§
Drug Regulatory Affairs
Institute of Drug Regulatory Affairs
Faculty of Pharmacy
University of Szeged
1
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
2
Where are you from?
3
Technical details
• The slides of the lectures will appear on the
University LAN
www.pharm.u-szeged.hu/gyfi/GyIgaz
Do
not
know!
The files starting with W!
• 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!
4
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)
8
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
9
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 (cont’d)
•
•
•
•
•
•
•
(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 man’s
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…”
cont’d
20
Rules governing our life… Cont’d
• 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, Court’s
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
•
•
•
•
•
• Soft law
• ministerial guidelines
• methodological letters of
National Boards/Institutes
• scientific literature
HIERARCHI
+
-
Constitution
Acts of Parliament
Governmental Decree
Minister’s Decree
(Municipality Decree)
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 man’s 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 Firm’s 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” = 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
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 > Gov’nmental 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 coauthority’s), but
• if the co-authority has a negative opinion
the application must be refused (Veto!)
• The co-authority’s 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
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