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280 Cobert’s Manual of Drug Safety and Pharmacovigilance
be of added value. For pharmaceutical companies
with a large portfolio, the number of signals can
easily be in the hundreds. A specific IT system may
facilitate periodic overviews for the Safety Commit-
tee and may help to manage and track any “open”
safety signals. Links to relevant ICSRs can be a time
and resource saving tool if available in this IT tool/
database.
The Safety Committee
Following the prioritization and workup, a mechanism
to conclude and act on the signals is needed. This may
be a senior safety/risk management committee or it may
be an individual (the chief medical officer, for exam-
ple). Whatever mechanism is used, there must be a for-
mal written procedure to review and adjudicate signals
on a regular basis, as well as documentation of consen-
sus decisions. There should be an empowered decision
maker in the form of either a person or a committee.
For emergency signals, the committee should be able
to meet within 24 hours (or even sooner). In a pharma-
ceutical company, this could be a senior safety commit-
tee composed of the chief medical officer, chief safety
officer (if not the same person), and heads or senior
people from drug safety/pharmacovigilance, regulatory
affairs, labeling, clinical research, the legal department,
non-clinical toxicology/pharmacology, risk manage-
ment, epidemiology, and other corporate subject matter
experts as needed (e.g., formulations).
If the product is studied or marketed outside the
home country, the needs of these countries must also be
represented in the decision and action steps. The mar-
keting and sales and similar departments should not,
in general, be represented on this committee, as this
must be a medical–public health decision. In occasional
instances, outside expert consultants, as neutral as pos-
sible, given that they are paid consultants to the com-
pany, may be invited to join if appropriate. In a health
authority, the committee structure should be constituted
in a similar manner, with senior medical, toxicology,
pharmacology, labeling, risk management, epidemiol-
ogy, and legal subject-matter experts as well as any other
members needed, depending on the structure of the
health authority. Attention should also be paid to actions
of other health authorities around the world.
The safety committee needs to come to conclu-
sions about issues presented to it. It should never rou-
tinely request more data at successive meetings for a
particular problem or use other bureaucratic mecha-
nisms simply to delay a decision. Relevant data should
be requested and rapidly obtained and decisions made.
These decisions should be documented in minutes and
archived.
The outcomes should consider the public health
and risk management/minimization and what action
steps, if any, need to be taken:
1. Label change, variation, and so forth, for mar-
keted drugs (e.g., new ADR, warning, precau-
tion, contraindication); dear doctor/healthcare
professional letter; drug withdrawal and, if so, to
what level (consumer, pharmacist, wholesaler);
and communication plan to the health authori-
ties, public, and healthcare professionals.
2. Further study and consultation regarding this
signal.
3. If in clinical trials, stop or change studies to
enhance patient protection, notification of the
data monitoring committee and/or IRB, adjudi-
cation committee, changes in the investigator
brochure, and informed consent.
4. Notification of the applicable health agencies
(competent authorities) by phone, e-mail, or
letter.
5. Other follow-up actions and further review by
the committee latere.
6. Effect on the Risk Management/REMS program
in place or, if one is not in place, whether to put
one in place rapidly. If non-routine risk mini-
mization tools are required, they should be the
least burdensome on the healthcare system that
will accomplish the goal of the plan.
7. Mechanisms to handle the public announce-
ment and any issues that might arise from that,
including legal actions and adverse publicity.
8. If a REMS or RMP is in place, the signal should
be considered in context with the plan. It may be
necessary to revise, change, or update the plan
in consultation with the relevant health author-
ities. Metrics on effectiveness of tools should be
applied at pre-determined periodicity.
Signals and Signaling in the Context of Risk Management 281
9. Either inside or separate from the plan, it may
be necessary to take further risk minimization
actions, keeping in mind the potential impact
on the healthcare system.
10. Recall, withdrawal, etc.
When the committee is in a health agency, depend-
ing on legal responsibilities and regulations, the com-
mittee needs to decide on label changes, withdrawal,
and study cessation in the same manner as noted above
for companies. All stakeholders should be engaged in
the process.
For an excellent review of signaling, see Practical
Aspects of Signal Detection in Pharmacovigilance, Report
of the CIOMS Working Group VIII (2010, CIOMS,
Geneva. ISBN: 9290360828).
Computerized Tools for
Signal Detection and Workup
Several companies now produce software or tools that
can be used as add-ons to a drug safety or clinical trial
database. These programs allow for graphic displays,
tables, cross-references, lumping, splitting, and vari-
ous other ways to look at data. They are useful for large
numbers of cases when “eye-balling” the data is not fea-
sible. The programs allow for aggregate charts or dis-
plays of data in which hyperlinks allow the reviewer to
click on a bar, point, or line and see the cases that lie
behind that data point. Thus, one can look at a chart of
the most frequent SAEs and then click to see the cases
either as a case series or as individual case data. Ad hoc
queries and analyses can be done, such as analyses by
age, sex, comeds, diagnosis, and so forth. One can focus
only on outliers or particular AEs. Comparisons over
time, with different drugs and other sorts of compari-
sons, can be made. Obviously, this is data-dependent. If
there is little data, no comparative data, or incomplete
data, the tool cannot really help.
These systems vary but functions found in these
tools include a drug profile portal to document and
track issues and potential signals with built-in work-
flow and using various statistical methods, including
empirical Bayesian geometric means, relative ratios,
proportional reporting, logistic regression, Bayes-
ian multi-item gamma Poisson shrinker (MGPS), and
Kaplan–Meier plots, drill down into the data to the
patient level, “what if” scenarios, and so forth. Most
can be used for clinical trial data and safety data from
different databases. Imports of FDA FAERS and other
external database information are also possible in most
cases. There are several commercially available prod-
ucts to facilitate this.
Key Documents on Signaling
and Good PV Practices
FDA Guidance on Good
Pharmacovigilance Practices
of 3/2005
In March 2005, the FDA (Center for Drug Evaluation
and Research and Center for Biologics Evaluation and
Research) released a Guidance for Industry entitled,
Good Pharmacovigilance Practices and Pharmacoepi-
demiologic Assessment. This is an excellent document
(though several years old now) and summarizes the
FDA’s thinking on the topic. It also, to a large degree,
reflects current practices in the industry. It references
three guidances initially issued in draft form in May
2004 and finalized in May 2005:
1. Premarketing Risk Assessment;
2. Development and Use of Risk Minimization
Plans (RiskMAP Guidance); and
3. Good Pharmacovigilance Practices and Pharma-
coepidemiologic Assessment.
Note that many of the items in these guidance doc-
uments have been changed or superseded by the 2007
PDUFA/FDAAA, such as the change from RiskMAPs
to REMS. Nonetheless, these documents are still well
worth reading, as their concepts remain the same. Key
parts of good pharmacovigilance practices document
concerning signaling are as follows:
Identifying and describing safety signals: From case
report to case series;
282 Cobert’s Manual of Drug Safety and Pharmacovigilance
Case reports. The FDA recommends that sponsors
make a reasonable attempt to get complete infor-
mation for case assessment during initial and fol-
low-up contacts. Companies should use trained
healthcare practitioners. If the report is from a
consumer, consent should be sought for follow-up
contact with the healthcare practitioner. The most
aggressive efforts should be directed at SAEs, partic-
ularly those not previously known to occur with the
drug.
Case series. After an initial post-marketing sponta-
neous case report is found, additional similar cases
should be sought in the sponsor’s database, the FDA
FAERS database, published literature, and other
databases. Cases should be evaluated and followed
up for additional information where needed and
where possible. Of importance are data that would
support or reject a causal association with the drug.
Although the FDA notes that there is no interna-
tionally agreed-on causality classifications, they do
note that probable, possible, and unlikely have been
used. Cases with confounders should be analyzed
too and not routinely excluded. A grading scale is
useful in working up a signal, although for regu-
latory reporting of Individual cases, the causality
decision is binary: either related or not.
After such a review, the cases that support the sig-
nal’s further investigation should be summarized in
a table or other manner to describe the important
clinical characteristics.
The FDA refers to the use of data-mining tech-
niques, but notes that their use “is not a required
part of a signal identification or evaluation”.
The FDA then gives guidance as to which signals
should be further evaluated: new unlabeled seri-
ous AEs; an apparent increase in the severity of
a labeled event; occurrence of serious AEs that
are extremely rare in the general population; new
drug–drug, drug–food, or drug–dietary supplement
interactions; identification of a previously unrecog-
nized at-risk population; confusion about a product
name, label, package, or use; concerns about prod-
uct usage, e.g., use at higher-than-labeled doses;
concerns that the current risk management plan is
not adequate; or “other”.
Calculation of reporting rates. In a somewhat con-
troversial section, the FDA recommends that the
applicant calculate the crude AE reporting rates
using the number of reported cases of that sig-
nal AE in the United States as the numerator and
the estimate of US patient exposure (as patients
or patient-time) as the denominator. Where fea-
sible, the reporting rates over time or versus sim-
ilar products or drug classes or versus estimates
of the background rate for this even in the general
population may be useful. The FDA does warn,
however, that these figures are generally used for
exploratory purposes or for hypothesis generation.
They note that reporting rates are not incidence
rates. In practice, use of these figures is fraught
with danger. The numerator is bad because there
is always underreporting of an unknown degree;
the denominator is worse because it is hard to
know how many patients truly took the drug (as
opposed to filling the prescription) and for how
long. Thus, the ratio is often meaningless. A high
reporting rate may suggest that the signal is real,
but a low reporting rate does not exonerate the
drug.
Investigating a Signal
Pharmacoepidemiologic studies are cited
by the FDA. There are various types of non-ran-
domized trials that can be done, including cohort
(prospective or retrospective), case-control, nested
case-control, and others. They can be done at any
time (before or after marketing), although they
are often done after a signal has been suggested
by post-marketing adverse events. The FDA sug-
gests that bias be minimized and that confound-
ing be accounted for. They also suggest that “it is
always prudent to conduct more than one study, in
more than one environment and even use different
designs”.
Registries. The FDA defines a registry as “an
organized system for the collection, storage,
retrieval, analysis and dissemination of information
on individual persons exposed to a specific medical
intervention who have either a particular disease, a
condition (e.g., a risk factor) that predisposes
[them] to the occurrence of a health-related event,
or prior exposure to substances (or circumstances)
Signals and Signaling in the Context of Risk Management 283
known or suspected to cause adverse health
effects”. A control or comparison group should be
included where possible.
Surveys. Without clearly defining surveys, the
FDA recommends that they be done when infor-
mation gathering is needed. For pharmacoepide-
miologic studies, registries, and surveys, the FDA
encourages consultation with the agency before
beginning.
Interpreting a Signal
The FDA recommends that the sponsor conduct a case
level/case series review, using data mining and calcu-
lating reporting rates where feasible. Then the sponsor
should consider a further study to establish whether a
safety risk exists.
When the applicant believes an important safety
risk is possible, a synthesis of all information should
be prepared and submitted to the FDA, including the
following:
Cases (spontaneous and literature) with exposure
information;
The background rate for the event in general and
the specific patient population(s);
Relative risks, odds ratios, or other pharmacoepide-
miology study results;
Biologic effects from animal work and pharmacoki-
netic and dynamic studies;
Safety data from controlled clinical trials;
General marketing experience with similar
products.
The applicant should provide an assessment of the
risk-to-benefit balance for the population as a whole
and for at-risk groups (if any). The FDA notes that this
is an iterative process, and not all actions described in
the guidance are done at all times. Proposals on further
steps should also be provided along with risk minimi-
zation actions. The FDA then makes its own judgment
based on the data.
The FDA recommends that applicants develop
and continually reevaluate their risk management
plans. In some cases, post-marketing reporting of
spontaneous AEs will suffice. In other situations,
much more may be needed. The FDA notes it may
bring potential safety risks to its Drug Safety and
Risk Management Advisory Committee or the spe-
cific advisory committee dealing with the product in
question.
These actions described above represent a careful,
step-by-step, well-planned proposal for investigating a
signal that allows a thoughtful and logical response to a
signal. In many and probably most situations, especially
those for non-serious signals or drugs not in the public
eye, this process unfurls as described above. However,
for situations that make the public eye, e.g., Vioxx, Fen-
Phen, the pressures to act before all the evidence is in or
assessed are enormous.
Signal review does not occur in a vacuum. Multiple
influences play a role as follows:
Changes in personnel in the company or the reg-
ulator may cause loss of continuity in a signal
investigation;
Publicity from consumer groups, the media, patient
advocacy groups, and other companies, some of
which may be premature or unnecessarily scary and
inflammatory;
Lawsuits;
Actions by other health agencies outside your
jurisdiction;
The time needed to prepare and carry out whatever
actions are proposed, such as registries, studies,
data mining, and surveys;
Further spontaneous reports or lack thereof during
the investigation (“Oh no, we just got another
case!”);
Pressures from various areas to continue marketing
or to stop marketing;
Extreme positions based on little data;
Sponsor marketing and financial pressures (lost
market and money);
Pressures on the regulatory agencies (legislatures,
companies, consumer groups, media);
Pressure to do interim analyses or to stop ongoing
trials (often for different indications) of the drug in
question, which may jeopardize the integrity of the
study;
Privacy and data protection issues.
284 Cobert’s Manual of Drug Safety and Pharmacovigilance
In addition, the points of view (“agendas”) of the
protagonists in the drama are clearly different in many
regards, although everyone really does want to protect
the public health and not hurt people. The following
are the points of view using some of the language each
group might use to make its case:
The company wishes to protect its (enormous)
investment in a product that took years to develop
and to market and that is paying the salary of hun-
dreds or thousands of employees. A “handful” of
not clearly proven cases with causality in doubt
should not be made public and should not be
allowed to “destroy” the drug before the full sci-
entific and medical investigations are completed.
The drug is clearly helping the “vast majority” of
the patients using it, and the possible occurrence
of AEs (even serious ones) should not deprive the
rest of the public of the product. Because the drug
has a finite life, i.e., patent expiration, the com-
pany believes it must protect it as much as pos-
sible. The investigation of the signal should be
done in private without release of the “debate” to
the public. Even if the drug is totally exonerated
after the signal investigation, there is usually lost
market share and harm to the product. Within
the company, no one wants to be the one to “kill
the drug”, because this can be a career-ending
and a stock price-destroying event. Lawsuits will
doubtless follow (often no matter what the result
of the signal investigation), and the personal and
financial liability can be enormous. When law-
suits occur, employees move into defensive mode,
spending more and more time with attorneys. In
summary, the company will, of course, do the right
thing, but only when the data are in and the sci-
ence is clear. It will not act prematurely.
The regulatory authority wishes to protect the pub-
lic health as its primary goal. It wants to do this as
early as possible to minimize the risk to the public.
Better to err on the side of patient protection than
to allow a toxic product to stay on the market (or
remain inadequately labeled) for too long, partic-
ularly when therapeutic alternatives are available.
The agency cannot appear to be too cavalier with
the data or to “be in the pocket of the drug compa-
nies”. It is also far easier to take the position against
the “big bad drug companies”. In some sense, the
drug should be considered guilty until proven inno-
cent. Primum non nocere (“Above all do no harm”)
is an aphorism originally attributed to the ancient
Greek physician Galen, but it more likely arose in
the seventeenth century. If something bad happens
in the US, the Congress, the Secretary of the Depart-
ment of Health and Human Services, the media, and
the consumer groups will attack the companies and
the FDA unmercifully.
With various watchdogs in action, e.g., www.
drugwatch.com, more data (much unconfirmed
and incomplete) will be released earlier. This will
both help the agency protect itself and get the infor-
mation before the public, but it will also change the
shape of the investigation and diminish the use of
the drug, perhaps prematurely.
Consumers want totally safe and totally effective
drugs with no risk (and often for free). When bad
things occur (because the companies are suspected
of withholding data or did not do their job or the
FDA may have acted too quickly and did not do
its job), someone is at fault and someone must pay
and be punished. All data should be available, and
the entire process should be transparent. In general,
better to err on the side of stopping the use of the
drug than continuing its sale and use. And drugs
are, indeed, guilty until proven innocent. However,
this calculus may be different for products with
much competition versus a truly unique product
that treats an otherwise unmet medical need.
The media are delighted when the spectacle plays
out, especially with data dribbling out over time
and errors with alleged misdeeds by the company
or the FDA surfacing. The more sensational, the
more errors or inappropriate or illegal actions,
the more individuals hurt, the more stonewalling,
the more the story captivates the public, moving
into websites, and blogs, paywalls and TV time.
For competing pharmaceutical companies, there
are mixed feelings. Clearly, what is happening to
another company could happen closer to home at
any time, too, with one of their products. However,
the competitors are not unhappy if more patients
now switch to their drugs rather than using the
competitor product that is undergoing a signal
investigation. And finally, there is an element of
Signals and Signaling in the Context of Risk Management 285
Schadenfreude (from the German meaning “plea-
sure taken from someone else’s misfortune”) that is
common in human nature.
All of this suggests that, rather than thinking of the
signal investigation process as a careful, rational, well-
planned program done in a timely and deliberate manner,
one should rather think of the process, for dramatic or
serious issues, as the “fog of war”, with multiple pressures
(some known and some unknown to each player) acting
to force rapid and urgent “action” to protect the public.
The consequences of whatever action is taken may
have far-reaching and irreversible effects. Drugs that are
withdrawn rarely return to the market even if the signal
has subsequently been disproven. Label changes adding
a new safety warning, AE, or other are rarely taken out
of the label even if disproven. The change in medical
practice to the use of different drugs (which may be
more or less expensive, available, effective, safe, etc.) is
similarly hard to reverse.
EU GVP Module
IX — Signal Management
(2012: Revision 1, Delivered
Nov 2017)
This GVP module:
Provides general guidance and requirements on sci-
entific and quality aspects of signal management;
and
Describes roles, responsibilities and procedural
aspects in the setting of the EU signal management
process overseen by the Pharmacovigilance Risk
Assessment Committee (PRAC).
“This module is applicable to medicinal prod-
ucts for human use authorized in the EU
irrespective of the authorization procedure
(centralized or national procedure, including
mutual recognition and decentralized).”
“Unless stated otherwise, the guidance pro-
vided in the Module applies to all organizations
involved in signal management, i.e., market-
ing authorization holders, national competent
authorities and the European Medicines Agency
(the “Agency”).”
“Individual organizations may follow alterna-
tive signal management processes and termi-
nology but should encompass the general prin-
ciples outlined in this module.”
“An addendum to this module, the GVP Mod-
ule IX Addendum I, describes methodological
aspects of signal detection from spontaneous
reports of suspected adverse reactions.”
The EU signal management process includes the
following activities:
Signal detection: To look for or identify signals
from any source (spontaneous and/or clinical trials
ICSRs, post-marketing studies, publications, large
database analysis such FAERS, EudraVigilance,
etc.) and inform concerned competent authorities
(a 1-year pilot involving MAH evaluation of Eudra-
Vigilance data is conducted starting in 2018);
Signal validation: Process to conclude that the
available information to support or refute a new
potentially causal association;
Signal confirmation: Endorsement of the signal
by the PRAC for further work-up;
Signal analysis and prioritization: Process to
identify signals suggesting a potentially important
impact on patients or the public health or which
may significantly affect a product’s risk-benefit
balance;
Signal assessment: Further evaluation taking
into account all available evidence, to determine
new risks or whether known risks have changed;
Recommendation for action by the MAH:
May include, but not limited to, Product Informa-
tion update, additional risk minimization measures,
Direct Healthcare Professional Communication
(DHPC).
The description of the MAH signal management
process must be included in the Pharmacovigilance Sys-
tem Master File. Its performance must be kept under
control (KPIs and Governance). Within each MAH
286 Cobert’s Manual of Drug Safety and Pharmacovigilance
organization, the signal detection and management pro-
cess is under the full responsibility of the EU QPPV; the
EMA and/or the PRAC address questions and requests
directly to the EU QPPV without involving other teams
(Regulatory Affairs, for instance).
The EU QPPV is responsible for ensuring manage-
ment of emerging safety issues (safety issue considered
by the MAH to require urgent attention because of the
potential major impact on the risk–benefit balance and/
or on patients’ or public health, and the potential need
for prompt regulatory action and communication to
patients and healthcare professionals). Such issues are
to be reported to the concerned EU competent authori-
ties on an urgent basis.
Any signal, validated by an EU competent authority
or provided to the Agency by the MAH, must be con-
firmed (or not) within 30 days by the PRAC. It is then
entered into the European Pharmacovigilance Issues
Tracking Tool (EPITT) and requires further analysis
and prioritization by the PRAC.
Depending on the signal, various recommendations
can be delivered by the PRAC (non-exhaustive list) are
as follows:
MAH
Request for additional data;
Review of additional data in the next PSUR/
PBRER;
Update of the product information (labeling);
Submit an RMP or update the RMP;
Add risk minimization measures to the current
RMP;
Sponsor a post-authorization safety study.
Health Authority
Collect further information and/or perform
additional analysis (national Agency or EMA);
Consult other EMA scientific committees or
expert groups;
Initiate an MAH inspection.
Note: Figures detailing the process to be followed
by each stakeholder (MAH, National Agency, EMA,
PRAC, CHMP, CMDh, etc.) are appended to GVP
Module IX.
The following documents provide additional guid-
ance relevant to signal management:
Report of CIOMS Working Group VIII on Practical
Aspects of Signal Detection in Pharmacovigilance;
SCOPE Work Package 5 — Signal Management —
Best Practice Guide;
EMA Questions & Answers on Signal Management;
Screening for Adverse Reactions in EudraVigilance.
Further expectations for the signal manage-
ment process have been outlined by EMA in “Ques-
tions & answers on signal management” (2016,
EMA/261758/2013 Rev 2-Corr 2), Question 3, and are
as follows:
“The signal management process consists of
detection, validation, confirmation, analysis
and prioritization, assessment and recommen-
dation for action.”
“Signal detection is the act of looking for and/or
identifying signals using data from any source.
Signal detection usually involves a combination
of statistical methods and review of individual
case safety reports, as well as any relevant source
of information (e.g., scientific literature).”
“Signal validation is the process of evaluating
the data supporting the detected signal in order
to verify that the available documentation con-
tains sufficient evidence demonstrating the exis-
tence of a new potentially causal association or
a new aspect of a known association, and there-
fore justifies further analysis. The clinical sig-
nificance of the signal, its previous awareness,
the biological and temporal plausibility and any
relevant sources of information supporting the
association are taken into consideration. Sig-
nals validated by the EMA or Member States
are entered in the European Pharmacovigi-
lance Issues Tracking Tool (EPITT). EPITT is
a database developed by the EMA to promote
the communication of pharmacovigilance and
risk management issues between the EMA and
Member States. Signals for which the validation
Signals and Signaling in the Context of Risk Management 287
process was not supportive of a new potentially
causal association, or a new aspect of a known
association, are not entered in EPITT.”
“Signal confirmation means communication
via EPITT, within 30 days of its receipt by the
Rapporteur, the lead Member State or a national
competent authority that the validated signal
is confirmed or not confirmed. Any confirmed
signal should be analyzed and prioritized by the
Pharmacovigilance Risk Assessment Commit-
tee (PRAC).”
“Signal analysis and prioritization are per-
formed by taking into account the potential
impact of the signal on the benefit–risk profile
of the involved medicine(s). The prioritization
dictates the time frame for the subsequent steps
of the evaluation of the signal.”
“Signal assessment is the scientific evaluation of
all the evidence available, including additional
data from MAHs, where applicable.”
“The steps of analysis, prioritization and assess-
ment result in a PRAC recommendation.”
The EMA Q&A document contains additional
stakeholder questions on safety signal management and
EMA responses to those questions. The document is
based on an earlier Q&A document prepared by MHRA.
There is practical information on PRAC evaluation of
signals and, in addition to the above-captioned docu-
ments, is well worth reading.
These are the questions posed in the EMA Q&A
document:
1. What is the legal basis for signal management in
the European Union (EU)?
2. What is a safety signal?
3. What are the steps of the signal management
process?
4. Who is involved in the signal management
process?
5. What should MAHs do if they detect a signal?
6. Which medicinal products can be concerned by
a signal?
7. When and how are MAHs informed that a sig-
nal for their medicinal product is being investi-
gated by the PRAC?
8. How does the PRAC prioritize signals?
9. What could be the PRAC recommendation?
10. Where are the PRAC recommendations on sig-
nals published?
11. When and how are MAHs informed that addi-
tional data are requested?
12. Are additional data requested of all MAHs with
a marketing authorization for a medicinal prod-
uct concerned by the signal?
13. Can MAHs submit additional data on a volun-
tary basis?
14. How and to whom shall MAHs submit their
responses?
15. Who is the contact point for MAHs within the
regulatory network?
16. What are the timelines for assessment of addi-
tional data by the PRAC?
17. Do MAHs receive the assessment report (AR)
on the data submitted?
18. What should MAHs do if the PRAC recommends
a variation to their marketing authorization?
As noted earlier, it is likely that AI will introduce
major changes and (hopefully) improvements in the
field of signaling. Watch this space.
Frequently Asked Questions
Q: Again, why would anyone want to work in
drug safety for a living?
A: For many reasons. Signal detection, analysis, and
management usually present a fascinating exercise
requiring medical, investigative, tactical, logical, and
political skills. One really is acting to help the pub-
lic health. Most signals, perhaps the vast majority,
are rather unextraordinary and non-serious and can
be worked up in a thoughtful and timely manner. In
these instances, it is very satisfying. Similarly, even in
the dramatic instances, the right thing usually does end
up being done, and that also is quite satisfying. The
probability of a horror scenario is less likely, but that
288 Cobert’s Manual of Drug Safety and Pharmacovigilance
is the risk one takes in this business. As with signaling
(and most of life), it all boils down to a benefit-to-risk
analysis.
Q: Should the companies try to find signals
before the health authorities? If the FDA or
the EMA picks up the signal before the com-
pany, isn’t that a “failure” on the part of the
company?
A: This is not a contest in which the fastest pick-up
wins. The goal is bettering the public health. Sometimes
the company picks up the signal first; sometimes the
agencies do. Often, the health agencies see more data
than the companies and often the agencies see the safety
profile of similar drugs in that class. Also, when par-
ticularly gnarly safety concerns arise, regulators have
agreements to share information across jurisdictions
and they regularly do so. They may thus, have a broader
overview and their case series may be more complete
than that of the companies. What may be a weak sig-
nal to the company may be seen in many or all of the
drugs in the class, making it a much stronger signal.
Drug safety is tough enough as it is; don’t beat yourself
up any more than necessary!
CHAPTER
289
26
Risk Assessment,
Evaluation,
Management,
Mitigation, & Strategy
R
isk is a broad concept and applies
to everything in life. We take
risks when we drive a car, go to
work, eat a meal, walk across the street,
or take a drug. Benefit–risk manage-
ment of drugs continuously evolves as
a distinct science and is a very import-
ant function that aids the patient and
healthcare professional, as well as the
health authorities and drug companies,
in decision-making. This chapter looks
at risk, first from a global perspective,
and then as applied to drug therapy in
the United States with risk evaluation
and mitigation strategies (REMS), and
in the European Union with risk man-
agement plans (RMPs). We work on the
presumption that the ongoing process
of benefit-risk assessment will ulti-
mately lead to decreased harm caused
by products. This, in fact, remains to be
seen. Of course, risks must always be
considered in the context of a product’s
benefits.
Introduction
The ultimate goal for any new product when being
developed, or already on the market, is to prove (and
maintain through close and careful monitoring) that
the benefit of the product outweighs the known or
potential & perceived risks of that product. The ben-
efit-risk assessment of a product for its proposed indi-
cation is a case-specific determination that requires a
thorough assessment of the extensive evidence of safety