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110 Cobert’s Manual of Drug Safety and Pharmacovigilance
few spontaneous AEs received. In addition, because it
is often hard to identify the manufacturer of a generic
product, the AEs tend to get reported to the originat-
ing company that first created and sold the product
whether the actual AE occurred with that product or
not. An interesting situation occurs when the originat-
ing company no longer exists or no longer makes or
markets the product and has closed its NDAs and INDs.
In that situation, in the US, generic drug labeling must
be the “same as” the last approved reference listed drug.
Thus, the “reference product” may not be the origina-
tor and the innovator may not maintain the reference
labeling. In the US, when the innovator withdraws the
product, FDA may assign one of the generic manufac-
turers to this role. Generic labeling has been controver-
sial in regard to making changes in labeling. There are
also now branded generics which make up some 5% of
the US market.
Some big pharma companies have generic divisions
in addition to the innovator divisions. This is done, of
course, to make money but also to create generic ver-
sions of their branded products to sell after the branded
products go off patent. That is, a company may sell a
branded and a generic version of the same product.
Some companies are also investing in “nutraceuti-
cals.” Many such companies have one single drug safety
group or they have separate teams to handle these
products as well as a process for innovator products.
The regulation of nutraceuticals in most jurisdictions
is much more limited than for drugs. Companies are
organized to address the level and breadth of their obli-
gations (including those with business partners).
Biosimilar products are an expanding part of prod-
uct availability. These are in a sense “generic biologics”
but clearly are not since they are not relatively simple
molecules but rather “advanced therapeutics”. Many
biologics are complex proteins that cannot be created,
assembled, and “folded” except in living organisms.
Regulatory agencies and companies realize these bio-
similars cannot be handled like generic drugs of small
molecules. The rules are evolving, and it is likely that
pharmacovigilance (“biovigilance”) will need to be
done at the level of innovator products. In the US gen-
erally some sort of clinical trial is usually required for a
biologic to be approved by FDA.
Another trend is the outsourcing and offshoring of
many functions that formerly remained entirely within
the company as core competencies. Drug safety falls
into this category. The operational aspects of drug safety,
particularly case processing, are sometimes strong can-
didates for this. Processing individual case safety reports
has now become something of a commodity (Definition:
“a good or service whose wide availability typically leads
to smaller profit margins and diminishes the impor-
tance of factors [like brand name] other than price” —
Merriam-Webster’s Collegiate Dictionary), whereby the
place and personnel who do the case processing, data
entry, and follow-up are chosen almost entirely on the
basis of lowest cost; aggregate reports for older drugs
in particular are also more and more often outsourced
to these low cost countries. Thus, much of this drug
safety work is now being done in India, China, Brazil,
the Philippines, Costa Rica, Hungary, and elsewhere.
Manufacturing, toxicology, computer programming, and
other services are also following this route. The major
business, signal management, risk–benefit assessment,
and epidemiologic and management decisions tend to
remain in the home office. Although there is a trend to
automate and outsource some components of these core
activities (among others signal detection steps), artificial
intelligence will at some point be playing a major role
in safety with expected changes in the routine processes
described above.
Mid-sized and Small Pharma
Some pharmaceutical companies are mid-sized (sales in
the hundreds of millions of dollars) and are sometimes
located in a single country. They thus do not have to
establish worldwide expertise in the safety department
and can concentrate on the safety analysis and report-
ing in their one or two markets only. These companies
range from those that have significant sales figures (e.g.,
hundreds of millions of dollars) down to small biotech
start-up companies with only one product in clinical
research, no marketed products, and no sales. These
companies usually establish a safety function either as
a stand-alone unit with a handful of people if the vol-
ume warrants it, or they combine the function with the
medical/clinical research group or the regulatory affairs
Biopharmaceutical Companies 111
group. Sometimes the drug safety department is one
single person, often with other functions! (Usually Reg-
ulatory, Quality and/or Medical). The trend is to out-
source some or all of these functions (e.g., data entry,
aggregate report writing, etc.) to clinical or contract
research organizations (CROs) or other outsourcing
firms, though the pharma company will retain the final
say and accountability for the cases. In certain instances,
e.g., when a bolus of reports appears, the established
safety group will require supplementation with tempo-
rary resources to remain in compliance. Examples of
such situations include toxicology or registry reports or
emergence of a pandemic. Likewise, seasonal appear-
ance of influenza, etc., may cause pharmacovigilance
staff (company, vendors, regulators, etc.) to fall ill and
be unable to work
Sometimes, these companies have contractual
agreements for research or sales with other companies
both inside and outside their home country. These con-
tracts oblige the company to conform to safety and reg-
ulatory requirements if the partner is outside the home
country. A separate, detailed pharmacovigilance agree-
ment and relevant training are required. That is, the sec-
ond (or third, etc.) partner must send AEs and other
safety information to the contracting business partner
in a timely manner and in the proper format so that
the business partner can remain in compliance with its
local laws and regulations. These safety functions may
be kept inside the company or outsourced in whole or
in part.
Note: If a pharma company (large, middle-size or
small) has at least one medicinal product authorized/
registered in the EU, it must have an EU Qualified Per-
son for Pharmacovigilance and set up this function (EU
QPPV). For EU centrally authorized products, many
EU countries require a Local Person for PV (even if the
product is not marketed in these territories).
Contract/Clinical Research
Organizations (CROs)
CROs are companies that handle some or all clinical and
regulatory functions that pharmaceutical companies do,
including phase I–IV studies, regulatory submissions,
safety data, pharmacovigilance, IT matters, eCTD, IND,
NDA preparation, and so forth. There are large “full-
service” CROs that are almost mini-pharmaceutical
companies, and there are “niche”, or “boutique”, CROs
that specialize in one or two functions in the pharma
world, such as drug safety or pharmacovigilance CROs
or IT vendors supporting safety.
These CROs usually set up whatever safety sys-
tem(s) are needed for their functions. If they are doing
primarily clinical research, they often set up a database
for entering or uploading the individual case safety
reports (ICSRs) that are either sent to the sponsoring
company or to the Health Authorities (U.S. FDA, EMA,
etc.) For the “major” authorities, ICSRs can be sent
directly in structured electronic format (E2B). For some
clinical trials (per contract), the CRO sends case report
forms (CRFs) as electronic data capture files (EDC).
They may prepare IND or European Union DSURs/
PBRERs or handle investigator notification, IRBs/Eth-
ics Committees, and so on. Others that handle safety
as their primary function may set up multiple safety
databases so that they are able to use the same ones
that the sponsoring company(ies) use, both for clini-
cal trials and post-marketing data. Many of the CROs
will have to support multiple databases, as their clients
may use different safety databases and do not want their
data transferred to a new system. Other CROs will use
one single database for drug safety and arrange for data
imports or data reentry between their database and the
clients’ databases. The trend is to one database with
storage in The Cloud. There are many, many levels of
complexity in the business arrangements with CROs
(or other partners).
There are multiple other types of service organiza-
tions that serve the pharmaceutical industry. A listing
in the DIA’s (Drug Information Association) publication
“Contract Service Organization Directory” includes
companies providing the following services: abstract
preparation; advertising; specific types of trials (e.g.,
AIDS); analytic laboratories; bibliography preparation;
contract management; validation of assays and labora-
tories; specimen storage; preparation of NDAs, Biologic
License Applications, PSURs/PBRERs, clinical study
reports, investigator brochures, expert reports, publi-
cations, drug master files; creation and maintenance of
112 Cobert’s Manual of Drug Safety and Pharmacovigilance
Pharmacovigilance System Master Files, cardiovascular
monitoring; case report form preparation; central lab-
oratories; chemistry–manufacturing–control issues;
studies: phases I–IV, investigator-initiated trials, com-
passionate use trials, epidemiology trials, pharmaco-
epidemiology studies, claims support studies, safety
studies; information technology services (server man-
agement, programming and software development, data
migration, data management, validation); clinical phar-
macology; clinical packaging; clinical supply manage-
ment; study management; focus groups and consumer
testing; auditing; ethics committees and investigational
review boards; data safety monitoring boards; adjudi-
cation committees; digitized QTc analysis; dissolution
testing; DNA diagnostics; document imaging; paper and
electronic data management; translations; environmen-
tal assessments; formulation development; compliance
with Good Clinical Practices, Good Manufacturing
Practice, Good Laboratory Practice, Good Pharmacovig-
ilance Practices; home infusions; intranet, internet,
and website development; investigational site finding;
setting up investigator meetings; licensing and acquisi-
tions; market research; patient support programs; med-
ical communications; medical information/call centers;
medical science liaisons; microbiology testing; nursing;
patient compliance, education, recruitment; prepara-
tion of labeling and patient information leaflets; process
validation; project management; quality assurance and
quality control; quality of life assessment; randomiza-
tion; regulatory affairs; registries; remote data entry;
prescription to over-the-counter switch; stability test-
ing; standard operating procedure development; statis-
tical services; toxicology; training; transportation; and
reengineering and process redesign. New to the game
are social media niche companies that deal in X (for-
merly Twitter), Facebook, blogs, and other evolving
communication methods. Not all these organizations
deal with safety or pharmacovigilance issues, although
occasionally issues do come up, and the drug safety
department may need to work with these companies on
safety-related projects. Even if the primary purpose of a
social media program is not safety-related, the company
still has an obligation to assess any safety information
from two-way social media communication. Artificial
intelligence services are now being created to handle
many of these roles and the landscape is expected to
change significantly in the next few years.
The business models in the pharmaceutical world
are changing. Some of the bigger CROs are actually
becoming pharma companies as they in-license or pur-
chase early or even late-stage drugs and then continue
the development on their own.
Innovation is tending to come now from small
start-ups and biotechs as well as from large pharmaceu-
tical companies. The large pharma companies are now
downsizing in some areas in order to specialize more
deeply in fewer areas (e.g. cardiology) and outsourcing
many functions to CROs and other vendors that they
formerly kept in-house. They are, thus, transforming
into development and marketing companies, leaving
much of the innovative discovery to the smaller com-
panies. Similarly, when large pharmas purchase small
biotechs, they often inadvertently (or expressly) trans-
form the smaller innovator into a more classic company,
hobbling the innovation atmosphere. Any acquisition
will force changes in the handling of safety data as one
or both companies must adapt to the new products,
procedures, and relationships.
Mergers, Acquisitions, and
Bankruptcies
For better or worse, the pharma world is one where
companies join, split, merge, and occasionally go bank-
rupt. No matter what the outcome of such situations,
the responsibility for drug safety and pharmacovigi-
lance remains in place, even when production and mar-
keting cease.
When a corporate change occurs, it is the respon-
sibility of the company (in the European Union of the
QPPV) to ensure that a clear transition of responsibil-
ities occurs and that all drug safety activities are main-
tained. Specifically, there must be clarity on who will be
the new EU QPPV and when, what database(s) are in
place, and, if more than one is in use at one time, how is
compliance assured? Are all safety data exchange agree-
ments still in place and valid with other entities? If the
MA or NDA changes ownership, how is this handled to
ensure that all clinical trial and post-marketing SAEs,
PSURs/PBRERs, IND safety, or periodic reports are sub-
mitted correctly and on time? In other words, there
Biopharmaceutical Companies 113
must be a smooth transition to ensure that no safety
issues or responsibilities are missed.
The transition teams (both internal and external,
including consultants) must ensure a robust transi-
tion and make it a very high priority. There must be
total continuity. Safety activities cannot stop or dimin-
ish during the handover or transition period. The con-
cerned health authorities should be kept informed and
assured that all issues have been successfully dealt with
and other obligations, e.g., corrective actions, have been
fulfilled.
As the merger or acquisition is usually done for
financial and business reasons, safety and PV are often
an afterthought and may not be addressed until very
late in the negotiations, or sometimes not until after
the deal is concluded. A pharmacovigilance agreement
is usually a document separate from the commercial
contract. This can produce operational challenges for
all parties. It is desirable to have a separate document
so that it can be modified when pharmacovigilance
requirements change without renegotiating commercial
aspects of the arrangement.
Expect a governmental inspection from one or
more of the health authorities after a merger to ensure
that all the requirements and systems for drug safety
have been and are still in place and functioning well —
during and after the transition phase; health authorities
actually know that such a situation is challenging for
drug safety departments.
Bankruptcies (also called liquidations) can be espe-
cially tricky if the company ceases to exist. Legal coun-
sel should be obtained where necessary and the health
agencies contacted, as needed. As always, the safety
functions must continue uninterrupted.
Note: Whatever the policy defined by the pharma
company regarding the organization and/or outsourc-
ing arrangements, one main principle remains valid for
any drug safety group: have real and robust oversight on
all activities which are directly or indirectly part of the
PV roles and responsibilities. This is a required quality
function.
CHAPTER
115
10
The Safety
Department’s Role in
Cross-Functional areas
T
he safety & PV department works
closely with many other teams
within and outside the Pharma-
ceutical Company.
Introduction
Historically, those who worked in clinical safety and
or pharmacovigilance were locked away in their own
department and office space and rarely interacted with
other functional areas. Our job was mainly to receive
and process safety cases, maintain the safety database,
and report information to the regulatory authorities and
sites, the end. Thankfully, this mindset has changed,
and it will continue to develop as the cross-functional
areas are educated as to what safety and pharmacovigi-
lance truly is.
We will outline in this chapter the cross-functional
areas with which the safety and pharmacovigilance
function should interact and describe in what capac-
ity they should be working together. The relationship
between the safety department and others is improv-
ing in the larger scale organization space; however, this
symbiotic relationship is not always realized or appre-
ciated in small to mid-size biotech and pharmaceutical
companies.
When companies and institutions truly under-
stand the purpose of what pharmacovigilance is, and
how to monitor for it throughout the life-cycle of the
product, we can then understand how this function
relates to CMC and pre-clinical departments, Clinical
Operations, Clinical Development, Data Management,
Medical Affairs, Quality & Supply, Regulatory, Label-
ing, Epidemiology, Biostatistics, Business Development,
Marketing, Health Economics and Outcomes Research
(HEOR), Legal, and so on.
116 Cobert’s Manual of Drug Safety and Pharmacovigilance
If there is one chapter you could give to your Chief
Medical Officer or CEO, this would be the one.
General Remarks
During the development stage of a product, safety data
such as AE, SAE, pregnancy, overdose/underdose, AE
of Special Interest (AESI), and other special situation
reports are collected in a clinical trial database and fur-
ther collected and reported in a safety database. Some
other events, such as product quality events associated
with AEs, events from animal and in-vitro studies, and
reports of pregnancy are collected and reported outside
a clinical trial database but must have the means of get-
ting into the safety database for further evaluation and
reporting. Once a product is on the market, the sources
of safety data are less controlled and come from a vari-
ety of areas, most of which are not in a formalized data-
base or system. When we start to look at the flow of
safety data wholistically, we can start to appreciate how
important it is for cross-functional areas to interact with
pharmacovigilance groups to ensure the data is flowing
to the appropriate channels.
Clinical Operations &
Development
The clinical research (or medical research) department,
sometimes referred to as Clinical Operations, is the
section of a company (or CRO) that oversees the clin-
ical trials and studies. There are many ways to struc-
ture such departments. Some companies have their
research department do only phase 2 and 3 (develop-
mental) trials, with a separate group handling phase 1
(clinical pharmacology and early safety studies mainly)
and another group handling phase I4 (post-marketing)
studies and commitments. Alternatively, there may be
separate groups handling different types of products:
biologics, drugs, devices, or over-the-counter (OTC)
products. Other structures are by country or geographic
region: US studies, EU studies, and “rest of the world”
(ROW) studies. Multiple hybrids of these models exist
with and without outsourcing of some of the functions.
Whatever the structure of the research division(s)
may be, the drug safety department must play an active
and continuous role in these groups’ day-to-day activ-
ities because clinical studies almost always produce
adverse events (AEs). The main areas of interaction
between the two groups would be the following:
1. Project Planning and Development
a. Drug Safety should be a primary reviewer of
the protocol and Investigator Brochure, DSMB
Charters and TFL documents, and protocol
and site training materials
b. Secondary reviewer of the Clinical Trial Man-
agement Plan, Medical Monitoring Plans, trial
master file plans, clinical trial monitoring
plans, etc.
2. Interactions regarding Signal Detection and Ben-
efit Risk Assessment
3. Annual and Aggregate Reporting
The drug safety group must ensure that it receives
all appropriate AEs from all trials. “Appropriate” usually
means all serious AEs (SAEs), some or all non-SAEs,
and all pregnancy cases (pregnancy is not an AE, of
course, but in practice handled like AEs from a logistic
point of view). In most regions there is a requirement to
report certain events to the health authorities in either
7- or 15-calendar day (expedited reports) or periodi-
cally (e.g., yearly). Unless the clinical research divisions
are able to receive and process such AEs themselves,
these cases must be sent to the drug safety department.
The clinical research and drug safety groups must
establish a process to ensure that all SAEs are reported
to the company by the investigator within 24hours after
occurrence at a clinical site. Note that the obligation of
the investigator to report SAEs to the sponsor is clearly
stated in almost all countries’ regulations; e.g., FDA
regulations: “An investigator must immediately report
to the sponsor any SAE, whether or not considered
drug-related, including those listed in the protocol or
investigator brochure and must include an assessment
of whether there is a reasonable possibility that the drug
The Safety Department’s Role in Cross-Functional areas 117
caused the event” (21CFR312.64(b)). This allows the
company to process them and report the cases to the
appropriate health authorities, particularly for the 7- or
15-calendar day SAEs.
Investigator Training and Meetings
The investigators must be trained to report SAEs, or
other events of special interest according to the proto-
col. This is typically done during an Investigator Meet-
ing prior to the conduct of the trial and through Site
Initiation Visits (SIVs) where general protocol, prod-
uct, and trial conduct information is shared. What
does this mean? The safety group should be involved
in the review and dissemination of safety reporting for
the protocol at the Investigator Meeting and should
also be involved in the development of the SIV slide
decks.
Interim Analysis, Annual and final
study reporting
The drug safety group should generally be involved in
the creation and review of reports generated for interim
analysis and for annual and final study reporting (such
as DSURs and final Clinical Study Reports (CSRs)),
including the final integrated safety summary for the
submission dossier (e.g., CTD, MAA or NDA). This
includes data reconciliation as well as supplying the
“narrative” (or “capsule summary”) or other data sets
prepared for each case to clinical research to aid them
in preparing their final study reports. Some companies
now use an “automated case narrative” for SAEs. They
are usually included in the CSR and the CTD/MA dos-
sier. They are derived from the recorded information
in the ICSRs in the company drug safety database.
If there are post-marketing data held by drug safety,
these will usually need to be supplied to the dossier as
well. Any analysis or summary of data which includes
AE event summaries should include a review by the
appropriate drug safety and pharmacovigilance team
members for accuracy and completeness. The annual
and periodic reports are generally overseen by the PV
groups along with regulatory, with input from the clin-
ical operations and development groups; whereas the
final clinical study reports (CSRs) are generally owned
by the clinical operations and development groups.
Regardless of how this is structured at a company, it
is imperative that drug safety and pharmacovigilance
place a significant role in the generation and review of
data included in each type of report.
Signal Detection & Benefit Risk
Assessment
The clinical operations, clinical development, and drug
safety groups usually collaborate when a signal is being
worked up or an ad hoc health authority question is
received. For example, if a health agency asks about a
particular AE or groups of AEs (e.g., acute pancreatitis
or all pancreatic AEs), it is usually necessary to pull the
non-SAEs from the clinical research database and the
SAEs from the drug safety database to capture all similar
AEs in question. Because of the way data are entered
into the clinical research database (either at the end
of the study or when batches of data arrive at the data
entry site), the drug safety database is usually more up
to date for SAEs at any one time because drug safety
usually enters data immediately upon receipt, and clin-
ical research may enter data periodically, when a group
of CRFs arrives, or even at the end of the study. If EDC
is used and the data are efficiently collected and dis-
tributed to both databases, this problem may be largely
alleviated.
In addition, the clinical research group deals with
both safety and efficacy and may feel they have a bet-
ter appreciation of the balance between risk and ben-
efit compared with the drug safety folks, who tend to
see the risk side and rarely are involved in the benefit
side. However, the drug safety personnel usually have
better understanding of seriousness, labeledness, and
(perhaps) causality, because they have more experience
across many drug classes. From a practical point of
view, a system of adjudication, escalation, and resolu-
tion of disagreements (e.g., serious versus non-serious)
must exist and must function rapidly. In most, but not
118 Cobert’s Manual of Drug Safety and Pharmacovigilance
all situations, drug safety tends to have the final say on
reportability of cases to the health authorities. The com-
pany does not want to be in a position where clinical
research does not want a case reported as a 7- or 15-day
report and drug safety does. A paper trail showing that
the company did not take the most conservative posi-
tion (i.e., reporting the case when there is some doubt)
may be embarrassing at best and harmful at worst.
Project Planning & Development
The clinical research department and the safety depart-
ment also interact at development, project planning,
and risk management meetings as well as on signaling,
training sessions, preparation of annual reports, inves-
tigator brochure updates, and so on. The drug safety
group is also frequently charged with sending blinded
or unblinded safety information to Drug Safety Moni-
toring Boards (DSMBs) or other data monitoring com-
mittees. These are outside independent groups that
evaluate the safety profile and status of a study on an
ongoing basis during the study to ensure patient safety
and data integrity. This may become tricky if the drug
safety group breaks individual patients’ blinding codes
to report the case unblinded to the health agencies and
data committees but, at the same time, endeavors to
maintain the blind for the clinical research and biosta-
tistics departments. Drug safety may also assist the clin-
ical research department in preparing data for meetings
with health authorities, health agency advisory commit-
tee meetings, responses to ad hoc queries, and so forth.
Abstracts and Poster Presentations
Throughout product development, companies may
choose to publish abstracts, white papers, and present
at scientific conferences on the status of their clinical
trials. This may be done to support additional funding
from outside sources and to show advancement and
benefits of their product compared to other competi-
tors. Typically these presentations are developed by the
clinical development team, but should be reviewed by
the safety department for accuracy and care of report-
ing any statistics or reported outcomes relevant to
perceived/potential benefits and risks. Often
Sometimes the dealings between the two depart-
ments may become strained. The clinical research phy-
sicians and staff dealing with the drug in question often
feel it is “their baby” and become protective and defen-
sive about it. This may be because they “believe” in the
drug and want to give it the benefit of the doubt clin-
ically but also for potential financial reasons: bonuses
and rewards are better for drugs that succeed in clinical
trials and get approved for marketing. They also may
feel (sometimes correctly) that they are much more
familiar with the drug, its activity, safety, and behavior,
than the drug safety group, which may handle a whole
array of drugs and must, of necessity, devote less time to
the drug in question.
Data Management
Another area for cross-functional collaboration
involves the Data Management group, along with
Clinical Operations and safety. The question we gen-
erally ask is “how we will collect the AE data on the
Case Report Form (CRF) in the electronic data cap-
ture (EDC) system”? How does this information get to
the safety team and when? What are the desired out-
puts for various working groups such as DSMBs and
IRBs? How will queries be addressed to the sites, via
email or EDC? These groups must all work together in
order to build the clinical trial database in such a way
that supports the protocol design and also allows for
appropriate measurement of the primary and second-
ary endpoints, of which often include safety data. Data
Management and the clinical operations team should
include safety and PV in the design, review, and edit
check process when building CRFs in any database.
Safety should be allowed to also review any other asso-
ciated forms such as the product page where the site
will capture dosing and dispending information, death
pages where the site will report on fatal outcomes, as
well other pages relevant to the reporting of safety
information such as laboratory results, medical history,
concomitant medication, and drug dosing pages. Set-
ting up such systems requires much thought and work
up-front before the study starts. Drug safety should
insist on being involved in creating the system, pro-
cesses, and data rules from the beginning.
The Safety Department’s Role in Cross-Functional areas 119
Examples of such documents which collaboration
is imperative include:
1. EDC development such as eCRF development
and completion guidelines, User Acceptance
Testing for electronic reporting of safety data
Tables, Figures and Listings (TFL) review and
development for summary data
2. Safety Reconciliation Plans
3. Secondary reviewer on Data Management Plans,
data migration documents, data coding tech-
niques, and any other operational document sup-
porting the clinical trial database.
The process for collection and reporting of AEs
involves the capture of the AE on the Case Report Form
(CRF) or in the Electronic Data Capture (EDC) system,
with transmission of the information to the company
or CRO. Transmission to the company or CRO is done
either electronically in the EDC system or by the older
means of written case report forms or dedicated SAE
collection forms that are faxed or e-mailed. This infor-
mation must contain all the data necessary for the SAE
case to be entered into the safety database and for prepa-
ration of an E2B transmission or a MedWatch or CIOMS
I form for submission to the concerned health authori-
ties, the clinical investigators, IRBs/Ethics Committees
when required, and IDMC/DSMB if applicable. This
process often involves queries to the investigator (done
either by drug safety directly or via the clinical research
department, or CRO). Care must be taken to avoid hav-
ing multiple company departments sending repetitive
questions to the investigator; usually a single point
of contact is best from the company and instructions
should be stated in the protocol as well as discussed at
investigator meetings. This process can become exceed-
ingly complex if SAE volume is very high, if multiple
worldwide sites are involved, if a clinical research orga-
nization or other intermediaries are involved, if a coop-
erative group is involved (e.g., in oncology studies), or
if a governmental agency (e.g., National Institutes of
Health) or (non-governmental organization (NGO) is
involved.
Some studies generate very large numbers of SAEs,
such as oncology studies in very ill patients receiving
toxic study drugs. If studies run long enough, just
about every patient (whether on study drug, compara-
tor, or placebo) will have an AE (though not necessar-
ily an ADR) at some point during the trial. Normally,
all SAEs are transmitted to the company within 1 or 2
days. However, for some studies, various protocol cus-
tomizations may be done to ensure that the critical and
important SAEs (those that are unexpected or related to
the study drug) reach the company within 1–2 days and
the health agencies within 7–15 days, though all SAEs
should be sent to the sponsor immediately. Non-serious
AEs may be reported to the company in a less urgent
fashion (e.g., FDA requires monthly reviews, although
observational data may be collected at the end of the
study) and to the agencies in the annual or special peri-
odic reports.
In some cases, arrangements may be made with
the health agencies overseeing a study to report cer-
tain expected and occasionally unexpected SAEs
periodically rather than as expedited reports. Most
health agencies (including the FDA and EU agencies)
are willing to negotiate such arrangements. For large
multi-national trials, this may require negotiations with
multiple national health authorities to reach a workable
consensus that meets all needs. For example, a protocol
might state that, because drug X in previous trials has
been shown to produce mild gastrointestinal, urinary,
and pulmonary hemorrhage in this patient group, these
cases will not be reported until the end of the trial unless
the patient dies or the patient requires a transfusion (for
example). Hemorrhage from other body sites would be
SAEs and reported to the company in 1–2 days. Never-
theless, before setting up such an option, careful anal-
ysis should be done regarding the implications of this.
It means the company must run a continuous signal
detection process on SAEs and maybe non-serious AEs.
The goal is to ensure that no signal will be missed from
these non-reported cases.
Many companies, especially the larger ones, main-
tain two “safety databases”. One very common model
has a safety database maintained by the drug safety
department and a clinical trial database maintained by
the clinical research/statistics groups. The drug safety
database holds two sets of data: (1) the SAEs from
clinical trials and (2) all spontaneous serious and non-
serious reports; that is, most non-serious clinical trial