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Harmonisation of the Quality Dossier

by Means of the Worksharing Procedure:

A Look at Execution and Advocacy

from Applicant's Perspective

Wissenschaftliche Prüfungsarbeit

zur Erlangung des Titels "Master of Drug Regulatory Affairs" vorgelegt von

Alexander Dziambor

aus Kirchheim unter Teck

Bonn, 2020

Betreuer und 1. Referent: Susanne Winterscheid

Zweiter Referent: Prof. Dr. Michael Gütschow

Table of Contents

Table of Contents ....................................................................IV Abbreviations ..........................................................................VI List of Figures ....................................................................... VIII List of Tables ..........................................................................IX

1 Introduction ........................................................................ 10

Initial Situation and Goal of Thesis ................................................. 10 Structure of Thesis ......................................................................... 11

2 What Is Worksharing? ......................................................... 13

Background .................................................................................... 13

2.1.1 Legal Basis ........................................................................... 13

2.1.2 Variations ............................................................................. 14

2.1.3 Groupings ............................................................................ 16

Application for Worksharing ........................................................... 16 Statistics - WS Procedures by Time Period and Type ..................... 18

3 The Quality Dossier ............................................................. 21

Common Technical Document ....................................................... 21

3.1.1 Quality Overall Summary (Module 2.3) ................................ 22

3.1.2 Chemistry, Manufacturing and Controls (Module 3) ............. 23

4 Module 3 Harmonisation ...................................................... 26

Regulatory & Legal Background ..................................................... 26 Why Harmonise the Quality Dossier? ............................................. 28

4.2.1 Decision Tree ....................................................................... 29

Pre-Submission Activities ............................................................... 30

4.3.1 Gap Analysis and Possible Show-Stoppers ........................... 30

4.3.2 Most Common Deficiencies in Module 3 .............................. 33

4.3.3 Cost Analysis of EU-Countries .............................................. 35

4.3.4 Letter of Intent ..................................................................... 36

4.3.5 Advice Procedures ............................................................... 37

4.3.6 Other Pre-Submission Activities ........................................... 38

Application for Module 3 Harmonisation ........................................ 38 V

4.4.1 Application & Documents to be Submitted .......................... 38

Procedure ....................................................................................... 40

4.5.1 Timetable ............................................................................. 40

4.5.2 Preliminary Variation Assessment Report ............................ 41

4.5.3 CMS Comments and Clock Stop ........................................... 42

4.5.4 Final Variation Assessment Report ...................................... 42

4.5.5 End of Procedure .................................................................. 43

Post-Authorisation .......................................................................... 43

4.6.1 National Approvals of EU-Countries ..................................... 44

4.6.2 Post-approval Measures ....................................................... 46

5 Experiences of Different Applicants ..................................... 48

The Questionnaire .......................................................................... 48 Graphical Evaluation of the Results ............................................... 49 Evaluation of Individual Responses ................................................ 61

5.3.1 Largest Companies .............................................................. 61

5.3.2 Smallest Companies ............................................................ 62

5.3.3 Medium Sized Companies .................................................... 62

5.3.4 Other Distinctions ................................................................ 63

6 Discussion .......................................................................... 66

Discussion of Results ..................................................................... 66 Other Points to Consider ................................................................ 68

7 Conclusion .......................................................................... 70

References ............................................................................. 72 VI

Abbreviations

API Active Pharmaceutical Ingredient

BfArM Bundesinstitut für Arzneimittel und Medizin- produkte (Federal Institute for Drugs and Me- dical Devices)

BPI Bundesverband der Pharmazeutischen Indus-

trie e.V. (German Pharmaceutical Industry As- sociation)

CAP Centrally Authorised Product

CEP Certificate of Suitability to the monographs of the European Pharmacopoeia

CESP Central European Submission Portal

CHMP Committee for Medicinal Products for Human

Use

CL Cover Letter

CMC Chemistry, Manufacturing and Controls

CMDh Coordination Group for Mutual Recognition and Decentralised Procedures - Human

CMS Concerned Member State

CP Centralised Procedure

CTD Common Technical Document

DC Decentralised

DCP Decentralised Procedure

DE Deutschland (Germany)

eAF electronic Application Form eCTD electronic Common Technical Document

EMA European Medicines Agency

EoP End of Procedure

FVAR Final Variation Assessment Report

HA Health Authority

ICH International Council for Harmonisation of

Technical Requirements for Pharmaceuticals

for Human Use

MA Marketing Authorisation

Mfg Manufacturing

MR Mutual Recognition

MRP Mutual Recognition Procedure

MS Member State

NAP Nationally Authorised Product

VII

NCA National Competent Authority

NP (Purely) National Procedure

Ph. Eur. European Pharmacopoeia

PI Product Information

PIL Patient Information Leaflet

PoP Proof of Payment

PSRPH Potential Serious Risk to Public Health

PVAR Preliminary Variation Assessment Report

QC Quality Control

QOS Quality Overall Summary

RMS Reference Member State

RSI Request for Supplementary Information

SmPC Summary of Product Characteristics

WS Worksharing

VIII

List of Figures

Figure 1 Classification of Variations ......................................................... 15 Figure 2 Number of WS Procedures by Year ............................................ 18 Figure 3 Status of WS Procedures 2010-2018 .......................................... 19 Figure 4 WS - product composition - relative comparison by period ........ 19 Figure 5 WS - relative distribution of scope ............................................. 20 Figure 6 Common Technical Document ................................................... 21 Figure 7 Quality Part of the Dossier ......................................................... 22 Figure 8 Classification Guideline 1 ........................................................... 26 Figure 9 Classification Guideline 2 ........................................................... 27 Figure 10 Harmonisation Decision Tree ................................................... 29

Figure 11 Question 1 ................................................................................ 50

Figure 12 Question 2 ................................................................................ 50

Figure 13 Question 3 ................................................................................ 51

Figure 14 Question 4 ................................................................................ 52

Figure 15 Question 5 ................................................................................ 52

Figure 16 Question 6 ................................................................................ 53

Figure 17 Question 7 ................................................................................ 54

Figure 18 Question 8 ................................................................................ 55

Figure 19 Question 9 ................................................................................ 55

Figure 20 Question 11 .............................................................................. 56

Figure 21 Question 12 .............................................................................. 56

Figure 22 Question 13 .............................................................................. 57

Figure 23 Question 15 .............................................................................. 58

Figure 24 Question 16 .............................................................................. 58

Figure 25 Question 17 .............................................................................. 59

Figure 26 Question 18 .............................................................................. 60

Figure 27 Question 19 .............................................................................. 60

IX

List of Tables

Table 1 Gap Analysis ................................................................................ 32

Table 2 Cost Analysis ............................................................................... 36

Table 3 Timetable (60 days) ..................................................................... 41 Table 4 National Approvals ...................................................................... 46

Table 5 Conclusion ................................................................................... 70

1 Introduction

Initial Situation and Goal of Thesis

Drug regulatory affairs is without doubt an indispensable field in the pharma- ceutical industry and inseparable from the authorisation of new medicinal products and the maintenance of established products. Within the regulatory landscape worksharing is still rather young among pro- cedures. Marketing authorisation procedures are evidently very important for the emergence and approval of new medicinal products. However, also meth- ods to make changes to the regulatory documentation - commonly named variations - can be considered equally crucial. One method to submit and handle single variations or groupings of variations is the worksharing proce- dure. The word "worksharing" consists of "work" and "sharing". "Work" can be un- derstood as assessment by a scientist or an assessor of an authority and "sharing" can be seen as division of labour, i.e. sharing the work with other competent authorities. [1] Worksharing has been around since the beginning of 2010. For nationally au- thorised products the procedure is possible for applications submitted as of 4 August 2013. Since then, also harmonisations of the quality dossier - Module

3 of the Common Technical Document (CTD) - were made possible. [2] [3]

The purpose of Module 3 harmonisations is to align the quality dossier of the same products authorised through national, MR or DC procedures in different Member States of the EU. It has become more important over time as scien- tific standards and knowledge have changed. The worksharing procedure pro- vides the means to achieve a harmonised outcome. [4] Looking at the statistics one can acknowledge that numbers of started and finalised worksharing procedures have generally risen over the past 10 years, although there is still room for improvement. This view is also shared by rep- resentatives of NCAs and Medicines for Europe: Question to Industry: Why is worksharing still not used more often?

Could it [WS] be used more frequently?

[5] [6]

1 Introduction

11 The reasons for the lack of applications is unknown. Is it due to obstacles before or during the procedure? Perhaps there is an absence of a need to harmonise (national) authorisations? Or are the procedures just not familiar enough? This thesis aims to find out those reasons and provide a conclusion at the end to summarise the advantages and difficulties. It also aims to provide guidance on the legal and regulatory backgrounds of worksharing and Module 3 harmonisation, the activities around the execution and the execution of the method itself and an assessment on past experi- ences with worksharing in general and Module 3 harmonisation in particular, as well as determine the overall advocacy along with possible improvements to the procedure. The thesis will only cover human medicinal products and primarily the situa- tion in the European Union. It only focuses on the voluntary type of Module 3 harmonisation and not on the mandatory form after Union referral. Referrals are used to resolve issues such as concerns over the safety or benefit-risk balance of a medicine. The information in the thesis is based on own experience in the field of drug regulatory affairs in the pharmaceutical industry, on the results gathered from a questionnaire specifically created within this framework, as well as on sources stated at the end of the document.

Structure of Thesis

Apart from the introduction, there are six main parts to the thesis, which are further divided into more specific sections. Parts 2, 3 and 4 of the document focus on the legal and regulatory background of worksharing, the significance and contents of Module 3 of the product dos- sier and the core subject of the thesis, which is the consolidation of the quality dossier. These parts are meant to present the relevant legislation as well as insight into the proper guidelines. The harmonisation part of the thesis includes the legal background, the deci- sion-making process, the pre-submission activities, the execution of the pro- cedure itself and the post-approval period. It serves to introduce the prepara- tion for a Module 3 alignment, the specific steps applicants pass through

1 Introduction

12 before and during the procedure and activities they to perform after approval on European and national level. Parts 5 and 6 of the thesis focus on concrete worksharing experiences by the pharmaceutical industry. In order to ascertain this information, an online questionnaire was created and presented to different companies that are ei- ther headquartered in Germany or have an affiliate there. The survey focuses on the number of worksharing procedures conducted in the past, the advantages and difficulties encountered during and before the procedure, the overall impression of worksharing and suggestions for im- provement. The survey also addresses past encounters of the companies regarding the subject of Module 3 harmonisation, as well as their advocacy on the matter. After the questionnaire the answers are evaluated graphically and compared by company size as well as other characteristics in order to paint a picture of the different experiences. Other important points to consider are further re- viewed and a conclusion is given at the end in part 7.

2 What Is Worksharing?

Background

2.1.1 Legal Basis

The definition for worksharing can be found in article 20 of Commission Reg- ulation (EC) No 1234/2008, as amended by Commission Regulation (EU) No

712/2012, often referred to as the Variation Regulation:

In order to avoid duplication of work in the evaluation of variations to the terms of several marketing authorisations, a worksharing procedure should be established under which one authority, chosen amongst the competent authorities of the Member States and the Agency, should examine the varia- tion on behalf of the other concerned authorities. [2] [7] Member States refer to the Member States of the European Union and the Agency refers to the European Medicines Agency (EMA). Article 20 sets-out the possibility for a marketing authorisation holder to sub- mit the same Type IB or Type II variation or the same group of variations affecting more than one marketing authorisations from the same holder in one application. [8] Worksharing is possible since the coming into effect of the Variation Regula- tion, which was January 1 st, 2010. [2] The Regulation is applicable to nationally authorised products (NAPs) as well as to centrally authorised products (CAPs). There are certain changes, how- ever, that cannot be described by the Variation Regulation and follow national legislation instead, for example, change of a manufacturing authorisation holder or purely editorial changes to the product information of a medicinal product. Worksharing is feasible for several MAs owned by the same holder. However, as there are different definitions of MAs in different Member States, some- times that may include one strength or more than one strength of the same medicinal product. For a worksharing, at least two Member States have to be involved.

2 What Is Worksharing?

14 Coordination Group for Mutual Recognition and Decentralised Procedures - Human (CMDh) has agreed that the marketing authorisation is defined through the procedure (MR-)number, e.g. DE/H/1000/001-010. [1]

2.1.2 Variations

The basis for any worksharing is at least one variation. Any amendment to the regulatory documentation triggers a variation. If there is a change that does not alter the regulatory information, i.e. the information in the dossier, no variation is needed. An amendment can be the addition, deletion or change of a document. [9] Variations are categorised into Types IA, IB, II and extension applications. Type IA variations require no assessment by an authority and are only vali- dated. They are regarded as "do and tell" changes, which means that the change can and has to be performed before the actual approval and the rel- evant authority doesn't need to be informed until after implementation, e.g. through an annual report. The annual report is a grouped application including all IA variations from the previous 12 months and can be filed at any time, but not later than 12 months after the implementation date of the first change. There is an exception, however, which is Type IA

IN. This type of

change requires an immediate notification to the authorities. It can also be included in the annual report but would then trigger the submission of the report immediately. An example of a Type IA

IN would be an address change

of a manufacturer. The procedure lasts 30 days. Type IB variations are usually categorised "by default". This means that if the variation can neither be classified as Type IA nor Type II, it is automatically classified as Type IB. The procedure lasts 30 days with the possibility of a clock stop (pausing the procedural clock) and an additional 30 days of assess- ment. A validation phase of 7 days is due prior to the start of the procedure. Before the planned changes can be implemented, approval by an authority is needed. If no official approval is issued there is the possibility of an implicit approval (see also section 4.6). The procedures for Type II variations usually require a lot more time and as- sessment. They are commonly applicable if there are major changes to the product's documentation, like a change to the indication or a more extensive change to the manufacturing process. In order to be able to implement the changes, prior approval is also required. The procedure can take 30, 60 or 90

2 What Is Worksharing?

15 days, depending on the type of change, with the possibility of a clock-stop.

The 60-day procedure is the standard operation.

Extension applications (or line extensions) are an exceptional type that con- cern more severe changes to a marketing authorisation, like changes to the strength, the pharmaceutical form or the route of administration. It is usually approved according to the same procedure as for a new MA and follows the same timeline. It is defined in Annex I of the Variation Regulation. [2] [9] Variations are classified by means of a risk-based approach (Figure 1). The higher the level of risk, the higher the classification. The higher the classifica- tion, the longer the assessment and (usually) the greater the fees. The level of risk can be understood as the extent of impact on the quality, safety and efficacy of a medicinal product.

Figure 1 Classification of Variations

[9, p. 204] The tool for the correct classification of variations is the Guideline on the de- tails of the various categories of variations to the terms of marketing author- isations for medicinal products for human use and veterinary medicinal prod- ucts of the European Commission, often just referred to as the Classification

Guideline. [10]

2 What Is Worksharing?

16

2.1.3 Groupings

According to article 7.1 of Commission Regulation (EC) 1234/2008, each var- iation requires one notification to the relevant authority. Under certain cir- cumstances, according to article 7.2 of this Regulation, the applicant may de- viate from the aforementioned process and several variations may be grouped into a single notification. Possible cases for groupings are listed in Annex III of the Regulation. Any other groupings have to be justified and the relevant authority has to agree to sub- ject those variations to the same procedure. For products authorised via MRP or DCP, the CMDh also features examples for acceptable groupings. [2] [11] Type IA variations can always be grouped, e.g. within an annual report (unless other types of variations are included). It can also include a Type IA

IN, but the

Type IA

IN would need to be submitted immediately. Unlike other types, for Type IA it is also possible to group changes for more than one marketing au- thorisation (but for the same MAH). Other possibilities for groupings are an extension application with associated variations, a Type II with consequential changes, a Type IB with consequential minor variations, administrative changes to the SmPC, PIL and labelling etc., as described in Annex III of the Variation Regulation. [2] The timetable for the procedure follows the timetable of the highest variation type included in the grouping. [12] The specific case of groupings of purely national marketing authorisations is described in article 13d of the Variation Regulation. [7]

Application for Worksharing

Worksharing procedures are either coordinated by the EMA, if a centrally au- thorised product is included, or by the CMDh, if only nationally authorised products are included. The submission of a worksharing is made to the NCAs of all Member States concerned in the procedure. For worksharing, the Reference Member State is usually called the reference authority, but both terms are sometimes used synonymously. The reference authority takes the lead in the assessment and takes care of the validation of the application. In the validation phase, it

2 What Is Worksharing?

17 examines the application in line with the validation procedure followed for Type II variations (chapter 2 of the Best Practice Guides of the CMDh) and checks for any missing documents. If documents are incomplete, the appli- cant can usually file them later during validation, but this may delay the start of the procedure. As distinguished from the assessment phase (procedure), during validation, no content-related scientific analysis is performed. [8] [13] Once the procedure has started, independent from the variation type applied for, it follows the timeframe of a Type II variation, i.e. an initial assessment phase of 60 days, a possible clock-stop and another 30 days as 2 nd assess- ment phase, which is then followed by either an approval, a refusal or a re- ferral (see also sections 4.4.1 and 4.5.1). [1] Worksharing procedures of 30 days (urgent safety related procedures) and

90 days (e.g. change or addition of an indication) are also generally possible.

During a 60-day procedure relevant authorities are requested to approve or send additional comments to the FVAR (Final Variation Assessment Report) of the reference authority within 20 days (Day 80). In case PSRPH (Potential Se- rious Risk(s) to Public Health) are identified, the CMS may ask the reference authority to refer the application to the CMDh, resulting in a referral (see also section 4.5.1). In the case of at least one centrally authorised product the opinion of the CHMP has to be recognised by the CMSs. Worksharing is possible for products approved through the Centralised Proce- dure (CP), Mutual Recognition Procedures (MRP), Decentralised Procedures (DCP) or authorised purely nationally and can also be combined among these authorisation types. It is an optional procedure, but there are instances when it is highly recommended. Variations of Type IB and Type II and groupings can be included. Type IA var- iations (unless part of a grouping) and line extensions (extension applications) are excluded from worksharing. All grouped applications are allowed for worksharing because groupings es- sentially define what is placed in an application and worksharing defines howquotesdbs_dbs33.pdfusesText_39

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