Regulatory Issues

1
Regulatory Issues Clinical Trials A Focus on
Europe
MassMEDIC International Marketing Seminar 27
February 2004
Waltham, Mass.
Maria E. Donawa, M.D. President, Donawa
Associates Ltd.
2

Purpose of this presentation
To provide an overview of European regulatory
and clinical investigation requirements and
issues, which should be considered and addressed
during international product introduction
planning
3
European regulatory fundamentals

• Understand the basic principals of European
  regulation and how to access information on these
  requirements, which are currently evolving
• Realize that European regulatory harmonization
  has not removed all country-to-country
  differences (e.g., registration, labeling,
  clinical investigation)
• Be aware that conducting clinical studies in
  Europe may be less costly and burdensome, but
  require knowledge of European regulatory and
  investigational site requirements

4
European Single Market

• European Community (EC) Treaty of Rome, 1957
• European Union (EU)
• Austria, Belgium, Denmark, Finland, France,
  Germany, Greece, Ireland, Italy, Luxembourg,
  Netherlands, Portugal, Spain, Sweden, United
  Kingdom
• New members as of 1 May 2004
• Cyprus, the Czech Republic, Estonia, Hungary,
  Latvia, Lithuania, Malta, Poland, Slovakia and
  Slovenia
• European Free Trade Association (EFTA)
• Iceland, Liechtenstein, Norway, Switzerland
• European Economic Area (EEA)
• EU Iceland, Liechtenstein, Norway
• Switzerland
• EU-Switzerland bilateral trade / mutual
  recognition agreements

5
Principles of New Approach Directives

• New Approach introduced by Council Resolution of
  May 1985
• Directives contain a list of Essential
  Requirements (ERs)
• Detailed technical provisions in harmonized
  standards adopted by European standards
  organizations (CEN, CENELEC)
• Harmonized standards are voluntary, but confer
  presumption of conformity with the relevant ERs
• Directives are not directly legally binding. They
  must be transposed into national laws
  regulations
• Products that comply with the Directives are
  affixed with the CE mark and can circulate
  throughout the EEA

6
European Directives

• Active Implantable Medical Device Directive
  (90/385/EEC)
• Medical Device (MD) Directive (93/42/EEC)
• In Vitro Diagnostic (IVD) Medical Device
  Directive (98/79/EEC)
• Directive on Medical Devices Incorporating Human
  Blood and Human Plasma (2000/70/EC)
• Council Directive 2003/32/EC of 23 April 2003
• specifies mandatory requirements for medical
  devices using non-viable animal tissue

7
European Directives

• Requirements apply to
• Manufacturers
• Competent authorities
• government body in each Member State responsible
  for implementing and enforcing the Directives
• Notified bodies
• designated by competent authorities to perform
  one or more of the conformity assessment
  procedures for devices in class I that are
  sterile or have a measuring function class IIa,
  class IIb, and class III
• Authorized representatives
• defined in Article 1(2)(j) designated by
  manufacturers to act or be addressed by
  authorities and bodies in the EC

8
MD Directive Classification

• Depends upon
• risk, duration of use, invasiveness, anatomy
  affected by use of the device, whether or not
  device is active or non-active
• Determines conformity assessment options
• Annex IX - 18 classification rules
• Four classes, increasing in risk from class I to
  III
• Class I - hospital beds, corrective glasses
• Class IIa - syringes for infusion pumps,
• Class IIb - hemodialyzers
• Class III - angioplasty balloon catheters
• Classification guidance document

9
Conformity Assessment

• Manufacturers can demonstrate conformity through
• testing alone
• testing plus quality system certification
• quality system certification alone
• Most common methods are
• certification of full quality assurance
• EC Type-Examination (product testing) plus
  certification of production quality assurance,
  and
• for class I devices, self-declaration procedure

10
Risk Analysis Risk Management

• European Directives for medical devices require
  risk analysis for all devices
• Important part of Technical File or Design
  Dossier
• EN ISO 14971, Medical devices Application of
  risk management to medical devices
• Applied to the medical device

11
Adverse event reporting

• Any malfunction or deterioration in the
  characteristics and/or performance of a device or
  any inadequacy in the labelling or instructions
  for use
• which might lead to (near incident) or
• might have led (incident) to the death of a
  patient or user or to a serious deterioration in
  state of health
• Any technical or medical reason in relation to
  the characteristics or performance of a device
  for the reasons stated above leading to
  systematic recall

12
Adverse event reporting

• Similarities differences between European and
  US Medical Device Reporting requirements
• Reporting timeframes differ
• Terminology differs
• US FDA requires that unanticipated adverse
  events that occur during clinical investigations
  be reported
• Therefore, specific procedures for meeting
  European adverse event requirements should be
  developed

13
National regulatory variations

• Medical device registration under Article 14 of
  the MD Directive some countries require
  registration of
• only class I and custom-made devices (UK)
• class I, custom-made, and higher risk devices
  (France)
• all devices regardless of class (Italy)
• Labelling some Member States allow labelling
  and instructions for use in English, while others
  require local language
• Clinical investigation notification some Member
  States require Ethics Committee approval before
  notification to the Competent Authority
  (regulatory authority) and some do not

14
European harmonized standards

• EN ISO 134852000, Quality systems - Medical
  devices - Particular requirements for the
  application of EN ISO 90011994
• EN ISO 134882000, Quality systems Medical
  devices - Particular requirements for the
  application of ISO 90021994
• EN ISO 14155-12003 Clinical investigation of
  medical devices for human subjects - Part 1
  General requirements
• EN ISO 14155-22003 Clinical investigation of
  medical devices for human subjects - Part 2
  Clinical investigation plans
• EN 375 2001, Information supplied by the
  manufacturer with in vitro diagnostic reagents
  for professional use
• EN 455-1 Medical gloves for single use - Part 1
  Requirements and testing for freedom from holes
• Many others

15
European guidance

• Guidelines for the Classification of Medical
  Devices (MEDDEV 2.4/1 Rev.8, July 2001)
• Guidelines on a Medical Devices Vigilance System
  (MEDDEV 2.12-1 rev 4, April 2001)
• Demarcation between medical devices and medicinal
  products (MEDDEV 2. 1/3 rev 2, July 2001)
• Evaluation of Clinical Data, A Guide for
  Manufacturers and Notified Bodies (MEDDEV 2.7.1,
  April 2003)
• Medical Devices Utilizing Tissues or Derivatives
  Originating from Animals for Which a TSE Risk Is
  Suspected A Guide For Manufacturers and
  Notified Bodies (MEDDEV. 2.11/1 rev.1, February
  2004)
• Over 20 guidance documents
• issued by the European Commission

16
Technical documentation

• Required for all devices, regardless of device
  class
• Includes
• Declaration of conformity
• Documentation required by conformity assessment
  route
• Documentation of conformity with applicable
  Essential Requirements
• Results of Risk Analysis
• Results of clinical investigation or literature
  review
• If applicable, statement for devices for clinical
  investigation or custom devices

17
Major Steps in CE Marking Process

• Determine if product is a medical device
• Identify applicable Directive
• Identify likely conformity assessment route
  (e.g., Annex II)
• Identify applicable Essential Requirements (ERs)
• Identify relevant harmonized standards, EP
  monographs, other standards
• Conduct risk analysis plan risk management

18
Major Steps in CE Marking Process

• Determine clinical evaluation needs (scientific
  literature or clinical investigation)
• Select Notified Body, if necessary
• Comply with ERs and standards and follow
  conformity assessment procedures
• Select Authorized Representative, if appropriate
  or required
• Ensure that Technical File is complete, accurate
  and controlled
• Draw up declaration of conformity and apply CE
  mark

19
European Commission Website
http//europa.eu.int/comm/enterprise/medical_devic
es/index.htm
20
Clinical Investigation Requirements

• The requirements for conducting European clinical
  investigations are becoming more stringent due to
  
• a perceived lack of adequate clinical data to
  support some device safety and performance claims
• inadequate expertise for evaluating clinical data
  within some Notified Body organizations
• sufficiently detailed guidance documents for
  clinical investigations involving some types of
  products

21
Clinical Investigation Requirements

• Article 15, Clinical investigation (MD Directive)
• Must follow procedure in Annex VIII, Statement
  concerning Devices for Special Purposes
• Must notify Competent Authority
• Sixty-day waiting period for some categories of
  devices (requirement differs somewhat among
  Member States)
• Must conduct investigation in accordance with
  Annex X, Clinical evaluation
• EN ISO 14155-12003, Clinical investigation of
  medical devices for human subjects Part 1
  General requirements
• EN ISO 14155-22003 Clinical investigation of
  medical devices for human subjects - Part 2
  Clinical investigation plans

22
Clinical investigation guidance

• Check for existence of national guidance
  documents
• E.g., UK Medicines and Healthcare products
  Regulatory Agency (MHRA) guidance documents and
  forms
• Information for Clinical Investigators (UK)
• Guidance for Manufacturers on Clinical
  Investigations to be Carried Out in the UK
• Pre-Clinical Assessment (PCA) Forms, PCA1 and
  PCA2
• Evaluation of Clinical Data, A Guide for
  Manufacturers and Notified Bodies (MEDDEV 2.7.1,
  April 2003)

23
Clinical investigation standards

• EN ISO 14155-12003 Clinical investigation of
  medical devices for human subjects - Part 1
  General requirements
• harmonized standard that ensures that clinical
  study requirements in the Directives are met
• EN ISO 14155-22003 Clinical investigation of
  medical devices for human subjects - Part 2
  Clinical investigation plans
• harmonized standard that specifies the content,
  review, and control of the clinical investigation
  plan (CIP or protocol)

24
Conducting successful
European clinical studies

• Evaluate and select investigational sites in a
  formal manner to ensure that the site can fulfil
  study requirements and has the capability of
  recruiting adequate numbers of patients
• Conduct on-site training to ensure that
  investigators, site support personnel, and
  monitors understand company procedures,
  regulatory requirements, and good clinical
  practice principles
• Develop easy-to-understand and convincing study
  materials for regulators, ethics committees, and
  investigators to aid in the acceptance of the
  study

25
Questions?
Maria E. Donawa, M.D. President Donawa
Associates Ltd. Via Fonte di Fauno, 22 ? 00153
Rome, Italy 39 06 578 2665 ? FAX [phone]
3786 donawa_at_srd.it ? www.donawa.com