EU的小兒科醫療規範

Abstract

The EU' s Paediatric Medicines Regulation will come into effect on 26 January 2007. Its main aim is to increase the availability of properly tested and authorised medicines for paediatric use.

Patented products will be required to be studied in the paediatric population whenever the manufacturer applies for a marketing authorisation, whether for initial approval or for a line extension. As a reward, they will receive a six month extension of their supplementary patent certificate. The requirement will be waived if the product is not suitable for paediatric use, and may be deferred in order not to delay the approval of adult indications.

Orphan products must also comply with the paediatric study requirements. Their reward will be a two year extension to their ten years of market exclusivity.

For off-patent products, there are incentives for voluntary studies, rather than requirements and rewards. The Paediatric Use Marketing Authorisation will give ten years of data exclusivity for off-patent medicines that obtain a paediatric indication, while the EU' s Paediatric Study Fund will support paediatric research into commercially unattractive medicines.

All paediatric trials should comply with an agreed Paediatric Investigation Plan, which will be approved and monitored by the new Paediatric Committee to be set up within the European Medicines Agency. Paediatric studies of patented and orphan products that comply with the PIP will qualify for the SPC extension even if the trial results do not support a paediatric use; off-patent products will have to successfully develop a paediatric indication to receive the ten years of data protection.

For the industry, the Regulation will be most advantageous for R&D-based companies. This report calculates that cost to European healthcare systems of delayed generic entry due to the six-month SPC extension could exceed €1 billion. Generic companies face a loss of market share, although the offpatent incentives offer some consolation.

The Regulation was fiercely debated, with the six-month SPC extension proving particularly controversial. It is likely that there will be calls for a reduced extension period for blockbuster drugs when the Regulation is reviewed six to ten years after it enters into force.

Table of Contents

CHAPTER 1 INTRODUCTION

• 1.1 The Paediatric Medicines Regulation
• 1.2 The need for paediatric testing
• 1.3 The history of the Regulation

CHAPTER 2 THE PAEDIATRIC REGULATION

• 2.1 The text of the Regulation
• 2.2 The Paediatric Committee
  • 2.2.1 Committee composition
  • 2.2.2 Objectives
  • 2.2.3 Safeguards
• 2.3 Marketing authorisation requirements
  • 2.3.1 General authorisation requirements
  • 2.3.2 Waivers
  • 2.3.3 Paediatric investigation plans
  • 2.3.4 Deferrals
  • 2.3.5 Compliance with the PIP
  • 2.3.6 Procedure
  • 2.3.7 Advice
• 2.4 Marketing authorisation procedures
  • 2.4.1 Patented products
  • 2.4.2 Off-patent products
  • 2.4.3 Identification
    • 2.4.3.1 Choice of symbol
• 2.5 Post-authorisation requirements
• 2.6 Rewards and incentives
  • 2.6.1 Patented products
  • 2.6.2 Orphan products
  • 2.6.3 Off-patent products
  • 2.6.4 Additional funding
• 2.7 Communication and co-ordination
  • 2.7.1 Clinical trials register
  • 2.7.2 Paediatric therapeutic needs inventory
  • 2.7.3 European network of expertise
  • 2.7.4 Paediatric study reporting requirements
• 2.8 General and final provisions
  • 2.8.1 Reports and analyses
  • 2.8.2 Annex
• 2.9 Amending Regulation
• 2.10 Deadlines

CHAPTER 3 THE EMEA AND THE PAEDIATRIC COMMITTEE

• 3.1 EMEA funding
• 3.2 EMEA implementation priorities
• 3.3 EMEA paediatric activity 1995-2005
  • 3.3.1 Analysis
  • 3.3.2 Conclusions
• 3.4 Paediatric Expert Group (PEG)
  • 3.4.1 Mandate and objectives
  • . . . Product-related tasks
  • . . . Non-product related activities
  • . . . Activities with external parties
  • 3.4.2 PEG publications
  • 3.4.3 The PEG and the Paediatric Committee
• 3.5 Paediatric Committee

CHAPTER 4 TEDDY

• 4.1 Objectives
• 4.2 Partners
• 4.3 Activities
  • 4.3.1 Ethics
    • 4.3.1.1 Ethics and pharmacogenetics
  • 4.3.2 Pharmacoepidemiology
  • 4.3.3 Genomics and paediatric pharmacogenetics
  • 4.3.4 Methodology of paediatric clinical trials
  • 4.3.5 Key therapeutic questions in children
  • 4.3.6 Rare diseases
  • 4.3.7 Post-marketing studies
  • 4.3.8 Paediatric drug databases
  • 4.3.9 Gender issues in drug evaluation

CHAPTER 5 US AND EU APROACHES

• 5.1 The US paediatric initiatives
• 5.2 Evaluation of the US paediatric initiatives
  • 5.2.1 FDA assessments
    • 5.2.1.1 2001 status report
    • 5.2.1.2 Recent FDA data
  • 5.2.2 Tufts Impact Report
  • 5.2.3 Congressional criticisms
  • 5.2.4 Public Citizen
• 5.3 Lessons from the US experience
• 5.4 What the EU has learned from the US experience

CHAPTER 6 OPPORTUNITIES AND COSTS: RAND AND THE EUROPEAN COMMISSION

• 6.1 R&D-based companies
  • 6.1.1 Costs
  • 6.1.2 Rewards
• 6.2 Generic companies and SMEs
  • 6.2.1 Costs
  • 6.2.2 Incentives
  • 6.2.3 Orphan drugs
  • 6.2.4 Paediatric study programme
• 6.3 The EMEA
• 6.4 Healthcare systems
  • 6.4.1 Costs
  • 6.4.2 Benefits
• 6.5 Children
• 6.6 EU research bodies
• 6.7 Impact outside the EU

CHAPTER 7 OPPORTUNITIES AND COSTS: AN ALTERNATIVE ANALYSIS

• 7.1 Criticisms of the Rand report
• 7.2 An alternative calculation of rewards and costs
• . . . Calculation 1
• . . . Alternative calculation 1
• . . . Calculation 2
• . . . Alternative calculation 2
• . . . Calculation 3
• . . . Alternative calculation 3
• . . . Calculation 4
• . . . Alternative calculation 4
• 7.3 Impact on R&D-based companies
  • 7.3.1 Costs
  • 7.3.2 Rewards
• 7.4 Impact on generic companies
• 7.5 Impact on regulatory agencies
  • 7.5.1 The EMEA
  • 7.5.2 National regulatory authorities
• 7.6 Impact on healthcare systems

CHAPTER 8 WHAT HAPPENS NEXT

• 8.1 Requirements for companies
  • 8.1.1 All companies
  • 8.1.2 Companies seeking SPC extensions
  • 8.1.3 Companies discontinuing a paediatric product
  • 8.1.4 Pharmacovigilance
• 8.2 Approval routes
  • 8.2.1 Centralised approval
  • 8.2.2 Decentralised approval
• 8.3 Penalties for non-compliance
• 8.4 Clinical trials
• 8.5 Databases
  • 8.5.1 EudraPharm
  • 8.5.2 EudraVigilance
  • 8.5.3 EudraCT
• 8.6 Identifying unmet paediatric needs
  • 8.6.1 Paediatric research needs
  • 8.6.2 Paediatric research priorities for off-patent drugs

CHAPTER 9 CONTROVERSIES AND UNCERTAINTIES

• 9.1 SPCs - too much?
  • 9.1.1 Political disagreements
  • 9.1.2 Alternatives
  • 9.1.3 Support for six months
• 9.2 PUMAs and MICE - too little?
  • 9.2.1 Data protection
  • 9.2.2 Formulations and formularies
  • 9.2.3 Paediatric Study Fund
  • 9.2.4 Potential PUMA applicants

CHAPTER 10 CONCLUSION

• 10.1 What the Regulation should achieve
• 10.2 What the Regulation may not achieve
• 10.3 Summary of benefits

APPENDIX A

APPENDIX B

REFERENCES

LIST OF TABLES

• Table 2.1: Deadlines set out in the Paediatric Regulation
• Table 3.1: Table EMEA Paediatric Costs in € millions, 2007-2012
• Table 3.2: Priorities for implementing the Paediatric Regulation in 2006 and 2007
• Table 6.1: Children in EU-27 by Age Groups (millions), 2005-2015
• Table A.1: EMEA priority list of off-patent products

LIST OF FIGURES

• Figure 5.1: New label information for paediatric use by therapeutic area in the US, 1998-2005
• Figure 5.2: Prescription drugs awarded paediatric exclusivity according to total brand sales in 2004 ($mn)
• Figure 5.3: Estimates of paediatric drug study costs over time