Helping the people of Canada maintain and improve their health

Aider les Canadiens et les Canadiennes maintenir et amliorer leur sant

Overview of Clinical Trials in Canada International Regulatory Forum, 2013

Tanya Ramsamy, PhD, Office of Clinical Trials Therapeutic Products Directorate Health Products and Food Branch Health Canada

gust 22, 2007

Objectives

Overarching principles Regulatory framework (focus on drugs) Comparative bioavailability (BE) trials for generics

Organizational structures
CTA statistics

Drug Molecule Life as Seen by Regulator

New disease indications Exploring other applications New route of administration New population
1 st ap Re pr gu ov lat al or y

III

Ph as e

Ph as e

Ph as e

Continuous monitoring and assessment of safety

Small scale Non-clinical testing Larger scale Commercial scale Impact of generics

8 12 16 20 Years since patent first filed by innovator

1 st

Ge

ne r

II

ics

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Trial has Scientific merit

Data integrity

Protection of Clinical trial subjects

Regulations

Ethics review

Health Products And Food Branch

HPFB Inspectorate

Therapeutic Products Directorate

Biologics and Genetic Therapies Directorate

Biologics Radiopharmaceuticals

Natural Health Products Directorate

Pharmaceuticals Medical devices

Natural Health Products

FOOD AND DRUGS ACT

Food and Drug Regulations

PART C: DRUGS Division 1 Division 1A: Establishment Licences Division 2: Good Manufacturing Practices Division 3 Division 4 Division 5: Drugs for Clinical Trials Involving Human Subjects Division 6 Division 7 Division 8 Division 9

Medical Devices Regulations Natural Health Products Regulations (Part 4)

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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

Division 5 (Contd)
Applies to the sale of a drug for the purposes of
clinical testing in or on humans, independent of who is sponsoring the trial

Include several definitions Requirements for authorization of a clinical trial

Clinical trial application (CTA)

Division 5 (Contd)
Post-authorization requirements Gives the Minister clear authority to reject,
suspend or cancel the authorization of a clinical trial

Good Clinical Practice (GCP) & inspection

CTAs are required for

Phase I, II, and III clinical trials Comparative bioavailability (bioequivalence) trials
for generics

Study of a product outside the parameters of the

marketing authorization

E.g., change in: indication, patient population, dosage regimen, route of administration

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CTAs are not required for

Phase IV trials (investigations on-label)
But:
REB approval is required GCP must be observed record-keeping is required

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Authorization Requirements
Clinical Trial Application (CTA):

Attestation protocol informed consent form investigators brochure chemistry & manufacturing information

2-day turnaround request for additional

information

30-day review default period

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Authorization Requirements (Contd)

REB refusals, if any, must be reported Sponsor must specify the Qualified
Investigator(s) and trial site(s) REB approval at each trial site

Changes to the protocol or chemistry &

manufacturing that impact on safety must be filed as an amendment (CTA-A)

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Post-authorization Requirements
Changes that do not impact on safety are filed
as CTA-Notifications Labelling Record-keeping (25 years) Reporting of serious unexpected adverse drug reactions Premature discontinuation of clinical trial Submission of information and/or samples

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Comparative Bioavailability (BE) Trials

Same regulatory requirements as for other trials Product monograph may be submitted in lieu of IB Some different quality requirements, specified in
guidance

7-day administrative review target for studies in healthy

volunteers

The majority of studies are not intended to support

registration of the generic drug in Canada

Review of comparative bioavailability studies focuses on

safety of clinical trial subjects (usually healthy volunteers)
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Safety Considerations in BE Trials Include:

Study design, choice of dose, and pharmacodynamics The contraindications, warnings and precautions for the drug

Tuberculosis screening
Pregnancy testing Hb and hematocrit check if total blood volume > 500 mL

Intravenous catheter for multiple blood draws, if appropriate

The risks related to the drug are listed in the informed consent form and acceptable contraceptive methods are defined

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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
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Pre-CTA Meetings

Present relevant data, clarify requirements,

discuss concerns, and resolve potential issues

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Clinical Trials for Natural Health Products (NHP)

Part 4 of the Natural Health Products Regulations In effect June 2003 August 2012: Office of Clinical Trials authorizes
CTA of NHP for conditions of use not appropriate for self-care (exception: hormones and probiotics)

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Part 4 NHP Regulations

Authorization requirements are similar for drugs
and NHP except:
Request for additional information is not limited to

2 days
No 30-day review default period

(CT for NHPs cannot start until a NOA is issued)

CTA Investigators Brochure must include

preclinical and clinical information if any

REB one member knowledgeable in

complementary or alternative health care

Quality requirements
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Guidance Documents for CTAs for drugs

Guidance for Clinical Trial Sponsors Clinical Trial Applications Quality (Chemistry and Manufacturing) Guidance: Clinical Trial
Applications (CTAs) for Pharmaceuticals

Various quality guidance documents for biologics Requirements for tuberculosis screening Inclusion of women in clinical trials Standards for clinical trials in type 2 diabetes in Canada Submission of pharmacogenomic information Various ICH guidelines

Registration and disclosure of clinical trials

Guidance documents from other regulators (e.g., FDA, EMEA)

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Biologics/Radiopharmaceuticals
2500

Bioequivalence
Pharmaceuticals

Number of CTAs

2000

1500

1000

500

0 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012

Year

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1000 900

Pharmaceuticals

Biologics/Radiopharmaceuticals

Number of CTAAmendments

800 700 600 500 400 300 200 100 0 2004 2005 2006 2007 2008 2009 2010 2011 2012

Year

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References
Division 5 Regulations Guidance for Clinical Trial Sponsors Quality (Chemistry and Manufacturing) Guidance: Clinical Trial Applications (CTAs) for Pharmaceuticals Quality requirements for biologics and radiopharmaceuticals http://laws.justice.gc.ca/en/F-27/C.R.C.c.870/ http://www.hc-sc.gc.ca/dhpmps/prodpharma/applic-demande/guideld/clini/ctdcta_ctddec-eng.php http://www.hc-sc.gc.ca/dhpmps/prodpharma/applic-demande/guideld/clini/qual_cta_dec-eng.php

http://www.hc-sc.gc.ca/dhpmps/brgtherap/applicdemande/guides/qualit/index-eng.php
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Thank you for your attention!

Questions?

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