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Regulatory Affairs: paths to approval
by Charles Hackett
The FDA peri-approval Phase
New Drug Application (NDA) to FDA
Application includes:
• Results of clinical trials
• All additional scientific data
Microbiology Review Biopharmaceutical Review
Only required for NDA for • speed & extent of active
anti-infectives, to include: ingredient’s availability to the body
• biochemical basis of drug’s action • method of distribution,
• drug’s antimicrobial spectra metabolism & elimination for
• mechanisms of resistance to drug the body
Statistical Review Review by Center for Drug Chemistry Review
• statistical relevance of Evaluation & Research (CDER) • drug identity
submitted data • to ensure the drug has • stability
• proposed statistical sufficient levels of safety, • manufacturing procedures
methodology for clinical trial quality and efficacy in humans
Pharmacology Review Medical Review
• toxicological effects of drug • clinical trial design
• mechanism of action in the • clinical trial protocol
body
FDA & Sponsor Meetings
• easily corrected deficiencies
Advisory Committee
in application
Meetings
• scientific & medical issues
arising during review process
Labelling Review Site Inspection
• review of official • manufacturing sites
instructions for use • clinical trial sites
Marketing Approval
for the US
"Regulatory authorities are
responding to pressure from
pharmaceutical companies
and healthcare providers alike
to cut market approval times”
Regulatory Affairs: paths to approval
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Biochemie Glaxo Wellcome Ranbaxy
Biogal-Teva Hoechst Marion Roussel Recordati
Biogen Hoffman La Roche Rhône-Poulenc Rorer
Your guide to success
Global median approval time for New Chemical The steady overall increase in the time taken for a drug to gain
Entities, 1992-97
marketing authorisation has led to increased pressure on regulatory
30 authorities to modify and improve the drug approval process.
20
Regulatory authorities are trying to streamline their review
Months
10
procedures, but there is still a great need for companies to
0
understand the recent developments and the hurdles that are
Canada
UK
US
France
Germany
Spain
Japan
Australia
Italy
presented by different authorities.
1992/93
1994/95
1996/97
The Business Insights report, ‘Regulatory Affairs: Paths to
Approval’, draws upon extensive primary research from industry
“The UK has the shortest NCE approval executives and regulatory authorities, to provide an overview of the
time, despite having the most popular present state of the drug approval process as well as the ongoing
regulatory authority for the EMEA developments in this area. The report analyses the current hurdles
decentralised and centralised and opportunities for both pre-clinical and marketing applications,
procedures”
assessing the present systems, the future role of
pharmacoeconomics, and the impact of recent developments in
Regulatory Affairs: paths to approval
international harmonisation.
Research methodology
CEEC ethics committee characteristics Regulatory Affairs: paths to approval benefits from 40 in-depth
interviews with senior executives in all the major pharmaceutical
s
ne
s
eli
ic
id
th
gu
e s al e
tria e
ls
ic tim
P
itte c
C
m l/lo
lin al
w
G
al
r c rov
la
m tra
ed
as
p
en
as
Ap
and healthcare sectors to ascertain each company’s strategic
P
C
-b
C
co
fo
EU
G
L
Poland up to 42 days
C if multi-centre
positioning and future plans, together with their individual view of
C
Hungary up to 60 days
& L for Phase III
Czech
L mean of 60 days
Republic
Slovakia
Bulgaria
L
C for Phase I,II & III
not specified
not specified
the marketplace in which they operate:
L for Phase IV
Romania L not specified
Russia L not specified
Estonia C up to 60 days
30 industry executives evaluated the impact of new regulatory
Latvia C up to 30 days
Lithuania C not specified hurdles and guidelines, and the future of pharmacoeconomics.
C Central ethics acommittee
L Local ethics committees
To be implemented following EC Directive on GCP
Called ‘Rules for Clinical Trials’ , not GCP
Despite an Order from the Ministry of Health setting out GCP standards,
as yet there are no inspections in Romania
10 regulatory authorities highlighted recent and upcoming
“Interest in Central and Eastern European regulatory guidelines, giving details of time frames and approval
Countries (CEECs) as locations for clinical
procedures.
testing is increasing, due to the ready
availability of willing trial subject and
increasing levels of GCP compliance”
Regulatory Affairs: paths to approval
Structure and scope
Time between start of 90-day period and Area Specific Chapters - The regulatory systems governing clinical
issuing of licence
trials and drug approvals are examined for the US, Europe, and
Australia, Canada and Japan, including analysis of the implications
of recent developments and initaitives.
400
300
200
Days
100 End of 90-day
discussion
Glossary - A comprehensive list of abbreviations frequently used,
and a glossary of regulatory affairs terms, are given.
period
0
Belgium
Luxembourg
Netherlands
UK
Denmark
Spain
France
Ireland
Sweden
Germany
Greece
Portugal
Austria
Finland
Italy
Comparisons - The lengths of time taken for drug approval
procedures in the major pharmaceutical markets are also
compared.
“Though the EMEA decentralised
procedure is, at present, the most
COMMON EU marketing approval Global Issues - The future role of pharmacoeconomics in the drug
procedure, future inclusion of CEECs in approval process; recent initiatives in harmonisation within the EU
the EU, and harmonisation of the US,
and international, are analyses and assessed.
Japan and the EMEA, will lead to greater
use of the centralised procedure to cut
overall sponsor time spent on regulatory
affairs”.
Regulatory Affairs: paths to approval
Key benefits
• Understand the procedures involved in gaining marketing
Clinical Trials approval, and how to optimise them.
Up to 10 years • Realise the benefits and additional hurdles of conducting
Mainly tests safety phases of drug development in different locations.
Of the drugs which start Phase I, 70% pass
Phase I
20-10 subjects
• Minimise the overall number of clinical trials and regulatory
reviews needed for multinational approval.
Tests short-term safety & efficacy
Phase II
Of the drugs which start Phase II, 50% pass
• Evaluate the impact of recent developments in electronic
several hundred subjects
Test safety & efficacy
Of the drugs which start
Phase III, 75% pass
communication on the management of new drug submission.
Phase III
several thousand subjects
• Assess the future of the FDA in the light of the Modernisation
Act.
• Understand the trends in obtaining pan-EU marketing
“Pharmacoeconomics is starting to affect
most countries, but in many it is not yet authorisation.
the codified regulatory burden it is in
• Comprehend the implications of recent and future progress in
Australia and particular Canadian
provinces”. international harmonisation.
• Identify present and future strategies for speeding a
Regulatory Affairs: paths to approval
pharmaceutical product to market, and so maximise patent
exclusivity and return on R&D investment.
The industry standard
EMEA mean approval times, 1995-97 Business Insights’ ‘Regulatory Affairs: paths to approval’ is
clearly ahead of the competition, thanks to its quality research and
analysis content.
8 60
7
50
6
Do the sources of information that you are using fully meet your
No. of applicants
40
5
needs?
Months
4 30
3
20
2
1
10
Business Insights provides you with a comprehensive and detailed
0 0
1995
Average time
1996 1997
analysis of opportunities for pharmaceutical companies, based on a
Number of applicants
combination of in-depth primary research with key personnel and
opinion leaders, and the utilization of reliable in-house databases.
“The average total EMEA centralised Complete the following checklist . . . Business |nsights’ Competitor
procedure application processing has Regulatory Affairs Reports
Analysis of the procedures involved in gaining marketing
fallen, despite the increase in approval, and how to optimise them + -
applications, and is shorter than either the
Identification of the benefits and hurdles of conducting
FDA or the MCA”.
phases of drug development in different locations + -
Regulatory Affairs: paths to approval Assessment of the future of the FDA in the light of the
Modernisation Act + -
Analysis of the implications of recent and future progress
in international harmonisation + -
Who can benefit from this report?
Sample approval dates for US and EU
Are Business Insights’ reports for you?
Examine the Target Index below.
Jan-99
Jan-98 Company type
Date of US
marketing approval Ethical Biotech Diagnostic
Jan-97
Manufacturers Companies Companies
Date of EMEA
Jan-96
marketing approval
Business √ √ √
Jan-95
Development
Jan-94
Clinical Strategy √ √ √
Jan-93 Managers
Jan-92
R&D Program √ √ √
l
ra
e
n
ivir
a
l
an
xo
Managers
vix
a
ca
as
ra
ex
er
ag
Ta
ixiv
Ep
ni
Pla
ig
vir
pr
th
Vi
Xe
Im
Zy
ab
In
Cr
M
Clinical Trial √ √ √
Planners
Job title
Marketing √ √ √
Professionals
Product √ √ √
Managers
“Due to the sheer size of the market, US
New Product √ √ √
approval is usually still a pharmaceutical Development
company's priority”. Finance √ √ √
Directors
Outcomes √ √ √
Regulatory Affairs: paths to approval Directors
Market Research √ √ √
Managers
Table of Contents
EXECUTIVE SUMMARY Post Launch
Pharmacovigilance
Introduction FDA Modernisation Act
Regulation in the US Time frames
Europe: Centralised and fragmented regulation Prescription user fees
Other markets, other hurdles Access to experimental therapies
Comparison & global harmonisation Contracting out
Efficacy standard
CHAPTER 1 INTRODUCTION
CHAPTER 3 EUROPE: CENTRALISED AND FRAGMENTED
Summary REGULATION
Outline of clinical trials
Clinical criteria Summary
Quality UK
Safety Medicines Control Agency (MCA)
Efficacy Committee on Safety of Medicines (CSM)
Pharmacoeconomics - the fourth hurdle Pre-clinical development
Clinical studies Pre-clinical trials
Pre-clinical trials Clinical Trial Certificates/Exemptions
Clinical trials: Phase I, II & III Phase I trials
Controlled trials Research Ethics Committees
Blind trials Clinical trials
Phase IV trials New Drug Applications
Electronic application
CHAPTER 2 REGULATION IN THE US Review times
Inspection and enforcement
Summary Post-launch
The FDA Post-market evaluation
Pre-clinical Development Pharmacovigilance
Pre-clinical Trials Fees
Synthesis & Purification Pharmacoeconomic - National Institute of Clinical Excellence
Animal testing Germany
Investigational New Drug (IND) application Marketing authorisation applications
Medical Review Approval times
Statistical Review Development
Pharmacology Review France
Toxicology Review Clinical trials
Clinical Trials Ethics committees
Institutional Review Boards Approval times
Phase I The EMEA - EU regulation
Phase II Pre-clinical procedure
Phase III Declaration of Helsinki
New Drug Application EU Directive on GCP
NDA Classifications Centralised procedure
CDER Review CPMP drug evaluation
Microbiology Review Approval times
Biopharmaceutical Review Decentralised registration
FDA & sponsor meetings The Mutual Recognition Facilitation Group
Advisory committees Selection of Reference Member State
Site inspection Issue-raising by CMSs
NDA Review Times License issue
Generic drug applications (ANDA/AADA) Number of MR procedures finalised
Bioequivalence review Central & Eastern European Countries
Chemistry/microbiology An increase in clinical trials
Generic drug review times CEEC ethics committees
Electronic applications Development
Fast-tracks
Priority Drugs
Treatment INDs
Accelerated Review
Parallel track
User fees
Table of Contents
CHAPTER 4 OTHER MARKETS, OTHER HURDLES Figure 3.12: Median approval time for NCEs
Figure 3.13: Median approval time for NCEs
Summary Figure 3.14: Pre-clinical phase in France
Japan Figure 3.15: Median approval time for NCEs
Pre-clinical research Figure 3.16: EU pre-clinical procedure
Clinical trials Figure 3.17: Centralised Procedure
Institutional review boards Figure 3.18: Rapporteur selections, 1995-1997
Phase I Figure 3.19: Mean approval times
Phase II Figure 3.20: Decentralised Procedure
Phase III Figure 3.21: Selection of Reference Member State, 1995 to July
New drug application 1998
Commercial implications Figure 3.22: Mean number of issues raised by CMS since 1995
Differing regulatory burdens: Pharmacoeconomics Figure 3.23: Time between start of 90-day period and issuing of
Australia licence
Drug approval and reimbursement Figure 3.24: Number of MR procedures finalised, 1995-1997
Fourth hurdle Figure 3.25: Number of clinical trials in CEECs, 1994 to 1996
Commercial impact of Australian guidelines Figure 3.26: CEEC ethics committee characteristics
Canada Figure 4.27: Clinical trials
CCOHTA guidelines Figure 4.28: New drug application
Commercial implications of CCOHTA guidelines Figure 4.29: The drug approval and reimbursement process in
The worldwide future of pharmacoeconomics Australia
Figure 5.30: Global median approval time for NCEs
CHAPTER 5 COMPARISON & GLOBAL HARMONISATION Figure 5.31: Sample approval dates for US and EU
Summary LIST OF TABLES
Comparison of Regulatory Authorities
Speed of approval Table 2.1: NDA classifications
Date of approval Table 2.2: FDA user fees, 1995-1997
Harmonisation - the future of regulatory affairs Table 3.3: MCA Fees from 1 April 1998
International Conferences on Harmonisation Table 5.4: ICH procedure
The work of ICH
The ICH procedure
Good Clinical Practice/Good Manufacturing Practice guidelines
Regulatory Communications
Standardising Terminology
Standardising electronic transfer of regulatory information
Common Technical Document
The future of ICH
Other harmonisation initiatives
The World Health Organisation
Pharmaceutical Mutual Recognition Agreement: the US and the EU
The European Free Trade Association
EU and CEECs
CHAPTER 6 APPENDIX
Abbreviations
Glossary of terms
LIST OF FIGURES
Figure 1.1: Clinical Trials
Figure 2.2: Pre-Clinical Phase
Figure 2.3: Clinical Phase
Figure 2.4: Peri-Approval Phase
Figure 2.5: NDA Approvals
Figure 2.6: NDA Rejections and Approvals
Figure 2.7: Generic Drug Approval Applications
Figure 2.8: Generic approval times
Figure 3.9: Pre-clinical phase in the UK
Figure 3.10: Clinical trials in the UK
Figure 3.11: Mean NAS assessment times
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