Overview of Drugs and Biologics
Dr Léo Bouthillier, Therapeutic Products Directorate
&
Dr Omar Tounekti, Biologics and Genetic Therapies Directorate
Health Products and Food Branch
Health Canada
Health Products and Food Branch
Mandate: Manage the health-related risks and benefits of health products
Therapeutic
Products
Pharmaceuticals and
Medical Devices
Biologics
& Genetic
Therapies
Natural and NonPrescription
Non-prescription
drugs, vitamins,
herbal products,
minerals, etc.
Blood, vaccines, biological
drugs, tissues,
radiopharmaceuticals
Veterinary
Drugs
Marketed
Health
Products
Inspectorate
Post-Market
Surveillance
Veterinary drugs
administered to foodproducing animals (e.g.,
milk, egg, meat, etc.) and
companion animals
Inspections,
Investigations,
Establishment and
Site Licenses
2
Lifecycle of a Drug
Post-Market Changes to
Marketed Products
Pre-Market
Post-Market
Market
Drug
Review Authorization
Submission
Decision
Drug
PreClinical
Discovery clinical Trials
studies
Public
Access
Revisions
To Product
And Use
Surveillance,
Inspection and
Investigation
The Food and Drugs Act and Regulations authorize the Therapeutic Products
Directorate and the Biologics and Genetic Therapies Directorate to regulate the
safety, efficacy and quality of pharmaceutical and biologic therapeutic products.
3
Pre-clinical Studies
Objectives:
- Identify the pharmacological properties:
- PD (mode of action)
- PK (metabolism)
- Comparative physiology (extrapolation of animal data to
humans)
- Understand the toxicological profile:
- Establish a safe initial dose level of the first human exposure
- Identify parameters for clinical monitoring of potential adverse
effects
- Special toxicity (e.g. genotoxicity, carcinogenicity,
reproduction toxicity)
4
Pre-clinical Studies
Toxicity studies are expected to be performed in
compliance with Good Laboratory Practice (GLP).
Good Laboratory Practice (GLP) embodies a set of
principles that provides a framework within which
laboratory studies are planned, performed, monitored,
recorded, reported and archived.
GLP helps assure regulatory authorities that the data
submitted are a true reflection of the results obtained
during the study and can therefore be relied upon when
making risk/safety assessments.
5
Pre-clinical Studies
Toxicity studies are expected to be performed in compliance with Good
Laboratory Practice (GLP).
The GLP regulations are found in 21 CFR Part 58.1: Good Laboratory Practice
for Nonclinical Laboratory Studies (USA). These regulations set the minimum
basic requirements for:
- study conduct
- personnel
- facilities
- equipment
- written protocols
- operating procedures
- study reports
- and a system of quality assurance oversight for each study to help assure the
safety of FDA-regulated product
6
CLINICAL TRIALS
•
Overarching principles
•
Regulatory framework (pharmaceuticals)
•
CTA statistics
7
Lifecycle of a Drug
Post-Market Changes to
Marketed Products
Pre-Market
Post-Market
Market
Drug
Review Authorization
Submission
Decision
Drug
PreClinical
Discovery clinical Trials
studies
Public
Access
Revisions
To Product
And Use
Surveillance,
Inspection and
Investigation
The Food and Drugs Act and Regulations authorize the Therapeutic Products
Directorate and the Biologics and Genetic Therapies Directorate to regulate the
safety, efficacy and quality of pharmaceutical and biologic therapeutic products.
8
Trial has
Scientific merit
Data integrity
Protection of
Clinical trial
subjects
Regulations
Ethics review
9
Drug Molecule Life as Seen by Regulator
New disease indications
Exploring
other
applications
New route of administration
ics
ne
r
Ge
1 st
1 st
ap Re
pr gu
ov lat
al or
III
Ph
as
e
Ph
as
e
Ph
as
e
I
II
y
New population
Continuous monitoring and assessment of safety
Small scale
Larger scale
Commercial scale
Impact of generics
Non-clinical testing
4
8
12
16
20
Years since patent first filed by innovator
10
24
Division 5: Drugs for Clinical Trials
Involving Human Subjects
• In effect since September 1st, 2001
• Two overarching objectives:
 strengthen protections for human research
subjects
 increase R & D investment in clinical trials in
Canada
11
Division 5 (Cont’d)
• Post-authorization requirements
• Gives the Minister clear authority to reject,
suspend or cancel the authorization of a
clinical trial
• Good Clinical Practice (GCP) & inspection
12
Authorization Requirements
• Clinical Trial Application (CTA):





Attestation
protocol
informed consent form
investigator’s brochure
chemistry & manufacturing information
• 2-day turnaround request for additional
information
• 30-day review default period
13
Statistics for CTs (pharmaceuticals)
Numbers of Applications Received by CY
in the Office of Clinical Trials
3000
2645
2617
2655
2595
No. Received
2218
2500
2132
2095
2096
2235
2129
Total
2000
1500
CTA-A
1000
CTA
500
0
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
Calendar Year (CY)
14
GOOD CLINICAL PRACTICES
• Health Canada has adopted the International
Conference on Harmonization (ICH) Guideline on
Good Clinical Practices (ICH E6)
• Clinical trials should be conducted in accordance
with the ethical principles that have their origin in
the Declaration of Helsinki, and that are
consistent with GCP and the applicable regulatory
requirement(s).
15
GOOD CLINICAL PRACTICES (Cont’d)
• Research Ethics Board
• Compliance with protocol
• Informed consent form
• Documentation and record keeping
• ADR reporting (REB, sponsor)
16
Inspection Program
• Conducted by the HPFBI, with authority under
section 23 of the Food and Drugs Act
• Inspections conducted against requirements of
Division 5 and generally accepted principles of
GCP
• Sites chosen at discretion of HC or if complaints
arise
• Sites may or may not be forewarned of the
planned inspection
17
Pre-CTA Meetings
• Present relevant data, clarify requirements,
discuss concerns, and resolve potential issues
18
References
Division 5 Regulations
http://laws.justice.gc.ca/en/F-27/C.R.C.c.870/
Guidance for Clinical Trial
Sponsors
http://www.hc-sc.gc.ca/dhpmps/prodpharma/applic-demande/guideld/clini/ctdcta_ctddec-eng.php
Quality (Chemistry and
Manufacturing) Guidance:
Clinical Trial Applications
(CTAs) for Pharmaceuticals
http://www.hc-sc.gc.ca/dhpmps/prodpharma/applic-demande/guideld/clini/qual_cta_dec-eng.php
Quality requirements for
biologics and
radiopharmaceuticals
http://www.hc-sc.gc.ca/dhpmps/brgtherap/applicdemande/guides/qualit/index-eng.php
19
Lifecycle of a Drug
Post-Market Changes to
Marketed Products
Pre-Market
Post-Market
Market
Drug
Review Authorization
Submission
Decision
Drug
PreClinical
Discovery clinical Trials
studies
Public
Access
Revisions
To Product
And Use
Surveillance,
Inspection and
Investigation
20
Pre-submission Meetings
Sponsors can deliver a brief presentation to the appropriate Directorate within Health
Canada prior to filing an NDS, SNDS, ANDS, SANDS, CTA or request for Priority Review
or Notice of Compliance with Conditions status.
Purpose:
•
•
•
•
•
Discuss data in support of the submission.
Familiarize review staff with the submission prior to its filing.
Obtain feedback regarding areas of concern based on current experience and
regulatory requirements.
Identify potential problems and manage disputes early in the submission process.
Provide the Directorate the opportunity to re-align resources, if necessary, to
accommodate the filing of the submission.
21
Submission Process – Major Steps
Receipt &
Processing
Data entry
File preparation
Screening for
acceptability
Chem. & Man.
evaluation
Label review
Clinical
evaluation
Screening Deficiency
Notice
Notice of Deficiency
(gross deficiencies)
Management of Drug
Submission Policy
Health Santé
Canada Canada
Response to
SDN, NOD,
NON
Market
Authorization
Notice of
Compliance
and/or DIN
or
Notice of Noncompliance
Health Products and Food Branch
Direction générale des produits de santé et des aliments
Screening (all submission types):
- 45 days
NDS - Review Clinical/C&M:
- 300 days
priority - 180 days
23
Review
Purpose: Assess the safety, quality and effectiveness of a pharmaceutical.
•
Review is organised by stream:
Clinical
Non-clinical
Chemistry and Manufacturing
Labelling (Review of Product Monograph, Inner/Outer Labels)
Brand Name Analysis
Other (Biopharmaceutic Evaluation, Biostatistics, Risk Management Plan,
etc.)
24
Lot Release Program: Legislative Authority
 The Lot Release Program derives its legislative authority
from section C.04.015 of the Food and Drug Regulations
C.04.015 On written request from the Director, every fabricator, packager/ labeller, tester,
distributor referred to in paragraph C.01A.003(b) and importer of a drug shall submit
protocols of tests together with samples of any lot of the drug before it is sold, and no person
shall sell any lot of that drug if the protocol or sample fails to meet the requirements of these
regulations
 Each lot of a Schedule D (biologic) drug is subject to the Lot
Release Program before sale in Canada.
25
Lot Release: Life Cycle Approach
Canada’s lot release program spans
the product lifecycle :




Clinical Trials
Consistency Testing
Routine Lot Release
Response to Emerging issues
Support for
investigations
and response to
emerging issues
Clinical Trials
Lot Release
Program
Routine Lot
Release
Pre-Market
Review
26
Evaluation Groups
 Pre-approval
 Group 1: a) clinical trial lots & b) consistency lots
 Post-approval
 Group 2: Protocol review & test each lot (vaccines)
 Group 3: Protocol review & periodic testing
 Group 4: No testing: results reported through fax-back
27
Lot Release: Risk-Based Oversight
While all biologics on the
Canadian market are within the
scope of the lot release
program, activities carried out
range from:



Product by Activity
Key tests
139
Products
Receiving notifications only
Doc
review 152
Products
Document review only
Document review and targeted
testing
Notice
155
Products
28
Lifecycle of a Drug
Post-Market Changes to
Marketed Products
Pre-Market
Post-Market
Market
Drug
Review Authorization
Submission
Decision
Drug
PreClinical
Discovery clinical Trials
studies
Public
Access
Revisions
To Product
And Use
Surveillance,
Inspection and
Investigation
29
QUESTIONS???