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172
P. Biswas et al.
Reporting Timelines
Only US regulations give a clear, 15-day timeline
for reporting SUSARs to clinical investigators.
The EU Clinical Trials Directive [6] states that
“The Sponsor shall also inform all investigators,
but gives no timeline on reporting to investigators, except that reporting should be prompt”.
Similarly, the Japanese regulations indicate that
reporting should not be delayed but does not
specify reporting timelines.
Format ofReport
Both the US and Japanese regulations indicate
that individual reports of SUSARs should be provided to investigators in the same format they are
provided to the regulatory authorities. However,
the EU Guidance states that line listings accompanied by a summary is an appropriate format for
informing investigators.
Reporting to Ethics Committee and
Institutional Review Boards
EU regulations give the same 7 and 15-day timelines for reporting to regulators as to ECs and
clearly state the sponsor is responsible for reporting to EthicsCommittee(EC). Japanese regulations also have the responsibility for reporting to
the IRB on the sponsor, but US regulations give
investigators the responsibility for reporting to
the IRB.
4.6.2 China
Clinical Trials Safety Data Reporting
In China, the Clinical Trials Management Ofce
[13] is responsible for the reception, analysis,
and evaluation of SUSARs during clinical trials,
as well as DSURs.
China: Expedited Adverse Event Reporting
inClinical Trials
In China, any SAEs that occur during the trial
should be reported to the EC in time. Regulations
state that if any SAE occurs during the clinical
trial, the investigators will be responsible for
reporting to the drug regulatory departments of
the relevant provinces, autonomous regions, or
municipalities directly under the Central
Government. The applicant must be notied
within 24h and report to the EC in time.
If there are large numbers of unexpected
adverse reaction or SAEs, the China Food
andDrugAdministration (CFDA) may order to
change the protocol, suspend, or terminate the
clinical trial. This is also the case for SAEs unreported within the specied timeline [SFDA Order
No. 28, Chapter III, Article: 42–43] [13].
When conducting an international multicentre clinical trial in China, if there are observed
serious adverse reactions and unexpected adverse
reactions associated with the drug in any country,
the applicant shall, in accordance with relevant
regulations, report to the CFDA in time [SFDA
Order No. 28, Chapter III, Article: 44] [13].
4.6.3 India
The Indian Good Clinical Practice (IGCP) guidelines, published in 2001, provided denition of
AE and ADR and dened responsibilities of the
investigator and sponsor regarding safety reporting during clinical trials. As per this guideline,
investigators should promptly report all ADRs
and AEs that are serious and/or unexpected to the
EC and the sponsor, while the sponsor should
expedite reporting of all serious and/or unexpected ADRs to all concerned, including EC and
regulatory authorities [14].
In 2005, Schedule Y was amended and came
into existence with several updates to the Indian
pharmacovigilance [15]. Amended Schedule Y
marked the beginning of compulsory and timebound pharmacovigilance practice in India and
specied reporting timelines for SAEs for sponsors and investigators, enlisted data elements
required for reporting of SAE, andgeneral reporting structure for such events.
Amended Schedule Y [15] requires “all serious and unexpected AEs” to be reported to the
regulators and other investigators, but the trial
approval letter issued by the ofce of Central
Drugs Standard Control Organisation (CDSCO)
states that, “in case any unexpected serious
7 Clinical Trials Safety Data
173
adverse reaction (SADR) is observed during trial,
the same should be immediately communicated”
[15]. It should be noted that while both ICH E2A
and 21 CFR 312.32 dene the term “unexpectedness”, neither Schedule Y nor Indian GCP claries the criteria of “unexpectedness”.
India: Reporting Timelines forSerious
Adverse Events
The reporting timelines as per Schedule Y for
SAEs are as follows:
• All unexpected serious AEs are to be reported
by the investigator within 24h of the occurrence to regulatory authority and to site EC
within 7 working days, while globally the
timeline for reporting fatal/life-threatening
SUSAR to regulatory agencies is 7 calendar
days.
In the event of death or fatality, the site EC
will be aware of the event in 7 working days,
which in practice may exceed 7days, considering
public holidays/weekends.
Expedited Reporting Requirements
andReporting Requirements forGlobal
Sites
In the amended Schedule Y, there is no mention
in the denition and standards for expedited
reporting. Thus, as per Schedule Y, any “unexpected and serious” adverse events can be
reported to CDSCO and other investigators
within 14 calendar days.
There is no requirement to prioritise report-
ing of events that are suspected of having a
causal association, nor is there any provision to
differentiate reporting timelines for unexpected
deaths or life-threatening events that are suspected to be due to study medication. This contrasts with both ICH E2A and 21 CFR 312.32,
which mandate reporting of fatal or life-threatening SUSAR to regulators within 7 calendar
days, while other SUSARs can be reported in
15days time.
There is also no mention of reporting require-
ments from foreign sites for multinational trials
and Schedule Y does not include the term
“SUSAR” and does not specify expedited reporting requirements for SUSARs. Since CDSCO
does not specify the expedited reporting timeline,
the event can be reported to CDSCO anytime
within the 14-day timeframe.
Development Safety Update Reports
inIndia
The concept of a DSUR was rst introduced by
the Council for International Organizations of
Medical Sciences (CIOMS) VI working group
and taken forward by the CIOMS VII working
group.
Both the US FDA and EU Clinical Trial
Directive required what is termed as IND Annual
Report and Annual Safety Report (ASR), respectively, the content, format, and timings differed
between the US and EU reports [16, 17]. CDSCO
does not require DSUR for Indian pharmaceutical companies undertaking global trial for a
locally developed drug. However, sponsors are
required to submit a status report on the clinical
trial to the licencing authority at the prescribed
periodicity.
4.7 Australia
4.7.1 Clinical Trials Safety Data
Reporting in Australia and
Therapeutic Goods
Administration Notication and
Safety Reporting Requirements
In Australia, the Therapeutic Goods
Administration (TGA) has set clear regulations
and guidelines for clinical safety data reporting.
It is advised that trial sponsors should refer to
the NHMRC Safety Monitoring and Reporting in
Clinical Trials Involving Therapeutic Goods
(2016) (NHMRC Guidance) [18], for safety
reporting requirements. The National Health and
Medical Research Council (NHMRC) guidance
addresses the monitoring, collection, and reporting of AEs that occur in clinical trials. This
involves therapeutic goods conducted under the
Clinical Trials Notication (CTN) or Clinical
Trials Exemption (CTX) schemes. The NHMRC
174
P. Biswas et al.
Guidance has aligned with the European Union’s
Clinical Trial Regulations: Regulation EU No.
536/2014 [6].
According to the NHMRC Guidance, the trial
sponsor is responsible for reporting to the
TGA. The NHMRC Guidance outlines the trial
sponsor’s safety reporting responsibilities for
CTN and CTX trials. Further information on how
the trial sponsor should notify all relevant safety
Australian sites must be reported to the TGA [18],
even if initial information is limited (i.e. less than
the minimum information required for expedited
reporting as outlined in the CPMP/ICH/377/95
Guideline for Clinical Safety Data Management:
Denitions and Standards for Expedited
Reporting), and these details should still be forwarded to the TGA pending receipt and provision
of further data (Tables 7.1 and 7.2) [ 18].
reports for CTN and CTX trials isin the following Tables7.1 and 7.2.
4.7.2 Safety Reporting Timeframes
forCTN andCTX Trials Single
Case Events fromAustralian
Sites: Suspected Unexpected
Serious Adverse Reactions
andUnanticipated Serious
Adverse Device Eects
Individual SUSARs and Unanticipated Serious
Adverse Device Effects (USADEs) from
Table 7.1 Suspected Unexpected Serious Adverse Reactions and Unanticipated Serious Adverse Device Effects
Type of event Type of good Report format Timeline
Suspected
Unexpected
Serious Adverse
Reactions
(SUSARs) from
Australian sites
only
Unanticipated
Serious Adverse
Device Effects
(USADEs) from
Australia
Medicines and
biologicals
Medical
devices
The new Electronic Data Interchange
(EDI) functionality allows sponsors to
submit adverse event reports directly
from their system to Therapeutic
Goods Administration
OR
Adverse event reports can be submitted
using the new online reporting form.
This can be accessed from the
reporting problems page—https://
www.tga.gov.au/safety/
reporting- problems
OR
Blue Card or CIOMS form emailed to
adr.reports@health.gov.au
Medical device incident reporting
system
OR
Users medical device incident report
form emailed to iris@health.gov.au
Other Report Types
Annual Safety Report
Summary of all new available safety information
relevant to a trial that is received over a 12-month
period (the Executive Summary of safety
information produced for international regula-
tors, such as the DSUR may serve as the Annual
Safety Report). The reporting timelines for
annual safety report and single AEs is represented
in Table7.3 [18].
For fatal or life-threatening Australian
SUSARs, immediately, no later than 7
calendar days after being made aware
of the case, with any follow-up
information within another 8 calendar
days
For all other Australian SUSARs, no
later than 15 calendar days after being
made aware of the case
For fatal or life-threatening Australian
USADEs, immediately, no later than 7
calendar days after being made aware
of the case, with any follow-up
information within a further 8 calendar
days
For all other Australian USADEs, no
later than 15 calendar days after being
made aware
7 Clinical Trials Safety Data
Table 7.2 SignicantSafety Issues and UrgentSafety Measures reporting timelines for Australia: signicant safety
issuesa and overseas regulatory action
Type of event Type of good Report format Timeline
Signicant safety issues
(SSIs) requiring
implementation of urgent
safety measure (USMs)
Action with respect to safety
that has been taken by
another country’s regulatory
agency (relevant to an
ongoing clinical trial in
Australia)
All other SSIs: Notication
of an amendment
Temporary halt of a trial for
safety reasons
Early termination of a trial
for safety reasons
Note: A Suspected Unexpected Serious Adverse Reaction or Unanticipated Serious Adverse Device Effect may also
meet the denition of an SSI
a
SSIs that arise from analysis of overseas reports (relating to a clinical trial in Australia) should be reported to the TGA
as per the timeframes above
b
Therapeutic Goods Administration should receive notication that an SSI has occurred but the amendment revising
trial documentation should be submitted to the HumanResearchEthicsCommittee only
b
All therapeutic goods In writing to the
pharmacovigilance and special
access branch via email to clinical.
trials@health.gov.au
All therapeutic goods In writing to the
pharmacovigilance and special
access branch via email to clinical.
trials@health.gov.au
All therapeutic goods In writing to the
pharmacovigilance and special
access branch via email to clinical.
trials@health.gov.au
Within 24h (where
possible) and in any
case, no later than 72h
of the measure being
taken
Without undue delay,
no later than 72h of
the trial sponsor
becoming aware of the
action
Without undue delay,
no later than 15
calendar days of the
trial sponsor becoming
aware of the issue or
temporary halt or early
termination
175
Table 7.3 Annual safety report and single adverse events
reporting timelines for Australia
Type of
event
Other
single
case AEs
Annual
safety
reports
Type of
good Report format Timeline
All
therapeutic
goods
All
therapeutic
goods
Up-to-date
tabulations or line
listings
Development
safety update
reports or other
annual safety
reports
On
TGA’s
request
On
TGA’s
request
5 Collection andManagement
ofSafety Data Arising
fromClinical Trials
Regulatory authorities worldwide critically
review whether a drug is safe for its intended use
during the safety review of a New Drug
Application (NDA). They assess safety and
determine the signicance of the AEs, including
their impact on the approvability of the drug.
Finally, regulatory authorities determine the
safety issues to be included in the product label-
ling should the drug be approved and decide
whether additional safety studies are needed [19].
Data collected during clinical trials serve as
an important source of safety information that
generates evidence for regulators, sponsors,
physicians, and patients. Data collection methods used during the conduct of clinical trials are
important part of the process of safety monitoring to investigators, sponsors, regulators, and
patients. In the pre-approval setting, comprehensive safety data collection is required to
understand the frequency, severity, seriousness,
and dose–response of AEs, including potential
differences across subsets, e.g. demographic,
concomitant illnesses, and/or concomitant therapy. Hence, when a clinical trial is being
designed, it is important to plan how and what
type of safety data will be collected and captured during the trial.
176
P. Biswas et al.
5.1 Types ofData Collection
Methods inClinical Trials
Safety data from clinical trials are usually generated and collected by the following:
• Study investigator
• Study sponsor
• Directly by patients called patient-reported
outcomes (PROs)
Throughout the clinicaldevelopment process
of the medicinal product, safety data are collected through various ways.
5.1.1 Traditional Data Collection
• On paper such as Case Report Forms (CRFs),
patient diaries, or questionnaires
Paper CRFs are common and usually designed
for collection from handwritten information.
This method of data collection is cheap and
allows for creation of direct copies and faxing;
however, there are several disadvantages such as
storage issues for large volume of paper, space,
and correction limitations of the form itself and
scope of mistakes and errors while transferring
information from paper to electronic database.
5.1.2 Electronic Data Collection
every correction that is made to the data entered
must be traceable and only authorised persons
have access to the programme.
Regulatory requirements that eCRFs must
conform to are as follows:
• In Europe: ICH GCP E-6, Section 5.5.3 [20]
• In the USA: FDA—21CFR Part 11 and
Guidance for Industry—Computerised
Systems used in Clinical Trials [21]
If data collection is through eCRFs, validation
of electronic systems is mandatory. The system
must have an audit trail; any change made should
be electronically recorded and traceable; be protected against unauthorised access; and data
should be backed up regularly on a different
server or computer that can be accessed for the
lifetime of the product.
5.1.3 Patient Reported Outcomes
(PROs) andElectronic Captured
PROs (ePROs)
In this method of data collection, data is directly
provided by patients, which includes all types
of questionnaires and diaries that are recorded
on paper or via electronic systems. Typically,
electronic data are either in the form of a daily
diary at the patient’s home or quality of life
(QoL) questionnaires administered during site
visits.
• Electronic CRFs (eCRFs)
• Through dedicated Apps—mobile phones or
tablets to collect data directly from patients
through patient-reported outcomes (ePROs)
• Direct Data Capture (DDC)—here data is
directly generated by electronic devices and
entered directly into the database, for example, laboratory data, ECG data, central image
reading data, i.e. MRI results, electronic
patient questionnaires, or patient diaries
eCRFs are a very popular method of data col-
lection, but they are more complicated to produce
and have to adhere to strict data regulations. In
this method of data collection, the computer programmes and software should be validated, and
5.2 Available Safety Data Sources
fromPremarketing Clinical
Trials
Throughout the drug development process, safety
data is continuously evaluated at all stages of
drug development. The safety prole of an investigational drug is determined from the analysis of
safety information obtained from both nonclinical and clinical studies.
The clinical phase of development involves
the following:
• Phase 0 usually only involves a small number
of subjects and very small dose of a drug, and
7 Clinical Trials Safety Data
177
the aim is to nd out whether the drug reaches
the cells.
• Phase I studies determine safety and dosing in
healthy volunteers (patients in oncology
studies).
• Phase II studies determine efcacy and safety
in patients with the disease or condition.
• Phase III studies determine safety and efcacy
in sufciently large number of patients with
the disease or condition.
The safety information collected from clinical
trials during the drug development process
include AEs, laboratory measurements, vital
signs, clinical investigations such as ECGs,
X-ray, MRI, and CT scan and other tests relevant
to the indication being studied. Randomised controlled trials are the gold standard of scientic
testing for new drugs, and this is based on the
premarketing safety data.
AEs are normally collected according to the
following domains:
• Seriousness
• Expectedness of the event
• Relatedness
• Intensity or severity
• Incidence
• Duration
• Latency
• Time to resolution
The relationship between drug exposure and
AEs is also assessed through causality assessment
using several algorithms. However, there are several limitations from the premarketing safety database based on clinical trials for several reasons.
5.3 What Data Should
BeReported?
5.3.1 Single Cases ofSerious,
Unexpected ADRs
All ADRs that are both serious and unexpected
are subject to expedited reporting. This applies
to reports from spontaneous sources and also
from any type of clinical or epidemiological
investigation, independent of design or purpose.
It also applies to cases not reported directly to a
sponsor or manufacturer (e.g., those found in
regulatory authority-generated ADR registries or
in publications). Expedited reporting is inappropriate for serious events from clinical investigations that are considered not related to study
product, whether the event is expected or not.
Similarly, non-serious adverse reactions,
whether expected or not, are usually not subject
to expedited reporting. Information obtained by
a sponsor or manufacturer on serious, unexpected reports from any source should be submitted on an expedited basis to appropriate
regulatory authorities if the minimum criteria for
expedited reporting are met.
5.4 Baseline Data Collection
Baseline data are needed to ensure that subjects
meet inclusion and exclusion criteria for study
enrolment and are important in safety assessment. For example, particular SAEs may occur
more frequently in subgroups dened based on
ICH E19 Guideline demographics, baseline disease characteristics, coexisting illnesses, or concomitant therapies; analyses of such information
can be important in considering the benet–risk
prole of the drug. Use of a selective safety data
collection approach does not change considerations for baseline data collection.
5.5 Blinded Data inClinical Trials
A “blind” study is a clinical trial in which the
subject or the investigator (or both) are unaware
of which trial product/drug the subject is taking
[22]. In a clinical trial, blinding is necessary to
prevent observer bias.
When the term “double blind” is mentioned, it
usually refers to keeping the study participants,
those involved with the trial management, and
those collecting/analysing clinical data unaware
of the assigned treatment to prevent inuence.
Different parties that are involved in a clinical
trial are possible sources of bias and therefore
178
P. Biswas et al.
should be blinded to ensure trial objectivity,
including:
• The patient being treated
• The clinical staff administering the treatment
• The physician assessing the treatment
• The team interpreting the results
There are different types of blinded studies
and these include the following:
• Single-blind studies are those where the subjects in the trial are unaware of which treatment group they are in, but the sponsor team
knows about it.
• Double-blind studies are those where both the
sponsor team and subjects do not know which
subject is assigned to which treatment group.
• Triple-blind studies are those that further
extend the blinding to the data analysts, so the
subjects, clinicians/data collectors, and outcome adjudicators/data analysts are all unaware
of the treatment the participant has received.
5.5.1 Unblinding ofClinical Trial Data
Unblinding in a clinical trial refers to as codebreak, and the process by which the treatment or
allocation details are made available either purposefully (i.e. according to the code-break procedures) or accidently.
The main aim and purpose of unblinding are
as follows:
6 Drug Safety Monitoring
Board (DSMB)/Drug
Monitoring Committee
(DMC)
A Drug Safety Monitoring Board (DSMB) or
Data Monitoring Committee (DMC) is an independent committee consisting of a group of three
to seven expert members who are independent
from the entity conducting clinical trial [23, 24].
The main activity of the DSMB/DMC is to protect patient safety. The DSMB/DMC serves as an
advisory body, responsible for the oversight of
the activities related to the clinical trial and more
specically, the monitoring of safety and conduct to ensure patient safety, adherence to the
clinical protocol, overall performance of the
study, including study ofcer, coordinating centre, clinical sites, and integrity of the data being
collected. The committee also ensures that safety
monitoring is carried out while maintaining the
blinding of the trial so that the trial remains
valid.
The composition of the DSMB/DMC consists
of at least one independent statistician and clinicians who have sufcient knowledge about the
disease indication and major suspected safety
effects, as well as ethicists or representatives
from patient advocacy group, especially for trials
involving vulnerable populations.
DSMB/DMC is indicated by the clinical and
safety departments in the following situations:
• Unblinding a subject in an emergency
situation
• Unblinding data for the purpose of notication to Drug safety monitoring board/Drug
monitoring committee
• Manage accidental unblinding
• Unblinding at the end of the trial
Blinding in clinical trials is a vital procedure
that needs to be handled withattention and condentiality to prevent any form of bias. Blinded
data is an important piece of information, and the
unblinding process should be mentioned clearly
in the clinical study report (CSR) in detail at the
end of the study and to the regulatory authorities.
• If the trial is intended to provide denitive
information about effectiveness and/or safety
of a medical intervention.
• If there are prior data to suggest that the intervention being studied has the potential to
induce potentially unacceptable toxicity.
• If the trial is evaluating mortality or another
major endpoint, such that inferiority of one
treatment arm has safety as well as effectiveness implications.
• If there are questions of ethical importance for
the trial to stop early, if the primary question
addressed has been denitively answered,
even if secondary questions or complete safety
information were not yet fully addressed.
7 Clinical Trials Safety Data
179
It is generally expected by the clinical and
safety department that a DSMB/DMC will be
needed in the following situations:
• All Phase III studies require a DSMB, with the
exception of low-risk behavioural and nutri-
tional studies.
• Multi-centre randomised Phase II clinical
trials require a DSMB, with the exception of
low-risk behavioural and nutritional
studies.
• Phase II studies which are “high risk” require
a DSMB.In this context, high risk is usually
referred to trials or interventions that are asso-
ciated with substantial adverse effects that are
usually serious and could result in serious
morbidity or death.
• For some studies involving particularly vul-
nerable study participants (e.g. children or
persons with impaired ability to consent), it
may be benecial to utilise a DSMB as an
additional measure of subject protection.
A DSMB/DMC is not generally needed in the
following situations:
• Single-centre open-label Phase I and II clini-
cal trials generally do not need a DSMB since
the local investigator will have access to all
data.
• A multi-centre, high-risk Phase I clinical trial
should not require a DSMB if there are very
clear rules for stopping the trial. For example,
a DSMB is generally not required for a classic
open-label dose escalation trial with clear and
objective criteria for halting the dose escala-
tion when unacceptable side effects are
observed.
• A DSMB may not be feasible for clinical trials
that are expected to accrue too quickly to
allow for a DSMB to be constituted and com-
plete data and safety monitoring.
The role of DSMBs/DMCs is of importance
for both industry-sponsored and investigatorinitiated trials due to the increasing number of
industry-sponsored trials with mortality and
major morbidity endpoints.
7 Types ofSafety Data That
Should Generally
BeCollected Under All
Circumstances
For detailed analysis of the event that is received,
the following types of events/data, comprehensive
details should generally be provided to allow adequate assessment of the event/data, e.g. history,
associated AEs, relevant underlying disease of the
patient, laboratory values, concomitant medications, vital signs, and/or follow-up outcome. The
following information detailed below are also
required for complete assessment of products in
clinical development [19].
1. Deaths
2. SAEs
3. Signicant AEs that led to an intervention,
including withdrawal or dose reduction of
IMP or addition of concomitant therapy
4. Marked laboratory abnormalities (other than
those meeting the denition of serious)
5. Overdose
6. Pregnancies
7. AEs of special interest (if dened). These AEs
may warrant collection of additional information across the entire study population to better
characterise these events (e.g. particular laboratory parameters, vital signs, risk factors, concomitant therapies, and/or concomitant
illnesses). For example, if gastrointestinal
haemorrhage was an AE of special interest, one
might want to proactively collect concomitant
antithrombotic therapy across the entire study
population
8. Laboratory data, vital signs, electrocardiograms of special interest (if dened)
Sponsors should be aware that the following
types of data are generally not appropriate for
selective safety data collection and should always
be collected:
• Data on all SAEs
• Data on non-SAEs that lead to dose modica-
tion, drug discontinuation, or withdrawal from
the trial
180
P. Biswas et al.
• Data on unscheduled study visits, hospitalisations, and accidental injuries because these events
may reect SAEs of the drug
• In an oncology setting, data from all Grade 3
and Grade 4 AEs, as well as Grade 2 AEs that
affect vital organs (e.g. heart, liver)
• Pregnancy data
7.1 Selective Safety Data
Collection Considerations
Selective safety data collection is considered for
studies using lower doses and/or shorter durations than in previous studies. Selective safety
data collection would generally not be acceptable
if higher doses and/or longer treatment durations
than previously studied are planned.
When sponsors choose to implement selective
safety data collection for a clinical study, a scientic justication should be provided. Factors that
contribute to a determination that selective safety
data collection would be appropriate include the
following:
• The medicinal product has received marketing
authorisation from a regulatory authority for
the indication under investigation.
• Availability of post-approval safety data and
ndings.
• The dose, dosing regimen, dosage form, route
of administration and treatment duration used
in the previously conducted studies are comparable to the planned use of the drug in the
proposed study.
• The patient population from previously conducted studies is representative of subjects in
the planned study regarding demographic
characteristics, underlying medical conditions, concomitant drugs, and other important
factors (e.g. Cytochrome P450 enzymes
(CYP) metaboliser status).
• Exposure in previously conducted (or ongoing, if applicable) studies that contribute to the
overall safety database, i.e. number exposure
to drug, treatment duration
• Consistency of the safety prole across previous studies.
• Characteristics of previous studies, e.g. study
design, study conduct, adequacy of safety
monitoring/safety data collection, availability
of protocols, statistical analysis plan, and/or
access to data.
• Knowledge of the mechanism of action of the
medicinal product under study.
• Knowledge of the safety prole of approved
drugs in the same pharmacologic class.
In the pre-approval setting, selective safety
data collection may be justiable if sufcient
safety data are available from completed studies.
Furthermore, when sufcient safety data becomes
available from one or more ongoing late-stage
study(ies), selective safety data collection may be
appropriate for a concurrently conducted studyinitiated pre-approval.
7.1.1 Examples Where Selective
Safety Data Collection May
BeConsidered
Selective safety data collection may be appropriate in studies used to evaluate some of the following objectives. These are not the only
circumstances where selective safety data collection may be appropriate.
• New indications of approved drugs
• To study additional endpoints, e.g. patientreported outcome for symptomatic improvement, quality of life, and/or outcome studies
(e.g. mortality, morbidity, and/or specic
safety issues)
• To study comparative effectiveness/efcacy
• Demonstration of superiority when noninferiority has been demonstrated
• Characterisation of AEs of special interest
• Fullment of post-approval requirements, postauthorisation safety studies based on data collection from registries or electronic health records
• Late-stage premarketing outcome study in a
large population
7 Clinical Trials Safety Data
181
7.2 Types ofSafety Data Where It
May BeAppropriate toLimit
or Stop Collection
• Non-SAEs
• Routine laboratory tests
• Information on concomitant medications
• Physical examinations (including vital signs)
• Electrocardiograms
7.3 Collection ofSafety Data
forClinical Trials inRare
Diseases
For drug development studies for rare disease
indications, complete safety data should be collected because these trials generally have limited
patient populations and are unlikely to meet the
recommendations for selective safety data collection. For these types of safety data, it is generally
important to collect information on all occurrences to better understand the following:
• Causality
• Incidence
• Severity of AEs
• Populations that are at risk
• Dose–response
• Other factors that contribute to our understand-
ing of the nature of the event and who is at risk
8 Safety Data Output(s)
Originating fromClinical
Trials
8.1 Integrated Safety Summary
At the end of a clinical development programme
for a medicinal product, sponsors are required
to summarise the safety information from all
clinical trials for submission to the regulatory
authorities along with the marketing registration
application. Detailed analyses of integrated data
of multiple studies from several treatment arms
of a clinical development programme are
required to identify safety signals that may not
be detected in individual trials. Integrated Safety
Summary (ISS) is required for regulatory submission in applications submitted to the FDA
and other regulatory authorities in accordance
with the regulations for New Drug Applications
(NDA) submissions (21 CFR 314.50(d)(5)(v)
and 21 CFR 314.50(d)(5)(vi)(a), respectively)
[25]. The Clinical Trial Directive (CTD)/elec-
tronic CTD (eCTD) Module 2 contains several
clinical sections that include the summaries of
ISS.
ISS is dened as a section of the NDA that
provides comprehensive safety data information
collected throughout the drug development process. ISS is the most important safety data output
from all the clinical trials from various treatment
arms in the drug development process and a team
consisting of regulatory affairs, pharmacovigilance safety physicians and scientists, biostatisticians, data managers, and medical writers are
involved in writing the report. The ultimate goal
of the ISS is to characterise the overall safety
prole of the drug and to identify risks that should
be included on the Reference Safety Information
(RSI) or the product label. The ISS-related sections with corresponding regulations are reported
in Table7.4 [25].
The aim of the ISS is to provide an overall
analysis and summary of the safety data arising
from the various treatment arms of the clinical
development programme. The following are the
key elements in an ISS, as detailed below:
• A summary of the safety proles from all clin-
ical studies and assessment of summaries and
statistical analysis of safety data collected
from various clinical studies (can include
Phase I studies in healthy volunteers; nor-
mally presented separately from study
patients).
• AEs
– Overall analysis of AEs including event
rates, deaths, adverse dropouts, and other
potentially serious events.
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