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Overview of the
Canadian Federal Drug Review Process
University of Toronto – Faculty of Pharmacy
Marilyn Schwartz
A/Director, Bureau of Operational Services
Therapeutic Products Directorate
September 27, 2004
Health Products and Food Branch
Direction générale des produits de santé et des aliments
Responsibilities for Drugs

Federal





Regulates the safety, efficacy and quality of drugs
Ensures patent linkage
(Health Products & Foods Branch)
Controls the price of patented medicines
(Patented Medicines Prices Review Board)
Coordination and leadership on FPT pharmaceutical issues
Provincial




Delivery of healthcare
Practice of Medicine/Pharmacy
Reimbursement issues
Drug Formularies
Health Santé
Canada Canada
Health Products and Food Branch
Direction générale des produits de santé et des aliments
2
Federal Legislation and
Guidance for Drugs

Food and Drugs Act and Regulations



Governs the safety, effectiveness and quality of
drugs and medical devices available to Canadians.
Patented Medicines (NOC) linkage Regulation
Financial Administration Act
(fees for review-cost recovery)


Access to Information and Privacy Act
Controlled Drugs and Substances Act
(governs narcotic & controlled drugs)

Policies and Guidelines (including International Guidelines ICH) in support of the Acts and Regulations
Health Santé
Canada Canada
Health Products and Food Branch
Direction générale des produits de santé et des aliments
3
Health Canada
Healt h Canada
M
i ni st er
Deput y Mi ni st er
Associ at e
Deput y Mi ni st er
Pest M anagem en
t
Regul at or y Agency
Of f i ceof t he
Chi ef Sci en
tis
t
Audi t and
Account abi li t y
Bur eau
Br anches
Healt h Po
l i cy
and
Com muni cati ons
Popu
l ati on
and
Publ i c Healt h
Heal t h
Pr oduct s and
Food Br anch
Healt hy
Envi r on
ment s
and Consumer
Saf e
ty
Fi rs t Nat i ons
and
I nu
i t Hea
lth
I nf or m a
t i on
,
Anal y
si s
and
Connect i vi t y
Cor por at e
Ser v
i ces
Regi ons
Br i t i shCol umiba
and
Yukon
Al be
rt a
and
Nor t hwest
Ter ri t ori es
Health Santé
Canada Canada
M an
i t oba
and
Saskat chewan
Ont ari o
and
Quebec
At l an
tic
Nunavut
Health Products and Food Branch
Direction générale des produits de santé et des aliments
4
Health Products and Food Branch
Health Santé
Canada Canada
Health Products and Food Branch
Direction générale des produits de santé et des aliments
5
Therapeutic Products Directorate
Therapeutic Products Directorate
Effective April 1, 2002
Health Santé
Canada Canada
Health Products and Food Branch
Direction générale des produits de santé et des aliments
6
Health Products and Food Branch (HPFB)
Responsibilities for Drugs

Therapeutic Products Directorate
(TPD)
Responsible for evaluating the safety, effectiveness and
quality of pharmaceutical drugs and medical devices
available to Canadians.
o

Similar to CDER in U.S. – F.D.A.
Biologics and Genetic Therapies Directorate (BGTD)
Responsible for evaluating the safety, effectiveness and
quality of biological and radiopharmaceutical drugs, as
well as blood and blood products, viral and bacterial
vaccines, genetic therapeutic products, tissues, organs
and xenografts.
o
Similar to CBER in U.S. – F.D.A.
Health Santé
Canada Canada
Health Products and Food Branch
Direction générale des produits de santé et des aliments
7
Health Products and Food Branch (HPFB)
Responsibilities for Drugs - cont’d

HPFB Inspectorate – Compliance & Enforcement


Responsible for delivery of inspections and
investigations, and for most establishment licensing
and related laboratory analysis functions.
Marketed Health Products Directorate (MHPD)

Responsible for post-market assessment and
surveillance of pharmaceutical and biological drugs,
medical devices, natural health products, radiopharmaceuticals.
Health Santé
Canada Canada
Health Products and Food Branch
Direction générale des produits de santé et des aliments
8
Health Products and Food Branch
Natural Health Products Directorate (NHPD)
Ensures that Canadians have ready access to health
products that are safe, effective, and high quality by
maintaining proper labelling and implementing regulatory
framework which supports freedom of choice and cultural
diversity
New regulations came in Jan 2004
Veterinary Drugs Directorate (VDD)
Ensures the safety of foods such as milk, meat, eggs, fish
and honey from animals treated with veterinary drugs, and
that veterinary drugs sold in Canada are safe and effective
for animals
Health Santé
Canada Canada
Health Products and Food Branch
Direction générale des produits de santé et des aliments
9
Product Types Regulated as “Drugs”




Pharmaceuticals (prescription, non-prescription, brand
name, generic)
Biological drugs (vaccines, recombinant drugs, blood
products)
Radiopharmaceuticals
Natural Health Products (Transition to NHPD, January 1st, 2004)





Homeopathic products
Traditional herbal medicines
Other Herbals
Disinfectants for use on medical instruments, hospital and
food preparation surfaces
Veterinary Drugs
Health Santé
Canada Canada
Health Products and Food Branch
Direction générale des produits de santé et des aliments
10
Life of a New Drug
Research
Create/Isolate Chemicals
Tissue/Culture
(14,000 tested to get one as marketable)
small animals
Special Access Program (SAP)
(emergency release)
More Specific animal
testing and in vitro tests
(e.g. carcinogenicity, reproductive studies)
Human Testing
(Clinical Trial)
HC approval required
(Food & Drug Act & Regulations 30 day default)
Post Market Surveillance
Provincial Formulary
Decisions
PMPRB
(price controls)
All testing is done, drug company completes
analysis of data, prepares New Drug
Submission (NDS)
HC Review Decision
Health Santé
Canada Canada
Health Products and Food Branch
Direction générale des produits de santé et des aliments
11
Life of a New “Drug” – cont’d
Industry
Government
Create/Isolate Chemicals
Tissue/Culture
More Specific Animal Tests
Human Testing (Clinical Trials)
Complete Analysis of data
Prepare New Drug Submission
Negotiate with Provinces
Marketing and Promotion to Physicians
Updates to Product Monographs
Dear Health Care Provider Letters
Product on Market or Removal
Health Santé
Canada Canada
HC Approval required
Special Access
HC Review / Decision
PMPRB Federal Price Control
P/T Formulary Decisions
Post-Market Surveillance
Post-Market Regulatory Actions
Health Products and Food Branch
Direction générale des produits de santé et des aliments
12
Drugs Sold in Canada
 All
drugs sold in Canada must be approved
by Health Canada. These include but are
not limited to the following:



drugs imported from other countries;
drugs manufactured in Canada;
drugs for export where the exporting company
needs a Canadian approval in order to enter
into another country.
Health Santé
Canada Canada
Health Products and Food Branch
Direction générale des produits de santé et des aliments
13
New Drug Approval Process
Drug Submission Filed
Central Submission Processing
Cost Recovery
Applicability of Patented
Medicines (Notice of
Compliance) Regulations
Initial Processing
10 days
Screening Validation
45 days
Scientific
Review
Quality
(Chemistry and Manufacturing)
Safety and
Efficacy
Priority - 180 days
Non-Priority - 300 days
Labelling
Approval - recommendation /
rejection ( NOC,NON, DIN)
Final Processing
* calendar days
Health Santé
Canada Canada
DIN Issuance
Final Patent Check
Final Invoicing
NOC for sign-off
Health Products and Food Branch
Direction générale des produits de santé et des aliments
13
14
New Drug Approval Process – More Details
Submission
Processing
Screening for
acceptability
for review
Data entry
File preparation
Quality (C&M)
evaluation
Clinical
evaluation
Screening Deficiency
Notice (SDN)
Notice of Deficiency (NOD)
(gross deficiencies)
Management of Drug
Submission Policy
Health Santé
Canada Canada
Response to
SDN, NOD,
NON
Labelling
evaluation
Approval
Notice of
Compliance
and/or DIN
or
Notice of Noncompliance
(NON)
Health Products and Food Branch
Direction générale des produits de santé et des aliments
15
Submission Processing – more details
Verification
submission
content, forms
Classification
submission
type, class,
Cost Recovery
invoicing
verification of
company info
Administration
DSTS,
acknowledgement,
packing, storage
Health Santé
Canada Canada
Patent Check
Patent Register,
forms
TPD/BGTD
Health Products and Food Branch
Direction générale des produits de santé et des aliments
16
Submission Type (examples)

Submission Type Examples:
NDS – New Drug Submission
SNDS –
Supplement to New Drug Submission
ANDS – Abbreviated New Drug Submission
(generics)
Health Santé
Canada Canada
Health Products and Food Branch
Direction générale des produits de santé et des aliments
17
Classifying Submissions
 The
submission package determines the class
of the submission. Listed below are examples
of submission classes.
 NAS: New Active Substance (pharmaceuticals &
biologicals)
 Clin
Only: clinical data only (e.g. new indication)
 Clin/C&M: clinical and chemistry &
manufacturing data but is not a NAS (e.g. new
dosage form, new use)
Health Santé
Canada Canada
Health Products and Food Branch
Direction générale des produits de santé et des aliments
18
Classifying Submissions – cont’d
 Comp/C&M:
comparative (clinical,
bioavailability, etc.) data and C&M (e.g. generics;
new dosage forms for innovator products)
 C&M/Labelling:
no clinical data (e.g. ANDS
where no clinical data is required - injectable,
ophthalmic, nasal sol’n)
 The
submission class determines the
performance target.
Health Santé
Canada Canada
Health Products and Food Branch
Direction générale des produits de santé et des aliments
19
Data Requirements Summary

New Drugs typically require preclinical, clinical,
chemistry & manufacturing data

Generics typically require bioequivalence and/or
pharmaceutical equivalence data

Other Drugs (not new) - information ranging from
chemistry & manufacturing data and/or only
formulation and labelling
Health Santé
Canada Canada
Health Products and Food Branch
Direction générale des produits de santé et des aliments
20
Priority Review
 ...
for a drug submission for a serious, life
threatening or severely debilitating disease or
condition for which there is substantial clinical
evidence that the drug provides:
 effective
treatment/prevention/diagnosis of a
disease or condition for which no drug is
presently marketed in Canada…
http://www.hc-sc.gc.ca/hpb-dgps/therapeut/zfiles/english/policy/issued/prirevw_e.
pdf
Health Santé
Canada Canada
Health Products and Food Branch
Direction générale des produits de santé et des aliments
21
Performance Targets
The type of data package (safety, efficacy, quality) submitted
and whether or not it is accepted for priority review
determines the performance target
Examples:


Processing
Screening priority
Screening
NDS – Review

ANDS - Review



Health Santé
Canada Canada
: priority
non-priority
:
- 10 days*
- 25 days*
- 45 days*
- 180 days*
- 300 days*
- 180 days*
* Calendar days
Health Products and Food Branch
Direction générale des produits de santé et des aliments
22
Performance Reporting
 Drug
submission performance is reported
quarterly and annually
 Reports
are posted on our website:
http://www.hc-sc.gc.ca/hpb-dgps/therapeut/htmleng/drug_submission_reports
Health Santé
Canada Canada
Health Products and Food Branch
Direction générale des produits de santé et des aliments
23
Cost Recovery

Involves the processing of fees for:




Annual authority to market a drug in Canada ($8-10
million)
o 1300 companies
o 22,000 marketed products
Submission evaluation fees (determined by data
package submitted i.e. number of indications, number
of dosage forms, etc.) $20 million
Fees for Establishment Licences for drugs (1000
licences) and medical devices (900 licences) $6 million
As outlined in the Financial Administration Act
Health Santé
Canada Canada
Health Products and Food Branch
Direction générale des produits de santé et des aliments
24
Submission Evaluation Fees

The type of data package submitted determines
the submission evaluation fee
Examples: New Drugs
 Preclinical & Clinical
 Clinical (no preclinical)
 Comparative data
 C& M for active ingred.
 C&M for 1 dosage form

Health Santé
Canada Canada
- $117,000
- $ 52,900
- $ 17,200
- $ 11,500
- $ 15,300
Health Products and Food Branch
Direction générale des produits de santé et des aliments
25
Drug Identification Numbers (DINs)
and Notices of Compliance (NOC)

DINS are issued to all drugs approved for
marketing in Canada.
(8 digit number generated by DPD)



Must appear on the label
Notification of first sale
NOC are issued to all new drugs that are
approved.
Health Santé
Canada Canada
Health Products and Food Branch
Direction générale des produits de santé et des aliments
26
Tracking Drugs in Canada
 Health
Canada keeps records of drugs
marketed in Canada – it does not keep
records of drugs approved in the US or any
other country.
web query – a database on our
website http://www.hc-sc.gc.ca/hpb/drugs-dpd/
listing all products marketed in Canada.
 DPD
Health Santé
Canada Canada
Health Products and Food Branch
Direction générale des produits de santé et des aliments
27
Tracking Drugs in Canada – cont’d

Continued monitoring, enhancement, synchronization for:
 Drug Submission Tracking System (DSTS)
 Drug Establishment Licensing System (DEL)
 Drug Product Database System (DPD)
 SAP Financial System

6000 Licence / DIN holders / importers / agents / sites
Mergers, buyouts, bankruptcies, licence agreements
Account access, training, management of pick lists and
linkages between systems


Health Santé
Canada Canada
Health Products and Food Branch
Direction générale des produits de santé et des aliments
28
Why are Some Drugs not Approved?

All drugs must be reviewed to ensure that they meet the
requirements of the Food and Drugs Act and Regulations

Drug must have sufficient evidence to support the safety,
efficacy or quality claims, to be approved

Drug companies may submit further info. to ensure that
the safety, efficacy, and quality standards are met
(e.g. may require further research in animals and/or humans)

HPFB decision not to approve a drug may be appealed by
applicant
Health Santé
Canada Canada
Health Products and Food Branch
Direction générale des produits de santé et des aliments
29
Biologics and Genetic Therapies Directorate
Biologics and Genetic Therapies Directorate
(BGTD)
Julia Hill
Director General
Associate Director
General
Elwyn Grifftihs
Office of Strategic and
Operational Planning
including
Correspondence
Barbara Be nning
Communications & Liaison
Unit
(e.g. EAC logistics, etc.)
Manager
(TBD)
Office of Quality
Management including
Situational Review
Centre for Policy &
Regulatory Affairs
Biologics &
Radiopharmaceutical
Evaluation Centre
A/Director
Catherine Hanson
Director
Dr. Peter Ganz
- Policy & Promotion
- Blood Establishment
Regulation
- Submission Management
Health Santé
Canada Canada
- Clinical Evaluation
- Vaccines
- Blood,Tissues &
Organs
- Biotherapeutics
Centre for Biologics
Research
A/Director
Larry Whitehouse
-Biomolecular&StructuralChemistry
- Cellular & Molecular
- Biology
Health Products and Food Branch
Direction générale des produits de santé et des aliments
30
Key Differences with Biologicals

Biological drug review also includes:

On-site evaluations
o

Additional GMP (Good Manufacturing Practices)
o

Assessment of the production process and facility for a specific
product which ensures that the manufacturing process conforms to
information described in the submission.
Special considerations and issues pertinent to manufacturing and
control of biological drugs, blood and blood components.
Lot-release
o
o
Laboratory work on samples received from drug companies to confirm
potency, purity and safety.
Only high risk products are tested (new products and vaccines).
Health Santé
Canada Canada
Health Products and Food Branch
Direction générale des produits de santé et des aliments
31
Review of Generic New Drugs
Federal Level

Food & Drugs Act and Regulations amended
1995
o
o
o
o
o
Allows for a generic manufacturer to file an ANDS
Establishment of bioequivalence by requiring a
Canadian Reference Product (CRP)
Same route of administration as CRP
Same conditions of use as the CRP
Ensured safety, efficacy and high quality
Health Santé
Canada Canada
Health Products and Food Branch
Direction générale des produits de santé et des aliments
32
Review of Generic New Drugs – cont’d
ANDS
Patent check
Pharmaceutically equivalent and/or Bioequivalence data
(Canadian Reference Product required)
Review
Chemistry & Manufacturing
Pharmaceutical equivalent
Bioequivalence info
PM/ label
Approval recommended
NOC on HOLD
(until patent issued get resolved
Patent Check
NOC issued
(approval & declaration of
Bioequivalence)
Provincial Assessment
Health Santé
Canada Canada
Health Products and Food Branch
Direction générale des produits de santé et des aliments
33
Patented Medicines (NOC) Regulations

Protect intellectual property while allowing generics to
come on the market immediately after patent expiry.

Brand name companies can file a patent to protect a
drug which is added to the Patent Register.

Generic companies have to clear all patent issues
before being allowed to market.
Health Santé
Canada Canada
Health Products and Food Branch
Direction générale des produits de santé et des aliments
34
Regulatory Scheme
Food and Drugs Act
Food and Drug Regulations
NDS
NOC
Market
ANDS
PM(NOC) Regulations
Patented Medicines
Patent Act
Health Santé
Canada Canada
Health Products and Food Branch
Direction générale des produits de santé et des aliments
35
Patented Medicines (NOC) Regulations
GENERIC SUBMISSION FOR PATENTED
MEDICINE
INNOVATOR SUBMISSION
Patent lists filed
with submission
Patent lists filed within
30 days of patent grant
Patent Check
Patent Check
Drug submission
filed
Patent Check
NO
Form Vs
Acknowledgement
Review Bureau*
NOC
preparation
YES
Patent
Hold
Review Bureau*
Patent
Register
Review Complete
Review Complete
NOC
preparation
Patent Check
Patent Check
24 m onths laps ed
or
application in favor of generic
or
patents expire
NOC issued
*Bureau of Pharmaceutical Assessment
Biologics and Genetic Therapies Directorate
Veterinary Drugs Directorate
Health Santé
Canada Canada
NOC issued
Patent Hold
Health Products and Food Branch
Direction générale des produits de santé et des aliments
36
Post Market Roles and Activities

Role


Legislated responsibilities, ‘Duty of Care’ regarding
safety of new drugs
Activities

Monitor and collect adverse drug reaction and
medication incident data and communicate these to
health professionals and public
(e.g. Advisories for therapeutic products, Canadian Adverse Drug
Reaction Newsletter, Health_Prod_Info)



Review and analyze safety data
Conduct risk/benefit assessments of marketed products
Overview of regulatory advertising activities
Health Santé
Canada Canada
Health Products and Food Branch
Direction générale des produits de santé et des aliments
37
Strengthening Post-Market Safety
of New Drugs
Measures will include:




Moving from reactive to proactive and preventative measures
Expanding network of Regional Adverse Reaction Centers
Launching investigations and requiring manufacturers to conduct
post-approval clinical trials
More timely and accurate advice to health care professionals and
the public
Outcomes:

Will reduce risks to Canadians from preventable adverse drug
events
Health Santé
Canada Canada
Health Products and Food Branch
Direction générale des produits de santé et des aliments
38
International Harmonization

HPFB has been very active in helping develop and
implement international standards for the registration of
new drugs.

HPFB has contributed significantly to the development of
over 45 harmonized technical guidelines.

Canada is the only observer country to the International
Conference on Harmonization (ICH) and is committed to
implementing finalized ICH guidelines and standards
including the Common Technical Document (CTD).
Health Santé
Canada Canada
Health Products and Food Branch
Direction générale des produits de santé et des aliments
39
Drug Submissions Received Annually (approx.)
(TPD & BGTD)
Total: 4,400 per year

80 – NDS (New Drug Submission)
 35
for new active substances

170 – SNDS (Supplement to NDS)

80 – ANDS (Abbreviated New Drug Submission)

10 – SANDS (Supplement to ANDS)

800 – NC (Notifiable Change)
Health Santé
Canada Canada
Health Products and Food Branch
Direction générale des produits de santé et des aliments
40
Drug Submissions Received Annually (approx.)
(TPD & BGTD) – cont’d

1700 – DINA (Drug Identification Number Application)

360 – Administrative Change Submissions
 Change
in manufacturer’s name and/or product
name; cross-reference submissions

1400 – Clinical Trial Applications (previously INDs –
Investigational New Drug Submissions)
Health Santé
Canada Canada
Health Products and Food Branch
Direction générale des produits de santé et des aliments
41
Drugs Marketed in Canada
 22,000 (approx.)
Human Drug Products
6,000 Prescription
 9,000 Non-Prescription (includes natural health
products with DINs)
 6,000 Homeopathics
 1,000 Controlled Drugs, Narcotics & Biologics

 1,450 (approx.)
Health Santé
Canada Canada
Veterinary Drug Products
Health Products and Food Branch
Direction générale des produits de santé et des aliments
42
The expectations of stakeholders are
clear…..
A review process that is more:
 Timely
 Predictable
 Consistent
 Sustainable
 Transparent
Health Santé
Canada Canada
Health Products and Food Branch
Direction générale des produits de santé et des aliments
43
The TPD Journey from where we are….to
where we need to be
Current State
Some of the time
Not always
Not necessarily
Resource poor
Not very
Health Santé
Canada Canada
Desired State
Meet Performance Target
Predictable
Consistent
Sustainable
Transparent
Health Products and Food Branch
Direction générale des produits de santé et des aliments
44
Business Transformation Strategy – Plan for Change


Project Management Tools
Enhance Capacity – internal & external
eg: Expert Advise, Academic Instructions


Good Guidance Practices
Communication/Consultation
eg: Public Advisory Committee (PAC), ACM, PPF



International Regulatory Cooperation
E-Review – eCTD
Transparency eg: PM project, Summary Basis of Decision
Health Santé
Canada Canada
Health Products and Food Branch
Direction générale des produits de santé et des aliments
45
Strategic investments in key areas will drive our
Business Transformation Strategy
Investments
Objectives
Attributes
Project Management
Good Review Practices
Good Guidances
Enhanced Capacity
International Cooperation
Transparency
E-Review
Quality Submission
Predictable
Quality Review
Consistent
Quality Decision
Sustainable
Performance
Measurement
Transparent
Health Santé
Canada Canada
Results
A timely
drug
approval
process
Health Products and Food Branch
Direction générale des produits de santé et des aliments
46
Backlog Reduction – Milestones and
interim commitments
Health Santé
Canada Canada
Health Products and Food Branch
Direction générale des produits de santé et des aliments
47
Workload Management
TPD Workload/Backlog
No. of Submissions
Within Target
225
176
188
192
Backlog
188
190
175
133
125
119
105
81
75
51
25
Mar. 03
Health Santé
Canada Canada
Jun. 03
Sep. 03
Dec. 03
Mar.04
Health Products and Food Branch
Direction générale des produits de santé et des aliments
48
Continuous Balancing Act

Drug submission review performance is impacted
by the many other issues and challenges which
we strive to keep in balance:
o
o
o
o
advancements in science and technology
timeliness vs. ensuring safety / efficacy
adhering to strict regulations/policies and being
flexible and reasonable
participating in an international community while
respecting our domestic environment
Health Santé
Canada Canada
Health Products and Food Branch
Direction générale des produits de santé et des aliments
49
Lexicon
ADR
ANDS
API
C&M
CBER
CDER
CRP
DIN
Adverse Drug Reaction
Abbreviated New Drug Submission
Active Pharmaceutical Ingredient
Chemistry and Manufacturing
Center for Biologics Evaluation & Research
Center for Drug Evaluation & Research
Canadian Reference Product
Drug Identification Number
(an 8-digit number that all drugs in Canada must have)
DMF
DPD
FPT
Drug Master File
Drug Product Database
Federal / Provincial / Territorial
Health Santé
Canada Canada
Health Products and Food Branch
Direction générale des produits de santé et des aliments
50
Lexicon- cont’d
GCP
GMP
ICH
ICDRA
NDS
Good Clinical Practices
Good Manufacturing Practices
International Conference on Harmonization
International Conference of Drug Regulatory
Authorities
Natural Health Producs Directorate
New Drug Submission
NOC
Notice of Compliance
NHPD
(an approval letter to market a product in Canada)
NON
Notice of Non-Compliance
(letter outling deficiencies after completion of review)
PAAB
PM
Pharmaceutical Advertising Advisory Board
Product Monograph
Health Santé
Canada Canada
Health Products and Food Branch
Direction générale des produits de santé et des aliments
51
Lexicon - cont’d
PMPRB
Patented Medicines Prices Review Board
POA
QC
SDA
Plan of Action
SIPD
TCM
TOR
Submission Information Policy Division
US FDA
United States Federal Drug Administration
WHO
World Health Organization
WTO
World Trade Organization
Quality Control
State Drug Administration
Traditional Chinese Medicine
Terms of Reference
Health Santé
Canada Canada
Health Products and Food Branch
Direction générale des produits de santé et des aliments
52