Pharmaceutical Regulatory Affairs in the EU and US

Publication Date	December 2006
Publisher	Scrip Reports
Product Type	Report
Pages	208
ISBN Number	BS1327
Product Code	SCR00010

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Summary

Regulation affects all aspects of the pharmaceutical world, from independent innovators and pharmaceutical companies, to regulatory and administrative bodies, and most importantly, to the patients taking the medicines. This report provides an introduction to the world of regulatory affairs, describing the history behind the need to regulate medicines for human use and the key events helping to shape this.

In Chapter 1, there is an overview of EU regulation, outlining how it has transformed into the large, 25-country structure it is today. Ensuring that such a vast amount of countries regulate medicines in the same way is an immense task for the EU's regulatory and government bodies, and is explained in the later part of this chapter. It also provides an insight into the regulatory structures in place, the methods of regulating and some of the more important legislation adopted to achieve this.

Finally, the role of the Regulatory Professional is explained, enabling the reader to understand how they fit into the whole process of pharmaceutical regulation. Although it is unlikey that a professional would tackle all aspects of regulatory affairs, it is still important to understand the many varied tasks involved, enabling them to see the bigger picture.

Following the introduction to regulatory affairs and an EU overview, the second chapter provides an overview of the US regulatory system, starting with the history of how the FDA was formed and the key events that have shaped this.

The chapter continues with an explanation of the approaches used by the US in achieving the production of safe, efficacious and high quality products,which has helped to make them one of the most respected regulatory agencies in the world. This is followed by an overview of how the legislation is created in the US to enable the FDA to operate so efficiently, which includes an explanation of the well known Code of Federal Regulations (CFR) Title 21.

The Good Guidance Practice is a set of guidance documents created by the FDA in accordance with the relevant legislation for drug regulation. These are discussed here with a view to explaining their importance to the FDA, the applicants and the public.

Finally, the various international markets are discussed providing a more complete picture of worldwide regulatory affairs. It is important to be aware of the countries outside of the EU and US, as more often than not a Regulatory Professional will come into contact with them in one form or another.

Developing a medicine from its initial discovery as a molecule to the finished product seen on the pharmacist's shelf is an extremely long and involved process. Chapter 3 discusses this area in detail, covering the various stages involved and the role that regulatory affairs takes in bringing a product to market. There is a common misconception that regulatory affairs only become involved at the very end of this product development process, however, this could not be further from the truth as this chapter will explain.

There is extensive guidance from the EMEA, the FDA, the ICH and national guidelines regarding the format and content of a marketing authorisation application (MAA) in Europe, or New Drug Application (NDA) as they are known in the US. Due to the wide scope of this guidance this chapter can only summarise this information and cover the most pertinent points of the structure and requirements of an application, however, references and a list of the directives and guidelines for further information are provided.

The main focus of Chapter 4 is the content of the five modules that make up a Common Technical Document (CTD), or dossier. The implementation of the CTD in the EU and US is discussed as are the key differences between a
US and EU application.

Following a successful approval and launch of a product there is still the maintenance aspect of regulatory affairs. The process of varying, renewing and withdrawing a licence are all discussed, with particular attention to the differing market requirements in the EU and US.

An MAA or NDA can amount to thousands of pages and many hundreds of volumes of lever-arch files, and a typical delivery to a regulatory agency can occupy up to half of the capacity of a delivery van. Thus, the current move towards a fully electronic submission will save much time and resource in compiling and copying these dossiers. This and other considerations for MAAs and NDAs are the final topic for discussion in Chapter 4.

Chapter 5 begins to tackle the rather complicated but extremely important area of intellectual property (IP) and the rights of the innovator (or originator) of pharmaceutical products. It begins by describing what a generic medicine is and how they are licensed, priced and handled in both the EU and US. With the scene set, Section 5.2 moves on to describe what IP law is and the various types that are available, which help to provide market exclusivity to the originator company. This chapter also discusses the stages when a generic company is likely to try and exploit a weak or expiring patent, with a case study included to highlight this.

The chapter continues with two sections describing particular methods to enable a patent to be extended in both the EU and US, known as supplementary protection certificates (SPC) and patent restoration terms respectively.

The chapter concludes with a discussion of parallel trading of products from one country to another. The reasons for the differences between the EU and US are explained and a theoretical example of EU trade is provided. The subject of IP can become very complicated, particularly when a patent becomes challenged in court. Chapter 5 aims to provide a regulatory affairs professional with the level of knowledge they would require in their everyday work.

Chapter 6 begins by discussing over-the-counter (OTC) products, with an explanation of how a product is classified in this way, and the main differences between these and prescription-only medicines (POMs). Some of the key issues and latest changes in legislation surrounding OTCs are covered here, followed by the requirements for switching the classification of a medicine from a POM.

Alternative medicines are becoming increasingly more popular in both the EU and US. The rapidly changing perception of herbal medicines and the Executive Summary Pharmaceutical Regulatory Affairs in the EU and US growing legislation surrounding them in the EU is discussed in detail. In the US, herbals are better established; however a greater level of understanding of the effects of using these products is needed and the programme to achieve this is covered here.

Chapter 6 finishes by introducing another alternative medicine known as homeopathics. Their definition and history is discussed, followed by a summary of the key legislation affecting their use. The chapter is concluded with information on the potential for growth of homeopathics in the US and other areas of the world.

Chapter 7 discusses some of the most rapidly changing areas of the pharmaceutical industry, most noticeably biologics, gene therapy and other special categories such as nutrapharmaceuticals. It begins by discussing what a biological is and how they are derived via biotechnology. To assist, a background into biotechnology is provided, helping to set the scene. Section 7.1 continues with an explanation of the different approaches to registering a biological, alongside the various types of biologicals available. Biosimilars are then defined and discussed, with information on the legislation affecting them in both the EU and US.

The chapter then moves on to discuss a distinct subset of biologicals, called blood and blood products. This chapter provides an explanation of what they are and the key legislation affecting them.

Section 7.3 discusses gene therapy and cloning, with the latest information regarding the treatments currently being used, or intended to be used in the future. A case study is provided of the earliest case of gene therapy and there is also an explanation into the exciting possibilities of the future of cloning, via stem cell research.

Chapter 7 closes with a discussion of various other special categories of medicines that are currently hot topics in the pharmaceutical and regulatory world.

Chapter 8 is concerned with the safety and quality of pharmaceutical products. Section 8.1 begins by discussing the requirements for labelling a product both in the EU and US, with examples of theoretical products and the minimum requirements for the packaging. The details required for the Patient Information Leaflet (or Package Insert) are included, alongside the new EU requirements for conducting readability testing of this information.

Section 8.2 tackles the larger topic, known as pharmacovigilance. Although this has been discussed in previous chapters, this section covers it in much more detail and allows the reader to understand just how vital it is to carry out this function correctly, thus helping to ensure the safety of patients using marketed medicines.

The third and final section deals with the areas surrounding quality that have not previously been discussed in this report, for example counterfeit and defective products. The section defines exactly what both of these are and the systems that are in place at international and national levels to try and reduce the threat of harm to the consumer that they can cause.

Chapter 9 looks at the area of advertising/promotion in the pharmaceutical industry. Although the legal position differs vastly between the EU and the US, there are still a lot of similarities in the systems in place to regulate them.

Section 9.1 provides an introduction to the promotion of medicines and discusses the changing views of the public towards direct-to-consumer advertising (DTC). The various bodies and associations involved with the regulation of advertising are mentioned, with their key objectives described. The different styles of regulation are discussed, detailing the interaction between global, regional and national regulation.

Section 9.2 looks in more detail at the different styles of regulation mentioned in Section 9.1 and provides examples of the codes of practice found in the EU and US.

The third and final section deals with the compliance strategies that are required in the US. Reference to the relatively new California Law, which has made the introduction of Comprehensive Compliance Programmes mandatory, is provided and certain additional requirements resulting from it are discussed. The EU position on compliance is also discussed, with a view to future changes that may occur.

Chapter 10 is the final part of this report and begins by looking at various regulations in the EU and US that were not covered in earlier chapters.

Section 10.1 begins with the area of paediatric legislation, which is currently a hot topic in the EU. The latest legislation is discussed for both the EU and US.

Section 10.2 tackles the subject of risk management, which again in the EU is a currently evolving area of legislation. The very recently released EU Risk Management Plan and supporting guidance on each of the sections it includes are discussed.

The regulation of combination products in both the EU and US are covered in Section 10.3, including the definition of a combination product and the differing legislation and bodies involved with their regulation on both sides of the Atlantic.
Section 10.4 looks at the two distinctly separate programmes in the US, called Medicare and Medicaid. Details are provided on the eligibility for both, the methods for regulating them and the differences between them.

The final section helps to wrap-up the report by providing an overview of the core competencies expected of a Regulatory Affairs Professional (RAP). It also details where in the report information can be found on each of the competencies.

Content

Chapter 1 Introduction And Eu Overview
- 1.1 Origins And Purposes Of Regulation
- 1.1.1 Early British Regulation
- 1.1.2 Modern Regulation
- 1.1.3 Development Of Us Regulations
- 1.2 Basic Elements And Approaches In Regulation
- 1.2.1 Safety
- 1.2.2 Quality
- 1.2.3 Efficacy
- 1.2.4 Promotion
- 1.3 Eu Institutions And Legislation
- 1.3.1 Paediatric Legislation
- 1.4 Approaches To Eu Registration
- 1.4.1 Centralised
- 1.4.2 Mutual Recognition
- 1.4.3 Decentralised
- 1.4.4 National
- 1.5 Role Of The Regulatory Affairs Professional
- 1.5.1 Interactions Within The Company
- 1.5.2 External Interactions
- 1.6 Conclusion
Chapter 2 Us And International Overview
- 2.1 Introduction
- 2.1.1 Modern Regulation
- 2.2 Us Fda Regulatory Overview
- 2.2.1 Investigational New Drug (Ind) Application
- 2.2.2 New Drug Application (Nda)
- 2.2.3 Review
- 2.2.4 Inspection
- 2.2.5 Approval
- 2.2.6 Maintenance
- 2.3 Us Administrative Procedure
- 2.3.1 Emea And Fda Cooperation On Medicines Regulation
- 2.4 Fda Good Guidance Practices
- 2.4.1 Guidance Options
- 2.5 Regulatory Bodies In Other Countries
- 2.5.1 Tripartite Agreement
- 2.5.2 Hong Kong
- 2.5.3 Canada
- 2.5.4 South (Or Latin) America
- 2.5.5 African Countries
- 2.5.6 Australia And New Zealand
Chapter 3 Product Development
- 3.1 New Product Development
- 3.1.1 Steps Involved In Product Development
- 3.1.2 Attrition Rate For Drugs Selected For Development
- 3.2 Introduction To The International Conference On Harmonisation(Ich)
- 3.2.1 How Did Ich Come About?
- 3.2.2 The Beginnings Of Ich
- 3.3 Pre-Clinical Studies
- 3.3.1 What Is Toxicity?
- 3.3.2 Guideline For Toxicity Studies Before Clinical Studies(Phase I) In Healthy Volunteers:
- 3.3.3 Reproductive Toxicology
- 3.3.4 Mutagenicity Studies
- 3.3.5 Conventional Carcinogenicity Studies
- 3.4 Good Laboratory Practice (Glp)
- 3.4.1 What Is Glp?
- 3.5 Clinical Trials And Good Clinical Practice
- 3.5.1 So What Is A Clinical Trial?
- 3.5.2 Post-Marketing Surveillance (Pms) Studies
- 3.5.3 What Is Good Clinical Practice?
- 3.6 Eu Clinical Trials Directive
- 3.6.1 Clinical Trials Directive (2001/20/Ec)
- 3.6.2 What Regulatory Documentation Is Required For A Clinical
- Trial Application In The Eu?
- 3.6.3 Regulatory Documents Required For A Clinical Trial Application In Eu Member States
- 3.7 Eu Privacy Legislation
- 3.8 Fda Clinical Trials Regulation
- 3.8.1 Organisation
Chapter 4 Applications For Marketing Authorisations: General Approach
- 4.1 Ich Common Technical Document
- 4.1.1 Introduction
- 4.1.2 The Ctd
- 4.1.3 High-Level Structure Of Module 1 And The Ctd Modules 2,3, 4 & 5
- 4.1.4 Presentation Of The Application
- 4.2 Eu And Us: Similarities And Differences
- 4.3 Quality (Cmc)
- 4.4 Safety
- 4.4.1 Module 2: Overview And Summaries
- 4.4.2 Guidance Notes
- 4.5 Efficacy
- 4.5.1 The Clinical Overview
- 4.5.2 Structure Of Module 5
- 4.6 Product Maintenance
- 4.6.1 Variations
- 4.6.2 Renewals
- 4.6.3 Withdrawals
- 4.7 Other Considerations
Chapter 5 Regulation Of Generics And Innovator Rights
- 5.1 Generic Medicines
- 5.1.1 What Is A Generic?
- 5.1.2 Pricing Of Generics
- 5.1.3 Licensing A Generic Product
- 5.2 Intellectual Property Law
- 5.2.1 Patent Protection
- 5.2.2 Patent Expiration
- 5.2.3 Patent Challenge
- 5.2.4 Data Exclusivity
- 5.2.5 The Bolar Clause In The Eu
- 5.2.6 The Us 180-Day Generic Drug Product Exclusivity
- 5.2.7 Data Protection
- 5.2.8 Other Types Of Ip Protection
- 5.3 Supplementary Protection Certificates
- 5.3.1 What Is An Spc?
- 5.3.2 The Need For Spcs In The Eu
- 5.3.3 Obtaining And Maintaining Spcs
- 5.4 Us Patent Term Restoration
- 5.4.1 Length Of Patent Term Restoration
- 5.4.2 Applying For A Patent Extension
- 5.4.3 Determining The Length Of The Patent Extension
- 5.5 Parallel Trade Issues
- 5.5.1 Parallel Trade In The Eu
- 5.5.2 Parallel Trade In The Us
- 5.5.3 Counterfeiting Of Medicinal Products
- 5.5.4 Products Traded Over The Internet
Chapter 6 Over-The-Counter Drugs, Herbals & Homoeopathics
- 6.1 Over-The-Counter Drugs
- 6.1.1 Introduction
- 6.1.2 What Is An Otc Drug?
- 6.1.3 The '2001 Review'
- 6.1.4 Advertising And Branding
- 6.1.5 Safety Assessment For Pom To P Switches
- 6.1.6 What Is Involved In The Reclassification Of Medicines From Pom To P?
- 6.1.7 Switching From Pom To P
- 6.1.8 Other Considerations
- 6.1.9 Data Requirements
- 6.1.10 Product Information
- 6.1.11 Other
- 6.1.12 Us Otc
- 6.1.13 Drug Interactions
- 6.2 Herbal Medicines
- 6.2.1 Eu Legislation
- 6.2.2 Why Is There A Change In The Legislation With Respect To Herbal Medicines?
- 6.2.3 An Example Of An Eu Herbal Medicines Registration Scheme: Mhra
- 6.2.4 Product Information: Labelling And The User Package Leaflet
- 6.2.5 Advertising
- 6.2.6 Pharmacovigilance
- 6.2.7 Us Legislation
- 6.3 Homeopathy
- 6.3.1 What Is Homeopathy?
- 6.3.2 Homeopathic Preparations
- 6.3.3 Use Of Homeopathy Around The World
- 6.3.4 Homeopathic Legislation In The Eu
- 6.3.5 Homeopathy In The Us
Chapter 7 Biologicals, Gene Therapy And Other Special Categories
- 7.1 Biologicals, Biotechnology And Biosimilars
- 7.1.1 Biologicals
- 7.1.2 The History Of Biotechnology
- 7.1.3 Types Of Biological Products
- 7.1.4 Licensing A Biological Product
- 7.1.5 Biosimilars
- 7.2 Blood And Blood Products
- 7.2.1 Introduction To Blood And Blood Products
- 7.2.2 Eu Blood Legislation
- 7.2.3 Us Blood Legislation
- 7.2.4 Registering A Blood Product
- 7.3 Gene Therapy And Cloning
- 7.3.1 Gene Therapy
- 7.3.2 Cloning
- 7.3.3 Regulation Of Cloning
- 7.4 Other Special Categories
- 7.4.1 Radiopharmaceuticals
- 7.4.2 Nutraceuticals
Chapter 8 Safety, Quality And Regulation
- 8.1 Labelling Of Medicinal Products
- 8.1.1 Introduction To Labelling
- 8.1.2 Eu Labelling Requirements
- 8.1.3 Us Labelling Requirements
- 8.2 Pharmacovigilance
- 8.2.1 Introduction To Pharmacovigilance
- 8.2.2 When Does Pharmacovigilance Begin?
- 8.2.3 What Information Is Collected?
- 8.2.4 What Happens To The Collected Data?
- 8.2.5 Changes To An Ma As A Result Of Pharmacovigilance
- 8.2.6 Periodic Safety Update Reports
- 8.2.7 Content Of A Psur
- 8.2.8 Dear Dr Letters
- 8.2.9 Reporting Of Suspected Adverse Drug Reactions In The Eu
- 8.2.10 Reporting Of Suspected Adverse Drug Reactions In The Us
- 8.2.11 Black Triangle
- 8.3 Ensuring The Quality Of Medicinal Products
- 8.3.1 Introduction To Quality
- 8.3.2 Counterfeit Products
- 8.3.3 Defective Products
Chapter 9 Advertising And Marketing Practices
- 9.1 The Role Of The Pharmaceutical Industry In Promotion And Medical Education
- 9.1.1 Introduction To The Promotion Of Medicines
- 9.1.2 Looking After The Consumer
- 9.1.3 Defining Promotion
- 9.1.4 Eu Legal Requirements
- 9.1.5 Differences And Similarities Between Countries And Regions In The Regulation Of Advertising/Promotional Material
- 9.2 Organisations Responsible For Monitoring Promotional Activities Around The World
- 9.2.1 Introduction
- 9.2.2 Global Organisations
- 9.2.3 European Organisations
- 9.2.4 Uk Organisations
- 9.2.5 Us Organisations
- 9.3 Compliance Strategies
- 9.3.1 Compliance Strategies In The Us
- 9.3.2 California Law
- 9.3.3 Compliance Strategies In The Eu
Chapter 10 Other Eu And Us Regulations
- 10.1 Paediatric Medicines Legislation
- 10.1.1 The Need For Legislation
- 10.1.2 Legislation In The Eu
- 10.1.3 Legislation In The Us
- 10.2 Risk Management
- 10.2.1 Introduction To Risk Management
- 10.2.2 Risk Management Outside Of The Eu
- 10.3 Regulation Of Combination Products
- 10.3.1 Us Approach
- 10.3.2 Eu Approach
- 10.4 Medicare And Medicaid
- 10.4.1 Medicare
- 10.4.2 Problems Facing Medicare
- 10.4.3 Medicaid
- 10.5 Core Competencies Of A Rap
- 10.5.1 Introduction
- 10.5.2 Key Core Competencies
List Of Tables
- Table 1.1 The Changing Options Available To Applicants Intending To Register A Medicinal Product In The Eu
- Table 2.1 The Scope Of Fda Good Guidance Practices
- Table 3.1 Examples Of Product Failure Rates As They Move Through Developments
- Table 3.2 Reasons For Terminating A Product In Development
- Table 3.3 Chronological Events In The History Of Ich
- Table 3.4 Guidance For Toxicity Studies (Time Of Exposure) Before Clinical Trials In Patients: Ich M3
- Table 3.5 Toxicology Data To Support Phase Iii Trials In Eu
- Table 3.6 The Phases Of Clinical Development
- Table 3.7 Guidance For Patient Privacy Rights
- Table 4.1 General Differences Between The Eu And Us Applications
- Table 4.2 Module 3: Quality
- Table 4.3 Module 3: Ctd Organisation
- Table 4.4 General Guidelines
- Table 4.5 Active Substance Guidelines
- Table 4.6 Medicinal Product Guidelines
- Table 4.7 Module 4: Non-Clinical
- Table 4.8 Relevant Pharmacokinetic Documents
- Table 4.9 Relevant Toxicology Documents
- Table 4.10 General Guidelines
- Table 4.11 General Efficacy Clinical Safety
- Table 4.12 Clinical Pharmacology
- Table 5.1 Brufen (Ibuprofen) And Its Associated Generic Versions
- Table 5.2 Market Protection For An Originator's Theoretical Product In The Eu
- Table 6.1 Eu Member States And The Implementation Of Articles 16(1) Or 16(2)
- Table 9.1 Type Of Regulation And Legal Requirements For Advertising Of Medicines
- Table 10.1 Overview Of The Eu Risk Management Plan Template Produced By The Emea
- Table 10.2 Core Competencies Required By A Rap
List Of Figures
- Figure 1.1 Illustration Of Treatments Used By Physicians In Ancient Egypt
- Figure 1.2 Illustration Of How The Efficacy Of A Medicinal Product Is Determined By Weighing-Up
- The Risk Versus The Benefit To The Patient
- Figure 1.3 Simplified Flowchart Of The Process For Creating New Legislation In The Eu
- Figure 1.4 Timings And Key Features Of The Centralised Procedure
- Figure 1.5 Timings And Key Features Of The Mutual Recognition Procedure
- Figure 1.6 Timings And Key Features Of The Decentralised Procedure
- Figure 1.7 Role Of A Regulatory Affairs Professional
- Figure 2.1 A Typical Fda Project Team Responsible For Reviewing An Nda
- Figure 2.2 Appeals Procedure Following An Alleged Non-Compliance With Ggp By The Fda
- Figure 2.3 The Main International Regulatory Agencies
- Figure 3.1 Drug Development: From Idea To Market
- Figure 3.2 Phases Of Clinical Development (Ich E8)
- Figure 4.1 Diagrammatic Representation Of The Organisation Of The Ctd
- Figure 5.1 Explanation Of The 8+2+1 System For Market Exclusivity Of A New Branded Product In The Eu
- Figure 7.1 The Process For Producing A Medicine Via Recombinant Dna Technology
- Figure 8.1 Particulars To Appear On The Immediate Packaging Of A Product
- Figure 8.2 Particulars To Appear On The Outer Packaging Of A Product In The Eu
- Figure 8.3 Template For A Pil In The Eu (Where X Is The Product Name)
- Figure 8.4 Example Of The Use Of The 'Black Triangle' In Advertising Materials In The Uk
- Figure 9.1 Examples Of 'Bad Press' For The Promotion Of Medicines
- Figure 9.2 The Pmcpa Code Of Practice Review Document
- Figure 9.3 The Code On Interactions With The Healthcare Professionals
- Figure 9.4 Global, Regional And National Interactions
- Figure 9.5 An Example Of A Comprehensive Compliance Programme Statement Taken From The Company X's Website
Abbreviations<
- Abpi Association Of The British Pharmaceutical Industry
- Anztpa Australia New Zealand Therapeutic Products Authority
- Bce Before The Common Era (Also Known As Bc)
- Bla Biologic Licence Application
- Bse Bovine Spongiform Encephalopathy (Mad Cow Disease)
- Cber Center For Biologics Evaluation And Research
- Cder Center For Drug Evaluation And Research
- Chmp Committee For Medicinal Products For Human Use
- Cms Concerned Member States
- Comp Committee On Orphan Medicinal Products
- Cro Clinical Research Organisation
- Cta Clinical Trial Application
- Emea European Medicines Agency
- Fda Food And Drug Administration
- Ftc Federal Trade Commission
- Gc Gas Chromatography
- Gdp Good Distribution Practice
- Ggp Good Guidance Practices
- Gmp Good Manufacturing Practice
- Hplc High Performance Liquid Chromatography
- Ind Investigational New Drug
- Irb Institutional Review Board
- Maa Marketing Authorisation Application
- Ma Marketing Authorisation
- Mhlw Ministry Of Health, Labour And Welfare
- Mhra Medicines And Healthcare Products Regulatory Agency
- Mr Mutual Recognition
- Ms Member States
- Nda New Drug Application
- Nta Notice To Applicants
- Ppb Pharmacy And Poisons Board (Hong Kong)