 102.1 Good Manufacturing Practice 102.2 Good Distribution Practice 102.3 Good Laboratory Practice 112.4 Good Clinical Practice 112.5 Good Pharmacovigilance Practice 11

3. PHARMACEUTICAL DEVELOPMENT 124. PRE-CLINICAL DEVELOPMENT 145. CLINICAL DEVELOPMENT 166. MARKETING AUTHORISATION APPLICATIONS 18

6.1 Application types 186.2 Marketing authorisation procedures 20

6.2.1 Centralized procedure 206.2.2 Decentralized procedure 206.2.3 National procedure and Mutual-Recognition procedure 20

6.3 Content 216.3.1 Module 1 - Regional administrative information 21

6.3.1.1 Product information (Module 1.3) 226.3.1.2 Pharmacovigilance System Master File (PSMF) (Module 1.8.1) 236.3.1.3 Risk Management Plan (RMP) (Module 1.8.2) 23

6.3.2 Module 2 - Quality, Non-Clinical and Clinical Summaries 246.4 Compilation and submission 246.5 Timelines and steps 246.5 Data-exclusivity and market-exclusivity period for reference medicinal products 25

7. MAINTENANCE OF MARKETING AUTHORISATION 267.1 Pharmacovigilance 267.2 Variations 277.3 Renewals 27

8. MARKET ACCESS AND MAINTAINING A MEDICINAL PRODUCT ON THE MARKET 288.1 Market access 288.2 Price and reimbursement 288.3 Supply (distributors, pharmacies, hospital pharmacies) 298.4 Batch control 298.5 Marketing 298.6 Pharmacovigilance 298.7 Quality Assurance 308.8 Databases 308.9 Medical info 308.10 Mandatory reserve supplies 30

9. SCIENTIFIC ADVICE 31

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PART I: Medical Products

1. BASICS OF MEDICINAL PRODUCTS 1.3 Key operators around medicinal products

1.3.1 Pharmaceutical industry

The manufacture of medicines is a licensed and tightly regulated activity. All parties involved in the manufacturing shall be notified to the authorities.

A manufacturing authorisation is required for the manufacture of both active substances and finished products. Subcontracting can be used in the manufacture of medicinal products, the so-called contract manufacturing or contract analysis by another pharmaceutical company. The import and wholesale trade of medicinal products is also subject to a licence.

A MAH shall be normally indicated in the MAA for a medicinal product (who is often the MAA Applicant as well). The MAH has a broad responsibility and special obligations in relation to the marketing authorisation. The MAH must be established within European Economic Area (EEA), which include Member States of the European Union and Norway, Iceland and Liechtenstein

1.3.2 Competent authorities

In the EEA each MS has a Medicines Agency, which monitors the quality, efficacy and safety of medicinal products for human and veterinary use. These national medicines agencies are responsible for pharmacovigilance (PV) in cooperation with the European Medicines Agency (EMA) and the European Commission (EC). Together with EMA and Commission the European Network of National Medicines Agencies develops and guides all marketing authorization processes.

1.3.3 Other operators

Harmonization of practices and guidelines in the field is done worldwide, for example, by The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). ICH is unique in bringing together the regulatory authorities and pharmaceutical industry to discuss scientific and technical aspects of pharmaceuticals and in developing ICH guidelines. Another important harmonising body in the field is the EDQM (European Directorate for the Quality of Medicines & Healthcare), which is responsible for quality standards for safe medicinal products and their safe use.

1.1 Definition of a medicinal product

Medicinal product is a substance or combination of substances intended to treat, prevent or diagnose a disease, or to restore, correct or modify physiological functions by exerting a pharmacological, immunological or metabolic action.

Whether a substance or a product is considered a medicinal product or non-medicinal products (food products/food supplements, medical devices, biocides or cosmetics) is based on the composition and intended use of the product.

A medicinal product may only be placed on the market in the European Economic Area (EEA) when a marketing authorisation has been issued by the competent authority of a Member State for its own territory (national authorisation) or when an authorisation has been granted for the entire European Union by European Commission.

1.2 Categorisation of a medicinal product

Active substances of medicinal products can be inorganic, chemically or biologically manufactured, or herbal substances. Most commonly, active substances are synthetic and semi-synthetic chemical substances. There are special requirements in legislation and guidance documents for herbal and biological medicinal products. Also, homeopathic products and medical gases are under medicinal product legislation and they require a license or marketing authorisation.

Medicinal products are also classified according to their Anatomical Therapeutic Chemical (ATC) code: a unique code is assigned to a medicinal product according to the organ or system it works on and how it works.

Administratively, the products are commonly referred to as original or generic medicinal products. A generic medicinal product is a pharmaceutical product for which the data exclusivity and original patent has expired. They contain the same active ingredient (qualitatively and quantitatively) and are “essentially similar” to the original products (see section 6.1). Consequently, they can be used as equivalents to originator products.

A parallel imported product is a medicinal product that is imported into the country of destination by a third party other than the marketing authorisation holder (MAH) or his authorised representative. A concept of parallel distribution concerns the distribution of a centrally authorised medicinal product from one Member State (MS) to another by a pharmaceutical company independent of the MAH (see also section 6.2).

Each medicinal product and its package size have specific terms for supply. Those medicinal products sold without a prescription are called over-the-counter (OTC) drugs. An OTC status can be granted along with the marketing authorisation application (MAA) or applied for later. Some medicinal products in Finland can be dispensed without prescription but require additional advice from the pharmacy staff.

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PART I: Medical Products

2. GOOD PRACTICES (GXP)

2.3 Good Laboratory Practice

The principles of Good Laboratory Practice (GLP) define a set of rules and criteria for a quality system concerned with the organisational process and the conditions under which non-clinical health and environmental safety studies are planned, performed, monitored, recorded, reported and archived.

Exhaustive information about GLP can be found on the websites of the OECD and the EC. The GLP Directives are applicable: Directive 2004/9/EC and Directive 2004/10/EC. Questions and answers concerning the interpretation of the two GLP Directives and Fimea’s website can also be consulted.

2.4 Good Clinical Practice

Good clinical practice (GCP) is an international ethical and scientific quality standard for designing, recording and reporting trials that involve the participation of human subjects. Compliance with this standard provides public assurance that the rights, safety and wellbeing of trial subjects are protected, and that the results of clinical trials are credible.

The protection of clinical trial subjects is consistent with the principles set out in the Declaration of Helsinki. Requirements for the conduct of clinical trials in the EU, including GCP and GMP inspections, are implemented in the Clinical Trial Directive (Directive 2001/20/EC) and the GCP Directive (Directive 2005/28/EC).

2.5 Good Pharmacovigilance Practice

Good Pharmacovigilance Practices (GVP) are a set of practical measures drawn up to facilitate the performance of PV for authorised products in the EU. The guideline on GVP is divided into chapters that fall into two categories: modules covering major PV processes (I-XVI) and product- or population-specific considerations.

GVP apply to marketing authorisation holders, the EMA and national medicines agencies in EU Member States. It covers medicinal products authorised centrally via the Agency as well as medicines authorised at national level. GVP is based on EU PV legislation.

PV practices and legal requirements in Finland are in line with EU GVP and EU PV legislation, see also section 7.1.

2.1 Good Manufacturing Practice

Good Manufacturing Practice (GMP) is a set of principles and procedures followed in the manufacture and quality assurance of medicinal products to ensure the products meet all the requirements set for them in terms of production.

EC EudraLex Volume 4 contains guidance for the interpretation of the principles and guidelines of good manufacturing practices for medicinal products for human and veterinary use laid down in Commission Directives 2003/94/EC. The EMA Q&As provides additional interpretation of the European Union (EU) GMP and GDP (see section 2.2) guidelines.

EudraGMDP is a publicly accessible EU database which contains manufacturing and import authorisations, registration of active substance manufacturers, GMP/GDP certificates and non-compliance statements.

2.2 Good Distribution Practice

Good distribution practice (GDP) describes the minimum standards that a wholesale distributor must meet to ensure that the quality and integrity of medicinal products is maintained throughout the supply chain. GDP guidances lay down appropriate tools to assist wholesale distributors in conducting their activities and to prevent falsified medicinal products from entering the legal supply chain. Compliance with these guidelines will ensure control of the distribution chain and consequently maintain the quality and the integrity of medicinal products.

Directives 2001/83/EC and 2001/82/EC  lay down the provisions for distribution of medicinal products in the EU. Two EC guidelines establish the requirements of GDP (Guidelines on GDP of medicinal products for human use, Guidelines on principles of GDP for active substances for medicinal products for human use).

GMP = Good Manufacturing PracticeGDP = Good Distribution PracticeGCP = Good Clinical PracticeGVP = Good Pharmacovigilance PracticeGLP = Good Laboratory Practice

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PART I: Medical Products

The aim of pharmaceutical development is to design a quality product and its manufacturing process to consistently deliver the intended performance of the product. Harmonized scientific guidelines can be found on the ICH and EMA websites. The presentation and format of this part of the dossier (Module 3) accompanying the MAA for medicinal products for human use is set out in Volume 2B Notice to Applicants.

The pharmaceutical development section should describe the knowledge that establishes that the type of selected dosage form and the proposed formulation are suitable for the intended use. This section should include sufficient information to provide an understanding of the development of the drug product and its manufacturing process. At a minimum, those aspects of drug substances, excipients, container closure systems, and manufacturing processes that are critical to product quality should be determined and control strategies justified. Critical formulation attributes and process parameters are generally identified through an assessment of the extent to which their variation can have impact on the quality of the drug product.

Depending on the kind and classification of active substance (new or existing one, described or not described in pharmacopeia), the required data can be submitted as full details of manufacture, in an Active Substance Master File including detailed description of the manufacturing process or as a Certificate of Suitability to the Monograph of the European Pharmacopeia (CEP). The physicochemical and biological properties of the drug substance that can influence the performance of the drug product and its manufacturability specifically designed into the drug substance (e.g., solid state properties), should be identified and discussed. Examples of physicochemical and biological properties that might need to be examined include solubility, water content, particle size, crystal properties, biological activity, and permeability.

The compatibility of the drug substance with excipients should be evaluated. The excipients chosen, their concentration, and the characteristics that can influence the drug product performance (e.g., stability, bioavailability) or manufacturability should be discussed relative to the respective function of each excipient. Their choice and characteristics should be appropriate to the intended purpose.

A summary of formulation development should be provided describing the development of the formulation, including identification of those attributes that are critical to the quality of the drug product, taking into consideration intended usage and route of administration. Any changes between the proposed commercial formulation and those formulations used in pivotal clinical batches and primary stability batches should be clearly described and the rationale for the changes provided. Any overages in the manufacture of the drug product, whether they appear in the final formulated product or not, should be justified considering the safety and efficacy of the product. The physicochemical and biological properties relevant to the safety, performance or manufacturability

of the drug product should be identified and discussed. The selection, the control, and any improvement of the manufacturing process should be explained. It is important to consider the critical formulation attributes, together with the available manufacturing process options, in order to address the selection of the manufacturing process and confirm the appropriateness of the components and equipment. Any critical process parameters that should be monitored or controlled to ensure that the product is of the desired quality should be stated. The choice and suitability of the packaging material shall be justified, taking into account the intended use of the medicinal product and the storage and transport conditions. The compatibility of the packaging material with the medicinal product or other components, its tightness, its protection against moisture and light and the safety of the packaging material must also be demonstrated by appropriate studies and surveys. Stability testing has to provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity, and light, and to establish a re-test period for the drug substance or a shelf life for the drug product and recommended storage conditions.

Table 3.1: Overview of quality data.

PART GUIDANCE* RELEVANT eCTD SECTIONS

ACTIVE SUBSTANCE

• ICH Guideline Q11 on Development and Manufacture of Drug Substances EMA/CHMP/ICH/425213/2011

• Guideline on Summary of Requirements for Active Substance in the Quality Part of the Dossier CHMP/QWP/297/97 Rev. 1

• Guideline on Active Substance Master File Procedure CHMP/QWP/227/02, EMEA/CVMP/134/02

• European Pharmacopoeia, current edition

• Guideline on Excipients in the Dossier for Application for Marketing Authorisation of a Medicinal Product EMEA/CHMP/QWP/396951/2006

3.2.S.1 General Information

3.2.S.2 Manufacture

3.2.S.3 Characterisation

3.2.S.4 Control of Drug Substance

3.2.S.5 Reference Standards or Materials

3.2.S.6 Container Closure System

3.2.S.7 Stability

DRUG PRODUCT

• Pharmaceutical Development EMA/CHMP/ICH/167068/2004

• Guideline on Manufacture of the Finished Dosage Form EMA/CHMP/QWP/245074/2015

• Guideline on Process Validation for Finished Products EMA/CHMP/CVMP/QWP/BWP/70278/2012

• Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances CPMP/ICH/367/96

• Specifications and Control Tests on the Finished Product 3AQ11a

• ICH Topic Q 3B (R2) Impurities in New Drug Products CPMP/ICH/2738/99

• Guideline on Plastic Immediate Packaging Materials CPMP/QWP/4359/03

• Stability Testing of a New Drug Substances and Products CPMP/ICH/2736/99

• Stability Testing of Existing Active Substances and Related Finished Products CPMP/QWP/122/02

• Guideline on Declaration of Storage Conditions CPMP/QWP/609/96

3.2.P.1 Description and Composition of the Drug Product

3.2.P.2 Pharmaceutical Development

3.2.P.3 Manufacture

3.2.P.4 Control of Excipients

3.2.P.5 Control of Drug Product

3.2.P.6 Reference Standards or Materials

3.2.P.7 Container Closure System

3.2.P.8 Stability

3. PHARMACEUTICAL DEVELOPMENT

* List may not be exhaustive

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PART I: Medical Products

4. PRE-CLINICAL DEVELOPMENTThe goals of the nonclinical safety evaluation generally include a characterisation of toxic effects with respect to target organs, dose dependence, relationship to exposure, and, when appropriate, potential reversibility (ICH M3(R2)). This information is used to estimate an initial safe starting dose and dose range for the human trials and to identify parameters for clinical monitoring for potential adverse effects.

The ICH and EMA have published a number of scientific guidelines for preclinical studies, which deal with studies at a general level or in a specific area, e.g., by therapy class or indication. When preparing Module 2 and Module 4 of the MAA dossier, it is advisable to consult Volume 2B Notice to Applicants of EC (including detailed list of references to clinical guidelines) and the ICH M4S (R2).

STUDY TYPE

GUIDANCE* AIMTIMING IN RELATION TO CLINICAL DEVELOPMENT/DETAILS

RELEVANT eCTD SECTIONS

Pharmacology studies

ICH S7A

ICH S7B

Pharmacodynamic: investigate the mode of action and/or effects of a substance related (primary)/not related (secondary) to its desired therapeutic target

Safety: the potential undesirable pharmacodynamic effects of a substance on physiological functions in relation to exposure in the therapeutic range, normally conducted as core battery of effects on vital functions (cardiovascular, central nervous and respiratory systems), in accordance with GLP.

Generally conducted during the discovery phase of pharmaceutical development.

Should be investigated prior to first administration in humans, unless further studies are warranted.

4.2.1.1 Primary Pharmacodynamics

4.2.1.2 Secondary Pharmacodynamics

4.2.1.3 Safety Pharmacology

4.2.1.4 Pharmacodynamic Drug Interactions

Toxicokinetic and phar-macokinetic studies

ICH S3A

ICH 3B

Describe the systemic exposure achieved in animals and its relationship to dose level and the time course of the toxicity study. Normally integrated within the toxicity studies.

At least drug metabolism and plasma protein binding should be known before initiating clinical trials. Other pharmacokinetic properties must be known at the latest generally before Phase III clinical trial.

4.2.2.1 Analytical Methods and Validation Reports

4.2.2.2 Absorption

4.2.2.3 Distribution

4.2.2.4 Metabolism

4.2.2.5 Excretion

4.2.2.6 Pharmacokinetic Drug Interactions

4.2.2.7 Other Pharma-cokinetic Studies

Table 4.1: Overview of safety studies

STUDY TYPE

GUIDANCE* AIMTIMING IN RELATION TO CLINICAL DEVELOPMENT/DETAILS

RELEVANT eCTD SECTIONS

General toxicity studies

Guideline on repeated dose toxicity EMEA/CPMP/SWP/1042/99

ICH S4

Acute toxicity studies: to predict the consequences of human overdose situations.

Repeated dose toxicity studies: potential target organs of toxicity and exposure/response relationships and potential reversibility of toxic effects. The duration should be equal to or exceed the duration of the human clinical trials up to the maximum recommended duration of the repeated-dose toxicity studies.

Separate single-dose studies not recommended, can be assessed based on data from appropriately conducted dose-escalation studies or short-duration dose-ranging studies.should be available to support Phase III.

4.2.3.1 Single-Dose Toxicity

4.2.3.2 Repeat-Dose Toxicity

Genotoxicity studies

ICH S2(R1) In vitro and in vivo tests designed to detect compounds that induce genetic damage by various mechanisms.

Before initiation of Phase II trials

4.2.3.3.1 In vitro Genotoxicity

4.2.3.3.2 In vivo Genotoxicity

Carcinogenic studies

ICH S1A

ICH S1B

ICH S1C

For drugs that have special cause for concern or are intended for a long duration of use

To support the marketing application (in some to support clinical trials or concluded post-approval).

4.2.3.4.1 Long-term carcinogenicity studies

4.2.3.4.2 Short- or medium-term carcinogenicity studies

4.2.3.4.3 Other carcinogenicity studies

Reproduction toxicity studies

ICH S5 (R3)

Guideline on the need for non-clinical testing in juvenile animals of pharmaceuticals for paediatric indications EMEA/CHMP/ SWP/169215/ 2005

To reveal any effect of the pharmaceutical on mammalian reproduction relevant for human risk assessment. Include a fertility and early embryonic development study, embryo- fetal development studies and a pre- and a postnatal development study.

Juvenile animal toxicity studies considered only when previous animal data and human safety data are judged to be insufficient to support paediatric studies.

The timing for when to conduct specific assessment should take into consideration the need for these data to support the safe use of the pharmaceutical in clinical trials or the intended patient population.

4.2.3.5.1 Fertility and early embryonic development

4.2.3.5.2 Embryo-fetal development

4.2.3.5.3 Prenatal and postnatal development, including maternal function

4.2.3.5.4 Studies in which the offspring (juvenile animals) are dosed and/or further evaluated

Local tolerance studies

Guideline on non-clinical local tolerance testing of medicinal products EMA/CHMP/SWP/2145/2000

To support human exposure to a drug product at contact sites following normal clinical use, as well as after unintentional administration.

Whenever possible shall be part of other toxicity studies.

4.2.3.6 Local Tolerance

* List may not be exhaustive

Note: Other studies that shall be conducted on a case-by-case basis include phototoxicity (ICH S10), immunotoxicity (ICH S8) and abuse liability studies (Guideline on the non-clinical investigation of the dependence potential of medicinal products EMEA/CHMP/SWP/94227/2004). There are also separate guidelines for biotechnology-derived products (ICH S6), anticancer products (ICH S9) and other relevant position papers for specific product types (e.g., advanced therapies)

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PART I: Medical Products

5. CLINICAL DEVELOPMENT

Before any clinical trial is carried out, results of non-clinical investigations or previous human studies should be sufficient to indicate that the drug is acceptably safe for the proposed investigation in humans. Clinical trials are studies intended to discover or verify the effects of one or more investigational medicinal products.

The regulation of clinical trials aims to ensure that the rights, safety, and well-being of trial subjects are protected, and the results of clinical trials are credible. Regardless of where they are conducted, all clinical trials included in MAA for human medicinal products in the EEA must have been carried out in accordance with the requirements set out in Annex 1 of Directive 2001/83/EC. This means that clinical trials conducted in the EEA have to comply with EU clinical trial legislation (Directive 2001/20/EC) and those clinical trials conducted outside the EEA have to comply with ethical principles equivalent to those set out in the EEA, including adhering to ICH E6 Good Clinical Practice (the principles and practices concerning protection of trial subjects) and the Declaration of Helsinki. Guidelines on the conduct of clinical trials can be found in Eudralex Volume 10.

In 2014 the EC adopted the new Clinical Trial Regulation (EU No 536/2014), repealing Directive 2001/20/EC. Although the Clinical Trial Regulation was adopted and entered into force in 2014, the timing of its application depends on confirmation of full functionality of Clinical Trials Information System (a single-entry point for submitting, assessing, authorising, supervising and reporting a clinical trial in all MSs of the EU) through an independent audit (current aim is December 2021).

The ICH (with General Considerations for the Clinical Trials described in ICH E8) and EMA (Clinical pharmacology and pharmacokinetics, Clinical efficacy and safety guidelines) have published a number of detailed scientific guidelines for clinical trials that address trials at a general level or in a specific area (e.g., pharmaceutical form or indication). EMA encourages following the guidelines and prior discussion through scientific advice for any exemption before commencing the study. Deviations from the guidelines must be fully justified in the MAA.

EudraCT (European Union Drug Regulating Authorities Clinical Trials Database) is the European database for all interventional clinical trials on medicinal products authorised in the EEA and outside the EU/EEA, if they are part of a Paediatric Investigation Plan (PIP) from 1 May 2004 onwards. Protocol and results information on interventional clinical trials are made publicly available through the European Union Clinical Trials Register since September 2011.

Clinical drug development is often described as consisting of four temporal phases (Phase I-IV). It is important to recognise that the phase of development does not always correspond to clinical trials type, because one type of trial may occur in several phases. Temporal phases do not imply a fixed order of studies either. For example, although human pharmacology studies are typically conducted during Phase I, many such studies are conducted at each of the other three stages, but nonetheless sometimes labelled as Phase I studies.

Initial trials provide an early evaluation of short-term safety and tolerability and can provide pharmacodynamic and pharmacokinetic information needed to choose a suitable dosage range and administration schedule for initial exploratory therapeutic trials. Later confirmatory studies are generally larger and longer and include diverse patient population. Dose-response information should be obtained at all stages of development, from early tolerance studies, to studies of short-term pharmacodynamic effect, to large efficacy studies (see ICH E4).

Clinical study reports should be adequately documented following the approaches outlined in ICH guidelines (see ICH E3 and E6). The Clinical Summary (Module 2.7) provides a detailed, factual summarisation of all the clinical information and full reports are always presented in Module 5 of MAAs. Further details of Module 2 and Module 5 are available in Volume 2B Notice to Applicants of EC (including detailed list of references to clinical guidelines) and ICH M4E(R2).

Table 5.1: Overview of types of clinical studies

PHASE TYPE OF STUDY GUIDANCE* OBJECTIVE OF STUDY

I Human Pharmacology

• Guideline on strategies to identify and mitigate risks for first-in-human clinical trials with investigational medicinal products EMEA/CHMP/SWP/28367/07

• Guideline on the evaluation of the pharmacokinetics of medicinal products in patients with impaired hepatic function CPMP/EWP/2339/02

• Note for guidance on the evaluation of the pharmacoki-netics of medicinal products in patients with impaired renal functions CPMP/EWP/225/02

• Guideline on the investigation of drug interactions CPMP/EWP/560/95

• ICH E5

• Assess tolerance

• Define/describe PK and PD

• Explore drug metabolism and drug interactions

• Estimate activity

II Therapeutic Exploratory

• ICH E4 • Explore use for the targeted indication

• Estimate dosage for subsequent studies

• Provide basis for confirmatory study design, endpoints, methodologies

III Therapeutic Confirmatory

• ICH E1

• ICH E7

• Guideline on clinical trials in small populations CHMP/EWP/83561/2005

• Demonstrate/confirm efficacy

• Establish safety profile

• Provide an adequate basis for assessing the benefit/risk relationship to support licensing

• Establish dose-response relationship

IV Therapeutic Use • Refine understanding of benefit/risk relationship in general or special populations and/or environments

• Identify less common adverse reactions

• Refine dosing recommendation

* List may not be exhaustive

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PART I: Medical Products

6. MARKETING AUTHORISATION APPLICATIONS

6.1 Application types

Different legal basis for human marketing authorisation applications (MAAs) are primarily laid down in Directive 2001/83/EC of the European Parliament and of the Council on the Community code relating to medicinal products for human use. A MAA can be based on complete or abbreviated documentation. Product development and data generation need to be compatible with the legal basis of the application. Table 6.1 specifies different types of MAAs.

Table 6.1: Types/legal basis of marketing authorisation applications

Full (complete dossier) applications (Articles 8(3), 10a, 10b and 10c of Directive 2001/83/EC)

• Can be used for new or known active substances.

• Complete quality, preclinical, and clinical data (Modules 3-5)

• Published literature either supportive or in replacement of some of the non-clinical/clinical data

• Data- and market-exclusivity period 8+2+1 years (see also details in paragraph 6.5)

Abridged applications (Articles 10(1), 10(3) and 10(4) of Directive 2001/83/EC)

• Refer to the results of pre-clinical tests and clinical trials of the reference medicinal product

• Administrative part, overviews or expert statements, and complete quality parts are, however, always presented.

COMPLETE DOSSIER (Can be used as reference medicinal products. Protection period 8+2 years, with possible 1-year extension of market exclusivity period)

ARTICLE 8(3) Full applications Can be used for new or known active substances.

Complete dossier for Modules 3 - 5. In addition to own studies, literature references can be used as a supportive evidence.

ARTICLE 10a Well-established use applications (i.e., bibliographical applications)

If it can be demonstrated that the active substances of a medicinal product have been in a systematic and documented medicinal use within the Union for at least 10 years, with recognised efficacy and an acceptable level of safety.

Note! In certain cases, applicant’s own studies may be provided only to support the relevance of the literature to the product intended for marketing.

ARTICLE 10b Fixed combination applications Can be used if the pharmaceutical form contains known active substances which have not previously been used in combination for therapeutic uses. These are unique and independent marketing authorisations that are not considered to fall within the concept of a “global marketing authorisation”.

ARTICLE 10c Informed consent applications A prerequisite is that consent has been obtained from the MAH of the reference product to have permanent access to its pharmaceutical, pre-clinical and clinical data (Modules 3-5). These two medicinal products must be identical.

This application is used when reference medicinal product is still covered by data protection.

ABRIDGED APPLICATIONS

ARTICLE 10.1 Generic applications Refers to the information in the dossier of the authorisation of a reference medicinal product which is or has been authorised in Finland or in some other EEA MS. A generic medicinal product is defined as a medicinal product that has the same qualitative and quantitative composition in active substances and the same pharmaceutical form as the reference product, and whose bioequivalence with the reference medicinal product has been demonstrated by appropriate bioavailability studies.

ARTICLE 10.3 Hybrid applications This type is used where the strict definition of a ‘generic medicinal product’ is not met and where the bioavailability studies cannot be used to demonstrate bioequivalence or where there are changes in the active substance(s), therapeutic indications, strength, pharmaceutical form or route of administration of the generic product compared to the reference medicinal product. Rely in part on the results of pre-clinical tests and clinical trials for a reference product and in part on new data.

ARTICLE 10.4 Similar biological applications For biological medicinal products which are similar to a reference biological product, but do not meet the conditions in the definition of generic medicinal products, owing to, in particular, differences relating to raw materials or differences in manufacturing processes. There shall be no clinically meaningful differences between the biosimilar and the reference medicinal product in terms of safety, quality and efficacy.

Broad guidance available at EMA’s webpage.

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6.2 Marketing authorisation procedures

In the EU, a medicinal product for human use may be authorised either by the EC through the centralised procedure (CP) or by National Competent Authorities through a mutual-recognition (MRP), decentralised (DCP) or national (NP) procedures. Both the DCP and the MRP are based on the recognition by National Competent Authorities of an assessment performed by the Authorities of one member state (MS). A detailed explanation of the marketing authorisation procedures and other regulatory guidance is contained in Volume 2 Notice to Applicants.

The fees for applications in the national, mutual recognition and decentralised procedures are regulated by National Competent Authorities. The fees for applications in Finland are published on Fimea´s website and the fees for centralised marketing authorisations are published on the website of EMA.

6.2.1 Centralized procedure

An application must be submitted to the EMA. A scientific opinion, prepared by various scientific Committees, is then sent to the EC which drafts and adopts a Decision. Such a MA is valid for the entire Union market, which means the medicinal product, may be put on the market in all MSs.

All human medicinal products derived from biotechnology and other high-tech processes must be evaluated via the CP. The same applies to all advanced therapy medicines and medicinal products containing new active substances intended for the treatment of HIV/AIDS, cancer, diabetes, neurodegenerative diseases, auto-immune and other immune dysfunctions, and viral diseases, as well as to all designated orphan medicines intended for the treatment of rare diseases.

Centralised procedure can be optionally used if the medicinal product is a new active substance, constitutes a significant therapeutic, scientific or technical innovation, or is in any other respect in the interest of patients at EU level. Also, generics of centrally authorised products and applications for certain medicinal products for paediatric use may be authorised in centralised procedure.

6.2.2 Decentralized procedure

In decentralised procedure the MAA is submitted simultaneously in several EU countries. One of the MSs will take the lead in evaluating the application as reference MS (RMS).

6.2.3 National procedure and Mutual-Recognition procedure

To be eligible for the MRP, a medicinal product must already have received a national MA in one EU country (RMS). MRP procedure is based on the mutual recognition by concerned member state(s) -MS(s) (CMS(s)) of such national MA. MRP can be used several times for the same MA after completion of the first MRP, for the granting of a MA by additional MSs. This procedure is known as the Repeat Use Procedure (RUP).

6.3 Content

The content of Module 1 and Module 2 is described below. For the content of Modules 3-5 please refer to Chapters 3-5.

6.3.1 Module 1 - Regional administrative information

Module 1 Administrative part • EC, EudraLex Volume 2, Notice to Applicants• HMA webpage, CMD(h) Procedural Guidance (MRP/DCP)• EMA guidance, human and veterinary medicinal products (CP)• Fimea webpage, https://www.fimea.fi/tietoa_fimeasta/lomakkeet • HMA webpage, MRP/DCP templates

Module 2 Quality, Non-clinical and Clinical Summaries

Module 3 Quality

Module 4 Non-clinical reports

Module 5 Clinical reports

1.O COVER LETTER1.1 COMPREHENSIVE TABLE OF CONTENT

1.2 APPLICATION FORM + ANNEXES

1.3 Product Information (PI)1.3.1 SPC, Labelling and Package Leaflet 1.3.2 Mock-up 1.3.3 Specimen1.3.4 Consultation with Target Patient Groups

• Readability User Testing Reports or Bridging Reports 

1.3.5 Product Information already approved in the Member States 1.3.6 Braille

1.4 Information about the Experts 1.4.1 Quality 1.4.2 Non-Clinical 1.4.3 Clinical

1.6 Environmental Risk Assessment

1.6.1 Non-GMO 1.6.2 GMO

1.7 Information relating to Orphan Market Exclusivity

1.7.1 Similarity 1.7.2 Market Exclusivity

1.8 Information relating to Pharmacovigilance

1.8.1 Summary PSMF1.8.2 Risk-management System

1.9 Information relating to Clinical Trials

1.10 Information relating to Paediatrics

• Responses to Questions

• Additional Data

1.5 Specific Requirements for Different Types of Applications

1.5.1 Information for Bibliographical Applications 1.5.2 Information for Generic, ‘Hybrid’ or Bio-similar Applications1.5.3 (Extended) Data/Market Exclusivity 1.5.4 Exceptional Circumstances 1.5.5 Conditional Marketing Authorisation

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The electronic formats of the electronic Application Form (eAF) has to be used and are found on the EMA’s esubmission website.

6.3.1.1 Product information (Module 1.3)

MAHs must include proposals for (or revised) Summary of Product Characteristics (SmPC), labelling and package leaflet (PL) (in English) in their application. An SmPC is an agreement between the MAH and regulatory authorities on how and for what purpose a product is to be used. The SmPC contains the key information on how the efficacy and safety of the product have been proven, as well as on product quality. The PL is provided with the medicinal product package, and it contains relevant information of the medicinal product to the user. Also, the proposed package mock-ups are checked and approved during the MAA processes.

Table 6.3.1.1: Particulars of Product Information

6.3.1.2 Pharmacovigilance System Master File (PSMF) (Module 1.8.1)

A summary of the applicant’s PV system is to be included in the MAA, and shall contain the following elements in Module 1.8.1 of the dossier (Guideline on good pharmacovigilance practices (GVP), Module II – Pharmacovigilance system master file (Rev 1) EMA/816573/2011 Rev 1):

• proof that the applicant has at his disposal a qualified person responsible for PV;

• the MS s in which the qualified person resides and carries out his/her tasks;

• the contact details of the qualified person;

• a statement signed by the applicant to the effect that the applicant has the necessary means to fulfil the tasks and responsibilities listed in Title IX;

• a reference to the location where the PSMF for the medicinal product is kept

6.3.1.3 Risk Management Plan (RMP) (Module 1.8.2)

RMP includes information on a medicinal product’s safety profile, how its risks will be prevented or minimised in patients; plans for studies and other activities to gain more knowledge about the safety and efficacy of the medicinal product; and measuring the effectiveness of risk-minimisation measures.

Summaries of RMPs are required to be submitted for medicinal products authorised by NPs, MRPs and DCPs. Fimea publishes on its website the English versions of the summaries of the approved RMPs prepared by the MAH. For centrally authorised products, the RMP summaries are published on the EMA’s website.

Administrative data • Invented name, strength, active substance, pharmaceutical form

• Applicant, Applicant’s Representative

• Signature confirming that all relevant information is provided

Type of application • Procedure (CP, DCP/MRP, NP), CMSs

• Legal basis

• Studies / study plan in children or waiver / deferral

Marketing Authorisation Application Particulars

• Product name and ATC code

• Active substance, pharmaceutical form, composition, route of administration, packaging

• Legal status (Prescription or over-the-counter medicine)

• MAH and authorised persons

• Manufacturer(s)

Scientific advise details

Other Marketing Authorisation Applications

• Information on whether the same product has already been authorised in an EU country or whether the application (s) is / are pending.

Annexed documents

Product Information Language (In Finland)

Legal framework

Summary of Product Charac-teristics (SPC)

Aimed at healthcare professionals.

Note! All information provided about the product must be based on the SPC approved by the Authority!

Finnish, Swedish

EC A guideline on summary of product characteristics

EMA How to prepare and review a summary of product character-istics

EMA Product Information templates

Fimea Instructions for creating SPC files

Labelling Particulars to appear on product’s outer or immediate packaging, and small immediate packaging units.

Finnish, Swedish

Package Leaflet (PL)

Aimed for patients, included in the package. Finnish, Swedish

Annex I-III Product Information for products autho-rised by centralised procedure.

Includes SPC, PL and labelling, infor-mation of manufacturer responsible for batch release, as well as possible conditions or restrictions regarding supply and use.

Finnish, Swedish*

QRD Quality review document

The structure of PI texts is based on QRD templates published by EMA.

* From February 9, 2019, SPC as well must be submitted in Swedish

Table 6.3.1: Application form details (Module 1.2)

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6.3.2 Module 2 - Quality, Non-Clinical and Clinical Summaries

Module 2 contains high-level summaries of quality, the non-clinical and the clinical data presented in Modules 3, 4 and 5 of the dossier that must be prepared by suitably qualified and experienced persons (experts). Information on their educational background and specific expertise shall be included in Module 1.4.

Fimea’s national MA process broadly follows the principles of the DCP: the first assessment opinion will be completed approximately 120 days after the submission of the application, with a total processing time of approximately 210 days. The applicant must submit the national Product Information text (Finnish + Swedish) already with the original application data, unlike in the MRP/ DCP process.

Table 6.5.1 Comparison of processing times between DCP-procedure and a procedure, where first national marketing authorisation is applied for, followed by MRP.

A marketing authorisation may also be granted conditionally, for example for an orphan medicinal product, if there exists a clear unmet medical need and the benefit of immediate availability outweighs the risk of less comprehensive data than is normally required.

6.5 Data-exclusivity and market-exclusivity period for reference medicinal products

For reference medicinal product (granted in accordance with Articles 8(3), 10a, 10b or 10c of Directive 2001/83/EC), and to which the marketing-authorisation application for a generic, hybrid or similar biological medicinal product (i.e. application under Articles 10(1), 10(3) or 10(4) of the same Directive) refers, protection period is 10-11 years (8+2+1 years):

• 8 years of data-exclusivity: generic, hybrid or similar biological medicinal products cannot be submitted

• 2 years of market-exclusivity: generic, hybrid or similar biological medicinal products cannot be placed on the market

1 year of data exclusivity shall be granted for new indications for well-established substances provided that significant preclinical or clinical studies were carried out in relation to the new indication.

* The assessment time may be reduced to 150 days instead of 210 days, if the medicinal product developer is granted accelerated assessment

Step by step flow charts of evaluation of medicines are available for CP as well as for DCP and MRP/RUP procedures.

6.4 Compilation and submission

The preparation of the MAA shall be started well on time, as certain preparatory measures need to be agreed with the authorities before the application is submitted. For further information, see steps prior to submitting an application to EMA and request for RMS in a DCP.

Applications must be submitted electronically in eCTD (Electronic Common Technical Document) format primarily via Common European Submission Platform (CESP) (NP/MRP/DCP) or eSubmission Gateway and Common Repository (CP) portals (see e-submissions). Detailed instructions on the structure of the application, the format of submission and the number of copies of the application are given on Fimea’s and CMDh’s websites.

6.5 Timelines and steps

2.2 Introduction2.3 Quality Overall SummaryModule 3 summary

2.6 Non-clinical Summaries- summary of nonclinical studies results2.7 Clinical Summaries - Summary of clinical studies results2.7.1 Summary of BE studies

2.4 Non-clinical Overview- an integrated and critical assessment of Module 4, justifications for exceptions to official guidance, references to scientific literature2.5 Clinical Overview - an integrated and critical assessment of Module 5- an assessment of the benefit-risk balance based on the whole documentation

DCPApplication validation (14 days)Assessment step I (120 days)Clock-stop period (90 days)Assessment step II (90 days)National step (30 days)

Application validation (14 days)National assessment (210 days)Assessment report update, validation (90 + 14 days)MRP (90 days)National step (30 days)

Total at least 448 daysTotal about 344 days

DCP NP + MRP

PROCEDURE PROCESSING TIMES

210 days

90 days + 30 days for evaluation of national translations

210 days + 30 days for evaluation of national translations

210 days* + EC Decision Process time (within 67 days)

NP

MRP

DCP

CP

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7. MAINTENANCE OF MARKETING AUTHORISATION

7.1 Pharmacovigilance

The MAH is required to have a PV system in place to assess on continuous basis the benefit-safety profile of the product. A practical approach for establishing and maintaining the PV system is described in EU GVP Modules (see section 2.5), which are in line with the PV practices and requirements in Finland (Directive 2010/84/EU, Regulation (EU) No 1235/2010, Commission Implementing Regulation No 520/2012 (operational details on implementing the PV legislation), Further amendments strengthen the system, specifically by providing for prompt notification and assessment of safety issues: Regulation (EU) No 1027/2012, Directive 2012/26/EU, Lääkelaki 395/1987, Fimean määräys 4/2013 Lääketurvatoiminta, Fimean ohje 2/2013 Lääkkeiden haittavaikutusten ilmoittaminen).

An appropriate PV system and positive benefit-safety profile are necessary conditions for maintaining the medicinal product on the market.

A PV system in the EU/Finland includes but is not limited to:

• Establishment and maintenance of PSMF

• Nomination of EU-QPPV (Qualified Person for Pharmacovigilance) with 24/7 availability

• System for collection and reporting of safety information

• Global and local literature review for safety information

• System for risk management, signal management and safety communication

• System for periodic reporting of safety information

• PV quality system (e.g. auditing, deviation/corrective action control, training, business continuity planning)

7.2 Variations

The MAH has the obligation to monitor the scientific and technical development of the medicinal product and to maintain the marketing authorisation documentation with variation applications (Directive 2001/83/EC). Commission’s Classification Guidance lists four subtypes of variations: IA, IAIN, IB and II (Commission Regulation No 1234/2008, Commission Regulation No 712/2012, EC Guideline on the details of the various categories of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products, CMDh Variations Guidance).

Type IA changes are minor changes that do not require prior approval but can be implemented (‘do-and-tell’) and notified either immediately (type IAIN) or within 12 months after implementation (type IA). The changes are reviewed within 30 days. Type IB changes are more significant changes and must be reviewed by the authority before implementation (‘tell, wait and do’ procedure). The processing time is 30 + 30 days (depending on the need for supplementary information). Changes that may have a significant impact on the quality, safety or efficacy require a Type II change and can only be implemented after regulatory approval. The processing time for a Type II variation is 60 or 90 days, followed by 30 days of national phase.

If there is a suspicion that the product presents a serious risk during normal use in accordance with the SPC, urgent safety restrictions (e.g. restriction of indication or dosage) may be imposed. The processing time for these restrictions is fast, usually 24 hours. Following a safety restriction, the applicant must submit an appropriate application to the authorities within 15 days.

7.3 Renewals

A marketing authorisation is valid for 5 years from the date of issue. A renewal application must be submitted at the latest 9 months before the expiry date of the MA. Once renewed, the MA will be valid for an unlimited period, unless an Authority mandates, based on pharmacovigilance grounds one additional five-year renewal.

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8. MARKET ACCESS AND MAINTAINING A MEDICINAL PRODUCT ON THE MARKET When a marketing authorisation is granted, MAH has several tasks to do to ensure the product can access the market and be maintained there. In this section, the market access process and requirements related to the maintenance of a medicinal product on the market are discussed.

8.1 Market access

The marketing authorisation expires, if the medicinal product is not placed on the market within three years of grant of the marketing authorisation. In addition to launch notifications to Fimea and Kela (Social Insurance Institution of Finland), price of the product must be declared. In addition, e.g. the packaging of most prescription medicines should have the safety features (a unique serial number and anti-tamper mechanism) required by the Counterfeit Medicines Directive. Multi-country packaging is worth considering as it is often cost-effective in small market areas, such as Finland.

8.2 Price and reimbursement

When a medicinal product containing a new active substance is to be covered by a health insurance reimbursement scheme, in most countries a health economic report containing information on the costs and effectiveness of the medicinal treatment is required as an annex to the claim for reimbursement. The therapeutic and economic value of hospital medicines is also assessed before the product is used. In Finland, Pharmaceuticals Pricing Board (HILA) makes decisions on the reimbursement status and wholesale price of medicinal products.

The retail price of a medicinal product consists of the costs for wholesale and distribution, the pharmacy margin and taxes (VAT). If the medicinal product is not covered by the reimbursement of the sickness insurance institution (Kela) the pharmaceutical company is free to decide the wholesale price. The wholesale price is the same for all pharmacies and is independent of the purchase quantity. The retail price of a medicinal product in a pharmacy is calculated from the wholesale price in accordance with the Government’s pharmaceutical tariff table, and VAT is added to the price. The price of the medicinal product is thus the same in all Finnish pharmacies.

8.3 Supply (distributors, pharmacies, hospital pharmacies)

Pursuant to section 32 (3) of the Pharmaceuticals Act, wholesale trade in medicinal products may be carried out only with Fimea’s permission. Three wholesalers currently operate in Finland: Tamro Corporation, Oriola Corporation and Magnum Medical Finland Oy. Online pharmacy services are legal as well. A legitimate Finnish online pharmacy is identified by a common European logo in the online service, which has a link to the list of legal online pharmacy services. The list is maintained by Fimea.

8.4 Batch control

According to the EU GDP guideline, a batch of medicinal product released in the EU / EEA can be placed on the market only after EU batch certification by a QP (Qualified Person). Release certificate signed by the QP identifies the product, batch and country (or countries) of destination and states that the product has been manufactured in compliance with GMP and complies with a valid marketing authorisation. Fimea is responsible for the batch-specific control of plasma-derived medicinal products, antisera and immunoprophylactic vaccines, for products under special permits and those used in clinical trials.

8.5 Marketing

Advertising of medicinal products must encourage people to use the products appropriately in accordance with the Medicines Act (Lääkelaki 395/1987). The appropriate pharmaceutical marketing comprehensively presents the different effects of use of the medicinal products and guides correct and safe use. Fimea monitors the advertising of all medicinal products. In addition, The Code of Ethics issued by Pharma Industry Finland complements the supervisory activities of the Fimea. All member companies of Pharma Industry Finland are committed to the Code of Ethics and adhere to it.

8.6 Pharmacovigilance

For pharmacovigilance requirements related to maintenance of a marketing authorisation, see section 7.1. PV requirements, which are related specifically to the commercialization of a pharmaceutical product are the need to:

• have system for collection of safety information from the market (HCPs, consumers)

• train the MAH employees/partners for reporting safety information

• ensure there are written agreements in place with potential partners related to the supply/sales of the medicine describing the PV requirements of each party.

A medicinal product must be placed on the market within three years of grant of the marketing authorisation.!

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8.7 Quality Assurance

The MAH is primarily responsible for managing product defects. Pharmacies, hospital pharmacies and military pharmacies are responsible for managing any defects in the medicinal products they produce. All pharmaceutical sector operators are responsible for ensuring that all appropriate measures are in place in the event of a defect. Fimea is tasked with the supervision of all product defect procedures and ensuring that the measures put in place by the operators are appropriate and fit-for-purpose.

8.8 Databases

Information on authorised medicinal products is maintained and published in various databases. The basic register for medicinal products is a register maintained by Fimea on medicinal products and products with a temporary special permit. Some medicinal product databases are voluntary, such as Pharmaca Fennica, where the MAH or its representative can report the product information himself.

9. SCIENTIFIC ADVICEA medicinal product developer can ask guidance and direction from EMA on any quality, non-clinical or clinical aspects or methodological issues, during the initial development of a medicinal product before submission of a MAA or later on, during the post-authorisation phase and irrespective subsequent choice of procedure for approval. It is not legally binding for any party. The EMA is also involved in parallel scientific advice, where the other party may be another foreign Authority, such as the Food and Drug Administration or Health Technology Assessment bodies. Protocol assistance is the special form of scientific advice available for developers of designated orphan medicines for rare diseases (Regulation (EC) No 141/2000). Scientific advice with fee exemptions is particularly helpful for medicinal product developers who may have limited knowledge about medicine regulation, such as some academic groups or micro, small and medium sized enterprises (Commission Regulation (EC) No 2049/2005). There are various incentives available to paediatric drug developers, such as extending data protection period and regulatory advice (Regulation (EC) No 1901/2006, Regulation (EC) No 1902/2006).

The Innovation Office of Fimea offers Informal regulatory guidance at an early stage of drug development for clients without sufficient experience of regulatory requirements of drug development free of charge. Formal scientific advice is primarily meant for more advanced drug development programs.

8.9 Medical info

MAHs are required to have medical information service in place in countries where the medicinal product is available. Medical information service shall provide by request advice on correct and safe use of medicinal products of the MAH. Service is usually provided via phone/e-mail and through a contractual partner.

8.10 Mandatory reserve supplies

The Act on Mandatory Reserve Supplies (979/2008) defines how to ensure the availability of medicinal products in circumstances in which such availability is restricted or prevented as a result of suspension of deliveries, a serious crisis or other equivalent reason and the key government agencies are the Fimea and the National Emergency Supply Agency. The Government Decree on Mandatory Reserve Supplies of Medicines (1114/2008) provides more details and further terms and instructions.

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IN VITRO DIAGNOSTIC (IVD) IN VITRO DIAGNOSTIC (IVD) MEDICAL DEVICESMEDICAL DEVICES

PART II

1. BASICS OF IN VITRO DIAGNOSTIC (IVD) MEDICAL DEVICES   342. DEFINITIONS 35

2.1 Definition of an in vitro Diagnostic Medical Device 352.1.1 Genetic Testing 362.1.2 Software and Mobile Applications 36

2.2 Definition of an Accessory for an IVD Medical Device 373. LEGISLATION AND TRANSITION PERIOD BETWEEN THE OLD DIRECTIVE AND THE NEW REGULATION 374. CLASSIFICATION 385. CONFORMANCE CRITERIA 39

5.1 Device Conformance Criteria 395.1.1 Technical Documentation 395.1.2 Essential Requirements/ General Safety and Performance Requirements 40

5.1.3.1 Harmonised Standards 405.1.3.2 Common Specifications 41

5.1.4 Performance Evaluation 415.1.5 Technical Documentation on Post-Market Surveillance 425.1.6 Unique Device Identification (UDI) 43

6. CONFORMITY ASSESSMENT ROUTES 446.1 What is a Notified Body? 446.2 Conformance Assessment According to the IVDD 456.3 Conformance Assessment According to the IVDR 47

7. CE MARKING AND DECLARATION OF CONFORMITY 529. PERSON RESPONSIBLE FOR REGULATORY COMPLIANCE, PRRC 5310. AUTHORISED REPRESENTATIVE 5311. REGISTRATION OF DEVICE 54

11.1 Registration According to IVDD 5411.2 Registration According to IVDR 54

12. SUMMARY OF SAFETY AND PERFORMANCE 5513. EUDAMED 55

Part II Contents

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1. BASICS OF IN VITRO DIAGNOSTIC (IVD) MEDICAL DEVICES  

Part II text provides information on in vitro Diagnostic Medical (IVD) Devices, including IVD genetic tests and applications that have a medical purpose. In Finland, as well as in EU, medical devices shall bear a CE mark in order to be placed in the market. CE mark is a demonstration that the medical device fulfils all applicable obligations set in the legislation. Legal manufacturer of the device is responsible for demonstrating the conformity before placing the device on the market but is also responsible for the devices placed on the market.

Current provision regulating in vitro diagnostic medical devices in Europe is based on the IVD directive 98/79/EC (IVDD). In addition, MEDDEV instructions are referred to later on in this summary. MEDDEVs are published by the authorities and amend the directive and give further interpretation for stakeholders.

The new regulation 2017/746 (IVDR) was published in 2017 and has a five-year transition period until May 26, 2022. This guide gives a short but detailed introduction to in vitro diagnostic medical devices regulations, both the in vitro medical device directive and in vitro medical device regulation.

It should be noted that Medical Devices (MDs), which do not fall into the criteria of IVD, have their own regulation; MD Regulation (EU) 2017/745 (MDR).  

2. DEFINITIONS

2.1 Definition of an in vitro Diagnostic Medical Device

An in vitro diagnostic (IVD) medical device is a reagent, instrument, software or system intended to be used in vitro for the examination of specimens for the purpose of providing information:

• concerning a physiological or pathological process or state

• concerning congenital physical or mental impairment

• to determine the safety and compatibility with potential recipients

• to define or monitoring therapeutic measures

• Specimen receptacles are also deemed to be IVD medical devices.

Compared to The European Parliament and the Council directive 98/79/EC (https://eur-lex.europa.eu/legal-content/EN/ALL/?uri=CELEX%3A31998L0079) on in vitro diagnostic medical devices (IVDD, IVD directive), the definition an IVD medical device will change. The European Parliament and the Council regulation 2017/746 (https://eur-lex.europa.eu/eli/reg/2017/746/oj) on in vitro diagnostic medical devices (IVDR, IVD regulation) has specifically added sections on the purpose of providing information on concerning the predisposition to a medical condition or a disease and predicting treatment response or reactions. The addition described above is important as it clarifies the status of certain genetic tests. For example, tests intended for testing a young healthy person´s genetic susceptibility for heart and vascular diseases have been on a grey area. However, as the IVDR contains “susceptibility to disease or illness” these kinds of tests fall in the scope of the IVDR.

For more precise definition, please refer to the IVDD article 1(2)(b) and/or IVDR article 2(2).

2.1.1 Genetic Tests

From legislation perspective genetic tests that are intended to provide information on the state of the health of a human being or treatment of a disease are IVD medical devices. It’s important to distinguish these medical devices from genetic tests without a medical purpose. Hence, tests intended to determine for example paternity or ancestors are not medical devices. Neither are genetic tests intended for animal testing. In other words, whether a genetic test falls in the scope of an IVD medical device depends on the intended use of the device defined by the manufacturer.

It should be noted that Medical Devices (MDs), which do not fall into the criteria of IVD, have their own regulation; MD Regulation (EU) 2017/745 (MDR).   Such MDs are out of the scope of this guide.

!

!

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2.1.2 Software and Mobile Applications

Software or mobile application can also be an IVD medical device or an accessory for an IVD medical device.

IVDD guidance document Qualification and Classification of standalone software – MEDDEV 2.1/6 (https://ec.europa.eu/docsroom/documents/17921/attachments/1/translations) defines qualification of standalone software, when used in healthcare setting, as a medical device and the application of the classification criteria to such software. The criteria apply also to mobile applications.

MEDDEV 2.1/6 defines, inter alia, the following two terms: standalone software and software as medical device (SaMD). According to the guidance document, standalone software means software which is not incorporated in a medical device. SaMD is defined as software intended to be used for one or more medical purposes that perform these purposes without being part of a hardware medical device.

Respectively, guidance document MDCG 2019-11 Guidance on Qualification and Classification of Software in MDR and IVDR (https://ec.europa.eu/health/sites/health/files/md_sector/docs/md_mdcg_2019_11_guidance_qualification_classification_software_en.pdf) defines the criteria for the qualification of software falling within the scope of the new medical devices regulations and provides guidance on the application of classification criteria for software under Regulation 2017/745/EU – MDR and Regulation 2017/746/EU – IVDR.

In the MDCG 2019-11, which is the new guidance to be followed in line with IVDR and MDR, the term standalone software is no longer used. The rationale of the change is that software should be qualified and classified depending on its intended purpose uniquely, regardless of its location. Further, the MDCG 2019-11 replaces the term SaMD with medical device software (MDSW), which is, according the guidance document, software that is intended to be used, alone or in combination, for a purpose as specified in the definition of a “medical device” in the medical devices or in vitro diagnostic medical devices regulation.

The new guidance document contains decision trees, which are very helpful for classification. For example, to evaluate applicability of MDR or IVDR, the following decision steps should be taken: 1) Does the MDSW provide information within the scope of the IVD definition? 2) Does the MDSW provide information based on data obtained by IVD medical devices only? 3) Is the intended purpose substantially driven by IVD data sources? If answer to the three questions is yes, the MDSW is covered by Regulation (EU) 2017/746 (IVDR). If no, which is the answer in most of the cases, the medical device software is classified using Rule 11 of Regulation (EU) 2017/745 (MDR), which is out of the scope of this guide.

Despite the differences in the terminology between MEDDEV 2.1/6 and MDCG 2019-11, the main message of both documents is that software must have a medical purpose to be qualified as medical device. More precisely, only the intended purpose as described by the manufacturer of the product is relevant for the qualification and classification of any device and not by virtue of the way it may be called.

To simplify, when defining a qualification and classification of a software, the first step is to define, if the software qualifies a MDSW. The next steps are to define if the MDSW is regulated under MDR or IVDR and which risk class applies to the MDSW. According to the new classification rules and in line with MDCG 2019-11, software regulated by the IVDR are most likely classified in class B a minimum requiring a Notified Body assessment (For Notified Body, see chapter 6.1). A is the lowest and D the highest risk class for IVD medical devices. More precisely, unless classified to a higher class than class B by any of the specific rules, the rule 6 of the IVDR is the rule making the device at a minimum a class B device. Only if the software is an accessory to another IVD, it may be classified as class A IVD device. For more about device classification, see chapter 4.

2.2 Definition of an Accessory for an IVD Medical Device

An accessory for an IVD medical device means an article which, whilst not being itself an IVD medical device, is intended by its manufacturer to be used together with IVD medical device to specifically enable the IVD medical device to be used in accordance with its intended purpose or to specifically and directly assist the medical functionality of the IVD medical device in terms of its intended purpose. For more information, please refer to the IVDD article 1(2)(c) or IVDR artcle 2(4).

3. LEGISLATION AND TRANSITION PERIOD BETWEEN THE OLD DIRECTIVE AND THE NEW REGULATION

Current provision regulating in vitro diagnostic medical devices in Europe is based on the IVD directive 98/79/EC. In Finland the directive has been transposed into national law on health care products and equipment (laki terveydenhuollon laitteista ja tarvikkeista, 629/2010 in Finnish). However, the old directive will give way for the new IVD regulation. As the IVDR is a regulation, it is a binding legislative act meaning it must be applied in its entirety across the EU without transposing it into the national legislation.

The IVDR was published in 2017 and has a five-year transition period until May 26, 2022. During the transition period new IVD medical devices placed on the market can conform either with the IVDD or with the IVDR. May 26, 2022 is the date of application (DoA) of the IVDR. After the DoA, IVDD certificates cannot be renewed. However, even after the DoA, an IVD medical device having a valid IVDD certificate can be placed on the market until the certificate expiration date. However, the purpose and nature of the device cannot be changed.

IVDD certificates for products reclassified to a higher risk class under the IVDR respectively remain valid until their expiration dates. The IVDD classification rules for these products will continue to apply until the expiration of the IVDD certificates.

Starting from May 26, 2024 all IVD medical devices shall conform with the IVDR.

In Vitro Diagnostic Regulation (IVDR) Implementation Schedule

2017 2018 2019 2020 2021 2022 2023 2024 2025

5 May 2017IVD adoption 5 years transition period

26 May 2017IVDR entry into force

26 May 2022IVDR date of application

26 May 2024 - 27 May 2025 IVDD devices already placed on the market may continue to be made available

From 26 May 2024 All devices placed on the maerket must conform with the IVDR

From 26 May 2017Devices that conform with the in Vitro Diagnotic Medical Devices Regulations (IVDR) may be placed on the market

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PART II: In vitro diagnostic (IVD) Medical Devices

5. CONFORMANCE CRITERIA

In Finland (and in the European Economic Area), only compliant medical devices may be placed on the market and put into service. Before placing a medical device on the market, the manufacturer must demonstrate its safety, suitability for use and performance. The manufacturer must affix CE mark on the device before placing it on the market to indicate its compliance with the requirements. In addition to the device, medical device manufacturers have requirements to be complied, too.

5.1 Device Conformance Criteria

A manufacturer wishing to place an IVD medical device on the market under IVDD or the IVDR must

• assign the device to one of the relevant risk categories defined in the IVDD or IVDR as specified above

• ensure that applicable technical documentation including the essential requirements specified in the IVDD Annex I or correspondingly general safety and performance requirements specified in the IVDR Annex I and Declaration of Conformity have been drawn up

• follow the appropriate conformity assessment procedure.

5.1.1 Technical Documentation

The term technical documentation (or technical file) refers to all the documents required for the conformity assessment and, therefore, for the approval of the medical devices. IVDD Annex III and IVDR Annex II and Annex III describes the minimum content of the technical documentation.

4. CLASSIFICATION

One of the most significant changes while transferring from the IVDD to the IVDR is the IVD medical device classification system. IVDD includes four categories for the IVD medical devices: Annex II List A devices, Annex II List B devices, devices for self-testing and general devices, where Annex II List A devices represent the highest risk and general devices the lowest risk.

The current list-based approach will be superseded by a new rule-based system in the IVDR (Annex VIII). The rule-based approach in IVDR Annex VIII includes also four risk categories, from Class D (highest risk) to Class A (lowest risk). The rule-based classification system is less exclusive than the list-based system: instead of naming specific devices, the risk classification of the device is determined by its intended use and the analytes being measured.

Even though the IVDD and the IVDR classification systems are not fully comparable with each other many IVD medical devices will adopt a higher risk class when conforming with the IVDR. For example, some tests intended for blood screening belong to Annex II List B devices but will be re-classified as a Class D device according to the IVDR. Furthermore, human genetic testing was not included in the Annex II List A or B devices previously, but in the future will be classified at least as a Class C device. Please refer to the figure below.

The legal manufacturer is responsible for the classification of the device. If the Notified Body disagrees (please refer to the chapter 6) with the manufacturer’s classification, the matter should be referred to the Competent Authority (CA) of the country in which the manufacturer (or its authorized representative) is located.

Before placing a medical device on the market, the manufacturer must demonstrate its safety, suitability for use and performance.!

HIGH

RISK

LOW

IVDD 98/79/EC IVDR 746/2017/EU

Annex II List A

Class C

Class B

Class A

Annex II List B

Self-testing

General

- HIV- Hepatis- Blood screening: ABO,

Rhesus system, anti-Kell

- Blood screening (all systems)- Sample evaluation of suitability for

transfusion/ transplantation- Detection of life-threatening disease w ith high risk of propagation

- Companion diagnostics- Human genetic testing- Cancer screening

- Pregnancy and fertility tests- Home cholestrol tests

- Pregnancy test- Home cholestrerol test

- Test for hormones- Cardiac markers

Class D

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PART II: In vitro diagnostic (IVD) Medical Devices

5.1.2 Essential Requirements/ General Safety and Performance Requirements

An IVD medical device placed on the market in conformance with the IVDD must comply with the essential requirements specified in the IVDD Annex I. Correspondingly, an IVD medical device placed on the market in conformance with the IVDR must comply with the essential safety and performance requirements. The essential requirements/general safety and performance requirements aim to ensure that the products do not compromise the health and safety of the patients and users and are designed and manufactured to achieve the performance specified by the manufacturer for the stated medical purpose. Essential Requirements (ER) checklist/General Safety and Performance Requirement checklist (GSPR) is a document by which the manufacturer demonstrates conformity with the requirements. IVDD ER checklist/ IVDR GSPR checklist is a part of the technical documentation.

The essential requirements/general safety and performance requirements include requirements for performance, design and development, manufacturing and the information supplied with the device. Where the IVDD includes 8 main essential requirements with few sub-requirements, IVDR includes 20 general safety and performance requirements with several sub-requirements. The level of requirements increases with the transition to IVDR.

Not all the essential requirements/general safety and performance requirements will apply to all devices, hence the manufacturer of the device needs to assess which are appropriate for the particular medical device.

5.1.3 Harmonised Standards and Common Specification

5.1.3.1 Harmonised Standards

Manufacturers can demonstrate they have met essential requirements/general safety and performance requirements by complying with the relevant harmonized standards. A harmonized standard is a European standard version (EN) of an international ISO/IEC standard developed by a recognized European Standards Organization (CEN or CENELEC). All harmonized standards will contain an Annex Z, which is a cross-connection table between the standard and the directive/regulation under which the standard is harmonized. The use of these standards is voluntary. Manufacturers are free to choose another technical solution to demonstrate compliance with the mandatory legal requirements.

European Commission Implementing Decision (EU) 2020/439 lists the harmonized standards for in vitro diagnostic medical devices to support IVDD. At the time of writing this guide, harmonized standards to support IVDR is not existing yet.

5.1.3.2 Common Specifications

In the case no harmonised standards exist, or where relevant harmonised standards are not sufficient, or there is a need to address public health concerns, European Commission can adopt Common Specifications for specific categories of IVD medical devices. The Common Specifications may be laid down to provide means of complying with the general safety and performance requirements in the following regulatory areas:

• general safety and performance requirements

• technical documentation

• performance evaluation and post-market performance follow-up

• requirements regarding performance studies.

Devices that are in conformity with the Common Specification shall be presumed to be in conformity with the IVDR.

5.1.4 Performance Evaluation

Manufacturers are obligated to perform a pre-market performance evaluation by both IVDD and IVDR. However, none of the articles in the IVDD explicitly require the performance evaluation and thus the requirement is implied. Contrary to the IVDD, the requirement to conduct a pre-market performance evaluation is explicitly stated in the IVDR Article 56 and is detailed in the Annex XIII.

The performance evaluation shall be based on a performance evaluation plan, which describes the procedure, how the performance evaluation is to be carried out, which aspects are to be examined and how the results are to be documented. The IVDR Annex XIII describes minimum requirements for the content of a performance evaluation plan.

A performance evaluation report shall be compiled based on the performance evaluation plan. The performance evaluation report shall summarize data of clinical and analytical performance of the IVD medical device concerned. The level of clinical evidence needed to demonstrate the conformity of a device becomes progressively more stringent as the risk class increases.

The IVDR contains a new requirement for post-market performance follow-up to update the performance evaluation when needed throughout the life cycle of the device.

In addition, the IVDR describes the situations in which manufacturers must conduct performance studies, and how the studies should be carried out.

! Medical device placed on the market must comply with the essential requirements specified in the relevant regulations.

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PART II: In vitro diagnostic (IVD) Medical Devices

5.1.5 Technical Documentation on Post-Market Surveillance

The IVDR article 10 sets out a requirement for manufacturers to have a post-market surveillance (PMS) system in place. The detailed description of the PMS system is described in the IVDR articles 78-81. The purpose of the PMS system is to systematically gather, record and analyse data on the quality, performance, and safety of the device throughout its entire life cycle and when necessary, based on the conclusions of the PMS data, implement relevant preventive and corrective actions. The feedback information gathered through the PMS system shall be used to:

• update the benefit-risk determination and to improve the risk management

• update the design and manufacturing information, the instructions for use and the labelling

• update the performance evaluation

• update the summary of safety and performance (if applicable)

• detect reportable trends

• update the technical documentation

• identify necessary preventive, corrective, or field safety corrective action

• identify opportunities to improve the usability, performance, and safety of the device

• if applicable, to contribute to the post-market surveillance of other devices.

The post-market surveillance system shall be planned, established, documented, implemented, and maintained for each device. The post-market surveillance system must be based on a post-market surveillance plan. The IVDR Annex III describes the detailed requirements for the PMS plan. Based on the PMS plan, the manufacture shall prepare a post-market surveillance report for Class A and B devices and correspondingly a periodic safety update report (PSUR) for Class C and D devices. Post-market surveillance report (Class A and B devices) shall be updated when necessary. PSUR (Class C and D devices) shall be updated at least annually. PMS plan, PMS report and PSUR are part of the technical documentation.

5.1.6 Unique Device Identification (UDI)

The IVDR article 24 and Annex VI Part C describe the system of Unique Device Identifier (UDI). This is a new requirement in the IVDR compared to the IVDD. The purpose of the UDI system is to enhance the identification and traceability of IVD medical devices.

The UDI system consists of three levels (DI=Device Identifier and PI=Production Identifier):

1. Basic-UDI DI

2. UDI-DI

3. UDI-PI

The Basic UDI-DI is the main key in the database for relevant documentation (for example certificates, declaration of conformity, technical documentation etc.) to connect devices with same intended purpose, risk class, and essential design and manufacturing characteristics. It is independent and separate from the packaging and labelling of the device and it does not appear on any trade item.

The UDI on the device labelling contains two parts: a UDI-DI and a UDI-PI. The UDI-DI is a unique code (numeric or alphanumeric) specific to the model of the device. Production Identifier (UDI-PI) is a code that identifies the unit of device production. The different types of UDI-PI(s) include a serial number, lot number, software identification, and manufacturing or expiry date, or both.

The UDI shall be implemented in the labelling by means of automatic identification and data capture (AIDC) and human readable interpretation (HRI). The UDI shall be assigned to the device itself or its packaging. Higher levels of packaging shall have their own UDI. Only the manufacturer may place the UDI on the device or its packaging.

Manufacturers shall provide Basic UDI-DI and UDI-DI to the UDI database called Eudamed. For more information, please refer to the chapter 13.

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PART II: In vitro diagnostic (IVD) Medical Devices

6. CONFORMITY ASSESSMENT ROUTES

According to some estimates, approximately 10-20% of IVD devices conforming with the IVDD require certification by a third party called a Notified Body before placing the devices on the market. However, once the IVDR fully applies, approximately 80-90% of IVD devices will require Notified Body certification. Among the changes in the classification system, this is another significant change in the IVD medical device regulation while transferring from the IVDD to the IVDR.

6.1 What is a Notified Body?

A Notified Body is an independent organization that has been designated (“notified”) by an EU member state (the designating authority) to assess whether manufacturers and their medical devices meet the requirements set out in the legislation e.g., requirements for CE-marking. It is notable, that Notified Bodies who are designated under the IVDD will not automatically get designation under the IVDR. The designated Notified Bodies must apply new designation under the IVDR. Additionally, at the time of application submission of the IVDR all Notified Bodies lose their Notified Body statuses.

IVDR Annex VII lists requirements to be met by Notified Bodies. The requirements are more stringent compared to the IVDD. Slow designation process and low availability of IVDR designated Notified Bodies is a commonly recognized challenge within the industry.

At the time of writing this guide, there are no IVDR designated Notified Bodies available in Finland, and only one IVDD designated:

Eurofins Expert Services Oy PL 47 Kivimiehentie 4 FI-02150 Espoo Finland

Phone: +358406311311 Website: https://www.eurofins.fi/expertservices Notified Body number: 0537

Manufacturers are free to apply to any Notified Body in the EU designated to carry out the desired conformity assessment procedure, regardless of which Member State the Notified Body is designated in. The lists of Notified Bodies are given in the Nando (New Approach Notified and Designated Organisations) Information System database: https://ec.europa.eu/growth/tools-databases/nando/.

6.2 Conformance Assessment According to the IVDD

Despite the regulation (IVDD or IVDR), device category determines the options for conformity assessment. The conformance assessment routes for IVD medical devices classified according to the IVDD are summarized below.

SELF-TESTING IVDs

IVDD Annex III Declaration of Conformity

IVDD Annex III Section 6 Product Design Examination by NB

CEmark

GENERAL IVDs

Self-declaration according to the IVDD Annex III

CEmark

General IVDs (low risk)

For IVD medical devices belonging to General category, Notified Body is not required for conformance assessment, but manufacturer self-declares the device(s) after the applicable obligations of the IVDD are fulfilled.

Self-testing (low risk)

IVD devices meant for self-testing require Notified Body´s examination of the device design based on IVDD Annex III Section 6. This includes aspects affecting the device suitability for non-professional (lay) users. Alternatively, the manufacturer may follow the conformity assessment routes for higher risk products as detailed below.

Once the IVDR fully applies, approximately 80-90% of IVD devices will require Notified Body certification.

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PART II: In vitro diagnostic (IVD) Medical Devices

Annex II List B (moderate risk)

IVDD Annex II List B devices require Notified Body for the conformity assessment. Conformity assessment route options are:

1. Quality Management System audit based on IVDD Annex IV or

2. EC Type Examination based on IVDD Annex V and EC Verification (Product Examination) based on IVDD Annex VI or

3. EC Type Examination based on IVDD Annex V and Production Quality Assurance audit based on IVDD Annex VII.

6.3 Conformance Assessment According to the IVDR

IVDR CLASS A IVDs

Self-declaration IVDR Annex IV CE

mark

Class A (low individual risk & low public health risk)

IVDR CLASS As IVDs IVDR Annex IX

chapters I, III Quality Management System audit by NB

IVDR Annex XI Production Quality Assurance audit by NB

CE

CE

mark

mark

Limited to sterility aspects

Limited to sterility aspects

Annex II List A (high risk)

IVDD Annex II List A devices require Notified Body for the conformity assessment. Conformity assessment route options are:

1. Quality Management System audit based on IVDD Annex IV and Product Design Dossier examination based on IVDD Annex IV Section 4 and batch or product verification based on IVDD Annex IV Section 6 or

2. EC Type Examination based on IVDD Annex V and Production Quality Assurance audit based on Annex VII and batch or product verification based on IVDD Annex VII Section 5.

IVDD ANNEX II

LIST A DEVICES IVDD Annex IV

Full Quality System audit by NB

IVDD Annex IV Section 4 Product Design Dossier Examination by NB

IVDD Annex IV Section 6 Batch or Product Verification by NB

IVDD Annex VII Quality System audit by NB

IVDD Annex VII Section 5 Batch or Product Verification by NB

IVDD Annex V EC Type Examination by NB

CE

CE

mark

mark

CEmark

CEmark

CEmark

IVDD ANNEX LIST B

DEVICESIVDD Annex IV Quality System audit by NB

IVDD Annex V EC Type Examination by NB

IVDD Annex VII Quality System audit by NB

IVDD Annex VI Product Examination by NB

For Class A devices, Notified Body is not required for conformance assessment, but manufacturer self-declares the device(s) after the applicable obligations of the IVDR are fulfilled.

Class A sterile devices (As)

Unlike other Class A devices, Notified Body is required for Class As devices to assess the aspects related to establishing, securing, and maintaining sterile conditions in the device.

Class As assessment route options:

1. Quality Management System assessment based on IVDR Annex IX Chapters I, III (limited to the aspects related to establishing, securing, and maintaining sterile conditions) or

2. Production Quality Assurance assessment based on IVDR Annex XI (limited to the aspects related to establishing, securing, and maintaining sterile conditions)

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PART II: In vitro diagnostic (IVD) Medical Devices

Class B (moderate individual risk and/or low public health risk)

Class B devices require Notified Body for the conformity assessment. Conformity assessment is based on Quality Management System assessment according to IVDR Annex IX Chapters I, III and Technical Documentation assessment according to IVDR Annex IX Chapter II, Section 4. Notified Body will only assess a sample of the technical documentation for each device category.

Class C self-tests (ST) and near patient test (NP)

Also, Class C(ST) and C(NP) devices require Notified Body for the conformity assessment. Conformity assessment options are:

1. Quality Management System assessment based on Annex IX Chapters I, III and Technical Documentation Assessment (assessing per generic device group) based on Annex IX Chapter II, Sections 4 and 5.1 or

2. EU Type Examination based on Annex X and Production Quality Assurance assessment based on Annex XI excluding Section 5.

Class C (high individual risk and/or moderate public health risk)

Class C devices require Notified Body for the conformity assessment. Conformity assessment options are:

1. Quality Management System assessment based on IVDR Annex IX Chapters I, III and Technical Documentation assessment (assessing per generic device group) based on IVDR Annex IX Chapter II, Section 4 or

2. EU Type Examination based on IVDR Annex X and Production Quality Assurance assessment based on IVDR Annex XI excluding Section 5.

IVDR CLASS B (ST) and B (NP) IVDs

IVDR Annex IX chapters I, III Quality Management System audit by NB

IVDR Annex IX Chapter II, Sections 4 and 5.1 Technical Documentation assessment by NB

CEmark

IVDR CLASS B IVDs

IVDR Annex IX chapters I, III Quality Management System audit by NB

IVDR Annex IX Chapter II, Section 4 Technical Documentation assessment by NB

CEmark

Class B self-tests (ST) and near patient test (NP)

Class B(ST) and B(NP) devices have only a slightly different conformity assessment route compared to Class B devices: it consists of Quality Management System assessment (IVDR Annex IX Chapters I, III) and Technical Documentation Assessment based on IVDR Annex IX Chapter II, Sections 4 and 5.1. Also, Technical Documentation will be assessed for every device.

IVDR CLASS C IVDs IVDR Annex IX

chapters I, III Quality Management System audit by NB

IVDR Annex IX Chapter II, Section 4 Technical Documen-tation assessment by NB

IVDR Annex XI (excluding Section 5)Quality System audit by NB

IVDR Annex X EU Type Examination by NB

CE

CE

mark

mark

IVDR CLASS C (ST) and

C (NP) IVDs IVDR Annex IX Chapters I, III Quality Management System audit by NB

IVDR Annex IX Chapter II, Sections 4 and 5.1 Technical Documentation assessment by NB

IVDR Annex XI Quality System audit by NB

IVDR Annex X EU Type Examination by NB

CE

CE

mark

mark

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PART II: In vitro diagnostic (IVD) Medical Devices

Class C Companion diagnostic tests (CDx)

Companion diagnostic devices (CDx) provide information essential for the safe and effective use of the corresponding therapeutic product e.g., to determine applicability of a medicine to a specific person. For companion diagnostic devices, Notified Body is required for the conformity assessment. In addition, EU Member State Competent Authority (CA) or European Medicine Agency (EMA) consultation is always required. Class C (CDx) devices have two conformity assessment options:

1. Quality Management System assessment based on Annex IX Chapters I, III and Technical Documentation assessment (assessing per generic device group) based on Annex IX Chapter II, Section 4 and 5.2 and Member state CA or EMA consultation (as per Annex IX Section 5.2) or

2. EU Type Examination based on Annex X and Production Quality Assurance assessment based on Annex XI excluding Section 5 and Member state CA or EMA consultation (as per Annex IX Section 5.2).

Class D (High individual risk and high public health risk)

For Class D high risk IVD medical devices, the assessment includes mandatory batch verification in an EU reference laboratory (if designated for that type of device) to verify the performance claimed by the manufacturer and compliance with the applicable Common Specifications. For innovative Class D devices where no Common Specifications exist, an independent expert panel must provide its views on the performance evaluation report of the manufacturer. Two options for the Class D device conformity assessment exists:

1. Quality Management System assessment based on Annex IX Chapters I, III and Technical Documentation assessment (assessing per generic device group) based on Annex IX Chapter II, Section 4 including verification by an EU reference laboratory and Batch Verification based on Annex XI Section 5 or

2. EU Type Examination based on Annex X including verification by an EU reference laboratory and Production Quality Assurance based on Annex XI and Batch Verification based on Annex XI Section 5.

IVDR CLASS CDx IVDs IVDR Annex IX

chapters I, III Quality Management System audit by NB

IVDR Annex IX Chapter II, Sections 4 and 5.2 Technical Documentation assessment by NB

IVDR Annex XI (excluding Section 5) Quality System audit by NB

CA or EMA consultation

CA or EMA consultation

IVDR Annex X EU Type Examination by NB

CE

CE

mark

mark

IVDR CLASS D IVDs IVDR Annex IX

chapters I, III Quality Management System audit by NB

IVDR Annex IX Chapters II, Section 4 Technical Documenta-tion assessment by NB

IVDR Annex XI Quality System audit by NB

IVDR Annex XI Batch Verification Section 5

IVDR Annex XI Batch Verification Section 5

IVDR Annex X EU Type Examination by NB

CE

CE

mark

mark

Class D self-tests (ST) and near patient test (NP)

Conformity assessment of Class D(ST) and D(NP) devices require also Notified Body and EU reference laboratory verification for the conformity assessment. There are two options:

1. Quality Management System assessment based on Annex IX Chapters I, III and Technical Documentation assessment (assessing per generic device group) based on Annex IX Chapter II, Sections 4 and 5.1 and Batch Verification based on Annex XI Section 5 or

2. EU Type Examination based on Annex X and Production Quality Assurance based on Annex XI and Batch Verification by an EU reference laboratory based on Annex XI Section 5.

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PART II: In vitro diagnostic (IVD) Medical Devices

By affixing the CE mark on a medical device, a manufacturer is declaring, on its sole responsibility, conformity with all legal requirements applicable to that product. Hence, the CE mark shall be affixed only after all verification, validation (including performance evaluation) demonstrating the compliance and, when applicable, Notified Body certification has been completed.

In addition to the CE mark, manufacturer shall draw up and sign a Declaration of Conformity (DoC). The EC DoC claims conformity with the IVDD (Annex III of the IVDD) while EU DoC claims conformity with the IVDR (Annex IV of the IVDR). Therefore, the DoC is a mandatory document and by signing it the manufacturer declares the product meets the provisions of the IVDD or IVDR.

9. PERSON RESPONSIBLE FOR REGULATORY COMPLIANCE, PRRC

The IVDR article 15 requires manufacturers to have at least one designated person responsible for regulatory compliance, a PRRC. The PRRC shall have requisite expertise for the role. The IVDR article 15 describes the needed qualifications for educational level and work experience.

The PRRC is at least responsible for ensuring that:

• before devices are released to the market, the device conformity is checked in accordance with the quality management system

• technical documentation and the EU declaration of conformity are drawn up and kept updated

• the post-market surveillance obligations are complied

• the reporting obligations are fulfilled

If more than one person is jointly responsible for regulatory compliance, their responsibility areas shall be documented.

Micro and small businesses are not required to have the PRRC within their organization but shall have such person permanently and continuously at their disposal.

7. CE MARKING AND DECLARATION OF CONFORMITY

8. MANUFACTURER OBLIGATIONSCompared to the IVDD, manufacturer obligations are now clearly stated in the IVDR. However, both regulations require manufacturers to apply a conformity assessment procedure and maintain systems for vigilance to notify the regulatory authorities of adverse incidents and for post-market process to gain information on devices placed on the market and, when necessary, take appropriate corrective actions. In addition to these obligations, the IVDR article 10 expands the obligations of the manufacturers. Manufacturers shall have systems for risk management and quality management, conduct performance evaluations, and create and maintain the technical documentation. As manufacturers are responsible for their devices placed on the market, they must have systems in place to cover their financial responsibility for harm caused by defective devices. Every manufacturer shall have a designated person responsible for regulatory compliance.

10. AUTHORISED REPRESENTATIVEManufacturers who do not have a registered place of business in the EU or European Economic Area (EEA) must designate an authorised representative based inside the EU/EEA to perform certain obligations. The obligations include for example:

• verifying that the EU declaration of conformity and technical documentation have been drawn up and an appropriate conformity assessment procedure has been carried out by the manufacturer (when applicable)

• keeping available a copy of the technical documentation, the EU declaration of conformity and a copy of the relevant certificate(s) (when applicable)

• assisting with certain device registrations and

• communication and co-operation with Notified Body and competent authorities.

IVDR article 11 lists the detailed obligations for the authorised representative. The tasks to be performed by the authorised representative shall be specified in the mandate agreed between the representative and the manufacturer.

Manufacturer responsibilities are now clearly stated in the IVDR.

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PART II: In vitro diagnostic (IVD) Medical Devices

11. REGISTRATION OF DEVICE11.1 Registration According to IVDD

IVD medical device manufacturers established in Finland shall notify their contact details and information on the products they manufacture for the product register maintained by the Finnish Medicines Agency Fimea. Fimea’s contact information is listed below:

FIMEA - Finnish Medicines Agency P.O. Box 55 FI-00034 FIMEA FINLAND

Switchboard: +358 29 522 3341 firstname.lastname@fimea.fi

If the manufacturer is established outside of EU or EEA, an authorised representative established in Finland is required to submit a similar notification.

Notification shall be submitted within two weeks of the device and its conformity procedures meeting legal requirements and the placement of the device on the market, or when the device has been submitted for performance evaluation.

More information and the registration form can be found on Fimea´s webpage: https://www.fimea.fi/web/en/medical-devices/registration

11.2 Registration According to IVDR

Once the IVDR has fully entered into force, the registration process of medical devices will change. Instead of competent authorities’ databases, the registration database will be Eudamed (please refer to the chapter 13). An IVD medical device manufacturer shall assign a Basic UDI-DI and provide it to the UDI database (together with the other core data elements listed in the IVDR related to that device Annex VI Part B) before placing a device on the market. Further, for devices that are subject to a conformity assessment, the Basic UDI-DI shall be assigned before the manufacturer applies to a Notified Body for the assessment.

12. SUMMARY OF SAFETY AND PERFORMANCE

A summary of safety and performance is required for class C and D IVD medical devices. Manufacturer shall write the summary of safety and performance of the medical device in a way that is clear for the intended users and, if relevant, for the patients. The summary of safety and performance is made available to the public via Eudamed.

The draft of the summary of safety and performance shall be part of the documentation to be submitted to the Notified Body involved in the conformity assessment. Notified Body validates the summary of the safety and performance. After the validation, the Notified Body shall upload the summary to Eudamed. The manufacturer shall mention on the label or user instructions where the summary is to be found.

13. EUDAMEDEudamed is European Database on Medical Devices. Eudamed will improve transparency and coordination of information regarding medical devices available on the EU market. The system will be multipurpose. Eudamed includes the following electronic modules:

1. The electronic system for registration of devices

2. The UDI database

3. The electronic system on registration of economic operators

4. The electronic system on notified bodies and on certificates

5. The electronic system on performance studies

6. The electronic system on vigilance and post-market surveillance

The electronic system on market surveillance

More information on Eudamed can be found on the European Commission webpage: https://ec.europa.eu/health/md_eudamed/overview_fi

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RUSSIAN-FINNISH LIFE SCIENCE PARK 5 K, Karpovka River Emb. 197022 St. Petersburg, RUSSIA +7 812 670 10 85 info@rflsp.ru http://www.rflsp.ru

SAINT PETERSBURG TECHNOPARK 3A, Medikov Pr. 197022 St. Petersburg, RUSSIA +7 812 670 10 85 referent@ingria-park.ru https://ingria-park.ru

MUNICIPALITY OF THE CITY OF KOTKA Kustaankatu 2, FI-48101 Kotka, FINLAND +358 40 585 2540 nina.rauhala@kotka.fi https://www.kotka.fi

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