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120 Cobert’s Manual of Drug Safety and Pharmacovigilance
AEs are not kept in this safety database. This database
is used for the regulatory reporting of spontaneous and
clinical trial SAE expedited reports, Periodic Safety
Update Reports (PSURs/PBRERs), and annual clinical
trial safety reports (e.g., IND annual reports, DSURs).
The clinical research department maintains the other
database that holds all safety and efficacy data from clin-
ical trials (but no spontaneous reports) and is used in
preparing the final clinical study report for each study
as well as safety sections for Marketing Authorization
dossiers and integrated safety summaries for New Drug
Application (NDA) submissions.
The data in the two databases for any given clinical
trial patient may (unfortunately) be different. One rea-
son is due to different mechanisms of data collection and
collection at different times. In paper-based (non-EDC)
trials, the drug safety database usually receives data from
the investigator using a dedicated SAE reporting form
rather than multiple pages from the case report form.
The clinical trial database receives the data on the pages
in the CRF that are used for SAE/AE data collection.
The data may differ if the SAE collection form is
not filled in at the same time or by the same person as
the CRF. Thus, the same SAE information is collected
in two different places for each patient and may not be
fully reconciled at the investigator site. Also, follow-up
information may be entered into the CRF and not sent
on the separate SAE collection form or vice versa. In
addition, the drug safety group receives a clinical trial
SAE within 24–48 hours after the investigator first
notes it. The clinical trial database may not receive the
CRF data for several weeks if the CRFs are “harvested”
only every four weeks or so by the medical monitor.
The use of EDC usually alleviates this problem if all the
safety data are collected in the EDC and transmitted to
the drug safety group. If the EDC system only collects
safety data and notifies the company by an e-mail alert
that a new SAE has been collected, the investigator may
still end up sending a separate SAE sheet to the com-
pany, which could differ from the EDC data. So unless
the safety data are collected and transmitted in only
one place and manner, there is the risk of differing and
incorrect or out-of-date information being present in
the two company safety databases.
Other differences between the databases may
occur if different people (one person in the drug safety
department and one in the clinical research depart-
ment) code each case differently. Follow-up informa-
tion or corrected data may reach one database and not
the other. More subtle differences may arise in the data
that are collected. For example, for the clinical research
department, the drug compliance (what percentage of
the study drug was actually taken by the patient and
which doses were missed) is critical. To the safety
department, it is less important that the patient took
75% of the study drug versus 85% or 95%. To drug
safety, it is a much more binary (yes/no) question of
whether or not the drug was ingested at all (though,
of course, dose-related effects may occur). Drug safety
usually spends less time clarifying the dosing sched-
ule followed by the patients than the clinical research
department does.
It is thus necessary to reconcile the cases within the
two databases to ensure that the data, or at least the key
data, are identical. The process of reconciling the two
databases, clinical and safety, is typically called Safety
Database Reconciliation and should be conducted at
regular intervals throughout the conduct of the trial
based on either volume or timelines associated with
interim reviews by DSMBs/IDMCs or internal groups.
This can be a very time-consuming procedure requir-
ing detailed case review by the drug safety and clinical
research groups. Differences must be ironed out, and
sometimes new queries to the investigative sites are
generated from the reconciliation. The reconciliation
process is simplified thanks to the EDC (one single
source); but if a handwritten CRF has been used during
the clinical trial, a detailed comparison is to be led:
for each difference, a decision has to be taken to know
which database is to be updated. Follow-up expedited
SAEs can then be sent to health authorities depending
on the updated information. Successful reconciliation
needs to result in a high degree of medical consistency
and interpretation between the two datasets, but not
necessarily a 100% letter-for-letter match.
CROs
If the sponsor is using one or more CROs for various
clinical research (or safety or regulatory or drug sup-
ply functions), the safety department should be in close
and continued touch with the external CRO(s). If the
The Safety Department’s Role in Cross-Functional areas 121
CRO is handling some or all of the safety functions
for the company, there must be a clear written agree-
ment between the parties. One or more internal groups
should track, both in real time and with periodic audits
and quality reviews, how the safety work is being han-
dled. Although outsourced, the pharmaceutical com-
pany still has the legal (and moral) responsibility for
the safety of its drug. It is, therefore, critical to ensure
that a very detailed contract specifying which tasks are
to be covered by whom with timelines is put in place
prior to the start of work.
Marketing and Sales
Drug safety and marketing/sales interact in various
ways. At some level in each company, a medical group
(sometimes drug safety, sometimes medical affairs,
sometimes regulatory, sometimes another group) must
review advertising and promotional copy for drugs to
be sure that the medical and safety claims are correct.
That is, the claims made by the company must correctly
reflect the information contained in the official labeling
(approved Package Insert in the US, SmPC in the EU,
etc.).
Marketing will often ask drug safety for information
on AEs for their own uses (to help sell more product).
Although it is hard to refuse to supply such data, drug
safety should remind the marketers that spontaneous
drug safety data cannot, as a rule, be used for promo-
tional activities or safety claims.
Drug safety may also be asked to supply data that
the customer relations department (often within mar-
keting, where technical and scientific questions are
directed) uses to prepare responses to patients’ or
healthcare professionals’ medical queries (“Have you
ever seen pulmonary emboli with this drug in young
women? If yes, how did the patients do and how were
they treated?”). Some companies might make the safety
data available to more groups in the company than drug
safety. This may be a dangerous course to take if the
data are used for inappropriate (if not flat-out illegal)
purposes. It is a wise policy to let the drug safety group
be the gatekeeper for the drug safety data.
In the evaluation of signals and in the production
of certain reports (PSURs/PBRERs, PADERs, etc.) and
other required reports for regulatory agencies, it is nec-
essary for drug safety to obtain drug use data, such as
sales data, patients using the drug, tonnage shipped, or
prescriptions written, to estimate a reporting frequency
of AEs. These data are usually obtained and kept by the
marketing and sales departments. Sometimes they are
generated internally and sometimes they are purchased
from outside vendors who track prescriptions and sales.
This is another area of interaction between drug safety
and marketing/sales.
Drug safety often does training of sales representa-
tives, advertising copywriters, and others in the market-
ing and sales departments in regard to the reporting of
AEs. Although the sales force generally believes that its
job is to sell drugs and not collect AEs, it is now gener-
ally understood by all parties that sales representatives
(as well as all company employees, agents, etc.), when
they hear of AEs on their products, have an obligation to
report them to the safety department for follow-up and
regulatory reporting. For example, when the commer-
cial groups conduct customer engagement programs,
e.g., disease management, patient support programs
over the Internet or by phone or by personal visits, etc.,
they must have a way to assess the risk of these pro-
grams for non-compliance. If there is the possibility for
two-way communication between the company and its
customers, there is the possibility for the company to
receive safety information. Such information will usu-
ally be considered “solicited”, which requires a valid-
ity check, labeledness and seriousness determinations,
and also a causality assessment. Even though the main
purpose of the program is commercial and unrelated to
safety data collection, if the company becomes aware
of safety information on its products, there is a safety
obligation to address. This usually requires extensive
training.
In a more subtle way, drug safety must also influence
and reinforce its ethical and legal role with marketing
and sales. Many salespeople, particularly those han-
dling over-the-counter products, do not fully compre-
hend that the pharmaceutical industry, along with the
financial and nuclear power industries, is among the
most regulated industries in the world. The limitations,
reporting obligations, and safety issues are often not in
the mindset of marketers and salespeople, whose job
and pay depend on product sales. It is drug safety that
122 Cobert’s Manual of Drug Safety and Pharmacovigilance
often must set the limits on what marketing and sales
can and may do. For this reason, the marketers often
call the drug safety department the “sales prevention
department” and the head safety physician “Dr. No”.
If the company management does not appreciate this
and does not ensure that safety is handled properly, the
company may suffer severe regulatory, legal, and sales
consequences, particularly if a safety issue arises.
The drug safety department is a cost center that
never produces revenue and profit for a company. This
tends to produce, in some drug safety people, a siege
mentality because they carry little weight in the corpo-
rate hierarchy and are continually “fighting” to get their
message out. The primary goal of the safety department,
of course, is to prevent patient harm, ensure compliance,
and protect the public health. This viewpoint is some-
times not shared by others in the company who believe
that the safety department’s primary job is to protect
the company’s products at all costs. In fact, by doing
correct and complete safety work, the safety department
proactively protects the company’s products so that, at
some point down the road, when the safety issues arise,
they will not produce drug withdrawals, lawsuits, and
patient harm. However, this is often a hard concept to
“sell to the sales department”. Potential dollars not lost
in the future do not appear on balance sheets or get peo-
ple raises and bonuses.
The Labeling Department
The drug safety department will have some role in label
creation and maintenance. Labeling is defined broadly
and includes the marketed labeling (Package Insert,
SmPC, PIL, CCDS/CCSI, wording on the box or pack-
age, etc.) as well as the Investigator Brochure for drugs
in clinical trials (many companies still prefer the IB to
be created and updated by Clinical Development). At
the simplest level, drug safety supplies AE informa-
tion to the department (e.g., regulatory affairs, medical
writing, dedicated label departments) that creates and
maintains the label. The safety department may also
be charged with periodic or continuous label review to
ensure that the label contains the latest scientific and
medical information. This may mean that the safety
department must notify the appropriate departments
of new AEs worthy of being put into the label (usually
with due process and prior approval by a labeling or
safety committee), changes in the pregnancy status of
a drug, new warnings, contraindications, and precau-
tions both for the product and for the whole class of
drugs (“class labeling”). It is also worthwhile for the
drug safety or labeling department to scan the drugs
labels of other companies’ products for the appearance
in these other drugs’ labeling of a new drug interaction
with other marketed drugs. The actual division of these
duties is not clearly standardized and varies from com-
pany to company.
The Legal Department
The drug safety department may be involved with the
legal department when AEs are reported in cases under
litigation or when there is threat of litigation. In such
instances, the lawyers usually forbid the drug safety
department to have direct contact with the patient or
healthcare providers. All contact to obtain further safety
information is usually done through the company’s
legal department. In addition, one or more people from
the drug safety department (usually physicians) may be
subpoenaed to testify in cases involving the company
and safety issues related to its products. This involves
“witness training” for those at risk to be called on to
testify in court or to give depositions.
It is also common, when a company is being sued,
for the plaintiff’s attorneys to request copies of safety
information. This process is called “discovery”. The
safety department may be forced to stop work to pre-
pare or assist in preparing paper or electronic copies of
hundreds to thousands of pages of material needed in a
very tight time frame. In the worst case, the drug safety
department may have its paper or electronic files sealed
to prevent any changes or the adding of new informa-
tion. Drug safety is also heavily involved in preparing
the company’s defense in such cases and in evaluating
claims that have not yet reached litigation.
In some companies, the legal department may have
some say in review of the expedited reports, PSURs/
PBRERs, RMPs/REMS, submissions (MAAs, NDAs),
PVSMF and other documents and reports produced by
The Safety Department’s Role in Cross-Functional areas 123
the safety department. This may be a two-sided coin,
as the legal department will not want drug safety to
indicate that the drug may have caused an AE. This
can be very problematic as companies are expected to
make judgments in signaling reports, expedited reports,
PSURs/PBRERs, and other documents in regard to cau-
sality. The legal department may not want such “admis-
sions” made that could come back to bite the company
should a court case arise.
The legal department may be helpful in setting up
safety data exchange agreements with other companies
to ensure that the company receives all appropriate
safety information. In the same spirit, any outsourced
PV activity must be contracted with the support of
the legal department. Likewise, co-development and
co-marketing agreements must have clear responsibil-
ities written in a Pharmacovigilance Agreement (PVA).
In practice, when wisdom prevails, the drug safety
group and the legal department are allies in the desire
for the facts and the science to be handled correctly,
transparently, and honestly. This is always the best pol-
icy for the company, the patients, the healthcare pro-
fessionals, and the stockholders, though in the heat of
battle and fog of war this may not be evident.
Regulatory Affairs
Department
The drug safety department’s function is primarily reg-
ulatory. In some companies, particularly small ones,
the regulatory group may also handle some drug safety
functions, such as the submission of safety and aggre-
gate reports to the authorities.
Drug safety is typically responsible for the prepa-
ration and submission of expedited reporting (7- and
15-day reports, MedWatch for IND/CIOMS I reports,
E2B reports), IND Annual Reports/DSURs, PSURs/
PBRERs, and NDA periodic reports and such to the
health agencies and similar reports to business partners
and others. However, sometimes the regulatory depart-
ment will own the actual submission and maintain the
communication between the company and the agencies.
The regulatory department may sometimes have a role
in reporting cases to the health agencies depending on
the size and structure of the company (e.g., sometimes
assigning a special number to each submission, such
as a serial number for FDA reporting) or tracking such
cases. This requires careful and detailed procedures to
ensure that reports are not lost or sent in late. Regu-
latory affairs is usually the intermediary in any direct
contact between health agencies and the safety depart-
ment and other departments in the company, because
most companies prefer to carefully control and monitor
all communications with health authorities. Most com-
pany employees are not permitted to contact the health
agencies directly but must go through regulatory affairs,
whether in the home office or in subsidiaries or affil-
iates. Nevertheless, some functions/positions can free
themselves of such company constraints. For example,
the EU QPPV role, as designed by the EU regulations,
must be available 24/7 by the EMA and is required to
provide answers directly to the health agency contact-
ing him/her.
Some issues may arise if a company has been operat-
ing in only one country (studies and sales) and expands
to one or more other countries. The regulatory depart-
ment may be totally versed in US requirements but not
in the requirements elsewhere. Drug Safety and Regula-
tory will have to rapidly come up to speed on external
requirements.
The health authorities may approach the company
and request that a labeling change be made. Such com-
munications will usually go to the regulatory department
(whether in the home office or in the local affiliate, part-
ner, or subsidiary) as the point of entry into the com-
pany. This usually results in the company’s invoking an
SOP-defined process or setting up a rapid response team
or task force, including drug safety, clinical research, reg-
ulatory, medical affairs, legal and animal toxicology, to
respond to the request.
The Quality and Compliance
Department
The drug safety group interacts with the quality group
and the compliance group (which may be the same
group or different groups) both in regard to the safety
124 Cobert’s Manual of Drug Safety and Pharmacovigilance
department’s duties and in regard to assisting in techni-
cal matters when these groups are dealing with safety
issues in other departments.
For drug safety functions, the quality/compliance
group may assist and oversee preparation of SOPs, pro-
cesses, and interactions within the company to be sure
the group is handling its functions correctly. They may
also audit the drug safety group periodically and assist
in or oversee any Corrective Action/Preventive Action
Plans (CAPAs) that might be the outcome of the audit.
They will also assist in and sometimes take the oper-
ational lead in handling and responding to external
audits and governmental inspections of the drug safety
group. They may be involved in audits of investigator
sites, vendors and contract research organizations, busi-
ness partner standard operating procedures and safety
data, and manufacturing safety issues. This is highly
variable from company to company and with the terms
of the business agreement. As with legal, the quality and
compliance group should, ideally, work as partners with
the drug safety group rather than purely as overseers
and “police”.
New Business Due Diligence
When a company wishes to purchase or in-license or
out-license or co-develop a product, good business
practice requires examination of the data set for the
product to be acquired or divested. This includes the
review of manufacturing data, standard operating pro-
cedures, animal toxicology and pharmacology data,
clinical data, regulatory correspondence with the health
agencies, and so forth. The drug safety department may
be called in during this “due diligence” review to exam-
ine the clinical safety data, including expedited reports
(E2B, MedWatch and CIOMS forms), risk management
plans, PSURs/PBRERs and NDA periodic reports, clini-
cal trial annual reports and IND annual reports, health
agency queries and other interactions, documenta-
tion, archives, and all sorts of other safety information.
Sometimes the needed data are available electronically,
sometimes on paper, or both. Sometimes it is aggregate
data primarily, and other times it is less well-organized
individual patient safety information. For a drug that
has not been tested in humans or only minimally so,
the data may be sparse; for a marketed drug, it may be
extensive.
In general, the safety evaluation of a drug should
include all clinical trial and post-marketing safety data,
regulatory correspondence, and animal toxicology data.
Attention should be paid, in clinical trial data, to drop-
outs, deaths, lack of efficacy, and lost-to-follow-up cases
and any other areas where safety data might be lurk-
ing. The safety department should take the view that
the information supplied to them is data intended to
“make the sale” and as such it will highlight favorable
information and put less favorable data in the back-
ground. Although the outright hiding of safety data is
rare, it is not unheard of, and the safety reviewer should
approach the due diligence duty with healthy skepti-
cism. The safety reviewer cannot say yes or no to the
company’s in-licensing a product but must spell out the
safety and risk part of the “benefit–risk” analysis that
the company performs.
Pre-Clinical Toxicology
and Pharmacology
According to US FDA 21 CFR 312.32.c.iii, IND safety
reports are also required when there are findings from
animal and invitro studies. The regulation states: “The
sponsor must report any findings from animal or in vitro
testing, whether or not conducted by the sponsor, that sug-
gest a significant risk in humans exposed to the drug, such
as reports of mutagenicity, teratogenicity, or carcinogenic-
ity, or reports of significant organ toxicity at or near the
expected human exposure. Ordinarily, any such findings
would result in a safety-related change in the protocol,
informed consent, investigator brochure (excluding rou-
tine updates of these documents), or other aspects of the
overall conduct of the clinical investigation”. This means
that companies should have procedures in place to
review findings from such studies and make a deter-
mination of any of them pose a risk to humans. Indi-
viduals within the safety and pre-clinical teams should
ideally be asking the following questions:
The Safety Department’s Role in Cross-Functional areas 125
1. Is there an ongoing communication between
these two groups so that each are aware of the
number and type of animal and invitro studies
ongoing?
a. Is there a list of these types of studies?
b. How is safety informed of the outcome of
these studies?
2. Do we define what will constitutes a “significant
risk” when we are evaluating animal and invitro
data?
a. If defined in a SOP, who will review the cumu-
lative data to identify these risks and at what
frequency?
b. If a safety concern is identified, has the com-
pany defined day 0 for reporting purposes? It
generally is the date the decision was made
that the event may suggest a possible risk in
humans. This means that there should be a
documented decision tree, form, or minutes
that can clearly identify the time course for
identifying, evaluating, and then determining
a specific finding poses human risk.
Drug safety and PV must interact with these groups
when animal and laboratory testing results are needed
for safety evaluations and in ongoing drug life cycle risk
management evaluations. Sometimes the drug safety
group will need to go back to the animal data to ana-
lyze a signal or safety issue to see whether there were
any early clues in the pre-clinical data. Other times, the
toxicology group may call on drug safety should they
find a striking safety concern in an animal study that
may produce a 15-day expedited report. Sometimes, the
drug safety group is called on to assist, as these reports
are generally quite rare and the toxicology groups ask
for assistance from drug safety and regulatory in prepa-
ration of the submissions. But too often, the drug safety
group is forced to remind non-clinical team to contact
them if important toxicology or pharmacology finds are
noted which could impact the clinical safety.
In the EU regulations, the EU QPPV is expected
to be informed of such findings. The company may be
chastised if he/she is not informed in due time of such
safety issues.
Signaling and Epidemiology
Groups
Drug safety will often interact on a very tight basis
with these groups to supply data as well as to sit in
on sessions that analyze, evaluate, and prepare further
actions (e.g., clinical trials, epidemiology studies, regis-
tries). Coordination regarding signals noted in PSURs/
PBRERs or other reports prepared by drug safety should
be done with the signaling and epidemiology groups.
Joint meetings are usually held periodically. This varies
from company to company. In large pharma companies,
a Pharmacoepidemiology/Epidemiology group, at the
corporate level, is now a standard; this helps to manage
newly identified signals in the best and rapid manner.
The Medical Information/
Medical Affairs Department
Drug safety may interact with the internal or external
groups handling communications into and out of the
company. For incoming questions, this will include
complaints, AEs, product quality issues, and queries
from patients, consumers, and healthcare profession-
als. The safety group should ensure that SOPs are in
place that will get AEs, particularly SAEs, to the drug
safety group in a timely manner with all the appropri-
ate information allowing follow-up by the safety group.
The medical information department may also handle
after-hours communications. That is, they may set up
either internal or outsourced systems (e.g., phone cen-
ters, poison control centers) to receive after-hours AEs
and complaints. Drug safety should be sure that all pro-
cesses are in place to ensure that such AEs and com-
plaints get to drug safety promptly.
Drug safety may also supply safety information for
queries to the medical information department that go
beyond the official labeling. That is, most companies
do not allow their staff to make medical judgments or
give clinical advice on their drugs. The usual responses
follow the officially approved labeling and go no
126 Cobert’s Manual of Drug Safety and Pharmacovigilance
further. However, sometimes, physician-to-physician
requests come into the company, asking certain ques-
tions that go beyond the labeling (e.g., “Have pulmo-
nary emboli been seen with this drug and if so, what
was the course and treatment?”). The drug safety group
may be requested to supply data from its database to
answer such questions.
Manufacturing (Product
Quality Complaints)
In the signal analysis of a product, it is not sufficient to
simply examine AE data. The signal reviewer must also
review product quality complaints. It is entirely possi-
ble that the AE is due to a problem in the manufac-
turing process that produced an impurity, an unstable
product, an excipient issue, a manufacturing process, a
counterfeit product, or a vendor change that produced
unforeseen bad effects. This is surprisingly common, as
companies change vendors frequently for raw materi-
als and product containers and make process changes
when efficiencies or new machines are available. These
are all done under appropriate change control (or
should be), but unintended consequences can occur.
For this reason, the signal review must include product
quality complaints and drug safety must communicate
frequently with colleagues in the manufacturing area
when issues arise.
Falsified products (counterfeits) may lead to product
complaints or safety issues. There must be an estab-
lished process for the safety group to rapidly communi-
cate information on suspected or possible counterfeits
to the product complaint group. Whether the initial
report turns out to be a product complaint or a safety
concern the loop must be closed and supply chain secu-
rity will often engage, depending on initial findings.
General Remarks
Integrating pharmacovigilance and safety professionals
across a company is difficult and often challenging, no
matter the size of the company. One may find them-
selves often vying for “a seat at the proverbial table”,
if only to ensure the company is protected and adher-
ing to specific regulations. One of the ways to improve
cross-functional engagement is to first train and edu-
cate those in other areas. It may simply be a result of
others not knowing what our purpose is and how the
data and interactions between other GxP areas impact
pharmacovigilance. Giving the power of knowledge to
others will improve cross-functional outcomes and we
have found that by approaching other groups with an
attitude of “why we are asking these questions” instead
of “we must” and “we have to” attitudes, will lend to
a more productive and collaborative conversation. It
is also important that senior management is aware of
the need for cross-functional collaboration. Educating
them will also likely smooth the way for success.
CHAPTER
127
11
Organization of a
Typical Drug Safety
Department
T
his description covers a “stan-
dard” safety department found in a
large or mid-sized (multinational)
pharmaceutical company. Some func-
tions and divisions do not exist in
smaller companies or in companies that
do not have international or research
functions. Some functions are combined
with others. Some functions may work
with other divisions in the corporation
in addition to the safety department. In
a smaller company, one individual may
need to wear the proverbial “many hats.”
Finally, we summarize the skills needed
to work in pharmacovigilance (PV).
Introduction
There is not one single valid organization structure for
a pharmacovigilance (PV) department; each pharma
company has its own history, product types, territo-
ries, licensing partners, etc. which can explain or jus-
tify differences in each organization. The main principle
remains to ensure that the DS department head (or the
EU qualified person for pharmacovigilance (QPPV) or
the Chief Medical Officer) has real and robust oversight
of the DS organization and its performance. The goals
here are to (1) Ensure the best possible protection for
patients and the public health (2) Maintain all PV roles
and responsibilities in accordance with current regula-
tions and practices, and (3) Meet all PV obligations with
licensing partners. Below is an overview of the main
functions that are needed. Depending on the company’s
size and reach, some can be grouped or split, but gener-
ally, all of these areas should be covered in some fashion.
128 Cobert’s Manual of Drug Safety and Pharmacovigilance
Organization
The department which collects, studies, and reports
on safety information gathered from clinical trials and
postmarketing data can be called a variety of names:
Drug Safety Department, Clinical Drug Safety & Phar-
macovigilance, Global Safety & Pharmacovigilance,
Safety and Risk Management, Product Safety and Devel-
opment, etc. There isn’t one right or wrong way, but the
department title should reflect its goals and purpose
within an organization and should also have a clear
position and structure just like any other functional
area.
Generally, companies have a physician who is desig-
nated “chief safety officer”, “chief medical officer”,
or “QPPV” who is (usually) a senior-level physician
(e.g., executive or senior vice president) and is respon-
sible for the final decision on medical issues for the
corporation. This job includes decisions on product
restrictions and withdrawals, stopping clinical trials,
amending protocols, changing product labeling, and
so forth, for safety reasons. This person is either in the
senior management of the company or in regulatory
affairs or clinical research. In many companies, the
QPPV is different from the senior medical officer and
is sometimes not a physician.
There is also a functional head of drug safety, who
ensures that the department runs in a timely, orderly,
and professional manner. In smaller companies, the
chief safety officer and the functional head may be the
same person. That person is usually a healthcare profes-
sional. In larger companies, they tend to be separated,
especially if the company has several major safety units
around the world.
A typical chain of command within a safety organi-
zation would be that the unit reports directly into the
Chief Medical Officer and is overseen by a Head of Safety,
or President/Vice President of Global Safety Operations.
The remaining composition of the department will
depend on its size, the current stage of development,
and the number of products and types of products it
has. It will also depend on if the company has devel-
oped an in-house (most safety activities are performed
by company employees) or primarily outsourced (most
safety activities have been outsourced to vendors and
CROs) model.
Small to Mid-Size Companies
Small to mid-size companies can often function with
around 5–15 employees, but will also highly depend
on the structure. At a minimum, a safety department
should be overseen by a Head of Safety, reporting into
the CMO, and supported by at least 2 individuals for
business continuity purposes. Most companies in the
Phase 1 and 2 spaces will outsource these roles to
consultants or contractors until they are confident in
their products ability to meet primary and secondary
endpoints.
Large Companies
Larger sized companies, typically more than 800–1000
full time employees, will have a wider range of positions
within the safety department, and may also have different
“arms” that focus on a particular product, compound, or
device. Larger companies will also tend to bring more of
the safety operations in-house and primarily outsource
safety case processing, database management, literature
searching and social media monitoring to vendors, keep-
ing safety case medical assessment, reporting, signaling,
and benefit risk in-house.
Triage Unit
The triage unit is responsible for receiving and review-
ing, often at a single central point, all incoming adverse
events (AEs), plus, in many situations, product com-
plaints, requests for information from consumers and
healthcare professionals, requests for reimbursement,
and other medical information functions. Each incom-
ing contact is routed to the appropriate department
(person) for handling. Decisions have to be made if
a single incoming contact has several components: “I
took your pill, which was red instead of its normal blue
color; I had chest pain after I took it — is that normal?
And I want my money back.” This is a product quality
Organization of a Typical Drug Safety Department 129
complaint, an AE, a question, and a request for reim-
bursement. In general, the priority should go to the AE
and quality issue. Routes of entry of AEs are chang-
ing. Formerly, phone calls and letters were predomi-
nant. Now, phone calls, e-mail, websites, social media,
and other electronic avenues bring in many post-
marketing AEs. “Snail mail”, case reports of clinical
trial AEs, reports from a health authority, medical lit-
erature screening, lawsuits, and other assorted sources
also supply AEs.
Some drugs have more AEs reported by healthcare
practitioners and others by consumers and patients. Tri-
age must be rapid and in real time because expedited
(7- and 15-day) reports need to be acted on immedi-
ately. Serious AE cases should be reviewed with more
urgency than non-serious cases.
The triage is usually made up of both professional
and clerical personnel whose job is to do the first-level
screening of all incoming contacts. Telephone calls are
usually screened initially by call centers with or without
medically trained personnel (pharmacists, nurses) as
the initial responders. E-mail, website information and
social media as well as any other electronically arriving
AEs may first be seen by clerical or IT staff but must
be routed rapidly to medical professionals to perform
the medical triage. Snail (postal) mail with possible AE
information must be handled rapidly by personnel in
the mailroom. The clock for expedited reports begins
ticking when the information hits the mailroom or
when it is available to a member of company staff on a
computer, etc.
In multinational companies, there is usually a triage
group locally to handle phone calls and written com-
munications arriving in the local language. US phone
centers often are able to handle calls in English and
often Spanish and sometimes other languages. In Can-
ada, English and French are required. Many compa-
nies are now moving call centers “offshore”, especially
to India, the Philippines, Eastern Europe, and other
English-speaking countries, as well as to Latin America
for Spanish-language calls. Cost savings can be substan-
tial, though time zone and cultural differences may also
present significant challenges. Obviously, these centers
must function at the same level and under the same
regulatory requirements as if they were in the US. The
FDA will hold them to US standards if they receive calls
from US patients and physicians. Similarly, other health
agencies will require domestic standards to be applied
to external centers as well.
At this stage, many companies require the Triage
Unit team to record the basic information (mainly
administrative) for each case report in an IT system
(tracking tool or safety database). The purpose is not to
record exhaustive information but to check for duplicate
reports and to ensure that all case reports received are
actually recorded and not lost. If, when first received, a
report is not considered “valid”, i.e., does not include
the four validity criteria (identifiable patient, suspect
medication, AE and identifiable reporter) the report
should still be entered into the database in anticipation
of follow-up information. This will also facilitate the
next steps (assessment, prioritization, data entry, pro-
cessing, medical review, transmission) in the case han-
dling process.
Case Assessment and
Prioritization
A medical professional should rapidly review the cases
for seriousness, expectedness (labeledness), and causal-
ity (for clinical trial cases). Priority then goes to AEs
that are potentially 7- or 15-day expedited reports. The
personnel must have all the needed tools (computer
access and training, latest labeling and investigator bro-
chures, etc.).
Data Entry Unit
After triage, cases must be medically evaluated (if not
already done) and entered into the safety database (if not
already done either manually or electronically). Cases
that come in electronically, such as from clinical trial
electronic data capture programs or post-marketing
cases from online data entry forms, partner databases,
and so forth, usually do not need to be reentered unless
the sending database and the receiving safety database