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6 Principles ofPharmacovigilance andDrug Regulation
161
131. European Medicines Agency. EMA review of data
on paternal exposure to valproate—press release 16
Aug 2023. 2023. https://www.ema.europa.eu/en/
news/ema- review- data- paternal- exposure- valproate.
132. Medicines and Healthcare products Regulatory
Agency. Valproate: reminder of current pregnancy
prevention programme requirements; information on new safety measures to be introduced in
the coming months. 2022. https://www.gov.uk/
drug- safety- update/valproate- reminder- of- currentpregnancy- prevention- programme- requirementsinformation- on- new- safety- measures- to- beintroduced- in- the- coming- months. Retrieved 22 Oct
2023.
133. Watson OJ, Barnsley G, Toor J, Hogan AB,
Winskill P, Ghani AC. Global impact of the
rst year of COVID-19 vaccination: a mathematical modelling study. Lancet Infect Dis.
2022;22(9):1293–302. https://doi.org/10.1016/
S1473- 3099(22)00320- 6.
134. Mahase E.Vaccinating the UK: how the covid vaccine was approved, and other questions answered.
BMJ. 2020;371:m4759. https://doi.org/10.1136/
bmj.m4759.
135. Marinus R, Mod S, Mpandzou M, Kuhler
TC. Rolling reviews during COVID-19: the
European Union experience in a global context. Clin
Ther. 2022;44(3):352–63. https://doi.org/10.1016/j.
clinthera.2022.01.001.
136. Cavaleri M, Enzmann H, Straus S, Cooke E.The
European medicines Agency’s EU conditional
marketing authorisations for COVID-19 vaccines. Lancet. 2021;397(10272):355–7. https://doi.
org/10.1016/S0140- 6736(21)00085- 4.
137. Cavaleri M, Sweeney F, Gonzalez-Quevedo
R, Carr M. Shaping EU medicines regulation
in the post COVID-19 era. Lancet Reg Health
Eur. 2021;9:100192. https://doi.org/10.1016/j.
lanepe.2021.100192.
138. European Medicines Agency. Consideration on core
requirements for RMPs of COVID19 vaccines core—
RMP19 guidance v3.1 (EMA/PRAC/709308/2022).
2022.
139. European Medicines Agency. Report on pharmacovigilance tasks from EU Member States and the
European Medicines Agency (EMA) 2019–2022
(EMA/142695/2023). 2023.
140. Willame C, Dodd C, Duran CE, Elbers R, Gini
R, Bartolini C, Paoletti O, Wang L, Ehrenstein V,
Kahlert J, Haug U, Schink T, Diez-Domingo J,
Mira-Iglesias A, Carreras JJ, Vergara-Hernandez C,
Giaquinto C, Barbieri E, Stona L, etal. Background
rates of 41 adverse events of special interest for
COVID-19 vaccines in 10 European healthcare
databases—an ACCESS cohort study. Vaccine.
2023;41(1):251–62. https://doi.org/10.1016/j.
vaccine.2022.11.031.
Further Reading
Andrews EB, Moore N, editors. Mann’s pharmacovigi-
lance. 3rd ed. Wiley; 2014.
McBride L, Schmitt S, editors. Fundamentals of pharma-
ceutical and biologics regulations: a global perspective. RAPS; 2023.
Strom BL, Kimmel SE, Hennessy S, editors.
Pharmacoepidemiology. 6th ed. Wiley; 2019.
Clinical Trials Safety Data
PipashaBiswas, NilimaJustice, andHimalBiswas
7
Abstract
Patient safety monitoring is a critical component in the clinical development process. In
the last few decades, the regulatory landscape
has changed for safety data monitoring in clinical trials. The guidelines issued by regulatory
authorities specically for the collection of
safety data during clinical trials, documentation, and reporting of serious adverse events
have made a signicant impact to ensure the
safety of clinical trial subjects. The main
objective of collecting and reporting safety
data from clinical trials is early detection of
important safety signals to protect subjects,
provide information about new risks, assess
the potential risk to future patients, and
develop safety prole and product label of the
drug contributing to its benet–risk assessment throughout the life cycle of the productin clinical development.
P. Biswas (*)
Pharmacovigilance & RWE, Symogen Limited,
Marlow, UK
e-mail: pippa.biswas@symogen.com
N. Justice
R&I, V&I, AstraZeneca, Pipersville, PA, USA
H. Biswas
FY1, Cardiff University, Cardiff, Wales, UK
Keywords
Clinical trials · Data collection · Safety data
reporting · Worldwide regulations · Data Safety
Monitoring Boards · Data reconciliation · Data
integrity · Development Safety Update Report ·
Integrated Safety Summary · Signal detection
Learning Objectives
• Understand the importance of clinical trials
safety data collection, cleaning, and managing
safety data arising from patients treated with
the drug in clinical development in compliance with worldwide regulatory standards.
• Appraise the signicance of clinical trials
safety data for discovering new treatments for
diseases.
• Appreciate the importance of clinical trials
safety data analysis in research towards early
detection of adverse events arising from the
drugs in development, and associated risk mitigation and minimisation for the patients.
• Contemplate worldwide clinical trial safety
data management regulations from different
regulatory authoritiesto apply the knowledge
in day-to-day activities whilst handling data
originating from clinical trials.
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024
J. Jose et al. (eds.), Principles and Practice of Pharmacovigilance and Drug Safety,
https://doi.org/10.1007/978-3-031-51089-2_7
163
164
Key Points
• The goal of safety monitoring in clinical
trials is to identify, evaluate, minimise,
and appropriately manage risks.
• Monitoring patient safety during clinical trials is a critical component throughout the drug development life cycle that
must be adhered to as per different regulations worldwide to protect patients.
• Clinical trials safety data is importantfor discovering new treatments for
diseases, as well as new ways to detect
and reduce the chance of developing any
adverse effects to the drug and protecting the patients.
P. Biswas et al.
safety data generated from products in clinical
development and reporting of serious adverse
events (SAEs) have since evolved signicantly to
help ensure the safety of subjects and patients
involved in clinical trials [1].
This chapter provides a brief summary of the
tragic events of TGN1412 incident that led to an
overhaul of Phase 1 trials on the collection, documentation, and reporting of adverse events (AEs),
worldwide regulations of clinical trials safety
data collection and reporting, the importance of
Drug Safety Monitoring Board (DSMB)/Data
Monitoring Committee (DMC), reconciliation of
safety data on an ongoing basis, and clinical trials
safety data integrity that is very important in the
context of drug development and protection of
patients.
1 Introduction
Monitoring patient safety is an integral and
important part in the life cycle of drug development. One of the main objectives of drugdevelopment process is to collect safety data from
various phases of clinical trials, early detection of
important safety signals, and to evolve medically
relevant safety label information for the product
under development. This is important for protecting patients from risks and developing the safety
prole of the drug contributing to its benet–risk
assessment. Safety data collected during clinical
trials has a direct impact on the safety and clinical care of patients enrolled in the trials.
The regulatory landscape for safety monitoring
of healthcare products in clinical trials changed
signicantly in March 2006, after the rst-inhuman (FIH) study with TGN1412 (a CD28
superagonist mAb), resulted in life-threatening,
Serious Adverse Events (SAEs) known as
Cytokine Release Syndrome (CRS) in the United
Kingdom (UK). This tragic episode resulted in
several recommendations to improve the safety of
initial human clinical studies with drugs in clinical
development. This event initiated a new era, with
several changes and recommendations put forth by
the Medicines and Healthcare products Regulatory
Agency (MHRA) in the UK for handling of patient
2 The Events ofTGN1412
Incident: Learning
fromthePast
After a drug is considered safe and efcacious in
pre-clinical studies, it is tested in healthy human
volunteers for rst-in-human (FIH) trials. In
March 2006, a phase I clinical study was initiated
for a CD28 “superagonist” antibody TGN1412—a
new class of monoclonal antibody (mAb) with a
stimulatory mode of action on a subset of T cells
known as regulatory T cells. TGN1412 binds to
CD28 and activates T cells without the need for T
cell receptor (TCR) pre-activation, resulting in
polyclonal T cell expansion, activation, and
concentration- dependent IL-2 production, and
TGN1412 was termed a “superagonist”. The main
aim was to develop TGN1412 as a treatment for B
cell chronic lymphocytic leukaemia and for autoimmune diseases, such as rheumatoid arthritis.
1. Phase 1 clinical trial with this antibody was
initiated on 13 March 2006in six human volunteers. Within a span of 30min, all the six
volunteers had been administered TGN1412,
while two volunteers were administered a placebo. However, within 90 min of the rst
infused dose, those who had received
TGN1412 had a systemic inammatory
7 Clinical Trials Safety Data
165
response, characterised by a rapid induction
of proinammatory cytokines and accompanied by headache, myalgia, nausea, diarrhoea,
erythema, vasodilatation, and hypotension.
Further 12 and 16h post infusion, all the six
volunteers who had received TGN1412
became critically ill, with pulmonary inltrates and lung injury, renal failure, and disseminated intravascular coagulation. There
was severe and unexpected depletion of lymphocytes and monocytes which occurred
within 8 h, reaching a nadir at 24h. All six volunteers were transferred to an intensive care
unit, where they received intensive cardiopulmonary support, including dialysis, highdose methylprednisolone, and an
anti- interleukin- 2 receptor antagonist antibody.
Prolonged cardiovascular shock and acute
respiratory distress syndrome developed in two
of six patients, who required intensive organ
support for eight and 16days. It was concluded
that TGN1412 had caused a “cytokine storm”.
The patients later described huge swelling of
their body, resembling an elephant and subsequently termed as “The Elephant Man”. All six
volunteers survived, but the long-term prognosis for these subjects was dismal with one of
the volunteers since having to amputate his
toes and the tips of several ngers [2].
The MHRA reacted rapidly, immediately
suspending the Clinical Trial Authorisation
(CTA) and conrming that TGN1412 was not
in use in other trials anywhere in the world.
Additionally, MHRA also alerted international pharmaceutical regulatory authorities
worldwide of the events in case any similar
product of this class was in use.
A detailed investigation by the MHRA
identied and evaluated potential causes of
the adverse reactions. It was concluded that an
unpredicted biological reaction of the mAb in
humans was likely the cause of serious
adverse reactions observed in the trial participants, but not during the pre-clinical toxicity
studies conducted on animals.
This incident evoked changes in how
human trials are approved by the regulatory
3 Common Terminologies
This section describes common terminologies
and denitions that are used for clinical trial
safety data reporting, which is necessary to
understand while processing and reporting clinical trials safety data. The denitions, with input
from the World Health Organization (WHO)
Collaborating Centre, have been accepted for
monitoring of AEs arising from drugs in clinical
development [5].
authorities and the way clinical trials are conducted. The Expert Scientic Group [3] report
found that pre-clinical studies performed with
TGN1412 failed to consider what constituted
a safe dose for use in humans. In addition, it
made 22 recommendations for improving the
safety for Phase I trials of higher risk medicines described below [3]:
• Changes in calculations determining the
starting point for drug dosing.
• Early discussion between regulators and
sponsors with more scrutiny applied to
novel agents and access to independent,
specialist opinion.
• Sequential clinical testing—one person at
a time—rather than simultaneous, with an
appropriate period of monitoring for sudden ill effects.
• Careful consideration of the route and rate
of administration—i.e. drugs should be
administered via slow infusion rather than
an injection.
Following this event, the MHRA tight-
ened the UK clinical trial regulations. New
guidelines were put in place for trials of certain categories of drugs not yet tested in
humans [4].
The guidelines ranged from dosing proto-
cols, timelines for reporting of safety data
including AEs and training investigators.
Used inClinical Trials Safety
Data Reporting
166
P. Biswas et al.
3.1 Adverse Event
Any untoward medical occurrence in a patient or
clinical investigation subject administered a
pharmaceutical product and which does not necessarily have to have a causal relationship with
this treatment.
An adverse event (AE) can be any unfavourable and unintended sign (including an abnormal
laboratory nding, for example), symptom, or
disease temporally associated with the use of a
medicinal product, whether or not considered
related to the medicinal product.
3.2 Adverse Drug Reaction
In the pre-approval clinical experience with a
new medicinal product or its new usages, particularly as the therapeutic dose(s) may not be
established:
All noxious and unintended responses to a
medicinal product related to any dose should be
considered adverse drug reactions.
The phrase “responses to a medicinal product” means that a causal relationship between a
medicinal product and an adverse event is a reasonable possibility, i.e. the relationship cannot be
ruled out.
Thus, simply an Adverse Drug Reaction
(ADR) is dened as “any noxious and unintended
response at doses normally used or tested in
humans (in cases of approved pharmaceutical
products); a noxious and unintended response at
any dose(s) (in cases of new unregistered pharmaceutical products); an untoward medical
occurrence seemingly caused by overdosing,
abuse/dependence, and interactions with other
medicinal products (in clinical trials)”.
3.3 Unexpected Adverse Drug
Reaction
An adverse reaction, the nature or severity of
which is not consistent with the applicable product
information (e.g. Investigator’s Brochure for an
unapproved investigational medicinal product).
3.4 Expectedness ofAdverse
Drug Reaction
The purpose of expedited reporting is to make
regulators, investigators, and other appropriate
people aware of new, important information on
serious reactions. Therefore, such reporting generally involves events previously unobserved or
undocumented, so a guideline is needed to dene
an event as “unexpected” or “expected” (from the
perspective of previously observed, not on the
basis of what might be anticipated from the pharmacological properties of a medicinal product).
As stated in the denition, an “unexpected”
adverse reaction is one, the nature or severity of
which is not consistent with information in the
relevant source document(s). A few examples are
as follows:
• Acute renal failure assessed as an ADR with a
subsequent new event of interstitial nephritis.
• Hepatitis with a rst report of fulminant
hepatitis.
• Cerebral thromboembolism can be assessed as
unexpected if only cerebral vascular accident
is listed in the investigator brochure (IB).
3.5 Serious Adverse Event (SAE)
or Serious Adverse Drug
Reaction (SADR)
An adverse event (AE) or adverse drug reaction
(ADR) is associated with death, inpatient hospitalisation (in case the study was being conducted
on outpatients), prolongation of hospitalisation
(in case the study was being conducted on inpatients), persistent or signicant disability or incapacity, a congenital anomaly or birth defect, or
otherwise life-threatening.
Therefore, the criteria(s) for serious adverse
events are as follows:
• Results in death
• Is life-threatening, NOTE: The term “life-
threatening” in the denition of “serious”
refers to an event in which the patient was at
risk of death at the time of the event; it does
7 Clinical Trials Safety Data
167
not refer to an event which hypothetically
might have caused death if it were more severe
• Requires inpatient hospitalisation or prolongation of existing hospitalisation
• Results in persistent or signicant disability/
incapacity or
• Is a congenital anomaly/birth defect
Medical and scientic judgement should be
exercised in deciding whether expedited reporting is appropriate in other situations, such as
important medical events that may not be immediately life-threatening or result in death or hospitalisation, but may jeopardise the patient or
require intervention to prevent one of the other
outcomes listed above. These should also, usually, be considered serious.
3.6 Suspected Unexpected
Serious Adverse Reaction
(SUSAR)
This term is used to refer to an AE that occurs in
a clinical trial subject, which is assessed by the
sponsor and/or study investigator as being unexpected, serious, and as having a reasonable possibility of a causal relationship with the study
drug. Any AE that would have led to one of the
consequences that full serious criteria but did
not, owing to timely medical intervention, may
also be deemed aSuspected Unexpected Serious
Adverse Reaction(SUSAR).
of utmost importance. This section briey
describes the various worldwide regulations for
safety data monitoring and reporting for medicinal products during the entire life cycle of clinical development.
4.1 European Union Clinical Trials
Regulation
Since 2004, the European Union Clinical Trial
Directive 2001/20/EC (EU-CTD) [6] has governed the conduct of clinical trials in the European
Union (EU). However, after the implementation
of the EU-CTD, it created multiple challenges,
where each EU member state had to implement
its legal requirements through national legislation. There were several issues with the assessment process for multinational clinical trial
applications, as well as a complex data submission framework. Furthermore, the public had limited access to clinical trial applications and results
in the EU.In view of these issues, it was decided
the EU-CTD be replaced with the new European
Union Clinical Trials Regulation (EU-CTR).
As of 31 January 2022, the new
EU-CTR designed to simplify and harmonise
clinical trials in the EU began to replace EU-CTD,
and the new regulation repealed the Clinical
Trials Directive (EC) No. 2001/20/EC and
national implementing legislation in the EU
Member States, which regulated clinical trials in
the EU.
4 Current Regulations
Governing Clinical Trials
Safety Data inEurope, North
America, andAsia
Over the last few decades, the regulatory landscape for safety monitoring of medicinal products has rapidly changed and several regulations
have been updated on a regular basis. Regulatory
guidelines, issued by regulatory authorities
worldwide to guarantee documentation and
reporting of serious events, have evolved to
ensure that the safety of clinical trial subjects is
4.2 Aims andBenets ofEU
Clinical Trials Regulation
The main aims and benets of the EU-CTR are
illustrated below:
• Harmonise the processes for assessment and
supervision of clinical trials throughout the
EU.
• The evaluation, authorisation, and supervision
of clinical trials are the responsibilities of EU
Member States and European Economic Area
(EEA) countries.
168
P. Biswas et al.
The new regulation will enable sponsors to
submit one online application via a single online
platform known as the Clinical Trials Information
System (CTIS), which is a centralised electronic
database for approval to run a clinical trial in several European countries, making it more efcient
to carry out multinational trials. The regulation
makes it more efcient for EU Member States to
evaluate and authorise applications together, via
the CTIS.The CTIS will be used for safety reporting, modications, notications, corrective measures, results summaries, and other information.
Other key benets of the current regulation
include:
• Improving information sharing and collective
decision-making on clinical trials
• Increasing transparency of information on
clinical trials
• Ensuring high standards of safety for all par-
ticipants in EU clinical trials
Additionally, the new regulation has simplied safety data reporting, where a single safety
report can be submitted for clinical trials involving more than one Investigational Medicinal
Product (IMP), and all unexpected AEs which
affect the clinical trial’s benet–risk balance
must be reported within 15days. Additionally, all
safety assessments will be governed by separate
legislation created by the European Commission.
The European Commission is developing supplementary legislation to describe how member
states will interact to assess safety reports.
Finally, under EU-CTD multiple safety submissions to national competent authoritiesand ethics committes are permitted, whereas EU-CTR
requires all safety reporting via EudraVigilance.
4.3 New Timelines oftheEU-CTR
There is a 3-year transition period which started
on 31 January 2022:
• 31 January 2022 to 31 January 2023: sponsors
may submit clinical trials under the legal
framework of EU-CTD or EU-CTR.
• Starting 31 January 2023: all clinical trial
applications are subject to EU-CTR.However,
trials approved under EU-CTD before 31
January 2023 can continue to be regulated
under EU-CTD until 31 January 2025.
Since 31 January 2025, all clinical trials
must be regulated under EU-CTR, and sponsors have a maximum of 12 calendar days to
respond to application queries or requests for
information (RFI) under EU-CTR, otherwise,
applications will lapse by default. While
authorisations will not expire under EU-CTD,
it will, however, expire if no patient is recruited
within 2 years under EU-CTR. Similarly,
EU-CTR mandates reporting serious breaches
within 7 days and archiving the Trial Master
File (TMF) after 25years where EU-CTD sets
no timelines for either.
4.4 Medicines andHealthcare
Products Regulatory Agency,
UnitedKingdom
As of 1 January 2022, the combined review
service formerly known as Combined Ways of
Working [7] will now be the way forward for
all new Clinical Trials of Investigational
Medicinal Products (CTIMPs) where applications are prepared, submitted, and reviewed
[5]. Combined review will therefore offer a
single application route and co-ordinated
review leading to a single UK decision for
CTIMPs.
4.4.1 Suspected Unexpected Serious
Adverse Reactions
The sponsor of a clinical trial or any other person
to whom the sponsor has delegated this responsibility must report all suspected unexpected serious adverse reactions (SUSARs) which occur
during the trial to the MHRA.
Fatal or life-threatening SUSARs must be
reported as soon as possible, no later than 7days
after the rst aware date of the event. Additional
relevant information must be sent within 8days
of the initial report.
7 Clinical Trials Safety Data
169
Non-fatal or non-life-threatening SUSARs
must be reported as soon as possible, no later
than 15 days after the rst aware date of the
reaction.
The sponsor of a “trial performed in the United
Kingdom” (UK trial) must report the following
UK-relevant SUSARs to the MHRA:
• All SUSARs occurring in that trial in UK sites
• All SUSARs occurring in that trial in sites
outside the UK
• All SUSARs originating in a non-UK trial of
the same medicinal product if the trial is run
by the same sponsor of the trial running in the
UK
• All SUSARs originating in a non-UK trial of
the same medicinal product if the sponsor of
the trial outside the UK is either part of the
same mother company or develops the medic-
inal product jointly, on the basis of a formal
agreement, with the sponsor of the UK trial
A SUSAR can be reported to the MHRA in
one of the following ways:
• Using the eSUSAR website, by registering the
details before using the eSUSAR website and
completing the eSUSAR registration form and
email it to esusar@mhra.gov.uk.
• Using ICSR Submissions, the ICSR
Submissions route is used to submit single
reports.
• Using the MHRA Gateway, the Gateway route
is used to submit bulk reports.
• An analysis of the subjects’ safety in the concerned clinical trial(s) with an appraisal of its
ongoing risk/benet
• A line listing of all suspected serious adverse
reactions (including all SUSARs) that
occurred in the trial(s), including all SUSARs
from third countries
• An aggregate summary tabulation of SUSARs
that occurred in the concerned trial(s)
A DSUR should be submitted to the MHRA
by using Submissions via the Human Medicines
Tile. However, it should be noted that if at least
one of the trials covered by the DSUR has gone
through the combined review process, then the
report should be submitted via the Integrated
Research Application System.
4.4.3 Shortened DSUR Available
forNotication Scheme
Approved Trials
This is suitable for:
• Individual trials authorised under the
Notication Scheme which are not part of a
multi- study development programme.
• Phase 4 national (UK only) trials of licenced
products that commanded a low fee from the
MHRA and where all participants have completed treatment and are only in follow-up.
As an alternative to producing a full DSUR for
these trials, the Health Research Authority
Annual Progress Report is usually used.
If applicable, dual reports UK-relevant
SUSARs can be submitted to the European
Medicine Agency’s (EMA) EudraVigilance
Clinical Trial Module (EVCTM), as well as to
other national competent authorities, using the
European submission routes.
4.4.2 Development Safety Update
Reports
Development Safety Update Reports (DSURs)
should consider all new available safety information received during the reporting period. The
DSUR should include the following:
4.5 North America: USA
andCanada
4.5.1 UnitedStates-Food
andDrugAdministration
FDA released a draft guidance on 29 September
2021, with the focus on clinical investigators role
and responsibility rather than the sponsors [8].
The FDA cited that the current guidance from
2009 and 2012 on safety reporting should continue to be followed until the new document is
nalised.
170
P. Biswas et al.
As per the FDA, “Most of the information
about the safety of a drug prior to marketing
comes from clinical trials”, hence, “Adverse
event reports from investigators are therefore
critically important, given that it is the investigators who observe subjects’ responses to an investigational drug [8]”.
The new draft was published to separate sponsor responsibility and for clinical investigators. It
denes for the clinical investigators, how to identify safety information that raises an “unanticipated problem involving risk to human subjects
or others” for investigational drugs or “unanticipated adverse device effects” and how this information should be reported.
This applies to investigational new drug
(IND) application studies and investigational
device exemption (IDE) studies.
IND Studies
The reporting requirement for clinical investigators is that they must report SAEs to the trial
sponsor immediately after identifying the SAE,
no longer than one calendar day, regardless of:
• Relatedness of the event to the drug and/or
• Listedness in the safety surveillance plan or
the IB as an anticipated event
There can be an exception to this reporting
requirement regarding a study endpoint SAE and
should be outlined in the study protocol. However,
the endpoint SAE has to be reported if it is
assessed as having causal relationship that the
event was caused by the drug.
FDA requires an identiable subject, a suspect
drug, a reporter, if it is not the clinical investigator, and a description of the event for a case to be
valid. The report should include a causality
assessment from the clinical investigator of
whether there is a “reasonable possibility” that
the drug caused the AE, and it is the sponsor’s
responsibility to determine expectedness.
“FDA interprets reasonable possibility to
mean there is evidence to suggest a causal relationship between the drug and the adverse event”,
the FDA noted in its guidance to investigators.
“Factors that should be considered when making
a causality assessment include, but are not limited to, temporal relationship of the event to drug
administration; biologic plausibility, based on the
mechanism of action of the drug or similar drugs
in the same class; nonclinical evidence; and dechallenge- re-challenge information”.
The investigators are required to report all
serious and expected events to the Institutional
Review Board (IRB), collect all non-serious
AEs, and review all IND safety reports, including safety information from IND-exempt bioavailability/bioequivalence studies received
prior to submitting the reports to the IRB unless
it is communicated that the sponsor has sent the
information to the IRB.The investigators must
also report to the IRBs, medication errors,
breach of privacy or condentiality, and
untimely destruction of study records, as these
are considered unanticipated problems related
to study procedures.
IDE Studies
For IDE studies, investigators must report unanticipated adverse device effects (UADEs) to both
the trial sponsors and the IRBs as soon as possible, no later than 10 workingdays after the investigator discovers the effect.
In the guidance, the FDA writes “What qualies as a UADE is expected to vary depending on
the specic device and the way the device is used
within the study”. “Therefore, sponsors are
required to include risk information in the investigational plan, which may help investigators
identify and assess potential UADEs”.
As per the draft guidance, clinical investigators are also responsible for providing updates on
adverse device effects at regular intervals to
sponsors, monitors, and IRBs.
4.5.2 Health Canada
Biological Drugs, Pharmaceutical Drugs,
andRadiopharmaceuticals
All trial sponsors, or applicants, must report any
serious and unexpected ADR that occurred
inside and outside Canada to Health Canada,
7 Clinical Trials Safety Data
171
while the drug (including biological drugs) is in
clinical trials in Canada [9].
For clinical trials in Canada, only ADRs that
are both serious and unexpected are reported in
an expedited manner to Health Canada, regardless of whether the ADR occurred inside or outside of Canada. Expedited reporting of serious
and expected cases is not required as well as serious events from clinical investigations that are
considered unrelated to the study product,
whether the event is expected.
IND Annual Reports forBoth FDA
andHealth Canada
The sponsors have to provide IND annual reports
within 60 days of the anniversary date that the
application went into effect, and Form 1571 is
expected to be sent along with each annual report
submission [10].
The FDA will accept DSURs in lieu of IND
Annual Reports (76 Federal Register 52667 (23
Aug 2011) provided all the requirements of the
US Annual Report are provided in the regionspecic appendices of the DSUR.
4.6 Asia: Japan, China,and India
4.6.1 Japan
In Japan, sections 80-2-6 and 66-7 of the
Pharmaceutical Affairs Law includes information
on the AE and ADR reporting occurring during
clinical trials [11]. This section of the law
describes reporting to the Ministry of Health,
Labour, and Welfare (MHLW). However, in practice, AE and ADR reports are submitted to the
Pharmaceuticals and Medical Devices Agency
(PMDA).
Japanese regulation on Good Clinical
Practice (GCP) [12] requires sponsors to report
AEs and ADRs “immediately” to investigators
and to the heads of institutions involved in the
clinical trial. There are, however, several differences in reporting of safety data between
The International Council for Harmonisation
of Technical Requirements for Pharmaceuticals
for Human Use (ICH) E2A, US, and EU regu-
lations with that of the Japanese regulations as
detailed below.
Dierences Between ICH E2A, US, andEU
Regulations withtheJapanese
Regulations
Determination ofSerious AE
Per ICH E2A, US, and EU regulations, all hospitalisations are considered “serious”. However, in
Japan, only hospitalisations or extension of hospitalisation “for treatment” qualify as serious,
Section 66-7 of the Pharmaceutical Affairs Law
[11]. In practice, however, this situation can be
difcult to determine if hospitalisation is “for
treatment” and counts as serious under Japanese
regulations.
Another additional difference in the denition
of “serious” is that where the ICH, EU, and US
regulations use the phrase “persistent or signicant disability/incapacity”, the Japanese regulation uses a term equivalent to “disability”.
“Expectedness” ofaNew Event inJapan
In both the USA and Europe, an AE is considered
unexpected if its severity or nature are inconsistent with what is written in the IB, and all subsequent reports of a previously reported event
continue to be unexpected until the IB has been
updated to include it. However, in Japan, once an
event has been distributed to investigators as a
SUSAR, it is considered “expected”.
Expected Life-Threatening andDeath SUSARs
The USA, EU, and Japan all require 7-day
reporting to regulators of unexpected life-threatening and death SUSARs, although none of
these territories species a 7-day timeline for
reporting to investigators. In all three regions,
unexpected serious reactions, which are serious
by any of the other criteria, are to be reported to
regulators within a 15-day timeline. It should be
noted, however, that in Japan, unlike the USA
and EU, expected life-threatening and death
SUSARs qualify as 15-day reports to the PMDA
and must also be reported to investigators as
well.
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