Drug Regulatory Affairs

Institute of Drug Regulatory Affairs

Faculty of Pharmacy
University of Szeged

Introduction
Tams L. Pal, 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

Where are you from?

Technical details
The slides of the lectures will appear on the
University LAN
www.pharm.u-szeged.hu/gyfi/GyIgaz
The files starting with W!

Do
not
know!

They are detailed enough to learn

However, students are expected to attend the
lectures, otherwise it is extremely difficult
Blood
droplets

BAD NEWS: FAILING THE

EXAMINATION POSSIBLE!

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
5

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?)
6

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!)
7

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)

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
EU

former
EFTA

Drug Regulatory Affairs

What the hell
they are?

10

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!

11

Drug regulatory affairs

Any activity with drugs
Prior authorisation needed?

no (=does not belong to

drug regulatory affairs)

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)

12

Activities with drugs

research (chemical, biological)

clinical trials on human beings
manufacture
registration
evaluation
authorisation

(wholesale) distribution
continued

13

Activities with drugs (contd)

(retail) distribution
pricing
prescribing
reimbursement/subsidy
advertising (if any)
special control (e.g. narcotics)
post-marketing surveillance

poppy

national drug quality control lab

adverse effect reporting system

etc.
14

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!
15

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
16

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

17

Regulatory affairs
Our life is regulated in many
different ways continuously

18

Rules governing our life

hard law
custom/fashion,
common courtesy

Ethical rules

professional
rules
19

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
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
20

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

21

Hierarchy of the rules

(hard) law

Professional rules
(soft law)

Ethical rules

Custom, fashion, common courtesy

22

Hierarchy of the most important

professional rules in Hungary
Hard law

HIERARCHI

Soft law
-

Constitution
Acts of Parliament
Governmental Decree
Ministers Decree
(Municipality Decree)

ministerial guidelines
methodological letters of
National Boards/Institutes
scientific literature
23

Are there other rules in your

country?

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

24

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)
25

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

26

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)
27

Any other rules governing drug

affairs in your country?

28

Drug regulatory affairs

Can be taught in various ways...

Simply the
content of
the rule

As for law
graduates...

Or
29

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?

30

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!

31

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?

32

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!

33

Thus, this is not law or

theory but: how the
Pharmacy affairs (in their
broadest meaning) are
working!
?

34

It is true...
Knowing is not enough, we must
apply!
Willing is not enough, we must do!
Goethe

35

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...

36

Why do we teach regulatory

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

37

Thus: what is the guidance of

the European Union for the
pharmacy undergraduate
curricula?

38

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)
39

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

40

Let us have a closer look

41

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)!

42

New Chapter:

Why is the knowledge of rules

so important in the field of
Drug affairs?

43

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

44

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

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

Detailed

45

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)

46

Written national
standards are elaborated by nonprofit 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
47

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 lawmaker 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!)
48

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

49

New Chapter
How drug affairs have been
placed on the regulated field?

50

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.)
51

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
52

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
53

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

54

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

55

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

56

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
57

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)

58

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

59

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

60

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

61

Regulatory affairs and the

National Drug Policy

62

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
63

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 law64on

Components of Drug Regulatory

Affairs, 1
Research

on animals - ?
human clinical trials

Manufacture
Registration
Procurement
Distribution

authorised? Local healers?

assessed or simply registered?
State? Public service obligation?
wholesale
community pharmacies
hospital pharmacies
doctors
other
65

Components of Drug Regulatory

Affairs, 2

Narcotic drugs
Psychotropic substances
Precursor substances
Regulatory control
national lab?
quality defect reporting?
ADR monitoring?
inspections?
66

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
67

Components of Drug Regulatory

Affairs, 4
Pricing, reimbursement/subsidy
In relation to that:
The basic PHARMACOECONOMY

68

Getting started
(Maybe, some repetition from the
last Basic law Semester, but it
is important)

69

Getting started: certain

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

70

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
71

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?

72

Typical law-makers

(President of the State/King?)

Parliament
Prime Minister/Government
Minister
(Other National Body)
Municipalities - the Body?

73

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
74

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

75

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!

76

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)

77

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!

78

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.)

79

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
80

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
81

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.)

82

Hierarchy of the pieces of law

The inferior may not contradict the
superior (e.g. may not modify it)
Act > Govnmental Decree > 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...

83

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?

84

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...

85

Public Authorities, other Institutions

authorized with such tasks, coauthorities
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
86

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...

87

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

88

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
89

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!
90

(Co-)Authorities

YES

YES

IT WERE NOT
CITIZENFRIENDLY!

YES

YES
YES
YES
91

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 coauthority

92

What is (as a rule) the

responsibility of the coauthority?

If it approves, the authority still may

refuse the application (on the basis of its
own opinion, without prejudice of the coauthoritys), 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)
93

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

94

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

95

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

96

Exam topics!

97

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?

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?)
99

O.K., let us change the topic now

100