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310 Cobert’s Manual of Drug Safety and Pharmacovigilance
and excess use of limited resources. However, for many
reasons, risks in one country may be quite different
from those in other countries, and tailored country- or
region-specific plans may still be needed.
Risk Management within
Pharma Companies
As with most things in life, there is no single best way to do
something (or if there is, it is never clear whose way is the
best!) Broadly speaking, the fragmentation of risk evalua-
tion at each stage of drug development has changed. For
example, in the past it was often common for the clin-
ical team to develop phase I trials based on pre-clinical
data without significant input from the group handling
later-stage development, marketing, and safety. Now, the
tendency is to develop teams with broad cross-functional
representation to meet periodically, evaluate the data to
date, and outline broad and sometimes specific areas to
be examined to evaluate and minimize risk.
In practice, this means several ways of doing busi-
ness must change:
There needs to be clear responsibility and gover-
nance in risk evaluation, minimization, manage-
ment, and change management.
Cross-functional risk teams with clearly delin-
eated responsibilities need to be in place, need to
be empowered, and need to act throughout the life
cycle of the drug.
The global players (or stakeholders) include senior
management, pharmacology, toxicology, manufac-
turing, medical research teams, regional/ affiliate/
subsidiary personnel, legal, regulatory, finance, drug
safety/ PV, epidemiology, labeling, risk management
(in the financial/ insurance sense), marketing, sales,
corporate communications, and so forth. That is, at
some point, most if not all company groups will be
involved in a large or small way. A smaller, practi-
cable working group will usually need to be formed
that reports periodically to a senior risk team.
Tools and processes need to be developed so that
each team in the company doing risk does not work
“one-off” or ad hoc.
Realistic budgets and personnel must be allocated.
Resources will be needed for the team (operational
and subject matter experts), not all of whom will do
“risk management” in addition to their day job, for
data collection from external sources and databases,
epidemiologists, surveys and drug utilization stud-
ies, post-marketing commitments, external consul-
tants, communication, and so forth.
From the IT (Information Technology) point of
view, it will be necessary for all the data needed for
the risk function to be easily accessible. This has
broad implications in terms of normalization and
standardization of data, timing of data preparation
and delivery, accessibility and data security, oper-
ational planning, task and responsibility tracking,
and planning. There should also be good tools avail-
able for signaling and document preparation. The
agencies expect this and use these tools themselves.
Quality management systems are an integral part of
risk evaluation and management.
Understand that for innovative companies and even
generic and OTC houses, the old model of sponta-
neous reporting and PSURs is ending.
Understand that health agencies talk to one other
and that a company cannot say one thing to one
agency and another thing (or nothing) to another
agency. The world is becoming more risk-averse
and more and more will be asked for in terms of
risk management.
Agencies are doing inspections, looking at post-
marketing safety commitments and REMS/RMPs in
addition to the classic PV inspection. Commitments
must be taken seriously.
Expect that all safety problems and data will
become public rapidly both through the formal
outlets (release of data by health agencies) and
by the blogosphere and social media.
The world is flat and global. A core risk plan should
be developed that will be moldable and thus useful
throughout all jurisdictions.
We are now in the mid/post-Covid world where
risk evaluation and plans have looked at by many
more people who otherwise probably would not
have thought much about risk/benefit evaluations.
This seems widespread and includes the areas of
epidemics and pandemics, lockdowns for public
health reasons, vaccination, use of new vaccines
Risk Assessment, Evaluation, Management, Mitigation, & Strategy 311
and drugs which have not undergone classic test-
ing before approval for public use. Social media and
AI are playing larger and larger roles. Where this is
heading is unclear as of this writing.
The world is flat and global. A core risk plan should
be developed that will be moldable and thus useful
throughout all jurisdictions.
Many of the large multinational pharmaceutical
companies and CROs (Clinical Research Organizations)
are now investing heavily in setting up large, interna-
tional structures and teams to handle risk, REMs, RMPs,
and the like.
Comments and Suggestions
Determine whether your company can handle risk
management internally. If not, outsource the func-
tion but realize that this is not turnkey. The pharma
company must maintain clear and continuous over-
sight and input into the vendor’s actions. Delegating
a task does not mean transferring the responsibility
which remains of the MAH.
Create a risk function in the company with a desig-
nated chief and team. It may not be a full-time task
for the participants, but the function is now abso-
lutely necessary.
Understand that “lack of evidence is not evidence of
lack”. That is, risks and safety data will accrue over
time. The drug’s best profile is on the day of launch.
It is “downhill” from there.
Do periodic (e.g., yearly) internal audits of the risk
and PV functions.
Prepare and keep up to date a risk plan using the
European Union and US template and E2E princi-
ples, which is then tailored as necessary to national
or regional requirements. Prepare a PSMF and keep
it up to date. This may include a compliance report.
Appoint and empower a chief safety officer. In the
European Union, this is obligatory and is the EU
qualified person for PV (EU QPPV). Elsewhere,
this role of a “responsible individual person” (and
sometimes a deputy to ensure 24/7/365 coverage) is
often less clearly defined. Nevertheless, this person
should be a medical doctor (or have close access to
an empowered MD) with true and real engagement
in the company’s PV activities. If outsourced, the
outsourced QPPV should be an engaged and serious
participant in the company’s PV activities. Beware
of someone who is a QPPV for multiple companies.
It’s hard enough to do it for one company.
Create a system of documented internal company
communication to be sure of safety and risk issues
in faraway (from the home office) areas are carefully
followed by a local responsible person (whether
in-house or outsourced). This refers to specific
drugs as well as regulatory and risk requirements
from the local HA. Ensure that all licensing agree-
ments, particularly local contractual obligations,
are also covered in all jurisdictions.
Keep all reference safety information (e.g., US
PI, CCSI (Company Core Safety Information),
SmPC, investigator brochures, etc.) up-to-date,
consistent, and easily available electronically.
Prepare periodic aggregate reports (e.g., PSURs/
PBRERs) for all marketed drugs whether required
or not. This, in a sense, forces periodic signaling
and safety/risk evaluations (all of which should
have an audit trail).
Ensure adequate resources (not only computer sys-
tems and money, but also personnel with appro-
priate education, training, experience, and other
relevant skills, etc.) for risk detection, prioritiza-
tion, evaluation, and management. Depending on
the situation, this may include outsourced func-
tions, epidemiologic studies, and so forth. It will
certainly involve integration within the organiza-
tion’s overall PV system.
Appoint an experienced “point person” to pay
attention to risk management, attend national and
international meetings, interact with the key play-
ers, keep up to date with new requirements, and get
“intelligence”.
CHAPTER
313
27
Drug Interactions
A
nalyzing adverse events (AEs)
and ascribing the causality to
a particular drug can be quite
difficult. This difficulty, however, is
magnified when the patient also takes
additional drugs. This is sometimes
known as “polypharmacy”. It is gener-
ally believed that the more drugs taken,
the greater the risk of AEs and the greater
the risk of drug–drug interactions. As the
number of different products increases,
the ability to ascribe causality to a partic-
ular product decreases (or even becomes
impossible). There are also other possi-
ble interactions with food, herbal prod-
ucts, diseases and alcohol and other
foods or beverages.
Introduction
Drug–drug interactions: When multiple drugs are
taken, it may not be possible to ascribe the adverse event
(AE) to one particular drug. In most situations of regula-
tory reporting, the reporter or the company is generally
required to specify one or more “suspect drugs” and, if
present, one or more “concomitant drugs”. The former
are presumed to have a suspected causative role in the
AE and the latter not. In clinical trials, the investigator
and the sponsor are usually required to specify whether
the AE is “related” to the study drug. Study protocols
will usually list contraindicated products when known.
Further complicating matters are drug interactions,
a situation that occurs when two (or more) drugs are
taken that influence each other directly or indirectly.
That is, the pharmacokinetics (e.g., blood levels) or
pharmacodynamics (effects in the body) of one or all of
the drugs may be altered.
For example, the co-administration of deslorata-
dine (Clarinex
®
) and erythromycin, ketoconazole,
314 Cobert’s Manual of Drug Safety and Pharmacovigilance
azithromycin, or fluoxetine in pharmacology studies
produced increased plasma concentrations (Cmax and
AUC
0–24h
) of desloratadine and its major metabolite but
did not produce clinically relevant changes in the safety
profile. This is an example of a drug–drug interaction
producing changes in pharmacokinetics (the plasma
levels) but not in the pharmacodynamics (no clinical
safety untoward effects or beneficial impact).
A patient may suffer from a pharmacodynamic
interaction when taking several products that share the
same adverse reaction. For example, when simultane-
ously taking aspirin and clopidogrel (both reduce the
clotting mechanism) plus a non-steroidal anti-inflam-
matory drug like piroxicam and, unknowingly, another
non-steroidal anti-inflammatory drug like ibuprofen
(both weaken the gastric lining and promote bleeding),
the patient is at great risk of gastrointestinal bleeding.
At the other end of the spectrum is a drug like war-
farin, which can be lifesaving, but which has more than
55 potential drug interactions listed by drug class and
more than 150 drugs and dozens of botanicals (some of
which have anticoagulant properties) by specific name
in the US labeling. In addition, several “disease–drug”
interactions are listed whereby these specific diseases
may produce increases in the Prothrombin Time/Inter-
national Normalized Ratio (PT/INR). The interactions
may produce elevations or decreases in the PT/INR. In
some cases, the same drug with warfarin (Coumadin
®
)
may produce an elevation in these levels in one patient
and a decrease in another patient. These changes have
the potential to produce significant clinical effects by
putting the patient at risk for hemorrhage or clotting.
It is impossible, while testing new drugs, to run
drug–drug interaction studies against all drugs or even
all classes of drugs. At best, sponsors run selected inter-
action studies against the following:
The most commonly used drugs that the exposed
patients would be likely to take because of their age,
diseases, sex, and so on;
Drugs that might be expected to produce interac-
tions based on pharmacology or in vitro data (e.g.,
cytochrome P450 metabolism) or based on histori-
cal data from similar drugs in the class.
These studies tend to be done on healthy patients
in short-term clinical pharmacology trials using the
study drug and (only) one other drug. Drugs that are
suspected of producing interactions but are signifi-
cantly toxic by themselves (e.g., cancer drugs) gener-
ally cannot be studied in this manner because of ethical
considerations.
Note that there are enormous numbers of possible
interactions. In the US, there are about 1,500 approved
drugs (if you define “drugs” narrowly since there are
over 19,000 approved drug products in the US includ-
ing generics, different formulations of the same chemi-
cal substance etc.) For these 1,500 drugs, there are 1.1
million combinations of two drugs, 562 million combi-
nations of three drugs and 243 billion combinations of
four drugs! Using the larger number of 19,000 there are
more than 10
70
possibilities for two drugs!
It is hoped that one day pharmacogenetics may pro-
vide better means of answering drug–drug interaction
questions but we are not there yet.
Cytochrome P450
Many data on drug–drug interactions are based on study
of the cytochrome P450 (CYP) system. CYP represents
a large group of enzymes whose function is primarily to
catalyze the oxidation of organic compounds, in partic-
ular drugs but also lipids, hormones, and other chemi-
cals. The enzymes are found primarily in mitochondria
or endoplasmic reticulum in cells and are distributed
throughout the body. The enzymes we are most con-
cerned about are found mainly in the liver and handle
the biotransformation/metabolism of drugs in prepara-
tion for elimination from the body. Various drugs may
increase or decrease the activity of one or more CYP
enzymes by inducing the synthesis of the enzyme or
inhibiting the enzyme’s activity. Thus, if a drug inhib-
its an enzyme, then another drug that is metabolized
by this enzyme may accumulate to toxic (ADR-produc-
ing) levels. Conversely, synthesis of more enzyme may
increase metabolism of the second drug, lowering its
levels and thus producing less efficacy (and perhaps
fewer AEs). On the other hand, if the drug absorbed is
Drug Interactions 315
a prodrug (e.g., codeine, which is metabolized to mor-
phine), an increase in its metabolism may lead to an
increase in toxicity, whereas a decrease in metabolism
will lead to decreased efficacy This may be unimportant
if a drug has a wide therapeutic window but may be
life-threatening if the window is small and critical con-
centrations of the drug are needed for efficacy.
FDA publishes a list of “Drug Development
and Drug Interactions: Table of Substrates, Inhibi-
tors and Inducers”. See https://www.fda.gov/drugs/
development-resources/drug-interactions-labeling.
The EMA provides information on its website as
re gards to Drug-Drug Interactions (https://www.ema.
europa.eu/en/investigation-drug-interactions-scientific-
guideline)
Action on the CYP system is not limited to drugs
but can be caused by herbals, tobacco use (e.g., smok-
ing), and some foods. A good example is the herbal Saint
John’s wort, which is a potent inducer of CYP3A4. If Saint
John’s wort induces more CYP3A4, drugs metabolized
by this enzyme (the drugs are referred to as substrates),
such as cyclosporine or innadivir, may be cleared more
rapidly and have less efficacy. See the Australian TGA’s
site (https://www.tga.gov.au) on St. John’s Wort and the
article “St John’s wort (Hypericum perforatum): drug
interactions and clinical outcomes” https://www.ncbi.
nlm.nih.gov/pmc/articles/PMC1874438/.
As noted above with warfarin, certain patients who
are either debilitated or suffer from certain diseases
(e.g., autoimmune disorders, cardiovascular disease,
gastrointestinal disease, infection, psychiatric disor-
ders, respiratory disorders, seizure disorders, and oth-
ers) may be at greater risk for drug interactions, and
the more severe the underlying disease, the greater the
risk.
Note the marked complexity of the issue here if
patients are taking multiple drugs. The tables and mea-
surements, which are usually based on studies done
in normal individuals during phase I and are really
qualitative. They do not indicate whether the changes
(induction or inhibition) will be large or small. This is
usually due to the great variability in individuals that is
seen in clinical trials.
Add on multiple drugs, some of which may inhibit,
some of which may induce, some of which may do either
depending on the individual, and it becomes clear that
the tables of interactions are at best guides and alerts
to pay attention to the possibility of drug interactions.
Drug–drug interaction studies of three or more drugs
are rarely if ever performed due to the challenges of
interpreting results. Thus, it can be said that whenever
someone is taking three or more drugs, there is usually
no data available on how these drugs may interact. The
patient is, in effect, an n = 1 experiment. That is, it is
not possible to accurately predict how the patient will
tolerate the new drug. The prescriber and the patient
must pay careful attention to the clinical state of the
patient after any new drug is added since there is no
good way to predict what may happen.
Drug–Food, Drug–Alcohol, Drug–
Disease and Other Interactions
It should also be noted that there are possible drug–
food (e.g., grapefruit juice), drug–nutrient, drug–dis-
ease, drug–herbal, and drug–alcohol interactions. It is
also worth keeping in mind that drug–OTC interactions
may be missed if the OTC products a patient is taking
are not asked for by the questioner or remembered by
the patient. There have been attempts to mine data
on large databases, looking for drug interactions. One
method uses the disproportionality scores for the two
drugs in question for an ADR suspected of worsening
by an interaction. Individual scores are calculated and
then an “interaction” score is determined. This method
has not been too successful or widely used. Other meth-
ods calculate confidence intervals for each drug and
compare them to a confidence interval for a combined
“virtual drug” of the two drugs combined in an attempt
to estimate the drug interaction effect.
1
1
See Leone, Magro, Moretti, et al., Identifying adverse drug reactions
associated with drug-drug interactions: data mining of a sponta-
neous reporting database in Italy, Drug Safety 2010; 33(8): 667–675;
and van Manen, Fram, DuMouchel, Signal detection methodologies
to support effective safety management, Expert Opin Drug Safety
2007; 6(4): 451–464.
316 Cobert’s Manual of Drug Safety and Pharmacovigilance
The FDA issued a guidance entitled “Clinical Drug
Interaction Studies — Cytochrome P450 Enzyme- and
Transporter-Mediated Drug Interactions Guidance for
Industry” in January 2020. To find this and other rel-
evant drug interaction documents search for “Drug
Interactions | Relevant Regulatory Guidance and Pol-
icy Documents” on fda.gov. There are also drug inter-
action “checker” tools of variable quality for drugs,
foods, and alcohol freely available on the Internet.
Some of the “checkers” occasionally point to incorrect
information.
These are primarily aimed at clinical pharmacology
and drug development rather than pharmacovigilance.
Until better methodology is developed for ascertain-
ing drug–drug interactions before widespread use in
patients, we are still at the individual patient level.
Frequency
In reality, drug–drug interactions represent a major
problem in medicine today that is not well recognized
by many clinicians. We may consider some of these to be
“medication errors” because known drug interactions
where there are significant clinical risks of either lack
of efficacy or AEs should not occur. These drugs should
not be prescribed or taken together. Electronic prescrib-
ing has significantly helped to prevent this somewhat
for both prescribers and pharmacists However, the use
of bad drug combinations is common.
In a study in Toronto, Canada, 909 elderly patients
receiving glyburide were admitted with a diagnosis of
hypoglycemia. In the primary analysis, those patients
admitted for hypoglycemia were more than six times as
likely to have been treated with co-trimoxazole in the
previous week. Patients admitted with digoxin toxicity
(n × 1,051) were about 12 times more likely to have
been treated with clarithromycin in the previous week,
and patients treated with ACE inhibitors admitted with
a diagnosis of hyperkalemia (n = 523) were about 20
times more likely to have been treated with a potassi-
um-sparing diuretic in the previous week. The authors
concluded that many hospital admissions of elderly
patients for drug toxicity occur after administration of
a drug known to cause drug–drug interactions and that
many of these interactions could have been avoided.
2
In a database study of 1,600 elderly patients in six
European countries, the subjects used on average seven
drugs per person; 46% had at least one drug combina-
tion possibly leading to a drug–drug interaction. On
average, there were 0.83 potential drug–drug interac-
tions per person. Almost 10% of the potential interac-
tions were classified “to be avoided” according to the
Swedish interaction classification system, but nearly
one third of them were to be avoided only for pre-
disposed patients. The risk of a sub-therapeutic effect
as a result of a potential drug–drug interaction was as
common as the risk of adverse reactions. Furthermore,
differences in the frequency and type of potential inter-
actions were found among the countries.
3
In the US, it is estimated that 25% of the overall
population takes five or more drugs per week. Of those
over 65, 50% take five or more and 12% take 10 or more
drugs per week.
4
Another study
5
found the possibility of a drug inter-
action in 275 older adults with polypharmacy was 80%.
The probability of at least one interaction was:
50% for persons taking 5–9 drugs,
81% with 10–14 drugs,
92% with 15–19 drugs, and
100% with 20 or more drugs.
Addition of each new drug to a 5-drug regimen
increased the risk of an interaction by 12%.
A review of polypharmacy can be found at: Poly-
pharmacy. 2022. Dona Varghese, Cecilia Ishida, Hayas
2
Juurlink, Mamdani, Kopp, Laupacis, Redelmeier, Drug–drug inter-
actions among elderly patients hospitalized for drug toxicity, JAMA
2003; 289: 1652–1658.
3
Bjorkman, Fastbom, Schmidt, Bernsten, Drug–drug interactions
in the elderly, Ann Pharmacother 2002; 36: 1675–1681; Bjorkman,
Fastbom, Schmidt, et al., Ann Pharmacother 2002; 36: 1675–1681.
For an excellent review of drug therapy in the elderly, see Bressler,
Bahl, Principles of drug therapy for the elderly patient, Mayo Clin
Proc 2003; 78: 1564–1577.
4
Toxicol Int 2012; 19(1): 68–73.
5
Ann Pharmacotherapy 2013; 47(3): 324–332, doi: 10.1345/
aph.1R621. Epub 2013 Mar 12.
Drug Interactions 317
Haseer Koya. StatPearls Publishing https://www.ncbi.
nlm.nih.gov/books/NBK532953/.
Communication
There is a growing recognition that the mechanism for
communicating medical information (in this case drug
interaction information) is not adequate and is not
achieving its goals. FDA and others have embarked on
various newer mechanisms and procedures (including
the use of social media, sometimes curated) to better
communicate safety information. Interestingly, in the
US, the responsibility and liability for drug interaction
issues seem to be falling more on the pharmacist than
on the prescribing physician, perhaps for the following
reasons:
Colleges of pharmacy in the US include courses
in their entry-level degree programs designed to
instruct students on aspects of drug interactions,
including detection, incidence and significance,
types of drug interactions, mechanisms by which
interactions occur, and the role of the pharmacist in
monitoring drug therapy to either avoid or resolve
potential drug interactions.
Most pharmacies (particularly the large national
and regional chains in the United States) and health-
care systems are heavily computerized, allowing
pharmacists to screen patient medication profiles
for potential drug–drug interactions when process-
ing new and refill prescriptions. Some software auto-
matically flags this for the pharmacist and patient
and, in certain instances, can even provide feedback
alerts to prescribers. Smartphone “checker” apps
provide convenient tools for patients, although the
information is not always strictly controlled, How-
ever, the Chicago Tribune newspaper did a “study”
of 255 pharmacies (both chains and independent
pharmacies) in which reporters, who did not iden-
tify themselves, brought in two prescriptions for
drugs that clearly should not be given together (per
the drug labeling). The pharmacies missed inform-
ing the “patients” that these drugs should not be
given together in half the cases. The range was
from 30% failure in a large national chain to 72%
in independent pharmacies; subsequently some of
the pharmacies made changes in response to the
expose’. Although one cannot necessarily gener-
alize this to all pharmacies, the message is clearly
buyer beware.
The astute “pharmacovigilant” should always be
aware of the possibility of interactions and pay atten-
tion to other medications being taken as well as OTCs,
herbals, nutraceuticals, foods, alcohol, and the patient’s
diseases for clues to interactions. Not an easy task at all!
CHAPTER
319
28
The Many Players
in the World of
Pharmacovigilance
T
here are many players in the
world of pharmacovigilance
(PV) — Companies, Govern-
ments, Non-governmental Organiza-
tions, and Others. The interactions
are complex. Alliances are formed and
severed as issues or interests change.
The groups are active in various causes
in the medical and pharmaceutical
world, touching not just on safety but
on healthcare costs, drug prices, and
healthcare availability.
Introduction
Patients who take medicines and suffer from adverse
events (AEs) are the first and primary group involved
in drug safety. Healthcare professionals make up the
next category and include those who prescribe, sell,
or dispense medications and those who also help deal
with the AEs. Other participants in the medical world
include pharmaceutical companies, pharmacies, phar-
macy/formulation committees (in hospitals and medical
groups), insurance companies, drug/pharmacy benefit
managers (in the United States), technology assessment
groups, and others who decide which medications are
made available or reimbursed and which are not.
Patients suffer the consequences of adverse drug
reactions directly and personally, sometimes suffering
dearly or even dying. Patients and their families are
becoming more sophisticated about research drugs and
treatments they take or will be willing to take. They use
the internet to check social media, websites, apps, sup-
port groups, and more. The last or first resort is a Goo-
gle search or now AI. Some sites and sources, of course,
are far more accurate and unbiased than others. Some
are misleading or downright wrong.
Yet patient perceptions are quite variable. Some-
times there may be a perception that every AE that
occurs is due to the drug, and, at other times, there is