Drug Regulatory Affairs

1
Drug Regulatory Affairs

• Institute of Drug Regulatory Affairs
• Faculty of Pharmacy
• University of Szeged

2
Introduction

• Tamás L. Paál, Professor
• for 23 years Head of the Hungarian national
  competent drug (human) regulatory authority
• now retired, but President of the Scientific
  Board of the same authority
• Also President of the Hungarian
  PharmacopoeiaCommission
• World Health Organization (WHO) expert (quality
  assurance, drug regulatory affairs, herbal
  medicines, drug side effect signal assessment)
• Drug Regulatory Affair field project expertise
  (WHO or EU) Nicaragua, Uganda, Uzbekistan,
  Kazakhstan, Turkmenistan, Bosnia and Herzegovina
• Officially visited 58 countries until now

3
Where are you from?
4
Technical details

• The slides of the lectures will appear on the
  University LAN
• www.pharm.u-szeged.hu/gyfi/GyIgaz
• They are detailed enough to learn
• However, students are expected to attend the
  lectures, otherwise it is extremely difficult

Do not know!
The files starting with W!
Blood droplets
BAD NEWS FAILING THE EXAMINATION POSSIBLE!
5
Exam topics

• will be presented at the end of any lecture topic
• Not only topic titles! The Students will be
  provided also with the bullet points (subtopics
  they should deal with)
• An example is provided on the next slide
• As a rule, the exam covers 3-4 topics

6
Example for the exam topics

• Basic elements of law
• Speak about the definitions in a law, then
  discuss the following
• law
• law-maker (discuss various possibilities in
  different countries)
• law enforcing bodies/persons (name some of them)
• sources of law (both meanings)
• different pieces of law. as a rule, the type of
  their content, their hierarchy, where are they
  proclaimed
• what is soft law
• what is co-authority
• quasi authorities (what is the rigth for
  veto?)

7
Warning, 1

• In my lectures
• drug
• drug product
• medicine
• medicinal product
• pharmaceutical (product)
• are used as synonyms! (As a rule, drug appears
  on the slide for it is the shortest word!)

8
Warning, 2

• In my lectures
• drug, drug product, medicine, medicinal product,
  pharmaceutical (product)
• means the one that is ready to take by or
  administered to humans! ( Dosage-forms)
• When I speak about drug substances, I use the
  term active pharmaceutical ingredient (API)

9
For

• (English is a funny language and different
  countries and organisations use different
  terminologies, sometimes deliberately)
• E.g.
• Drug medicinal product
• pharmaceutical product

WHO
US FDA
former EFTA
EU
10
Drug Regulatory Affairs
What the hell they are?
11
Drug regulatory affairs

• Thus, what (the hell) they are?
• In some Universities part of Pharmacy
  Administration - is it right? To administer it
  or to know it?
• Better approach what knowledge is needed for a
  graduate pharmacist? (Who may work anywhere from
  a community pharmacy to drug research)
• An answer has been given by the European Union!
  see later!

12
Drug regulatory affairs

• Any activity with drugs

no (does not belong to drug regulatory affairs)
Prior authorisation needed?
yes
By whom? (the authority)
Based on which (objective and subjective)
criteria?
Subject to regular control (quality, inspection)?
Based on which (objective and subjective)
criteria?
By whom? (the authority)
13
Activities with drugs

• research (chemical, biological)
• clinical trials on human beings
• manufacture
• registration
• evaluation
• authorisation
• (wholesale) distribution

continued
14
Activities with drugs (contd)

• (retail) distribution
• pricing
• prescribing
• reimbursement/subsidy
• advertising (if any)
• special control (e.g. narcotics)
• post-marketing surveillance
• national drug quality control lab
• adverse effect reporting system
• etc.

poppy
15
Where to find regulations?

• The so called hard law (Acts of Parliament,
  Governmental and Ministerial Decrees, etc.)
• The so called soft law (guidelines,
  methodological letters, etc. showing how
  competent authorities understand and use the hard
  law)
• To some extent, also codes of conduct
  (professional and ethical ones)
• It will be discussed in detail later!

16
What to teach?

• It is so simple for, e.g. chemistry and
  technology they are the same everywhere (law
  love?)
• It is also simple for the Hungarian
  undergraduates the topic is the Hungarian/EU
  regulatory affairs
• But you have come from (and return to) different
  countries with equally different drug regulatory
  affairs

17
Principles of this course

• Teaching World Health Organization (WHO) advised
  rules, they are universal
• Always call the attention of the students to
  that is what you should clarify when returning
  home
• Show European Union (EU) and Hungarian rules as
  examples only

18
Regulatory affairs

• Our life is regulated in many different ways
  continuously

19
Rules governing our life
hard law
custom/fashion, common courtesy
Ethical rules
professional rules
20
Rules governing our life

• Costum/fashion, common courtesy not always
  written, varies with the cultures greeting, (not)
  taking mans hat off, cutlery, rolls
  left-hand-side but maybe serious position of
  children/women is certain cultures
• Ethical rules in a given professional circle
  mainly written partly sanctioned you are
  expected to do this Ethical Codes of
  Professional Chambers, of Industry Associations
  (e.g. on medical advertising), Helsinki
  Declaration of Physicians otherwise you are not
  accepted in the Golf Club
• contd

21
Rules governing our life Contd

• Rules of the profession (soft law) as a rule
  written this professional (e.g. pharmacist) is
  expected to do this (in a given situation) in
  case, the Court tends to follow it in its
  decisions
• (Hard) Law enforceable! Negative authority
  decisions, police measures, Courts judgement

22
Hierarchy of the rules
(hard) law
Professi-onal rules (soft law)
Ethical rules
Custom, fashion, common courtesy
23
Hierarchy of the most important professional
rules in Hungary

• Hard law
• Soft law

• Constitution
• Acts of Parliament
• Governmental Decree
• Ministers Decree
• (Municipality Decree)
• ministerial guidelines
• methodological letters of
• National Boards/Institutes
• scientific literature

HIERARCHI
-
24
Are there other rules in your country?

• Presidential Decree?
• Royal Decree?
• Common (precedent) law?
• Any other type of soft law?

25
Presidential rules

• Countries vary!
• strong president (USA, Germany head of the
  executive power)
• weak president only ceremonies, limited rights
  to interfere (e.g. decision on the date of the
  elections, etc., many European countries)
• In between (e.g. France)
• Hidden presidential ruling (e.g. in former Soviet
  Central Asia)

26
Royal ruling

• In some countries traditional, instead of State
  president (dinasties versus elected presidents).
  Also
• weak (only ceremonies)
• strong (admitted or hidden ruling)

27
Common law

• Anglo-saxoon system the precedent is binding
• If a Court delivered a decision in a case
• another (same level) Court
• in a similar case
• must deliver the same decision!
• Thus, Court decisions are taken as law (common
  law)

28
Any other rules governing drug affairs in your
country?
29
Drug regulatory affairs

• Can be taught in various ways...

Simply the content of the rule
As for law graduates...
Or
30
Everybody knows the football game (at least in
Hungary) (except the national coach!)

• Imagine a very good football player
• His only problem is that he does not know the
  rules e.g. hands-off, offside, etc.
• What is your opinion, can he be successful as a
  team member?

31
The same is valid for Drug Regulatory Affairs!

• It is more than simple administration!
• The Art of Pharmacy belongs to the Regulated
  Field! Thus, to know the relevant regulations is
  the professional life itself!
• This is the topic you must know, if anything!
• The problem is you can not simply learn it, the
  rather because the details may be different in
  your homelands! Instead, you must understand the
  logic behind it!
• This is when I try to help you!

32
You may think you are experienced already. Is it
true?

• Who is law-maker? Who is enforcing the law?
• Is a pamphlet of a drug wholesaler, describing
  regulations a source or interpretation of the
  law/regulations? (Must you obey it?)
• What is co-authority? e.g. corresponding
  authority?
• What is the answer to the question why so many
  similar drug products are registered?
• What to do, when a patient
• - makes a complaint in the pharmacy?
• - brings the medicine back, for, according to
  him/her, it had no efficacy?

33
Do you know the right answer?

• It is not very probable, although they were so
  simple questions
• At the end of this semester, however, not only
  these but much more difficult questions can be
  answered, and what is more

you will know, what to do!
34
Thus, this is not law or theory but how the
Pharmacy affairs (in their broadest meaning) are
working!
?
?
35
It is true...

• Knowing is not enough, we must apply!
• Willing is not enough, we must do!
• Goethe

36
Medicines regulatory affairs

• It is by no means boring! It has interesting
  stories and an inherent logic
• It can be taught very boring, but it is not the
  fault of the regulatory affairs...

37
Why do we teach regulatory affairs

• for pharmacy undergraduates?
• The best answer is given by the European Union!

38
Thus what is the guidance of the European Union
for the pharmacy undergraduate curricula?
39
The 85/432/EEC Council Directive...

• concerning the coordination of provisions laid
  down by Law, Regulation or Administrative Action
  in respect of certain activities in the field of
  pharmacy
• Article 2 summarises in seven paragraphs what
  should be covered during the under-graduate
  courses (not listing the disciplines, rather
  stressing their content)

40
The training shall ensure adequate knowledge of

1. medicines and substances used in their
   manufacture
2. pharm. technology and physical, chemical,
   (micro)biological testing of medicines
3. effect, metabolism and proper use of medicines,
   action of toxic substances
4. evaluation of scientific knowledge concerning
   medicines (to supply appropriate info on them)
5. legal and other requirements of the practice of
   pharmacy

41
Let us have a closer look
42
The training shall ensure adequate knowledge of

1. medicines and substances used in their
   manufacture
2. pharm. technology and physical, chemical,
   (micro)biological testing of medicines
3. effect, metabolism and proper use of medicines,
   action of toxic substances
4. evaluation of scientific knowledge concerning
   medicines (to supply appropriate info on them)
5. legal and other requirements of the practice of
   pharmacy

clear-cut Drug Regulatory Affairs!
partly belong to Drug Regulatory Affairs (drug
assessment for registration)!
43
New Chapter Why is the knowledge of rules so
important in the field of Drug affairs?

44
Regulated and standardised fields

• Two distinct fields of products and services can
  be identified. They can well be distinguished
  although, in the real World, they may be
  overlapping

45
Standard? Regulation?

• Standardised field
• Regulated by the market
• based on Standards (e.g. ISO)
• Agreements
• Accreditation (by non-profit) and certification
  (by private for-profit bodies)

• Regulated field
• Regulated by authorities
• based on Laws, Pharmacopoeia
• Authorisation, registration
• Certification by authorities

Detailed
46
Standards (e.g. ISO) as a rule, only an
agreement of the stakeholders in the market...

• 110 V 220
  V

?
plugs
AC voltage
?
Receptacles (sockets)
47
Written national

• standards are elaborated by non-profit bodies,
  appointed from the stakeholders (both
  governmental and the interested manufacturers)
• agreement of the stakeholders on the market
• as a rule, based on existing International
  Standardisation Organisation (ISO) standards

48
Standards

• as a rule, are not binding
• (only express the interest of the majority of the
  stakeholders, if you ignore it can not sell your
  product)
• may be taken mandatory by a law (the law-maker
  needs rules, there is a standard, instead of
  elaborating similar rules refers to the standard
  the standard becomes law)
• In some countries every standard is at the level
  of law (former Soviet Union!)

49
Thus, misunderstanding...

• the Pharmacopoeia is the standard of the quality
  of medicines
• Standard (set of requirements), but not in the
  ISO meaning...
• the word standard has broader and narrower
  meanings in English

50
New ChapterHow drug affairs have been placed on
the regulated field?
51
Some history of Drug Regulation (WHO)

• Drugs are special commodity, there have been
  always concerns about their quality regulated
  control (regulated field!)
• Ancient Egypt in the 1st century BC written laws
  regulated physicians how to treat patients with
  drugs punishment
• 1st century AD written methods to combat drug
  adulteration
• Medieval times in Muslim countries preparation
  of medicines inspected by the Muhtasib (an
  official supervising also bazaars, schools, etc.)

52
Some history of Drug Regulation

• Europe, 11th-12th Century laws on doctors
  forbidden to enter into common business with
  apothecaries
• In the UK a law passed in 1540 apothecaries to
  be inspected for drugs that were defective,
  corrupted or not convenient to be administered
  for the health of mans body

53
Some history of Drug Regulation

• And from the late 19th Century industrial drug
  production, trade gross adulteration possible
  social pressure for regulation and control (
  regulated field)
• To-day proliferation of products, manufacturers,
  suppliers, promotion activities, also drugs with
  serious side effects (the thalidomide affair
  fetal deformities), etc. even more pressure and
  more developed regulation

54
Should we know it? A little WHO statistics

• from 6 WHO member states
• 1 has well-developed drug regulation
• 3 have some
• 2 have no Drug Regulatory Authority but limited
  capacities that hardly can function

55
Further arguments for drug regulation, 1

• Many interested intermediaries
• In ancient times the competent healer (also
  producing medicines) the patient
• To-day researchers, manufacturers, distributors,
  promoters and medical sales representatives,
  private insurers, dispensers variety of third
  party interactions

56
Further arguments for drug regulation, 2

• Information
• Drugs are not selected by patients but mostly
  prescribed by physicians, who depend mostly on
  manufacturers/sellers information. In
  unregulated markets this info were completely
  influenced by profit motives

57
Further arguments for drug regulation, 3

• Financial considerations
• If there are no or inadequate rules, the
  prescriber is completely nonsensitive to
  treatment expenses resources wasted (it may also
  happen if the drug costs are totally paid by the
  Government!)
• If pharmacists income is simply linked to the
  price of non-prescription drugs sold financial
  interest to advise the more expensive one

58
Further arguments for drug regulation, 4

• Drug testing and outcomes
• For registration, drug manufacturers are required
  to perform various (incl. animal) studies to
  demonstrate therapeutic benefits. If no such
  regulation exists, expensive or lengthy studies
  were omitted that would give rise to marketing of
  drugs of poor safety and/or efficacy (but with
  higher profit)

59
Further arguments for drug regulation, 5

• Misuse of drugs and drug shortages
• They may have serious impact on the health of
  both the individual and the entire population.
• Example antibiotic misuse (low or not enough
  doses, e.g. for shortages) ? microbial resistance
  ? other patients in danger
• Example curing a communicable disease patients
  prevents further transmissions

60
Further arguments for drug regulation, 6

• Storage
• Drugs have limited shelf-life. Improper storage
  deteriorates them rapidly. Consequences
• no (decreased) therapeutic value
• even toxic degradation products

61
Newer arguments for drug regulation

• New phenomenon counterfeit medicines
• Imitating a marketed product, but
• with no active ingredient at all
• with decreased active ingredient content
• with a purer quality (content, bioavailability)
• sometimes simply using the reputation of another
  Firms medicines

62
Regulatory affairs and the National Drug Policy
63
What is the content of Drug Regulatory Affairs?

• According to WHO, it is part of the National Drug
  Policy
• Why a Drug Policy?
• Practically in all countries (from the Third
  World to USA), problems
• ensuring availability of safe, efficacious and
  good quality drugs to the whole population (
  affordability and/or distribution),
• rational drug use

64
Components of the Drug Policy

• Legislation, regulations and guidelines
• Selection of drugs
• Supply
• Pharmaceutical Quality Assurance
• Rational use of drugs
• Economic strategies for drugs
• Research
• Human resources development
• Monitoring of the drug policy

Drug Regulatory Affairs themselves / hard and
soft law on
65
Components of Drug Regulatory Affairs, 1

• Research on animals - ?
• human
  clinical trials
• Manufacture authorised? Local healers?
• Registration assessed or simply registered?
• Procurement State? Public service obligation?
• Distribution wholesale
• 
  community pharmacies
• hospital
  pharmacies
• doctors
• other

66
Components of Drug Regulatory Affairs, 2

• Narcotic drugs
• Psychotropic substances
• Precursor substances
• Regulatory control
• national lab?
• quality defect reporting?
• ADR monitoring?
• inspections?

67
Components of Drug Regulatory Affairs, 3

• Product service liability
• Patients rights
• Drug advertising/promotion
• for health
  professionals
• for the
  general public
• Prescribing rules
• Wasting drugs
• Professional Chambers, Societies

68
Components of Drug Regulatory Affairs, 4

• Pricing, reimbursement/subsidy
• In relation to that
• The basic PHARMACOECONOMY

69
Getting started(Maybe, some repetition from the
last Basic law Semester, but it is important)
70
Getting started certain fundamental conceptions

• Law statutory regulation
• Law-maker corporate body or person authorised to
  issue a piece of law
• Person applying/enforcing law an official who,
  on the basis of law, may make (civil service)
  decisions

71
Law-maker, 1

• You must consult the legal system in your
  country!
• Is it a Federal country? If yes, what legislative
  tasks have the lands (territories?) What is
  covered by the Federal and what by the Lands
  legislation?
• E.g. medicines registration is federal in the USA
  and Switzerland, semi-federal in Germany

72
Law-maker, 2

• Do you have Republic, Kingdom, etc.?
• If Parliamentary Republic, are there two Houses?
  E.g. House of Common and House of Lords in the
  UK, Congress and Senate in the USA
• Any law-making power of the former?

73
Typical law-makers

• (President of the State/King?)
• Parliament
• Prime Minister/Government
• Minister
• (Other National Body)
• Municipalities - the Body?

74
Law-enforcement organs

• (Head of an) Authority or his/her authorised
  colleague(s)
• Part of the Ministry or independent Agency?
• (Head of) another Body, authorised for certain
  law-enforcement tasks
• Judge (Court, Jury)
• (Municipality) clerk

75
Plus one further issue

• What law-making/enforcing authorisation for the
  President of State or the King in your country?
• more Presidential systems USA, BRD, France
• less Presidential UK (the king or queen), many
  European countries

76
In certain countries (like Hungary), the
law-enforcement authority is given...

• to single persons! (Even if more such persons
  are acting!)
• Thus, civil service law-enforcement is bound to
  authorised persons here!

77
Pieces of law 1

• Sources of law (two meanings both the law-maker
  and where the law is published)
• Parliament
• Government
• Minister
• (Municipality, President, King)

78
Pieces of law 2

• You should identify what kind of pieces of law do
  and did exist (some outdated forms might remain
  in force)
• Soft law e.g. guidelines, methodological
  letters, etc. of authorities or professional
  Bodies NOT pieces of law!

79
Typical pieces of law

• Act of Parliament (Bill before)
• Created by the Parliament According to its
  accepted plans. Modification is this Act open
  for it?
• What is contained in an Act? What concerns every
  citizen!
• Signed by e.g. President of the Parliament and
  State President or King (why! Veto for one
  occasion, or this right for the Senate etc.)

80
Typical pieces of law 2

• Decree of a Minister
• Created by the Minister (Ministry?) When as a
  rule when an Act gives the authorisation for it!
  (In general or concrete)
• What is contained? What concerns the
  professionals in the given field under the
  supervision of that Ministry
• Signed by the Minister

81
Typical pieces of law 3

• Governmental Decree
• Created by the Government when an Act gives the
  authorisation for it! (In general or concrete)
• What is contained? What relates professionals
  working under the supervision of various
  Ministries
• Signed by the Prime Minister

82
Examples in what pieces of law to specify
certain rules

• Hungarian Health-care Act (e.g. human clinical
  trials only informed volunteers, consent can be
  withdrawn any tim, etc.)
• Hungarian Decree of the Minister of Health on
  Clinical Trials (e.g. which authority to approve,
  which Ethical Committee competent, what is to be
  assessed for approval, etc.)

83
Hierarchy of the pieces of law

• The inferior may not contradict the superior
  (e.g. may not modify it)
• Act gt Govnmental Decree gt Minist. Decree
• E.g. if the definition of medicine is specified
  in an Act, the Health Minister may not issue an
  overlapping definition to nutraceuticals (food
  for special dietary needs) in a Decree...

84
Where are pieces of law proclaimed

• Official Gazettes of the State Acts,
  Governmental Decrees
• Official Gazettes of a given Ministry
  Ministerial Decrees important! If such pieces of
  law relate Pharmacy affairs, these Gazetts should
  be available for the pharmacies. Is there any
  rule for their mandatory subscription?
• Is, e.g. an updated law-collection available on
  CD?

85
Soft law state-of-art rules of the profession

• Guidelines, methodological letters of Ministries,
  National Institutes, Boards
• Lawyers attitude not binding - true but do
  not deviate from them without a good reason! For
• some of them details the law
• piece of law refers to some of them
• their meaning is it is acceptable this way (you
  may deviate from it if the result is the same) -
  the majority do not want to litigate but wants to
  know the right solution...

86
Public Authorities, other Institutions authorized
with such tasks, co-authorities

• It is extremely difficult to understand for many
  people!
• Any authority (authoritative task) may be given
  by a piece of law, detailing the
  responsibilities!
• Public/Regulatory Authority, Civil Service
  Agency, etc. synonyms but the name may vary from
  country to country

87
Public Authority

• As a rule, appointed by an Act to execute
  regulatory tasks (almost) exclusively
• Ministries, Police, Municipality staff, Customs
  officers, Public Health Service officers
• Other name of the Organisation Office for...

88
Other institutions with authoritative tasks

• Principally (e.g. specified in their Foundation
  Document) not authorities
• As a rule, supervised by the Government or a
  Ministry
• A piece of law delegates given authoritative
  functions to them

89
A Hungarian example for delegation of
authoritative functions

• National Institute of Pharmacy - its Foundation
  Document
• in the field of Pharmacy, it is the
  organisational-methodological-scientific and
  postgraduate teaching institution of the Ministry
  of Health
• plus it fulfils the authoritative functions
  delegated by pieces of law

90
Co-authority

• NOT some sort of an inferior authority!
• When more then one authorities are concerned in
  one single civil service procedure, one is
  appointed (by law) as the authority (to issue
  the decision) while the others are named (in this
  procedure) co-authorities!

91
(Co-)Authorities
IT WERE NOT CITIZEN-FRIENDLY!
YES
YES
YES
YES
YES
YES
92
Co-authority

• Hungarian example
• Supervision of advertising of non-prescription
  medicines to health-care professionals
• The authority is the Ofice for Health Insurance
  Supervision, with the National Institute of
  Pharmacy as professional co-authority

93
What is (as a rule) the responsibility of the
co-authority?

• If it approves, the authority still may refuse
  the application (on the basis of its own opinion,
  without prejudice of the co-authoritys), but
• if the co-authority has a negative opinion the
  application must be refused (Veto!)
• The co-authoritys opinion, on its professional
  field, must be accepted (it has even right for an
  appeal)

94
Quasi right for veto

• An organ, not appointed as authority (often Trade
  Union or Chamber) has the right for agreement
  according to a piece of law. If it does not
  agree, the process is stopped (the regulation
  will not come into force, etc.). As written in
  the piece of law
• The (authority) authorises the with the
  agreement of XY

95
Right for expressing the opinion

• The (authority) may authorise the after
  asking for the opinion (or knowing the opinion)
  of XY
• It means that the opinion must be asked for but
  it should not obeyed

96
Other discussions before issuing a law

• E.g. opinion of professional Societies or
  Chambers or Associations ought to be requested
  for, but it is not obligatory and the opinion is
  by no means binding

97
Exam topics!
98
Regulated and standardised fields

• For what they apply? (2)
• Explain their 4 main differences (with examples)
• To which field drugs regulatory affairs belong to
  and why?

99
Basic elements of law

• Speak about the definitions in a law, then
  discuss the following
• law
• law-maker (discuss various possibilities in
  different countries)
• law enforcing bodies/persons (name some of them)
• sources of law (both meanings)
• different pieces of law. as a rule, the type of
  their content, their hierarchy, where are they
  proclaimed
• what is soft law
• what is co-authority
• quasi authorities (what is the rigth for
  veto?)

100
O.K., let us change the topic now