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220 Cobert’s Manual of Drug Safety and Pharmacovigilance
Thus, a PV specialist in the company or health
agency may want to attempt to obtain the sourcing
information. This may be difficult as the patient may
not wish to admit that he or she obtained the product
under risky or even illegal (in their eyes) ways.
The PV specialist should also consider the prod-
ucts in question. Some drugs are so cheap and so eas-
ily obtained in the US that it is less likely that patients
will seek to purchase the drugs online. One pharmacy
chain in the southeast of the US offers “free” two week
supplies of certain antibiotics and diabetic drugs (with
a prescription of course). Many generic drugs are now
very inexpensive and hardly worth using an Internet
pharmacy. So attention should be paid to sourcing of
expensive or hard to get products by the PV specialist
moreso than cheaper or generic products though these
too have been falsified.
Frequently Asked Questions
Q: If resources are limited and demand infinite,
should we even bother looking at all generics
and excipients? Shouldn’t we concentrate on
the newest or most used or most dangerous
products and concede such things as potential
excipient problems in little used products?
A: Yes, you are probably right. It is impossible to track
everything. In the US alone, some 4 billion (4 × 10
9
)
prescriptions are filled every year. Rather, a triage strat-
egy needs to be developed to make rational use of phar-
macovigilance resources and to avoid duplicative work
from agency to agency and company to company. Alter-
natively, the pharmacovigilance of a particular product
might be assigned to one national health agency, which
would be responsible for worldwide safety surveillance,
sort of the way the EU works regarding mutual recog-
nition. One might wish to look at a particular excipient
in only, say, five products in five countries periodically
to identify safety issues. One must also decide whether
to be proactive and do such investigations periodically
and in anticipation of potential safety issues or whether
to be reactive and start an investigation only after a
problem or signal arises. Lots of solutions are possible,
but none is on the horizon right now. In general, the
authors are pessimistic about this. The ICH attempted
to harmonize many aspects of the pharmaceutical busi-
ness and to a large degree succeeded. However, since
the high point of harmonization (the early and mid-
2000s) countries and regions are diverging with differ-
ent requirements (sometimes only mildly different but
sufficiently so to increase the overall reporting work-
load enormously). Broad international agreements on
matters such as this are universally agreed in theory
but, in practice, are often impossible to put in place.
Q: What about generics? Shouldn’t they all be
grouped under one marketing authorization
or NDA or something like that for AE and sig-
naling purposes?
A: Yes, that is probably a good idea but very difficult to
do under the current laws and regulations around the
world. Commercial competitiveness also complicates
this. Rather, the same result could be attained (and
is, in fact, done) at the database level, where data are
combined or analyzed over multiple products with the
same chemical entity. But this would probably require
cooperation among competitors, many of whom are in
different countries. Good in theory, not easy in practice.
Q: Do counterfeit products produce more AEs
than the branded products?
A: Since counterfeiters of drugs will often put into their
products whatever is on hand and cheap, there are
many instances of fake drugs that have been found to
contain toxic ingredients. The “formulation” may vary
from day to day and batch to batch. FDA has frequently
reported that various weight-loss products that con-
tained a chemical that could produce high blood pres-
sure, seizures, tachycardia, palpitations, heart attack, or
stroke. Similar reports abound. However, some coun-
terfeits will contain no active ingredients and inactive
excipients. In this case, the danger is lack of efficacy.
So, there is no way, a priori, to know or to predict what
effects (good or bad) counterfeits produce nor whether
they will produce more or fewer AEs than legitimate
products.
CHAPTER
221
19
Artificial Intelligence
and Pharmacovigilance
O
ne of the hottest topics in the IT
and social media world has been
artificial intelligence (AI). AI
in the context of product development
has been evolving and will continue to
evolve. There are now products being
developed using an AI model while
other products are still being developed
the traditional way.
Overview
Originally AI was used vaguely to mean “the past of com-
puter science concerned with designing systems that
exhibit the characteristics we associate with intelligence
in human behaviour”. Its use was relatively limited to
tasks that humans could not or would not do that could
be computerized. These tasks were programmed with
various algorithms that were largely static and only did
what they were programmed explicitly to do.
A sub-category of AI is “machine learning” which
is defined as the field of study that gives computers the
ability to learn as humans learn based on data, expe-
rience, and algorithms without being explicitly pro-
grammed. It was felt by many in the medical and IT
worlds that medicine would be an excellent place to
use AI. See: W.B. Schwartz, R.S. Patil, P. Szolovits Artifi-
cial intelligence in medicine. Where do we stand? N Engl
J Med, 316 (1987), pp. 685–688. And indeed, AI has been
used to develop many systems, software, apps etc. that
play a role in medicine and pharmacology.
AI and ML took off in 2022 as a potentially
“game-changing big idea” in 2022 with the develop-
ment of “large language models”. These are AI systems
that try to mimic human intelligence and analyses.
These systems have enormous amounts of data from
222 Cobert’s Manual of Drug Safety and Pharmacovigilance
many sources including books, websites, articles, social
media, databases and more.
The system then is trained (and/or trains itself) to
see patterns, trends, connections, possible relationships
in these data. The bigger the dataset the better the sys-
tem works as a general rule. It can then generate sum-
maries, reports, charts, graphs, photos, video and audio
files etc. from these data in fluent English (or any lan-
guage it is programmed to know). Some of the systems
can enter into a conversation back and forth. Sometimes
however, the system makes mistakes, is inaccurate or
even misleading. When this occurs, this information
is informally called “hallucinations”. In 2023 some
attorneys used AI to generate a submission to the court
which “cited several nonexistent cases, complete with
nonexistent quotes and holdings.” (Check out Mata v.
Avianca (No. 22-cv-01461) for reference).
These systems can be linked to other data sites (e.g.
a company’s or government agency’s data) to improve
accuracy and bring new data into the system. FDA
has been testing various natural language process-
ing AI systems in drug labeling and causal inference
using the FAERS database to review text documents
to assess safety. This is currently done largely man-
ually and creating software to enhance these major
efforts is the goal. See their BERTox Initiative (https://
www.fda.gov/about-fda/nctr-research-focus-areas/
bertox-initiative).
AI and PV
Much research is now underway using AI in pharma-
covigilance. Some of the challenges include finding the
appropriate and disparate sources of clinical safety data:
FAERS, EudraVigilance, hospital (e.g., electronic medi-
cal records), pharmacist and physician challenges, lack
of standard terminology and coding conventions, oper-
ating systems, software, social media, language and idi-
omatic phrases, corporate data, quality and validation
criteria, etc.
Research is ongoing two broad areas:
1. AE Case intake and processing. These areas
will replace or assist the manual review of cases to
eliminate duplicate cases (particularly nonserious
cases and instances of sudden increases in case
volume, e.g., during a pandemic, etc.) write case
narratives, QA and causality assessments. The first
two areas will likely be relatively straightforward
to develop but the assessment of clinical causal-
ity remains and is likely to remain very difficult to
automate efficiently because of the complexity of
the variables in causality assessment (incomplete,
incorrect or false data, bias in reporting, con-
founders in data, unreliable reporters, plausibility,
etc.). See the chapter in this Manual on causality
assessment for further detail.
2. Signal detection. Multiple techniques and
systems have been available for the last twenty
years for signal analysis including Bayesian anal-
ysis, Lasso shrinkage regression and many oth-
ers. These have not proved to be more success-
ful than skilled human clinical analysis by PV
experts though they are very useful adjuncts and
hypothesis generators for the clinician looking
for signals. AI and ML are being used in pharma-
coepidemiology and predictive modeling. See the
chapter in this Manual on the issues and tech-
niques in such analysis. As a start, FDA launched
a transformative national system in May 2008 to
explore distributed electronic healthcare data-
sets. There are several parts: the Sentinel System,
Postmarket Rapid Immunization Safety Monitor-
ing (PRISM) system, and Blood Safety Continu-
ous Active Surveillance Network (BloodSCAN).
Biologics are included. as part of the Biologics
Effectiveness and Safety (BEST) Initiative. To
begin to address some of the disparate challenges
noted above, a Common Data Model is used for
analysis; the System covers more than 10 million
lives. AI and ML have been used in “systematic
reviews” (“a research technique that attempts to
collect all empirical evidence in a particular field,
to assess it critically and to obtain conclusions
that summarize the research” See https://www.
sciencedirect.com/topics/medicine-and-den-
tistry/systematicreview. Early information sug-
gests that these techniques are more useful than
older human methods. As these approaches
mature, they may have a greater role in regula-
tory decision-making.
Artificial Intelligence and Pharmacovigilance 223
AI is being looked at in many other areas in phar-
macology, transitional medicine and clinical develop-
ment and product life cycle work.
A useful review of the work in PV by Bate and
Stegmann (“Artificial intelligence and pharmacovig-
ilance: What is happening, what could happen and
what should happen”) from June 2023 can be found
at https://www.sciencedirect.com/science/article/pii/
S2211883723000217#bib0006
As an example, a recent article confirmed the already
added value of AI for both diagnosis and treatment of
dermatological disorders (Dermatol Ther (Heidelb),
2022 Dec;12(12):2637–2651. doi: 10.1007/s13555-022-
00833-8. Epub 2022 Oct 28. Artificial Intelligence in
Dermatology: Challenges and Perspectives, Konstan-
tinos Liopyris, Stamatios Gregoriou, Julia Dias, Alex-
andros J Stratigos). Nevertheless, the need of an M.D.
remains key. For most AI involvements, the expected
benefit is linked to rapidity, effectiveness and reliability.
Obviously, this area is developing and it is likely that
this summary of AI will be out of date rapidly. Review
“AI and PV” in google frequently!
Comments
Are there potential downsides in this area? As with
pretty much everything in life, the answer is yes. It is
possible that with AI and ML systems easily and cheaply
available, the barriers to entry to do PV will fall such
that many people and groups will easily do PV. This can
lead to people who probably should not be doing PV will
come to erroneous, malevolent conclusions. There may
simply be too many voices in the field to easily make
sound medical judgments. We will need some mecha-
nism of curation to be sure the best and most valid data
and judgments are used to make clinical decisions.
Some things are for sure:
Changes will occur whether we like it or not.
Tasks that can easily be done by AI will be done by
AI, again whether we like it or not.
Jobs will change, disappear and new ones will open
up. Needed skill sets will change.
There will be multiple players in the field around
the world.
PV will look enormously different in 5 or 10 years
perhaps even sooner.
There will be some nasty and malevolent individu-
als attempting to subvert, game or manipulate the
system due to money, politics etc.
The criteria for success will initially be such things
as number of signals per week. Then, multiple “real”
(confirmed) signals identified per week, cost of an
identified signal and other measures will be more
important. After this wave of measurable opera-
tional and processing successes, it will be realized
that what really matters will be clinical successes
such as time to find a serious signal that leads to
product label changes and changes in patient care
after a new drug is introduced. Parameters such as
number of patient deaths, SAEs, hospitalizations
etc. will be the key indicators.
There will be many more lawsuits (at least in the US).
The initial stages of this development (say the
next 5 years or so) will be quite confusing and without
clear standards for success. As with most things in the
IT world, version 1.0 will be interesting and margin-
ally useful. But down the road, later versions will be
the game changers. Right now we are most likely in
version 1.2.
CHAPTER
225
20
Expedited and
Aggregate Reporting
in Clinical Trials
T
here are multiple safety reports
that pharmaceutical compa-
nies and other sponsors must
submit to health authorities. This
chapter reviews the key reports that
are required now by most health
authorities.
Expedited Reporting
Certain serious adverse events (SAEs) must be reported
to health authorities within 7 or 15 calendar days. Most
countries use “calendar days” rather than “business or
working days”, as holidays and working days are not
the same everywhere. Some countries still retain dif-
ferent rules for local cases, but by and large, thanks to
ICH, CIOMS, and common sense, most countries have
standardized on the same timing, format, and content
of expedited (also called “alert”) reports.
Clinical Trial Reporting
Another way to express “clinical trial reporting” is
reporting for drugs that are not yet marketed (no Mar-
keting Authorization or New Drug Application (NDA)
approval yet). Although this refers primarily to clin-
ical trials, it may also refer to SAEs found in named
patient use, compassionate use, solicited SAEs, epi-
demiologic studies, and other “non-classic” trials and
studies.
Most countries require that SAEs, which are unex-
pected (not labeled), that is, do not appear in the Ref-
erence Safety Information (RSI), which is usually the
Investigator Brochure, and also that have some possi-
bility (even if small) of being caused by the study drug
be reported in 15 calendar days of first awareness by the
sponsor. In other words, it must be reported within 15
days from the first notification of anyone in the com-
pany (or organization), including its agents, business
partners, contractors, distributors, and vendors. This is
called a “15-day report”, “an expedited report”, or “an
alert report”. In the US, this is referred to as an IND
226 Cobert’s Manual of Drug Safety and Pharmacovigilance
Safety Report. Note the triple requirement: serious,
unlabeled, and possibly related.
A subcategory of this is the “7-day report”. In a
7-day report, the patient in question has died or had
a life-threatening SAE, which is also unexpected and
possibly related (same as above). This report must be
sent to the health authorities within 7 calendar days.
Note that all 7-day reports are also 15-day reports.
Thus, if a report is communicated as a 7-day report,
it must also be followed up as a 15-day report, unless
full information on the case was provided in the 7-day
report. In some jurisdictions, the 7-day “alert” report
may be communicated as a phone call, fax, email,
or some other less formal communication compared
with the more formal 15-day report (on a CIOMS I
or MedWatch form, or an E2B electronic transmis-
sion). However, many of the key regulators, e.g., the
European Medicines Agency (EMA) and the Japanese
Pharmaceuticals and Medical Devices Agency (PMDA)
require and will only accept structured E2B electronic
transmissions from sponsors. If the 7-day report is
“informal”, then it must be followed up with the usual
15-day “formal” report. If the 7-day report is complete
and there are no outstanding follow-up questions, it
will cover both 7-day and 15-day requirements. Thus,
the 7-day report becomes a 15-day report with the
same requirements for follow-up and further report-
ing, as given in the following sections.
United States Requirements
for Expedited IND Reports
The Investigational New Drug (IND) obligations are
found in 21CFR312. An IND is usually opened and
held by a pharmaceutical company, but academics,
universities, and individuals may also do so. The term
that the FDA uses for the IND holder is generally “the
sponsor”. The sponsor is obliged to “review and eval-
uate the evidence relating to the safety and effective-
ness of the drug as it is obtained from the investigator”
(21CFR312.56(c)). This includes 7- and 15-day expe-
dited reports (21CFR312.32) and annual reports
(21CFR312.33). In March 2011, updates to these regu-
lations went into effect.
Expedited IND Reports
(Alert Reports, 7-Day and
15-Day IND Reports)
Serious, unexpected (unlabeled), AEs from clinical trials
for which there is some evidence that the drug caused
the event must be reported promptly. Each report iden-
tifies all similar case reports, and the sponsor analyzes
their significance.
Specifically the FDA regulations state 21CFR312(c)
(1): “The sponsor must notify FDA and all participat-
ing investigators (i.e., all investigators to whom the
sponsor is providing drug under its INDs or under any
investigator’s IND) in an IND Safety Report of potential
serious risks, from clinical trials or any other source,
as soon as possible, but in no case later than 15 calen-
dar days after the sponsor determines that the informa-
tion qualifies for reporting”. In each IND Safety Report,
the sponsor must identify all safety reports previously
received concerning a similar Suspected Adverse Reac-
tion (SAR) and must analyze the significance of the new
SAR in light of previous, similar reports or any other
relevant information. This analysis should be included
in the case narrative.
Unlike much of the rest of the world, in general, a
single case will not qualify for expedited reporting to
FDA. The regulation, clarified by guidance, expects a
sponsor to have the equivalent of an independent panel
of experts, a Safety Assessment Committee (SAC), to
review all safety data from all studies conducted with a
given active moiety. The committee must be composed
of qualified experts, who may be employees or non-
employees of the sponsor, but must be “independent”,
i.e., not have direct involvement in the conduct or
analysis of any of the studies in the program. The SAC
may review both blinded and unblinded data as part of
a prospective plan and may also request ad hoc analy-
ses. These analyses may include both serious and non-
serious AEs. The SAC can make a recommendation to
the sponsor regarding submission of IND Safety Reports,
but the sponsor alone has responsibility for decisions
regarding submission of reports to FDA. Thus, as a
practical matter, FDA may receive somewhat different
information at different times from other regulators.
Expedited and Aggregate Reporting in Clinical Trials 227
The focus is on informative information, which usually
requires aggregate analysis, rather than all individual
reports on a one-by-one basis.
Expedited reporting must be done for findings from
animal studies, epidemiological studies, pooled analy-
sis of multiple studies, or clinical studies, whether or
not conducted under an IND and whether or not con-
ducted by the sponsor, that suggest a significant risk in
humans exposed to the drug (312.32(c)(1)(ii)). Data
from in vitro studies (e.g., micro-susceptibility, drug
interaction, or genotoxicity) are to be sent as 15-day
IND reports if a significant risk to humans is deter-
mined (312.32(c) (1)(iii)).
Any clinically important increase in the rate com-
pared to that in the IB or protocol of a serious suspected
adverse reaction must be submitted as a 15-day expe-
dited report. Monitoring this is one of the functions of
the SAC. The sponsor, in conjunction with the SAC,
should assess the “clinical importance”. Consideration
should be given to the study population, nature and
seriousness of the AE, magnitude of the increase, and
other relevant factors.
1. The report must be made no later than 15 calen-
dar days after the sponsor’s initial receipt of the
SAC recommendation to report (which is day 0
and is considered the “clock start date”). Under
older regulations the clock start began when the
sponsor had sufficient information that the three
criteria were met (serious, unexpected, associ-
ated) for an expedited report and that the report
had the four criteria (reporter, patient, AE, sus-
pect drug) to be valid. This is still the case out-
side the US. However, FDA has changed these
rules as follows:
Because the four elements of the minimum
dataset are generally readily available in the
clinical trial setting, the agency has deter-
mined that the definition and the requirement
for the minimum dataset are unnecessary and
has decided not to require a minimum dataset
for IND Safety Reports.
The reporting time clock for FDA starts (i.e.,
day 0) as soon as the SAC informs the sponsor
of the recommendation to report to FDA on
an expedited basis. However, the SAC should
begin work on a new serious report right away
to determine the reporting timeframe, within
the rest of world clock requirements, not wait
for a weekly or monthly meeting. For the rest
of the world, day 0 would be the day the spon-
sor receives the information from the clinical
investigator of a serious suspected adverse
reaction from a clinical trial. Thus, there may
be different day 0s for the US and other coun-
tries. These dates must be carefully tracked to
avoid late reports.
While the IB contains safety information on
expectedness, it is the sponsor who makes this
determination. Investigators are asked to pro-
vide a causality assessment, and this is import-
ant outside the US. However, for reporting to
FDA, the sponsor alone is responsible for the
causality assessment.
If any information necessary to evaluate and
report the suspected adverse reaction is miss-
ing or unknown, the sponsor should actively
seek such information.
Thus, when a study site reports any SAE informa-
tion, the clock starts — even if the information is incom-
plete or does not meet the minimum requirements. The
sponsor must then rapidly obtain the rest of the (mini-
mum) information needed for the expedited report.
If the case has a serious outcome of fatal or
life-threatening at presentation (i.e., serious, unexpected,
associated, and fatal or life-threatening), the case is to
be reported as a telephone or fax report within 7 calen-
dar days of the first receipt. It is important to note that
the life-threatening situation is at the encounter, not
that it could become life-threatening if it progressed
or were more severe. However, there is a nuance here.
If the AE presents say as chest pain and is serious but
not life-threatening but then evolves over the next few
hours into a life-threatening massive myocardial infarc-
tion this probably would be life-threatening. This is usu-
ally a judgment call, but a rapid evolution of an initially
non-life-threatening event would probably qualify.
All 7-day reports are automatically 15-day reports
and must then be processed and submitted as expedited
228 Cobert’s Manual of Drug Safety and Pharmacovigilance
reports by day 15 unless the 7-day report was a com-
plete MedWatch or E2B expedited report. Follow-up
reports (also expedited reports) are submitted if new
information arrives. “Once an expedited report, always
an expedited report” (unless nullified).
For expedited reporting, there must be sufficient evi-
dence to suggest a causal relationship between the drug
and the SAE, thus creating a Suspected Adverse Reac-
tion (312.32(c)(1)(i)). FDA does not want to receive as
expedited reports those cases that are not likely to be
related to the drug or otherwise uninformative.
The FDA has clarified that it requires the investiga-
tor to report serious AEs rapidly to the sponsor along
with a determination of seriousness/life-threatening
as well as a determination of causality. However, the
sponsor alone is responsible for causality determina-
tion under an IND. The sponsor determines expect-
edness. The most conservative viewpoint ordinarily
prevails. That is, in terms of seriousness and causality, if
either the investigator or sponsor feels a case is serious,
unexpected, and that there is a “reasonable possibility”
the SAE was due to the drug, it should be expedited
(Table 1).
The events should be submitted in writing, usually
on a MedWatch 3500A form (or as E2B transmissions).
Reports of safety findings from animal studies and cer-
tain other reports (e.g., epidemiology studies) are usu-
ally submitted as narratives rather than on MedWatch
forms. Most companies do not want to put animal data
into their clinical safety database. Non-US cases may be
submitted on MedWatch or CIOMS I forms.
All SAEs from bioavailability and bioequivalence
studies, whether or not conducted under an IND, must
be reported to FDA as expedited reports. From FDA’s
perspective, reportability does not hinge on whether the
event is labeled or not (in the investigator brochure) or
whether considered related to the drug (causality) —
only on seriousness.
The sponsor must also notify all participating inves-
tigators of these reports. The investigators in turn notify
the investigational review boards (21CFR312.32(c)(i
and ii)). The notification procedure is complex, as not
every single individual report goes to the investigators
and IRBs (Table 2). Rather important reports or those
that alter benefit/risk should be reported. FDA has
issued a guidance on this: Guidance for Clinical Inves-
tigators, Sponsors, and IRBs: Adverse Event Reporting —
Improving Human Subject Protection (http://www.fda.
gov/downloads/RegulatoryInformation/Guidances/
UCM126572.pdf). The sponsor is also required to
report information to the FDA from any source, for-
eign or domestic; clinical, animal, or epidemiologic
investigations; commercial marketing experience; lit-
erature reports; unpublished papers; and foreign regu-
latory authorities (21CFR312.32(b)). The FDA retains
the right to change the format and frequency of the
reports. For marketed drugs, reporting to the IND is
not required unless that case is from an IND clinical
trial.
Follow-up is required on all safety information
received by the sponsor and submitted to FDA as a fol-
low-up to the original (initial) 15-day report. Follow-up
information is handled with the same 15-calendar day
clock. If a case is received and does not meet the criteria
of a 15-day report (e.g., reported as a non-serious case
initially) and only later does the receipt of follow-up
information show the case to meet the reportability
Table 1.
Responsibilities of Investigators and
Sponsors in Assessing Serious AEs
Determination Sponsor Investigator
Serious/Life-Threatening Yes Yes
Causality (Responsible Possibility) Yes Yes
Expectedness (Labeled/Unlabeled) Yes No
Table 2.
Impact of Investigator and Sponsor
Causality Assessment on Causality
Assessment for Regulatory Reporting
Purposes in the EU and the US
Investigator
Causality
Sponsor
Causality
Regulatory
Causality
=
Not related Not related Not related
=
Related Related Related
=
Not related Related Related
Related Not related Not related
Related Not related Related
Expedited and Aggregate Reporting in Clinical Trials 229
criteria, the clock starts when the follow-up informa-
tion is received, and the SAC makes a recommendation
to expedite. If a case becomes non-expedited on receipt
of follow-up information, the sponsor should submit
this new information as a follow-up 15-day report and
indicate that the case no longer meets the criteria for
expediting.
Other information the sponsor receives that does
not quite fall into these categories but which the spon-
sor wishes to report should be reported as an informa-
tion amendment or in the annual report. The FDA notes
that reporting of a case by the sponsor does not mean
that the FDA or the sponsor believes that the report was
necessarily due to the drug. This point may prove to be
important in any potential litigation in which the spon-
sor might become involved (21CFR312.32(c)(3,4)).
Post-marketing trials should be submitted to the IND
(whether conducted under an IND or not) only if the
case meets the three criteria (serious, unexpected, pos-
sibly related) as determined by the sponsor.
The FDA also notes that in some trials, the sponsor
and FDA may reach an agreement to be noted in the
protocol whereby certain study endpoints (e.g., a par-
ticular SAE such as a myocardial infarction or death)
which would normally be considered serious and, thus,
trigger expedited reporting will not be reported as 7-day
or 15-day reports but rather periodically or at the end of
the trial. This type of arrangement would be typical for
survival endpoints in oncology studies. In all instances,
this must be prospectively customized for each situ-
ation. FDA and IRBs, etc. must agree to it. Expedited
reports should be unblinded and placebo cases should
not be reported on an expedited basis. The SAC will
have access to the unblinded cases.
In summary, the sponsor (whether an individ-
ual, institution, or company) has full responsibility
for determining whether to submit 15-day expedited
reports to FDA for clinical trial AEs that are serious,
unexpected (not in the Reference Safety Information
(RSI)), and for which there is “evidence” of a causal
relationship to study drug. The RSI is the Investiga-
tor Brochure or Package Insert, depending on which
one is used: Investigator Brochure for non-marketed
drugs or new indications of marketed drugs and the
US Package Insert — usually — for marketed drugs
and post-marketing studies. The SAC plays a key role
in providing objective advice to the sponsor regarding
pan-program safety assessment.
Outside the US, the criteria for a causal relation-
ship are generally softer, i.e., a “reasonable possibility”
of association with the study drug rather than a require-
ment for “evidence”. As noted above, epidemiologic,
animal, and other studies may also trigger expedited
reporting. If the case is a death or is life-threatening at
presentation, a 7-day report (phone or fax) must also be
made in addition to the 15-day report.
Note that the submission of such reports has
become much more complex as divergences have devel-
oped from the original consensus documents. Spon-
sors must be very careful in tracking SAEs which may
now be expedited in one country and not expedited in
another. In addition, day 0 may not be the same. We are
deharmonizing.
IND Annual Reports
In addition to the 7-day and 15-day safety reports,
the IND holder must also submit annual reports
(21CFR312.33). In lieu of the annual report to the IND,
FDA accepts the Developmental Safety Update Report
(DSUR) that CIOMS and ICH have developed, as long
as the appendices required in the IND regulations are
provided. A waiver is not required to substitute a DSUR
for the IND Annual Report, but all time periods must be
continuously covered without interruption.
For the IND Annual Report, a brief summary of
the progress of the investigation(s) must be submitted
within 60 days of the anniversary date of the IND. This
summary must include the following:
1. Individual study information: A brief summary
of the status of each study in progress and each
study completed during the previous year:
The title and number of the study, its pur-
pose, a brief statement identifying the patient
population, and a statement as to whether
the study is ongoing or completed.
The total number of subjects initially
planned for inclusion in the study; the