Comparison of regulatory requirements in Canada and US

Regulatory Authority
Canada US
Health Canada (HC) is the competent The Food & Drug Administration (FDA) is
authority responsible for clinical trial the regulatory authority that regulates
approvals, oversight, and inspections in clinical investigations of medical products in
Canada. HC grants permission for clinical the United States (US). This profile is
trials to be conducted in the country, and specifically focused on the FDA’s role in
regulates the sale and importation of drugs reviewing and authorizing investigational
for use in clinical trials. new drug applications (INDs) to conduct
clinical trials using investigational drug or
HC is one (1) of five (5) federal agencies biological products in humans. Regulatory
within Canada’s “Health Portfolio” overseen requirements relating to compliance with
by the Minister of Health. HC assesses federally funded or sponsored human
clinical trial protocols to evaluate participant subjects research protections, known as the
protection and safety; reviews drug quality; Common Rule, as well as other Department
assures institutional ethics committee of Health & Human Services (HHS)
review; verifies principal investigator regulations, are also examined.
qualifications; and monitors and reviews
adverse drug reactions. HC’s Health The FDA, which is an agency within HHS,
Products and Food Branch (HPFB) is the started undergoing a reorganization on
national authority that regulates, evaluates, March 31, 2019. One of the purposes of the
and monitors therapeutic and diagnostic reorganization is to elevate the role of the
product safety, efficacy, and quality, and centers, officers, and field forces. Several
reviews the information submitted in the centers are responsible for pharmaceutical
clinical trial application. and biological product regulation, including
the Center for Drug Evaluation and
HPFB’s activities are carried out by eight (8) Research (CDER) and the Center for
Directorates and two (2) Offices, including Biologics Evaluation and Research (CBER).
the Therapeutic Products Directorate (TPD) Additionally, the Office of Good Clinical
and the Biologics and Genetic Therapies Practice (OGCP) plays a pivotal role in the
Directorate (BGTD). The TPD and the FDA’s oversight of good clinical practice
BGTD, respectively, regulate and human subject protection issues
pharmaceutical drugs and medical devices, stemming from clinical research.
and biological drugs and
radiopharmaceuticals for human use. In
addition, the TPD’s Office of Clinical Trials Implementation of the Revised Common
(OCT) and the BGTD’s Office of Regulatory Rule
Affairs (ORA), among others, are directly
involved with the clinical trial review and On January 19, 2017, HHS and 15 other
approval process for pharmaceutical, federal departments and agencies issued a
biological, and radiopharmaceutical drugs. revised Common Rule, which delineates
basic ethical principles surrounding
federally funded or sponsored human
subjects research. Institutions engaged in
this research and ethics committees (ECs)
reviewing this research were originally
required to comply with the revised
Common Rule starting in January 2018,
except for the new provisions on
multicenter clinical studies, also known as
cooperative research studies, which
institutions are required to comply with by
January 20, 2020. However, the
implementation date was delayed to
January 21, 2019, with the provisions on
multicenter clinical studies still taking effect
January 20, 2020.

Studies Initiated Before January 21, 2019

Per the revised Common Rule, the

Common Rule requirements apply to
research that, prior to January 21, 2019,
was either approved by an EC, had EC
review waived, or was determined to be
exempt from the Common Rule.

Institutions conducting research that was

approved prior to January 21, 2019, may
choose to transition to the revised Common
Rule requirements. The institution or EC
must document and date the institution's
determination to transition a study on the
date the determination to transition was
made. The research must comply with the
revised Common Rule beginning on that
date.

Studies Initiated On or After January 21,

2019

The revised Common Rule applies to all

research initially approved by an EC on or
after January 21, 2019, or to research that
had EC review waived or that was
determined to be exempt on or after that
date.

HHS’ Office for Human Research

Protections (OHRP) guides the agency’s
efforts to safeguard the rights, welfare, and
well-being of human research subjects for
studies conducted or supported by HHS.
OHRP also provides oversight to all federal
agencies engaged in human subjects
research under the Common Rule and the
revised Common Rule.
Scope of assessment
Canada
Health Canada (HC) reviews, evaluates,
and approves applications for drug clinical
trials using authorized therapeutic products.
HC also approves the sale or importation of
drugs for use in clinical trials.
A “therapeutic product” is defined as a drug
or device, or any combination of drugs and
devices, but does not include natural health
products; “therapeutic product
authorization” refers to a license that is
approved for the import, sale,
advertisement, manufacture, preparation,
preservation, packaging, labeling, storage,
or testing of a therapeutic product. HC’s
scope of assessment includes clinical trials
(Phases I - III) using:
 Drugs not authorized for sale in
Canada in development and in
comparative bioavailability studies,
and
 Marketed drugs where the proposed
use of the drug for one of the following
is different: indication(s) and clinical
use; target patient populations(s);
route(s) of administration; or dosage
regimen(s)
In addition, institutional ethics committee
(EC) review for each clinical trial site may
occur in parallel with HC’s clinical trial
application (CTA) review and approval. HC,
however, will not authorize the sponsor to
begin the clinical trial until he/she submits
an institutional EC approval (provided in the
required Clinical Trial Site Information form)
for each participating trial site.
Clinical Trial Review Process
Prior to initiating the trial, the sponsor must
file a CTA to the appropriate Health
Products and Food Branch (HPFB)
Directorate. CTAs involving pharmaceutical
drugs should be sent to the Therapeutic
Products Directorate (TPD), and CTAs
involving biologics and/or
radiopharmaceuticals should be sent to the
Biologics and Genetic Therapies
Directorate (BGTD).
US
The Food & Drug Administration (FDA) has
authority over clinical investigations for drug
and biological products regulated by the
agency. The scope of the FDA’s
assessment for investigational new drug
applications (INDs) includes all clinical trials
(Phases I-IV). Institutional ethics committee
(EC) review of the proposed clinical
investigation may be conducted in parallel
with the FDA review of the IND. However,
EC approval must be obtained prior to the
sponsor being permitted to initiate the
clinical trial. Note: Institutional ECs are
referred to as institutional review boards
(IRBs) in the US).
Sponsors are required to submit an IND to
the FDA to obtain an agency exemption to
ship investigational drug(s) across state
lines to conduct clinical trial(s). An IND
specifically exempts an investigational drug
or biologic from FDA premarketing approval
requirements that would otherwise be
applicable. “’IND’ is synonymous with
‘Notice of Claimed Investigational
Exemption for a New Drug.’"
The FDA categorizes INDs as either
commercial or non-commercial (research)
and classifies them into the following types:
 Investigator INDs - Submitted by
physicians who both initiate and
conduct the investigation, and who are
directly responsible for administering
or dispensing the investigational drug.
 Emergency Use INDs - Enable the
FDA to authorize experimental drugs
in an emergency situation where
normal IND submission timelines
cannot be met. Also used for patients
who do not meet the criteria of an
existing study protocol, or if an
approved study protocol does not
exist.
 Treatment INDs - Submitted for
experimental drugs showing potential
to address serious or immediately life-
threatening conditions while the final
clinical work is completed and the
 Upon receipt of a CTA, the HPFB
Directorate screens the application package
for completeness. If deficiencies are found,
the Directorate sends the sponsor a
Request for Clarification or a Screening
Rejection Letter. If the Directorate finds the
application complete, an acknowledgement
letter is issued to indicate the 30-day
default review period commenced on the
date of receipt.
A clinical trial is authorized and the sponsor
is allowed to sell or import a drug for use in
a clinical trial if a CTA has been filed with
HC and has not received an objection
within 30 days. During the review period,
the Directorate may request additional
information from the sponsor, who has two
(2) calendar days to provide such
information.
Regulatory Fees
Canada
There are no fees to submit a clinical trial
application in Canada.
Scope of Review
Canada
The primary scope of information assessed
by institutional ethics committees (ECs)
(called Research Ethics Boards (REBs) in
Canada) relates to maintaining and
protecting the dignity and rights of human
research participants and ensuring their
FDA review takes place.
Non-commercial products refer to products
not intended to be distributed commercially
and include the above listed IND types.
In general, human research studies must
be conducted under an IND if all of the
following research conditions apply:
 A drug is involved
 A clinical investigation is being
conducted
 The clinical investigation is not
otherwise exempt
Whether an IND is required to conduct an
investigation of a marketed drug primarily
depends on the intent of the investigation
and the degree of risk associated with the
use of the drug in the investigation.
US
The Food & Drug Administration (FDA)
does not levy a fee to review investigational
new drug (IND) submissions.
However, the FDA has the authority to
assess and collect user fees from
companies that produce certain human
drug and biological products as part of the
New Drug Application (NDA). The NDA is
the vehicle through which drug sponsors
formally propose that the FDA approve a
new pharmaceutical for sale and marketing
in the United States (US). The data
gathered during the animal studies and
human clinical trials of an IND become part
of the NDA.
US
The primary scope of information assessed
by the ethics committee (EC) (referred to as
an institutional review board (IRB) in the
United States (US)) relates to maintaining
and protecting the dignity and rights of
research participants and ensuring their
safety throughout their participation in a
clinical trial. ECs must also pay special
attention to reviewing informed consent and
to protecting the welfare of certain classes
of participants deemed vulnerable.
(See Informed Consent topic, and
the subtopics of Vulnerable
Populations; Children/Minors;
Pregnant Women, Fetuses &
Neonates; Prisoners; and Mentally
Impaired for additional information about
these populations.) Note that Health
Canada (HC)-implemented International
Council for Harmonisation (ICH) guidance
takes precedence over other HC guidance
when they are not consistent.
ECs are required to have procedures in
place to receive and respond to reports of
new information, including, but not limited
to, safety data, unanticipated issues, and
newly discovered risks.
ECs must ensure an independent, timely,
and competent review of all ethical aspects
of the clinical trial protocol. They must act in
the interests of the potential research
participants and the communities involved
by evaluating the possible risks and
expected benefits to participants, and they
must verify the adequacy of confidentiality
and privacy safeguards.
Role in Clinical Trial Approval
Process
Health Canada (HC) must approve a clinical study for the portion of the study conducted
trial application (CTA) and an institutional
EC(s) must give ethical clearance prior to a policy will streamline the EC review process
sponsor initiating a clinical trial. In addition, and eliminate duplicative reviews. The
institutional EC review for each clinical trial
site may occur in parallel with HC’s CTA
review and approval. Once HC completes
its review, the department issues a No
Objection Letter (NOL) if the CTA is
approved. HC, however, will not authorize
the sponsor to begin the clinical trial until
he/she submits an institutional EC approval
(provided in the required Clinical Trial Site
Information form) for each participating trial Common Rule, the National Institutes of
site. In addition, the EC must review and
approve any protocol amendments prior to
those changes being implemented.
The researcher must submit an annual
report to enable the EC to evaluate the
continued ethical acceptability of the
safety throughout their participation in a
clinical trial. The EC must also pay special
attention to reviewing informed consent and
to protecting the welfare of certain classes
of participants deemed to be vulnerable.
The EC is also responsible for ensuring a
competent review of the research protocol,
evaluating the possible risks and expected
benefits to participants, and verifying the
adequacy of confidentiality safeguards.
Role in Clinical Trial Approval
Process
The Food & Drug Administration (FDA)
must review an investigational new drug
application (IND) and an EC must review
and approve the proposed study prior to a
sponsor initiating a clinical trial. The
institutional EC review of the clinical
investigation may be conducted in parallel
with the FDA review of the IND. However,
EC approval must be obtained prior to the
sponsor being permitted to initiate the
clinical trial.
In the event of multicenter clinical studies,
also known as cooperative research
studies, which must comply with the revised
Common Rule, it is required that by
January 20, 2020, all federally-funded or
sponsored institutions that are located in
the US and engaged in multicenter
research to use a single EC to review that
in the US, known as the IRB policy. This
exceptions to this requirement are: when
multicenter review is required by law
(including tribal law); or for research where
any federal department or agency
supporting or conducting the research
determines that the use of a single EC is
not appropriate.
Designed to complement the revised
Health (NIH) issued a final policy requiring
all institute-funded multicenter clinical trials
conducted in the US to be overseen by a
single EC, unless prohibited by any federal,
tribal, or state law, regulation, or policy.
 research. In the event that an EC
terminates or suspends any prior approval
or favorable opinion, it must document its
views in writing, clearly identifying the trial,
the documents reviewed, and the date for
the termination or suspension.
CLINICAL TRIAL CYCLE
Submission Process
Canada
Canada requires the sponsor to obtain
clinical trial authorization from Health
Canada (HC) prior to initiating the trial The
sponsor must file a clinical trial application
(CTA) to the appropriate Directorate within
HC’s Health Products and Food Branch
(HPFB)—the Therapeutic Products
Directorate or the Biologics and Genetic
Therapies Directorate.
In addition, the sponsor may submit a CTA
for clinical trial authorization to the HC in
parallel with its submission to an
institutional ethics committee (EC) (known
as a Research Ethics Board (REB) in
Canada) for a favorable ethical opinion. HC,
however, will not authorize the sponsor to
begin the clinical trial until he/she submits
an institutional EC approval (provided in the
required Clinical Trial Site Information form)
for each participating trial site.
Submission Content
Canada
Health Canada (HC) Requirements
The clinical trial application (CTA) should be
organized into three (3) modules in
Common Technical Document (CTD)
format:
 Module 1 - Administrative and
Although the regulations do not specify an
expiration for EC approval, any clinical
investigation must not be initiated unless
the reviewed and approved study remains
subject to continuing review at intervals
appropriate to the degree of risk, but not
less than once a year. Per the Common
Rule, the EC must conduct reviews at
intervals appropriate to the degree of risk,
but not less than once per year.
US
The United States (US) requires the
sponsor to submit an investigational new
drug application (IND) for the Food & Drug
Administration's (FDA) review and
authorization to obtain an exemption to ship
investigational drug or biological products
across state lines and to administer these
investigational products in humans.
Whether an IND is required to conduct an
investigation of a drug to be marketed (this
includes biological products) primarily
depends on the intent of the investigation,
and, the degree of risk associated with the
use of the drug in the investigation.
In addition, institutional ethics committee
(EC) (institutional review board (IRB) in the
US) review of the clinical investigation may
be conducted in parallel with the FDA
review of the IND. However, EC approval
must be obtained prior to the sponsor being
permitted to initiate the clinical trial.
US
FDA Investigational New Drug
Application (IND) Requirements
 Cover sheet (Form FDA 1571)
(including, but not limited to: sponsor
contact information, investigational
product (IP) name, application date,
 clinical information about the proposed
trial
 Module 2 - Quality (Chemistry and
Manufacturing) summaries about the
drug product(s) to be used in the
proposed trial
 Module 3 - Additional supporting
quality information
The CTA should contain the following
information and documents:
 Protocol
 Summary of potential risks/benefits
 Clinical trial attestation, including
contact information, for each
institutional ethics committee (EC) that
approved the protocol, if known at the
time of submitting the application
 Contact information of any
institutional EC that previously refused
to approve the protocol, its reasons,
and refusal date
 Investigator’s Brochure (IB)
 Informed consent form (ICF)
 Information about use of a human-
sourced excipient
 Chemistry and manufacturing
information
 Proposed date for trial
commencement at each site, if known
Institutional EC Requirements
Each institutional EC has its own
application form and clearance
requirements, which can differ significantly
regarding the number of copies to be
supplied and application format
requirements. However, the following
requirements comply with the ICH Good
Clinical Practice Guidelines and are
basically consistent across all Canadian
ECs:
 Clinical protocol
 ICFs and participant information
phase(s) of clinical investigation to be
conducted, and commitment that the
ethics committee (EC) will conduct
initial and continuing review and
approval of each study proposed in
the investigation)
 Table of contents
 Introductory statement and general
investigational plan
 Investigator’s brochure (IB)
 Protocols
 Chemistry, manufacturing, and
control data
 Pharmacology and toxicology data
 Previous human experience with the
investigational drug
 Additional information
 Relevant information (e.g., foreign
language materials and number of
copies - see Submission Process
subtopic for details)
Ethics Committee Requirements
Each EC has its own application form and
clearance requirements, which can differ
significantly regarding the number of copies
to be supplied and application format
requirements. However, the requirements
listed below comply with the applicable
regulatory requirements and are basically
consistent across all US ECs.
The EC should obtain the following
documents and must ensure the listed
requirements are met prior to approving the
study:
 Clinical protocol
 Informed consent forms (ICFs) and
participant information, including
whether informed consent was
appropriately sought and documented,
or waived
 Participant recruitment procedures
 IB
 Safety information
 Participant payments and
  Participant recruitment procedures
 IB
 Safety information
 Participant payments and
compensation
 Investigator(s) current curriculum
vitaes (CVs)
 Additional required institutional EC
documentation
Clinical trial researchers are required to
include a plan for monitoring safety,
efficacy/effectiveness (where feasible), and
validity in their proposal for EC review.
Clinical Protocol
The clinical protocol should include the
following elements:
 General information
 Background information
 Trial objectives and purpose
 Trial design
 Participation selection/withdrawal
 Participant treatment
 Efficacy assessment
 Safety assessment
 Statistics
 Direct access to source
data/documents
 Quality control/quality assurance
procedures
 Ethical considerations
 Data handling and record keeping
 Financing and insurance
 Supplements
Timeline of Review
Canada
compensation
 Investigator(s) current Curriculum
Vitaes (CVs)
 Additional required EC
documentation
 Risks to participants are minimized
and are reasonable in relation to
anticipated benefits
 Participant selection is equitable
 Adequate provisions to protect
participant privacy and maintain
confidentiality of data are made,
where appropriate; the Department of
Health & Human Services (HHS) will
issue guidance to assist ECs in
assessing what provisions are
adequate to protect participant privacy
and maintain the confidentiality of data
Per the revised Common Rule, which took
effect January 21, 2019, where limited EC
review applies, the EC does not need to
make the determinations outlined above.
Rather, limited EC review includes
determinations that broad consent will
be/was obtained properly, that adequate
protections are in place for safeguarding
the privacy and confidentiality of
participants, and (for secondary studies)
that individual research results will not be
returned to participants.
US
The review and approval of a clinical trial
application (CTA) by Health Canada (HC)
and an institutional ethics committee (EC)
may be conducted in parallel. HC, however,
will not authorize the sponsor to begin the
clinical trial until he/she submits an
institutional EC approval (provided in the
required Clinical Trial Site Information form)
for each participating trial site.
HC Approval
An authorized clinical trial is one that has
been filed with HC and has not received an
objection within 30 days. All CTAs are
subject to the 30-day default period from
the date of receipt of the completed
application at the appropriate Directorate
within HC’s Health Products and Food
Branch (HPFB). While the Directorates can
establish shorter administrative targets of
seven (7) days for the review of
bioequivalence trials, the 30-day default
system remains the regulatory requirement.
Applications to conduct Phase I clinical
trials using somatic cell therapies,
xenografts, gene therapies, prophylactic
vaccines, or reproductive and genetic
technologies are not included in the seven-
day target system.
During the review period, the Directorate
may request additional information from the
sponsor, who has two (2) calendar days to
provide such information. If HC authorizes
the CTA, then it issues a No Objection
Letter (NOL). If HC rejects the CTA, it
sends a Not Satisfactory Notice (NSN). The
sponsor may resubmit the information and
material at a future time, and it will be
processed as a new CTA.
Ethics Committee Approval
The EC review and approval process
timeline varies by institution. Canada’s
research institutions recommend a
proportionate approach to ethics review—
the lower the level of risk, the lower the
level of scrutiny (delegated review); the
higher the level of risk, the higher the level
of scrutiny (full board review). In either
case, the institutional EC should make its
decisions in an efficient and timely manner.
nstitutional ethics committee (EC)
(institutional review board (IRB) in the
United States) review of clinical
investigation may be conducted in parallel
with the Food & Drug Administration’s
(FDA) review of the investigational new
drug application (IND). However, EC
approval must be obtained prior to the
sponsor being permitted to initiate the
clinical trial.
FDA IND Review and
Authorization
The FDA’s Center for Drug Evaluation and
Research (CDER) and the Center for
Biologics Evaluation and Research (CBER)
review teams will evaluate all initial INDs for
drugs and therapeutic biological products
respectively. Within 30 calendar days of
receipt of the original IND, the CDER/CBER
team will contact the sponsor when a
clinical hold is being imposed. A clinical
hold is an order the FDA issues to delay or
suspend a clinical investigation. If the team
determines there may be grounds for
imposing a clinical hold, an attempt will be
made to discuss and resolve any issues
with the sponsor prior to issuing the clinical
hold order. An IND automatically goes into
effect in 30 days, unless the FDA notifies
the sponsor that the IND is subject to a
clinical hold, or, the FDA has notified the
sponsor earlier that the trial may begin.
Once the FDA receives the IND application,
an IND number will be assigned and the
application will be forwarded to the
appropriate reviewing division. A letter will
be sent to the sponsor/sponsor-investigator
providing notification of the assigned IND
number, date of receipt of the original
application, address where future
submissions to the IND application should
be sent, and the name and telephone
number of the FDA person to whom
questions about the application should be
directed. Clinical studies shall not be
initiated until 30 days after the date of
receipt of the IND application by the FDA
unless earlier notification is received from
the FDA that studies may begin.
EC Approval

Trial Initiation
Canada
A clinical trial can only commence after the
sponsor receives authorization from both
Health Canada (HC) and an institutional
ethics committee (EC) (known as Research
Ethics Board (REB) in Canada). No waiting
period is required following the applicant’s
receipt of these approvals.
The sponsor is required to retain the REB
Attestation and Qualified Investigator
Undertaking (QIU) forms for each trial site,
while submitting the Clinical Trial Site
Information (CTSI) form in electronic format
to the appropriate HC Directorate for each
trial site.
In addition, if a sponsor (Canadian or
foreign) wants to import a drug into Canada
to conduct a clinical trial, he/she must
include a copy of HC’s clinical trial
authorization (i.e., the No Objection Letter)
with the drug shipment. If the sponsor plans
to import investigational drugs directly to
each trial site, then the sponsor must also
authorize the importer (i.e., the clinical trial
site) when submitting the clinical trial
application.
Clinical Trial Agreement
Prior to initiating the trial, the sponsor must
sign an agreement between all involved
parties, including ECs, Qualified
Investigators (QIs), contract research
organizations, and others, to ensure full
compliance with the regulatory
requirements.
Clinical trial sites and sponsors may use the
standard model Clinical Trial Agreement
(mCTA) in negotiating phase II and phase
Each EC maintains its own procedures
and processes for review.
Consequently, there is no stated
regulatory requirement for a standard
timeline of review and approval of the
clinical trial. However, the EC should
review a proposed clinical trial within
a reasonable time.
US
A clinical trial can only commence following
the Food & Drug Administration (FDA)’s
review of the investigational new drug
application (IND) within 30 calendar days of
receiving the IND and ethics approval from
an institutional ethics committee (EC)
(known as institutional review board (IRB) in
the United States (US)). No waiting period
is required following the 30 day review
period unless the FDA imposes a clinical
hold on the IND.
Once an IND has been submitted and has
been authorized following the 30 day review
period, the sponsor is permitted to import
an investigational product (IP).
Clinical Trial Agreement
All investigators must possess appropriate
qualifications, training, and experience.
Prior to the trial’s commencement, the
sponsor must obtain from the
investigator(s) a signed Statement of
Investigator form. This form serves as the
investigator’s agreement to provide certain
information to the sponsor and to assure
that he/she will comply with the FDA’s
clinical investigation regulations.
EC Confirmation of Review and
Approval
EC review of the clinical investigation must
be obtained prior to the sponsor being
permitted to initiate the trial.
Clinical Trials Registry
Either the sponsor or the principal
investigator (PI) designated by the sponsor
is required to register with the
III clinical trial agreements. The mCTA is a
direct response to recommendations from
the field for a standard clinical trial template
agreement that can help to streamline the
negotiating process and expedite clinical
trial start up times.
Institutional EC Confirmation of
Review and Approval
The sponsor must obtain institutional EC
approval for each participating site prior to
initiating a clinical trial.
Qualified Investigators (QIs)
Prior to initiating a clinical trial, the sponsor
must ensure that a QIU form (or similar
documentation) has been completed and is
kept on file by the sponsor. The form
certifies that the QI will conduct the clinical
trial in accordance with good clinical
practices and will immediately inform trial
participants and the institutional EC of trial
discontinuance and the reason for this
discontinuance. If there is a change in the
QI at a site, a new CTSI Form must be
submitted to HC, and a new QIU form must
be maintained by the sponsor.
Data and Safety Monitoring Board
(DSMB)
While not required, it is recommend that a
Data and Safety Monitoring Board (known
as an Independent Data-Monitoring
Committee in Canada) be established to
assess the progress of a clinical trial,
including the safety data and the critical
efficacy endpoints at intervals, and to
recommend to the sponsor whether to
continue, modify, or stop a trial. Note that
Health Canada (HC)-implemented
International Council for Harmonisation
(ICH) guidance takes precedence over
other HC guidance when they are not
consistent.
To determine whether a DSMB is needed,
researchers and ECs should consider the
following:
 The magnitude of foreseeable
research-attributable harms to
ClinicalTrials.gov databank. The sponsor/PI
must register 21 days after the first patient
is enrolled in a trial.
Data and Safety Monitoring Board
(DSMB)
Data and Safety Monitoring Boards
(DSMBs), (also known as a Data Monitoring
Committees (DMCs)), are not required by
FDA regulations, except in the case of
research conducted in emergency settings
in which fulfilling the informed consent
requirement is unfeasible. In this case, the
FDA requires the establishment of an
independent data monitoring committee to
exercise oversight of the clinical
investigation.
For all human subjects research funded
and/or sponsored by the Department of
Health & Human Services (HHS), the
institutional EC shall ensure that, when
appropriate, the research plan makes
adequate provisions for monitoring the data
collected during the study to ensure
participant safety and privacy. Moreover, all
National Institutes of Health (NIH) funded
clinical trials require a Data and Safety
Monitoring Plan and monitoring should be
commensurate with risk. DSMBs are also
required for multi-site clinical trials including
interventions that involve potential
participant risk.
 participants.
 Whether the circumstances of the
participants make them vulnerable in
the context of research.
 The feasibility of interim data
analysis.
 The complexity of the study.
 Conflicts of interest.

Clinical Trials Registry

While not a mandatory requirement,

HC strongly encourages sponsors to
register their clinical trials on one (1)
of two (2) publicly accessible
registries accepting international
clinical trial information and
recognized by the World Health
Organization, ClinicalTrials.gov and
the Current Controlled Trials
International Standard Randomised
Controlled Trials Number (ISRCTN)
Registry. However, clinical trials must
be registered before recruitment of
the first trial participant in a publicly
accessible registry that is acceptable
to the WHO or the International
Committee of Medical Journal Editors
(ICMJE). In addition, following
registration, researchers are
responsible for ensuring that the
registry is updated in a timely manner
with: new information; safety and,
where feasible, efficacy reports;
reasons for stopping a trial early; and
the location of findings.

Safety Reporting
Canada
The following definitions provide a basis for
a common understanding of Canada’s
safety reporting requirements:
 Adverse Event (AE) – Any adverse
occurrence in the health of a clinical
trial subject who is administered a
drug that may or may not be caused
by the administration of the drug, and
includes an adverse drug reaction.
 Adverse Drug Reaction (ADR) – Any
noxious and unintended response to a
US
The following definitions provide a basis for
a common understanding of safety
reporting requirements in the United States
(US):
 Adverse Event (AE) - Any untoward
medical occurrence associated with
the use of a drug in humans, whether
or not considered drug related
 Adverse Reaction (AR) - Any AE
caused by a drug. ARs are a subset of
all suspected adverse reactions where
 drug that is caused by the
administration of any dose of the drug.
 Serious Adverse Drug Reaction
(SADR) or Serious Adverse Event
(SAE) – Any untoward medical
occurrence that at any dose: results in
death, is life threatening, requires
hospitalization or prolongation of
existing hospitalization, results in
persistent or significant disability or
incapacity, or causes a congenital
anomaly/birth defect.
 Serious, Unexpected ADR – A
serious ADR that is not identified in
nature, severity or frequency in the
risk information set out in the
investigator’s brochure or on the label
of the drug.
Researchers are required to promptly report
new information revealed during the
conduct of the trial that might affect the
welfare or consent of participants to the
ethics committee (EC), to a publicly
accessible registry, and to other appropriate
regulatory or advisory bodies. In addition,
when new information is relevant to
participants’ welfare, researchers must
promptly inform all participants to whom the
information applies (including former
participants). Researchers must work with
their ECs to determine which participants
must be informed, and how the information
should be conveyed.
Reporting Requirements for
AEs/ADRs
Sponsor Responsibilities
The sponsor is required to expedite reports
of ADRs to Health Canada (HC) that meet
these three (3) criteria: serious,
unexpected, and having a suspected causal
relationship. ADR reports that are expected
or unexpected, but not serious, should not
be reported to HC, but rather monitored and
tracked by the sponsor.
During a clinical trial, the sponsor is
required to inform HC of any serious,
unexpected ADR that has occurred inside
or outside Canada. An ADR report must be
filed in the following specified timelines:
 When neither fatal nor life-
there is reason to conclude that the
drug caused the event
 Serious Adverse Event/Serious
Suspected Adverse Reaction
(SAE/SSAR) - An AE/SSAR that
results in death, is life-threatening,
requires inpatient hospitalization or
prolongation of existing
hospitalization, causes persistent or
significant disability/incapacity, results
in a congenital anomaly/birth defect,
or, leads to a substantial disruption of
the participant’s ability to conduct
normal life functions
 Suspected Adverse Reaction (SAR)
- Any AE where there is a reasonable
possibility that the drug caused the AE
 Unexpected AE/Unexpected SAR -
An AE or SAR that is not listed in the
investigator’s brochure (IB), or is not
listed at the specificity or severity that
has been observed; or, if an IB is not
required or available, is not consistent
with the risk information described in
the general investigational plan or
elsewhere in the application
 Life-threatening Adverse Event/Life-
threatening Suspected Adverse
Reaction - An AE/SAR is considered
“life-threatening” if its occurrence
places the participant at immediate
risk of death. It does not include an
AE/SAR that, had it occurred in a
more severe form, might have caused
death
Reporting Requirements for
AEs/ARs
Investigator Responsibilities
The investigator must comply with the
following reporting requirements:
 SAEs, whether or not considered
drug related, must be reported
immediately to the sponsor
 Study endpoints that are SAEs must
be reported in accordance with the
protocol unless there is evidence
suggesting a causal relationship
between the drug and the event. In
that case, the investigator must
 threatening, within 15 days after
becoming aware of the information
 When fatal or life-threatening,
immediately when possible and, in any
event, within seven (7) days after
becoming aware of the information
 Within eight (8) days after having
informed HC of the ADR, submit a
report that includes an assessment of
the importance and implication of any
findings
Qualified Investigator (QI)
Responsibilities
When evaluating whether an AE is serious
and unexpected, the Qualified Investigator’s
(QI) and sponsor’s determination of
causality is important. Only serious and
unexpected ADRs found to have a
reasonable suspected causal relationship to
the drug should be reported by the sponsor
to HC.
immediately report the event to the
sponsor
 Non-serious AEs must be recorded
and reported to the sponsor according
to the protocol specified timetable
 Report promptly to the institutional
ethics committee (EC) (institutional
review boards (IRBs) in the US) all
unanticipated problems involving risk
to human participants or others where
AEs should be considered
unanticipated problems
Sponsor Responsibilities
The sponsor must report any SAR/AR that
is both serious and unexpected. An AE
must only be reported as a SAR if there is
evidence to suggest a causal relationship
between the drug and the AE.
The sponsor is required to notify the Food &
Drug Administration (FDA) and all
participating investigators in a written safety
report of potential serious risks, from clinical
trials or any other source, as soon as
possible, but no later than 15 calendar days
after he/she determines the information
qualifies for reporting. Additionally, the
sponsor must notify the FDA of any
unexpected fatal or life-threatening SAR as
soon as possible, but no later than seven
(7) calendar days following his/her receipt
of the information. The sponsor is required
to submit a follow-up safety report to
provide additional information obtained
pertaining to a previously submitted safety
report. This report should be submitted
without delay, as soon as the information is
available, but no later than 15 calendar
days after the sponsor initially receives the
information.
The sponsor must also report the following:
 Any findings from epidemiological
studies, pooled analyses of multiple
studies, or clinical studies (other than
those reported in the safety report),
whether or not conducted under an
IND, and whether or not conducted by
the sponsor, that suggest a significant
risk in humans exposed to the drug
  Any findings from animal or in vitro
testing, whether or not conducted by
the sponsor, that suggest a significant
risk in humans exposed to the drug
 Any clinically important increase in
the rate of an SSAR over that listed in
the protocol or IB
In each safety report, the sponsor must
identify all safety reports previously
submitted to the FDA concerning a similar
SAR, and must analyze the significance of
the SAR in light of previous, similar reports,
or any other relevant information.

The responsible party, either the sponsor or

the principal investigator (PI) designated by
the sponsor, must submit three (3) tables of
AE/ adverse drug reaction (ADR)
information when providing study results to
ClinicalTrials.gov. The tables should consist
of the following summarized data:

 All SAEs/serious adverse drug

reactions (SADRs)
 Other AEs/ADRs that exceed a
frequency of five (5) percent in any
arm of the trial
 All-cause mortalities
This information must be submitted no later
than one (1) year after the primary
completion date of the clinical trial.
Submission of trial results may be delayed
as long as two (2) years if the sponsor or PI
submits a certification
to ClinicalTrials.gov that either: 1) the FDA
has not yet approved, licensed, or cleared
for marketing the investigational product
(IP) being studied; or 2) the manufacturer is
the sponsor and has sought or will seek
approval within one (1) year.

Form Completion and Delivery

Requirements

The sponsor must submit each safety

report in a narrative format, on FDA Form
3500A, or in an electronic format that the
FDA can process, review and archive, and
be accompanied by Form 1571 (cover
sheet).

The submission must be identified as


Reporting Process
Canada
Investigators and sponsors share
responsibility for submitting interim and
annual reports on the status of a clinical
trial. The investigator is required to provide
annual progress reports to the institutional
ethics committee (EC) and submit interim
progress reports to the EC and Health
Canada (HC) if there are any significant
changes affecting the trial or risk to
participants. The sponsor is required to
submit annual reports (in the form of an
updated Investigator’s Brochure (IB)) to HC.
Note that HC-implemented International
Council for Harmonisation (ICH) guidance
takes precedence over other HC guidance
when they are not consistent.
Interim Progress Reports
The investigator should promptly provide
written reports to the sponsor and the
institutional ethics committee (EC) on any
changes significantly affecting the conduct
of the trial, and/or increasing the risk to
participants.
Investigators must report new information
that may affect the welfare or consent of
participants to the institutional EC, Health
Canada (HC), and other appropriate
regulatory or advisory entities. When new
information is relevant to participants’
follows:
 “IND safety report” for 15-day
reports
 “7-day IND safety report” for
unexpected fatal or life-threatening
suspected adverse reaction reports
 “Follow-up IND safety report” for
follow-up information
The report must also be submitted to the
appropriate review division (Center for Drug
Evaluation and Research (CDER)/Center
for Biologics Evaluation and Research
(CBER)). Additionally, the FDA will accept
foreign SARs on a CIOMS Form I instead of
FDA Form 3500A.
US
The investigator and the sponsor share
responsibility for submitting progress
reports on the status of a clinical trial and
for submitting final study reports upon the
trial’s completion.
Interim/Progress Reports
The investigator should promptly provide
written reports to the sponsor and the
institutional ethics committee (EC) on any
changes significantly affecting the conduct
of the trial, and/or increasing the risk to
participants.
The investigator must furnish all reports to
the sponsor. In addition, the investigator
should submit written summaries of the trial
status to the institutional EC (institutional
review board (IRB) in the United States
(US)) annually, or more frequently, if
requested by the EC.
Annual Report
The sponsor must submit a brief annual
progress report to the Food & Drug
Administration (FDA) on the investigation
within 60 days of the anniversary date that
the investigational new drug (IND) went into
effect. The report must contain the following
information for each study:
welfare, researchers must promptly inform
all participants to whom the information
applies (including former participants).
Researchers should work with their ECs to
determine which participants must be
informed, and how the information should
be conveyed. New information may
comprise a range of issues, including, but
not limited to:
 Changes to the research design
 Evidence of any new risks
 Unanticipated issues that have
possible health or safety
consequences for participants
 New information that decisively
proves the benefits of one intervention
over another
 New research findings, including
relevant non-trial findings
 Unanticipated problems
 Closure of trials at other sites for
reasons that may be relevant to the
welfare or consent of participants in
the ongoing trial
Annual Report
The sponsor must submit annually an
updated Investigator’s Brochure (IB), which
serves as the annual report, including all
safety information and global status, to HC.
Revisions that are more frequent may be
appropriate depending on the stage of
development and the generation of relevant
new information. The annual updated IB
should be submitted electronically as a
CTA-Notification, and include a statement
confirming that the protocol and/or informed
consent form do not require changes as a
result of the updated IB. In all cases, the
updated IB should be accompanied by a list
of changes that clearly describe the
sections that have changed, including a
rationale for each change.
The investigator should submit written
summaries of the trial status to the
institutional EC annually, or more
frequently, if requested.
Final Report
Upon completion of the trial, the
 Title, purpose, description of patient
population, and current status
 Summary of the participants
screened (e.g., failed screenings,
participants enrolled, withdrawn, or
lost to follow-up, and other challenges)
 Summary information - including
information obtained during the
previous year’s clinical and nonclinical
investigations
 Description of the general
investigational plan for the coming
year
 Updated investigator’s brochure, if
revised
 Description of any significant Phase
1 protocol modifications not previously
reported in a protocol amendment
 Brief summary of significant foreign
marketing developments with the drug
 A log of any outstanding business
for which the sponsor requests a
reply, comment, or meeting
Trial updates must be submitted
to ClinicalTrials.gov according to the
following guidelines:
 Not less than once every 12 months
for updated general trial registration
information
 Not later than 30 calendar days for
any changes in overall recruitment
status
 Not later than 30 calendar days after
the trial reaches its actual primary
completion date, the date the final
participant was examined or received
an intervention for the purposes of
final collection data for the primary
outcome
Final Report
An investigator must provide the
sponsor with an adequate report
shortly after completion of the
investigator’s participation in the
investigation. There is no specific
timeframe stipulated for when the
report should be completed.
Upon the trial’s completion, the
investigator should inform the
institution and the
investigator/institution should provide
the EC with a summary of the trial’s
 investigator is required to submit a
final report to the institutional EC
summarizing the trial’s outcome.
HC encourages sponsors to submit a
notification to HC indicating that the
trial is complete.
Trial Authorization
Canada
The sponsor submits a clinical trial
application (CTA) or amendment to a
previously approved clinical trial application
(CTA-A) to Health Canada (HC) to obtain
authorization to conduct a clinical trial. In
addition, the sponsor may submit a CTA for
clinical trial authorization to HC in parallel
with its submission to an institutional ethics
committee (EC) (known as Research Ethics
Board (REB) in Canada) for a favorable
ethical opinion. HC, however, will not
authorize the sponsor to begin the clinical
trial until he/she submits an institutional EC
approval (provided in the required Clinical
Trial Site Information form) for each
participating trial site.
To complete the CTA, the sponsor must
submit a clinical trial application
electronically. The CTA package includes,
but is not limited to:
 Protocol
 Summary of potential risks/benefits
 Clinical trial attestation (including
contact information for the institutional
EC that approved the protocol, if
known at the time of application)
 Contact information of any
institutional EC that previously refused
to approve the protocol, its reason(s),
and refusal date
 Investigator’s brochure
 Informed consent form
 Information about use of a human-
sourced excipient
 Chemistry and manufacturing
outcome, and supply the FDA with any
additional report(s) required of the
investigator/institution.
The sponsor or the principal
investigator (PI) designated by the
sponsor must submit results for
applicable investigational product
clinical trials to ClinicalTrials.gov no
later than one (1) year following the
study’s completion date. (See the full
subtopic content in the single-country
view for exceptions to this timeframe
and the types of data to be reported).
US
The sponsor is responsible for submitting
an investigational new drug application
(IND) for the Food & Drug Administration's
(FDA) review to obtain an exemption to ship
investigational drug or biological products
across state lines and to administer these
investigational products in humans.
Institutional ethics committee (EC)
(institutional review board (IRB) in the US)
review of the clinical investigation may be
conducted concurrently with the FDA review
of the IND. However, EC approval must be
obtained prior to the sponsor being
permitted to initiate the clinical trial.
To complete the IND application package,
the sponsor must provide the following
information in paper format or electronically:
 Cover sheet (Form FDA 1571)
(including, but not limited to: sponsor
contact information, investigational
product (IP) name, application date,
phase(s) of clinical investigation to be
conducted, and commitment that the
EC will conduct an initial and
continuing review and approval of
each study proposed in the
investigation)
 Protocols
 Chemistry, manufacturing, and
control data
 Pharmacology and toxicology data
 Previous human experience with the
investigational drug
 information
 Proposed date for trial
commencement at each site, if known
If HC authorizes the CTA, then it issues a
No Objection Letter (NOL). If HC rejects the
CTA, it sends a Not Satisfactory Notice
(NSN). HC will issue a NSN if it identifies
significant deficiencies, or, if a timely
response to information requested has not
been provided. The sponsor may resubmit
the information and material at a future
time, and it will be processed as a new
CTA.