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Title: MEDICINE REGULATION REGULATORY DEPARTMENTS GOOD REGULATORY PRACTICE


1
MEDICINE REGULATIONREGULATORY DEPARTMENTS GOOD
REGULATORY PRACTICE
  • SAAPRA
  • 1 June 2012

2
OVERVIEW
  • Development of Legislation
  • Medicines Regulation and Regulators
  • Regulatory Affairs Department (RAD)
  • Good Regulatory Practice (GRP)

3
Development of Medicines Legislation
  • Typically medicine regulations have been
    developed after the fact
  • Triggered by unwanted and sometimes disastrous
    events
  • Information and knowledge on the use of
    medicines increases exponentially
  • Result - Medicines legislation proliferates

4
Development of Legislation
  • USA
  • 1846 1848 Mexican-American War
  • American troops supplied with substandard
    medicines
  • 1848 Import Drug Act passed
  • 1901 concern over unsanitary condition in meat
    packing industry and also quality of medicines
  • Medicines legislation outgrowth of food
    legislation

5
Development of Legislation
  • 1902 12 children died from contaminated
    diphtheria toxin in St Louis
  • Result - Biologics Act of 1902
  • Demanded licensing of biological products and
    facilities
  • 1902 1907 Study on safety of food additives
    with human volunteers
  • Led to - 1906 Pure Food and Drugs Act
  • First federal drugs law

6
Development of Legislation
  • Prohibited mislabelling and adulteration of
    medicinal products and
  • Introduced USP and NF as official standards
  • Legal system still allowed for unacceptable
    bizarre practices - false therapeutic claims
  • 1912 - US vs Johnson case promoters of Dr.
    Johnsons Mild Combination Treatment for Cancer
    challenged
  • 1912 Act amended prohibited labelling with false
    therapeutic claims

7
Development of Legislation
  • 1937 Massengill Company place throat lozenge on
    market
  • Sulfanilamide dissolved in diethylene glycol
    (common car antifreeze agent)
  • 107 people died (mostly children)
  • Legislators acted rigorously to prevent
    reoccurrence
  • 1938 Food, Drug and Cosmetic Act passed
  • Medicine could only be marketed after 60 days if
    no FDA objections

8
Development of Legislation
  • Required proof of safety and efficacy
  • 1951 another amendment to Act
  • Divided products into OTC and prescription
    requiring professional supervision
  • 1962 amendments made proof of efficacy mandatory
  • Introduced GMP

9
Development of Legislation
  • Further amendments over 20 years such as
  • - 1983 Orphan Drugs Act for marketing and
    commercialisation of medicines to treat rare
    diseases
  • - 1990 Nutrition and Labelling Act
  • - 1984 Drug Price Competition and Patent Term
    Restoration Act
  • - 1996 Generic Drug Enforcement Act

10
Development of Legislation
  • 1988 Prescription Drug Marketing Act
  • To ensure that medicines purchased by consumers
    are safe and effective, and
  • To avoid the unacceptable risk to American
    consumers from counterfeit, adulterated,
    misbranded, subpotent, or expired drugs.
  • Additionally Guidance documents to be taken into
    account by industry
  • Other reform bills constantly under consideration

11
Development of Legislation
  • EUROPEAN UNION (EU)
  • Germany and other countries originally focussed
    on pharmacies only
  • No Marketing Authorisation required for
    industrially produced medicines
  • 1961 registration introduced to determine what
    was on market notification process only
  • In Germany 55 000 medicinal products on market at
    time

12
Development of Legislation
  • Beginning 1960s sleeping pill Contergan
    (thalidomide) caused birth defects
  • Taken by mothers in early
  • stages of pregnancy
  • Children born without arms -
  • hands starting at the shoulders
  • Called flipper babies

13
Development of Legislation
  • An estimated 10 000 children were affected in
    Europe
  • 1968 appetite suppressant Menocil (aminorex)
    caused many deaths withdrawn from market
  • Led to implementation of medicines legislation in
    UK and other EU member states
  • Today legislation in EU member states mirrors EU
    Directive

14
Development of Legislation
  • SOUTH AFRICA
  • 1965 Medicines and Related Substances Control Act
    published and first medicines called up in 1968
  • 2002 Medicines and Related Substances Act
  • amended making provision for inter alia
    licensing of manufacturers, wholesalers,
    distributors, etc.
  • 2008 Amendment Act 72 introduced SAHPRA
  • Latest draft amendment makes provision for the
    structures required for the new juristic body

15
International Conference on Harmonisation(ICH)
  • ICH began to take place in 1989
  • Project of both Regulatory Bodies and
    pharmaceutical industry from EU, Japan and United
    States
  • Harmonisation the major factor
  • Goal - to expedite development and approval
    processes for medicinal products
  • Does not compromise safeguards on Q/S/E

16
World Health Organisation (WHO)
  • An intergovernmental organisation
  • 166 member states within the Charter of the
    United Nations
  • Activities include support for ministries of
    health concerning development of methods for
    assessing quality, effectiveness and efficiency
  • Publications cover
  • - essential drugs
  • - drug policies
  • - quality control
  • - ethical guidelines
  • - safety assessment, drug research and
    development and
  • - laboratories

17
Medicines Regulation and Regulators
  • Medicine legislation makes provision for
    Regulatory Authorities or Bodies
  • Have developed and continue to develop
    legislation
  • This had and continues to have a significant
    effect on pharmaceutical industry

18
Medicines Regulation and Regulators
  • Common misunderstanding that Regulators
    register our medicines
  • They keep medicines off the market unless the
    applicant can prove quality, safety and efficacy
  • Ensure compliance with legislation
  • Control the use and minimise the abuse of
    medicines
  • Re-evaluate the medicines on the market

19
Regulatory Affairs Departments (RAD)
  • Why have companies established Regulatory Affairs
    Departments ?
  • Simple answer because there are regulations and
    regulators
  • To understand and fulfil regulators needs as
    environment has become more and more complex

20
Regulatory Affairs Departments (RAD)
  • Mistakes cost a lot of money
  • Worst mistake calling in RA after plans have
    been finalised
  • Pitfalls of product development
  • - Not involving RA in plans
  • - Suppressing critics in the company they are
    valuable in identifying problems
  • - Hiding critical issues chances good reviewer
    will spot them
  • - Telling all you know leads to confusion

21
Regulatory Affairs Departments (RAD)
  • - Trying to make it perfect a lot of time will
    be lost
  • - Doing all the studies as early as possible
    e.g. marketing studies
  • - Using in-house methods to structure the
    documentation adapt to Regulators structure

22
Regulatory Affairs (RA)
  • RA is usually recognised as having three basic
    functions
  • - The outlet of the company to Regulatory Bodies
  • - The interpreter of regulations to companies
  • - The influencer of new regulations
  • Makes RA the interface between companies and
    Regulatory Bodies and
  • Key player in the product development and
    maintenance process

23
Activities of the Regulatory Affairs Department
(RAD)
  • Activities depend on each companys structure and
    organisation
  • Start at the initial development of medicinal
    products
  • Continue through until the launch of the product
  • Steer and maintain an application through the
    legislative framework - allows a Regulatory
    Authority to reach a scientific decision
  • Once launched, the RAD fully involved in
    Marketing Authorisation (MA) maintenance and
    post-marketing activities

24
Activities of the RAD
  • Product Development
  • RAD should be involved in the creation and
    evaluation of all aspects of research and
    development plans
  • Advise departmental heads and project managers on
    the requirements and any upcoming legal changes
    with potential impact for registration
  • RAD should give advice for optimising development
    plans
  • By an accurate interpretation of the requirements
    of the existing guidelines
  • Ideally should be done within the scope of a
    Regulatory Strategy Document

25
Activities of the RAD
  • Product Development
  • Ideally RAD should be able to liaise with
    Regulatory Authorities on any scientific aspect
    of
  • future Marketing Authorisation (MA)
  • dossier and co-ordinating with the other
    departments
  • the briefing document including the questions and
    companys positions
  • On our wish list!

26
Activities of the RAD
  • New Registrations
  • RAD responsiblities
  • - proposing the best registration strategy
  • - taking into account the possible registration
    procedures
  • - the impact of intellectual property rights
  • - the peculiarities of the product
  • - the scientific content of the different part
    of the dossier
  • RAD preparation of Regulatory Strategy Document
    (RSD)
  • - containing all the essential global regulatory
    aspects of product development
  • - including scientific advice
  • - meeting with the Regulatory Authority

27
Activities of the RAD
  • New Registrations
  • RAD ensure all activities related to obtaining
    registration comply with existing legislation
    i.e.
  • laws, regulations, directives and guidelines
  • need to be proactive
  • RAD - should establish ethical, practical,
    technical and regulatory standards
  • - laid down in policies and SOPs
  • - specify the responsibility of each staff
    member involved
  • - describe the process
  • - ensure content of dossiers in compliance with
    existing legislation and standard needed to
    obtain registration of the product

28
Activities of the RAD
  • New Registrations
  • RAD responsiblities
  • writing, co-writing, editing and/or authorising
    all documentsfor use in registration dossiers or
    communication with the Authority e.g.
    manuscripts, expert reports, method of use,
    standard advice for patients and labels
  • should strive for world-wide implementation of
    harmonised prescribing information
  • should be responsible for the accurate planning
    and co-ordination of compiling the dossiers
  • Take into account the possibilities for
    electronic submission of the dossier or parts of
    it especially in terms of submission of eCTDs

29
Activities of the RAD
  • New Registrations
  • Ensuring administrative validation
  • Chasing up the dossier throughout the assessment
    and
  • Anticipating the possible questions from the
    Regulatory Authority in order to optimise the
    timing, quality of the answer and Marketing
    Authorisation (MA) approval and package insert
    (PI) wording
  • Queries from the RA should be answered in a
    consistent manner and within the time limits set
    by the agency when indicated, according to
    internal guidelines
  • Status reports should be issued regularly in
    order to provide information on the world-wide
    registration situation

30
Activities of the RAD
  • Registrations
  • submission strategies (timing, responsibilities,
    free sale certificates and answers to the
    Authority, questions, intellectual property
  • dossier updates (variations and safety)
  • dossier renewals
  • Periodic Safety Update Reports (PSURs) planning
    and a contingency plan
  • must address the proposed labelling with
    Marketing and Sales
  • the impact on discussion with pricing and
    reimbursement authorities

31
Activities of the RAD
  • Maintenance of Existing Registrations
  • All existing registrations should be carefully
    maintained and regularly updated to reflect the
    current standards and knowledge
  • Variations and change control
  • Management of change control forms are an
    important element of GRP - Such changes include
  • Product data or specifications
  • Manufacturing of analytic methods
  • Facilities or suppliers as well as line
    extensions
  • Additional indications, etc.
  • All such changes have to be communicated to the
    RA in accordance with the respective legal
    requirements affected

32
Activities of the RAD
  • Maintenance of Existing Registrations
  • Queries raised by the RA to ensure regulatory
    compliance
  • RAD and quality assurance department should
    liaise closely on all aspects affecting
    variations and change control
  • Responsibility of RAD, Responsible Pharmacist and
    QA (Quality Assurance) to ensure manufacturing
    and QC (Quality Control) comply at all times with
    the registration dossier
  • RAD should assure regulatory compliance by the
    manufacturer, packager and marketing department

33
Activities of the RAD
  • Maintenance of Existing Registrations
  • Changes to PI and/or PIL
  • - Changes might be initiated by marketing or
    medical department
  • - Can also be requested for new safety data
  • - RAD and medical / pharmacovigilance c liaise
    closely for the preparation and timely
    implementation once the revised wording is
    approved
  • RAD in close collaboration with the Drug Safety
    department and a Qualified Person for
    Pharmacovigilance
  • - Do PSURs planning on a yearly basis for each
    product
  • - Collect all the information needed for their
    submission, taking into consideration
    post-approval commitment or follow-up measures

34
Activities of the RAD
  • Maintenance of Existing Registrations
  • It is the duty of RAD
  • to ensure activities related to post marketing
    studies are carried out in compliance with and
    reported according to, existing legislation.
  • to inform the Regulatory Authorities of any
    pharmacovigilance issue and to implement and file
    the necessary data into the official documents
  • this will be done in close co-operation with the
    medical department and Qualified Person for
    Pharmacovigilance

35
Activities of the RAD
  • Regulatory intelligence Objective 1
  • RAD should
  • have a system in place to ensure the tracking of
    all the versions, either approved or a draft for
    comment, of regulations guidelines and concepts
    papers
  • on an on-going basis review relevant world-wide
    legislation, guidelines, discussion papers, codes
    of conduct, etc.
  • interpret the scope and possible consequences
    arising from such legislation and codes and
    inform the company accordingly(may affect the
    activities of the company)
  • ensure and co-ordinate the necessary activities
    arising from changes to ensure that compliance
    with regulations will be met.

36
Activities of the RAD
  • REGULATORY INTELLIGENCE - Objective 2
  • RAD should
  • comment on new draft guidelines / draft
    legislation and take an active role in
    participating in the outcome of final regulatory
    comments.
  • for this purpose preferably join pharmaceutical
    associations to represent the needs of
    pharmaceutical industry on a higher level.

37
Good Regulatory Practice (GRP)
  • Problem today
  • Insufficient quality submissions to the
    Regulatory Authority
  • Industry and Regulator perceive each other as
    opponents rather than partners
  • We are like opposite sides of the
  • same coin -neither side detracts from the
  • value of the coin but rather together give it
  • its character and identity.

38
Good Regulatory Practice (GRP)
  • Present system based on mutual mistrust
  • Involves high cost i.t.o. time, manpower,
    rejects on both sides
  • Quality cannot be added by regulations,
    guidelines, etc.
  • Without any real dossier quality improvement
    timelines cannot improve

39
Good Regulatory Practice (GRP)
  • Could GRP be the solution to the problem?

40
Good Regulatory Practice (GRP)
  • What is GRP?
  • Establishment of a quality system
  • Involves both industry and Regulator
  • About trying to achieve quality by less rather
    than more control
  • About producing quality in the first place
  • Based on sound science, coupled with
    organisational ability

41
Good Regulatory Practice (GRP)
  • What are the goals of GRP?
  • Efficiency quick and qualified decisions on
    Q/S/E of products
  • Effectiveness/productivity effective use of
    resources, cost-effectiveness
  • Results achieve and preserve an image of high
    standing

42
Good Regulatory Practice
  • What are the advantages of GRP?
  • Quality medicines available to patients in timely
    fashion
  • Because global picture is seen and
  • Entire process is designed to produce quality

43
Good Regulatory Practice
  • How?
  • Decide on goals
  • What must be done by whom and how
  • Write it down
  • Adhere to it
  • Watch the results and if necessary modify the
    system

44
Good Regulatory Practice(GRP)
  • A pre-requisite to GRP - the communication of all
    relevant information, including its evaluation
    and relevance for the existing product, to ALL
    interested parties within the organisation
  • Pivotal to GRP is the need to keep abreast of
    world-wide legislation including potential
    changes and
  • The interpretation of possible consequences in
    the event of failure to meet requirements

45
Good Regulatory Practice(GRP)
  • The involvement of GRP in the concept of Total
    Quality Management (TQM) is essential from
    initial development phase of the product and
    continues for its entire life
  • Efficient RAD organisation and working methods
    are mandatory
  • RAD skills for communication and communicating
    information to other departments - a key
    parameter to ensure compliance with regulatory
    requirements

46
Good Regulatory Practice (GRP)
  • Implementation of GRP essentially contributes
    towards continuous Total Quality Assessment of
    all aspects of regulatory affairs and is
  • The essential link between each discipline in
    Total Quality Management
  • Increasing complexity of regulatory requirements
    especially as RADs operate numerous interfaces
    within a pharmaceutical company

47
Good Regulatory Practice (GRP)
  • GRP Guidelines define the role and position of
    the RAD within the organisation
  • Appropriate and effective management of the
    regulatory process is mandatory for
  • Bringing a medicinal product to the market and
    keeping it there
  • In compliance with legal, scientific, ethical and
    administrative requirements
  • To ensure the compliance of the relevant
    companys activities to the local and global
    regulations in terms of official and company
    regulations

48
PERSONNEL
  • There should be sufficient personnel at all
    levels within the organisation with the
  • Ability
  • Education
  • Training
  • Experience and
  • Appropriate professional skills to perform the
    tasks assigned to them
  • All personnel should be trained regularly in
    their skills to ensure they possess sufficient
    skill and knowledge of the procedures and
    policies of the organisation
  • Ideally, all graduate personnel should have a
    multidisciplinary background

49
PERSONNEL
  • Ideally, all graduate personnel should have
  • multidisciplinary background
  • scientific expertise
  • communication and negotiation skills
  • regulatory knowledge
  • planning capacity
  • be able to work in teams
  • to organize multidimensional projects
  • to work in a multidimensional manner
  • Standard operating procedures should be designed
    to deal with communication and flow of
    information

50
PERSONNEL
  • The responsibilities of the Responsible
    Pharmacist (RP) and the Qualified Person for
    Pharmacovigilance (QPPV) in relation to the RAD
    should be clearly defined
  • These responsibilities should be explained and
    written into the job description for each person
    together with any training and education required
    on product registration
  • Key personnel in responsible positions should be
    accountable for
  • authorizing procedures and tasks and
  • having adequate supporting staff
  • persons should be designated to deputise for them
    in their absence

51
PREMISES
  • Premises should be designed and maintained in
    good order
  • To provide sufficient space to suit the
    activities being carried out
  • Should allow efficient work flow
  • Should permit effective communication and
    supervision
  • Physical and non-physical working conditions
  • Ergonomics
  • Environmental factors
  • Stress
  • All necessary equipment for the activities to be
    performed efficiently should be provided
    personnel should be instructed in the proper use
    of equipment
  • Computer hardware and software
  • Printers and copiers
  • Archives and means of communication

52
QUALITY ASSURANCE (QA)
  • A good quality management system (QMS) should be
    set-up by RAD for all the activities under its
    responsibility

53
QUALITY ASSURANCE
  • Procedures
  • Procedures should be laid down in writing in
    standard operating procedures
  • Authorised by appropriate staff and communicated
    to the relevant personnel
  • This should be readily available and be checked
    and updated regularly
  • SOPs should be adapted / renewed in the case of
    new or amended standards
  • SOPs should be established on how to implement
    relevant legislation and codes and the
    consequences for the organisations policy
  • RAD should develop policies for situations in
    which changing legislation and codes make it
    necessary to adapt to it

54
QUALITY ASSURANCE
  • Procedures
  • Procedures should cover the different areas in RA
    to
  • Specify responsibilities and organisation
  • regulatory development plan
  • development of PI and PIL
  • preparation of CTD
  • compilation of dossier
  • change control
  • preparation of response documents
  • maintenance of registration
  • preparation of renewals, etc.

55
QUALITY ASSURANCE
  • Self-Inspection
  • Regular self-inspections should be performed by
    RAD in co-operation with QA to
  • - check and ensure compliance with the relevant
    regulations by staff at all levels
  • - check the compliance with the procedures and
  • - adapt the procedure according to current
    practices

56
QUALITY ASSURANCE
  • Training
  • An initial training program should be in place
    for new employees to ensure a good understanding
    and therefore compliance
  • All RAD staff should be regularly trained in
    procedures to ensure good understanding and
    therefore compliance
  • Each new procedure or update of existing
    procedure should also lead to a specific training
    on the changes implemented
  • Understanding of all these aspect of the
    procedure should preferably be assessed by
    knowledge control
  • A tracking system of the annual training should
    be organized

57
DOCUMENTATION
  • Good documentation is essential for the whole
    organisation and especially the RAD
  • All documentation should be prepared with great
    care and clearly written to prevent errors that
    can arise from oral communication

58
DOCUMENTATION
  • Documents should contain all the information
    necessary for proper use
  • Title, type and objectives should be unambiguous
    and clearly stated in SOPs
  • All documentation should be reviewed regularly
    and kept up to date
  • Amendments should be dated, authorized and signed
    by the appropriate personnel

59
DOCUMENTATION
  • An appropriate system should be in place to
  • ensure traceability of documents and their
    different versions
  • answers to the Regulatory Authorities
  • changes in PI
  • variations etc.
  • All documentation should be securely stored but
    readily accessible to RA personnel
  • When prepared or stored electronically validation
    processing programmes should be used

60
DOCUMENTATION
  • Data should be protected against loss or damage
    e.g.
  • Use of backup procedures
  • Only authorised personnel should be allowed to
    enter or change data

61
ARCHIVING
  • A good archiving system is mandatory
  • It should be described in a procedure
  • Describe, both the documentation and electronic
    documents,
  • The archiving plan,
  • The management of the different versions,
  • The answer to questions from Regulatory
    Authorities,
  • The traceability and the measures taken to ensure
    regular backup.

62
COMMUNICATION
  • Due to the multidisciplinary activities under the
    responsibility of RAD close relationship with
    almost all the departments is needed
  • Pre-clinical
  • Medical
  • Pharmacovigilance
  • Production
  • Quality Control
  • Quality Assurance
  • Marketing and sales etc

63
COMMUNICATION
  • RAD skills for communication and communicating
    information to other departments, Regulatory
    Authorities, Professional Associations
  • Communication - Key parameter to GRP in terms of
    compliance with regulatory requirements,
    lobbying, negotiation, effective relationship
    with external bodies

64
Checklist for Performance of RADs
  • Perceives disciplines and Regulators as partners,
    not enemies
  • Establishes/maintains efficient contact with
    Regulator
  • Works proactively
  • Proactive in product development/maintenance
    teams
  • Market orientated and customer focussed
  • Submits dossiers of sufficiently high quality in
    a timely fashion to obtain and maintain
    registrations
  • Maintains a quality system

65
Advice
  • Make your mission in the organisation clear.
  • Make your voice heard.
  • You are one of the most valuable team members if
    allowed to live up to full capacity.

66
Suggested Reading
  • Good Drug Regulatory Practices
  • A Regulatory Affairs Quality Manual
  • Helene I. Dumitri

67
  • Over to you!

68

  • MRA Regulatory Consultants
  • 381 Rossouw Street
  • Murrayfield
  • Pretoria
  •  
  • Tel 27 (0)12 803-6223
  • allison_at_mra-regulatory.com
  • henriette_at_mra-regulatory.com
  • robyn_at_mra-regulatory.com
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