This document discusses several challenges with conducting international clinical trials that involve Canada. It notes differences between countries in areas like costs, regulatory requirements, medical practices, and data use that can complicate multi-national trials. It also addresses specific issues in Canada around electronic submissions, data transparency, investigator oversight, and consistency with other jurisdictions. The conclusion is that while Canada remains an attractive location for clinical trials, its role may be increasingly shaped by policies from other countries if it does not further harmonize and clarify its own regulatory approach.

1. International Clinical Trials
Impact on Regulatory Affairs in
Canada

2. 11/4/2022
Western Europe Relative
Per Visit Grant Costs
0
20
40
60
80
100
120
US UK Sweden Germany Netherlands Italy Denmark France
Cost

3. 11/4/2022
Eastern Europe Relative
Per Visit Grant Costs
0
20
40
60
80
100
120
UK Czech Poland Russia Hungary Bulgaria Romania
Cost

4. 11/4/2022
Asian Relative
Per Visit Grant Costs
0
20
40
60
80
100
120
UK Australia Singapore Taiwan China India
Cost

5. 11/4/2022
Driver of Global Clinical Trials
Patient Access
Rest-of-
World 9 %
Europe
23%
Asia/Pacific
8%
U.S.
60%
Source: Jefferies, CRO Survey, March 2007 5
U.S.
40%
Asia/Pacific
19%
Europe
25%
Rest-of-World
16 %
Allocation of development spending by
global region – current
Expected development spending
allocation by 2010; significant increase
in A/P, ROW

6. 11/4/2022
Use of Foreign Data in
Canadian Applications
• Clinical trials may or may not be conducted in
Canada
• Must meet GCP ICH E6
• Disease being studied needs to be
representative of the disease in Canada
• Conditions of diagnosis and treatment need to
be consistent with Canadian practice
• Concomitant medications need to be consistent
with those used in Canada
• Consideration of racial balance
• Consideration of ethnicity

7. 11/4/2022
Regulatory Confusion
• Frequently drugs are developed for prescription
medications, e.g., diabetes, hypertension, where
the active ingredient may be natural.
• There is confusion in terms of the eventual NDS
to be filed and the input that may be necessary
to develop the right endpoints and phase 3 study
design for registration.
• Canada is inconsistent with other countries in
their approach to eventual prescription drugs
sourced from natural entities.

8. 11/4/2022
Regulatory Confusion
• For companies outside of Canada, there is
confusion in terms of the requirements that
apply under Division 2 of the Canadian
drug regulations.
• Label review
• Lot release
• Maintenance of files

9. 11/4/2022
Regulatory Filings
• eCTAs in Canada re far behind Europe
(where electronic CTAs are the
requirement in a number of countries) and
the US.
• Data not as easily available to reviewers in
Canada because of the heavier reliance
on paper filing systems.

10. 11/4/2022
Ability to Require Data
• Health Canada does not have the ability
under current legislation to require that
companies file data when a clinical trial is
stopped or for clinical trials that are not
done in Canada.
• Bill C-51 proposed to change this.

11. 11/4/2022
Transparency
• Transparency for clinical trials is lagging
the US where all phase II-III trials have to
appear on www.clinicaltrials.gov and the
data for those clinical trials also has to be
posted.
• Ghost writing of publications on clinical
trials by companies where the lead author
is the lead investigator has also been a
problem.

12. 11/4/2022
Advice Meetings
• When advice meetings are held in Canada and strategy
suggested is very different than US/Europe, Canada is
too small a market to warrant changing strategy.
• Joint advice meetings between the US and Europe will
harmonize advice even more and make other advice
received less useful.
• Depth of review staff in Canada (5 per Reviewing Unit vs
15 or so in the US) mean advice meetings may be less
valuable.
• Budget restrictions on Health Canada frequently mean
that Health Canada staff cannot attend scientific
meetings that would help keep staff current on leading
edge technology and thinking.

13. 11/4/2022
Dosage Form
• Must be manufactured under GMP
• Defined by Appendix to GMP Guideline
• Varies by Phase of Trial
• Emphasis is on labelling and packaging
• Drug product originating in US or Canada must
be re-analyzed in EU and vouched for by
“qualified person”
• Drug entering Canada must be approved (lot
release) by a “qualified person” (includes labels).

14. 11/4/2022
Dosage Form
• For Phase III studies should be to-be-
marketed formulation.
• Many companies have run into difficulties
in changing formulation and then having to
go back and bridge, especially when
bridging requirements are different from
country to country.

15. 11/4/2022
Dosage Form –
Comparator
• Provided that comparator is sourced from an ICH
country and the innovator and the dosage form and
strength is sold in Canada for the indication and at the
dose to be used in the study, there is no problem.
• Comparators sourced from India, South America, Israel,
Australia, China become problematic
• There is confusion regarding comparators not approved
in Canada for the indication or at the dosage to be used
in the clinical trial.
• There is also confusion if the dosage strength of the
dosage form is not approved in Canada.

16. 11/4/2022
Dosage Form –
Rescue Medication
• Frequently rescue medication is used in a
clinical trial, e.g., ad hoc analgesic medication.
• If the rescue medication is not Canadian, TPD
request complete manufacturing data which is
impossible to give.
• Little reason to request this. Should be treated
as comparator drug.
• Exceptions usually given on a case by case
basis – “for this time only…”

17. 11/4/2022
Dosage Form –
Importation
• Canadian regulations (present and as
proposed in Bill C-51) required that a CTA
be approved before dosage form could be
imported.
• Packaging for clinical trials is therefore much
more likely to be done outside of Canada.
• Packaging for international clinical trials will
almost always be done outside of Canada.
• Delays in trial start.

18. 11/4/2022
Medical Devices
• Medical devices may be used in a clinical
study to administer drug or to take a
biochemical test.
• These devices need to either be approved
in Canada or an Investigational Device
Exemption needs to be obtained.

19. 11/4/2022
NHPs
• Products that are drugs in other countries
may be NHPs here and may be used as
comparators or rescue medication.
• In these instances there is confusion as to
whether an NHP CTA is necessary and
what is required for filing.

20. 11/4/2022
Preclinical Differences
• Phase I studies
• Are two species (single dose) and 14 day studies in 2
species needed
• US exempts this on occasion.
• Ongoing preclinical studies
• Significant data needs to be filed in 15 days.
• No guidance on what is significant.
• Lack of Scientific Advisory Committee on these issues that
can provided advice to Health Canada.
• Biosimilar requirements for nonclinical data – will
it be harmonized?

21. 11/4/2022
Pharmacokinetic
Differences
• Other countries are making decisions about the
need or lack of need for clinical data (particularly
pharmacokinetic data) based on how soluble the
molecule is and how well it is absorbed.
• Canada has not accepted this at the moment.
• Can product be changed without food studies or
multiple dose studies.
• Pharmacogenomic testing in multi-national trials.

22. 11/4/2022
Regional Differences
in Medical Practice
• Treatment modalities
• Can impact inclusion/exclusion criteria
• Can impact available population due to
exposure
• Bladder cancer guidelines for US vs Canada vs EU
• Treatment of ulcerative proctitis in Poland (clinics
within hospitals) vs North America (outpatient)
• Treatment of cancer in US (cancer treatment
centres) vs Canada (hospital or outpatient)
• Hypertension (first line in US vs step care in
Canada)

23. 11/4/2022
Regional Differences in
Regulatory Requirements
• Canada on a given occasion required that
non-use of alcohol be an inclusion criteria
for a hypertension trial being conducted
over a 12 month period.
• Company agreed to this for Canadian
centres only.
• Led to a population difference, which
resulted in non-statistical significance.

24. 11/4/2022
Placebo vs Active
• Europe looks for active comparator
Non-inferiority vs superiority
• US looks for placebo comparator
• Canada can accept both, but also has a
tendency to prefer placebo comparators

25. 11/4/2022
Use of Primary Endpoints
• Primary measurements can vary from
jurisdiction to jurisdiction, e.g., pain
measurements.
• Many products are developed by small
companies approaching Phase 2 proof-of-
concept studies with endpoints different than big
pharma to whom they license.
• Primary endpoints change over time – when is
the time to shift, when will a shift be required are
difficult things to know, e.g., tumor regression vs
survival for cancer studies.

26. 11/4/2022
Newly Developing Areas
of Expertise
• As countries try to develop policies to deal
with emerging science, e.g., stem cell
research, requirements may vary from
start to finish of study and from country to
country.
• Unsure how this can be overcome other
than by harmonization of developing
requirements internationally, if possible.

27. 11/4/2022
Investigators
• FDA has a list of investigators that cannot
be used to do clinical trials.
• Canadians can appear on this list.
• Canada has no such list.
• Transparency of
investigators/IRBs/companies not
following GCP is not good in Canada (ATI
– but cumbersome to access)

28. 11/4/2022
Institutional Review
Boards
• FDA recently sent a dummy protocol that
should not have been approved to several
IRBs.
• One approved it anyway, and is now under
significant scrutiny by the FDA.
• Training and registration of IRBs is likely in
the future.
• International standards will be mandated.

29. 11/4/2022
Laboratory Specimens
• Standardize testing – e.g., H. pylori testing
• How to get in and out of country
• Biologic samples – some countries require
specialized approval, some countries do not allow
biological samples to leave the country
• Refrigerated or special transportation
• Timing requirements
• For inclusion/exclusion
• For integrity of specimens
• Lab normals vary across countries; can vary by
population.

30. 11/4/2022
Clinical Supply
Labelling Requirements
• Certified translations
• For Canada 2 main issues
• Need for expiration date
• Not needed in US
• Can Retest date suffice?
• Need for bilingual labelling

31. 11/4/2022
Safety Reporting
in Global Trials
• Generally Harmonized
• Must report unexpected and serious adverse
events to Regulatory Authorities in each
participating country, regardless of country of
origin
• Safety alert letters to update investigator
brochures
• Standardized coding – MEDDRA??

32. 11/4/2022
Protocol Violations
• Handling of protocol violations on a local
basis.
• When is a global protocol amendment
required.
• How many protocol violations are too
many?
• Is any protocol violation acceptable?

33. 11/4/2022
Fraud
• How to handle fraud at one site in a large
multi-centre trial
• Cull the bad data
• Cull the bad guy
• Who gets to know (agency, other PIs, ethics
committees?)

34. 11/4/2022
Audit Readiness
• Canadian Regulatory Authority
• Foreign Regulatory Authority, particularly FDA
• Audits most often occur because of:
• Large patient enrollment number
• Perceived irregularity or problem
• Areas of interest to Auditors
• Qualifications/training files of personnel/SOPs
• Familiarity with GCP including local interpretation
• Knowledge of trial protocol
• Trial master File – status
• All safety update information.

35. 11/4/2022
Statistical Analysis
• LOCF – last observation carried forward
• Has been standard for missing data for many
years.
• BOCF – baseline observation carried
forward
• Now the preferred standard for analgesic
analysis in the US
• Other comparisons to placebo group

36. 11/4/2022
Stopping a Multinational
Trial
• Many multinational trials allow patients to
enter a long term safety study.
• The long-term safety study is frequently
stopped after approval is obtained in the
US/Europe.
• This presents significant problems for
Canada where patients have been
stabilized on the drug.

37. 11/4/2022
Special Access Programme
• For orphan drugs or other drugs not available in
Canada the SAP programme can be a way to
obtain such drugs.
• Much more difficult to do so, preference is
clinical trial
• For companies with small monetary resources, this
becomes difficult to do.
• GCP requirements are sometimes overwhelming.
• Charging for such drugs creates other pressures
for payers and is a legitimate reason to try to
restrict drug distributed under this system.

38. 11/4/2022
Records
• Canada is the only country to have 25-
year requirements for clinical trials
records.
• For international trials, companies will
need to deal specially with records for
Canada.
• How those companies that are outside of
Canada will handle this has probably not
been seen at this time.

39. 11/4/2022
Publishing
• Ghost writing by company?
• Independence of investigator?
• Sea of doctors wanting recognition?

40. 11/4/2022
The Future
• With the Blueprint for Renewal and the lifecycle
management of drugs by Health Canada, there
appears to be a desire for Health Canada to be
involved in the nonclinical and clinical
development of drugs.
• With the current CTA system for reviewing drugs
(i.e., protocol by protocol) and the non-
involvement of the reviewing Divisions and the
non-submission of core scientific data, this may
be difficult.

41. 11/4/2022
Personalized Medicine
• Clinical trials with personalized medicine are
ongoing in Canada
• Drug is made specifically for each patient based on
cells from their own body.
• When this becomes a process that is done entirely in
the lab or locally, the trials are going to run into
significant regulatory hurdles.
• Will the product be a drug or medical device
• Should it be regulated under the Cells/Organs/Tissues
regulations
• What will those mean for clinical trials.

42. 11/4/2022
The Pharmaceutical Industry
• Death by Prescription is calling into
question a number of processes that have
been accepted in Canada, including
Research.
• There will likely be more involvement of
the academic sector in research, perhaps
more independent money and certainly
more regulation and transparency for our
future research.

43. 11/4/2022
Biosimilars
• Which reference product can be used?
• Can a trial in indication A be bridged to
indication B?
• How similar is similar?
• What kind of truncated clinical trials can be
done?

44. 11/4/2022
Summary
• Canada has always been a good location for
clinical trials
• Well respected investigators and medical centres.
• Good quality research.
• Recognized as “US” by the FDA.
• Canada will continue to be used by international
companies, but much of what is done in Canada
will be controlled by regulatory policies in other
countries until Canada steps more aggressively
into some of the issues discussed in this
presentation.