Mitigate

Data Overload
With Proactive
Pharmacovigilance

MITIGATE DATA OVERLOAD WITH PROACTIVE PHARMACOVIGILANCE / 1

 Surveillance of pharmacovigilance (PV) and product quality-complaint
(PQC) data is not a new activity. For years we have known that adverse
events temporal to drugs occur. Moreover, they are consistently
underreported, impacting analysis of the data in unknown ways.1,2
Nearly every regulatory authority across the world has guidance and
requirements in place for marketing authorization holders to monitor
the safety and risk/benefit profile of their products for potential “signals
and trends” and for an honest assessment of the risk/benefit profile
of the product over its entire lifecycle. The spirit of this monitoring is
to alert the healthcare provider, regulatory authority, and the patient of
any changes related to the product. This is to mitigate the risk of these
events occurring in excess and minimize the severity. In PV, the main
objectives are to keep patients safe, keep drugs in proper risk/benefit
balance with the disease for which they are intended to treat, and to
provide treatment options to patients quickly.
In a perfect world, utilizing PV data in real time can improve patient
outcomes by identifying potential drug-drug or drug-disease
interactions, AE trends, or benefits not realized in clinical trials. The
world is imperfect, however, and we are now rapidly moving to a more
1
Alatawi and Hansen
2
Bailie and Verhoef
2 / MITIGATE DATA OVERLOAD WITH PROACTIVE PHARMACOVIGILANCE
complex regulatory environment at a higher rate of speed. There are
several ways to overcome the challenges of complex large volume
data and resource constraints and still fulfill the responsibility of patient
safety, which is at the center of all we do. In addition, we utilize PV
data to be good stewards of organizational growth.
Despite technology advances supporting PV activities, not changing
the way of working with PV data leaves most researchers struggling
to obtain a deep understanding of the data. In analyzing the data
retrospectively, if a change to the AE profile occurs, one simply cannot
pivot early and control outcomes. The knowledge gap from the science
of pharmacovigilance to the actual implementation into clinical practice
still exists. Worse, the value of pharmacovigilance is underrated and
still considered by many as a necessary exercise and nothing more.
This lack of vision in the value of the PV data is unfortunate. A unified
community of mixed science, clinical, regulatory, and technology
providers, can partner to overcome the negative cloud of the cost of
good PV practices. View the data in a positive light to demonstrate that
it is not only for patient safety, but it can be used strategically within an
organization as a return on investment.
Historical Perspective of AEs, Pharmacovigilance,
and Clinical Therapeutics
As early as the 1980s, it was recognized
that prostaglandins were important in renal
function, especially in hypertensive patients.
Prostaglandins preserve and maintain renal
blood flow and thus healthy renal function.3,4
In 1982, one of the first peer-reviewed
publications appeared in the literature
indicating the adverse effect of non-steroidal
anti-inflammatory drugs (NSAIDs) in patients
with hypertension.5,6 NSAIDs were shown to
diminish the control of blood pressure in treated
hypertension patients. Common NSAIDs such
as ibuprofen, naproxen, and aspirin are staple
drugs for the treatment of mild/moderate pain
from a variety of conditions and are available
in most countries as OTC products. They are
effective analgesics because they block the
enzyme cyclooxygenase which downstream,
blocks the production of prostaglandins;
mediators of pain but also important mediators
of appropriate renal blood flow and protection
of the gastric mucosa. The protection of gastric
3
Vane and Botting 7
Bjarnason and Thjodleifsson
4
Vane 8
Prichard and Hawkey
5
Mills 9
Floor-Scheudering
6
Lewis 10
Varga S
mucosa lends a familiar reference to NSAIDs
and their known AE of gastric irritation. Ranging
from mild heartburn to severe ulcerations and
bleeding, NSAID inhibition of protective gastric
prostaglandins can limit the use of these drugs
in some patients.7,8
The use of NSAIDs in hypertensive patients had
both an interaction with antihypertensive drugs
and had negative impact on blood pressure
control. Since that time, there have been
hundreds of peer-reviewed studies confirming
this association.9,10
Despite the longevity of knowledge of this
therapeutic group of drugs, there continues to
be a high rate of adverse events in hypertensive
patients who are prescribed NSAIDs or
take them as OTC medications. The data
is conclusive that hypertensive, congestive
heart failure, and other cardiovascular disease
patients have a higher rate of adverse outcomes
of existing disease with NSAID use.11,12
11
Barthelemy
12
Zhao
13
Varga
MITIGATE DATA OVERLOAD WITH PROACTIVE PHARMACOVIGILANCE / 3
In a retrospective study by Varga et al. in
2019 involving more than one million patients
followed over 10 years, more than half of the
patients received a potentially inappropriate
(drug-drug or drug-disease interacting)
medication.13 Meaning, there was a known
risk of drug-drug or drug-disease or special
patient considerations where the drug should
not have been prescribed. In this patient
cohort, hospitalization risk was increased in
patients who received drugs that had known
drug-drug or drug-disease interactions.
Not surprisingly, NSAIDs were the drug class
with the highest rates of adverse events
that led to hospitalizations. As with any
product, AEs are temporal to the use of the
medication. They are not always causal, but
in the case of NSAIDs and certain patients,
there is enough data to confirm with clinical
and scientific certainty that the relationship
between out-of-control blood pressure and
NSAID use in hypertensive patients exists.
 In a comparative retrospective study in 2016 by Shehab et al., the
investigators found that in 56 Emergency Departments across the
US, 4/1000 visits were due to drug adverse events, and of those,
27% resulted in hospitalization.14 An adverse event so serious that it
requires hospitalization does no one any favors. Many in this study
could and should have been prevented. Shehab et al. reported that
34.5% of patients were older than 65 years of age (high-risk patient
population), a rise in hospitalization by 8% in less than 10 years. In this
study, anticoagulants and drugs for diabetes comprised 47% of the
ED (emergency department) visits and included known AEs such as
hemorrhage, allergic reactions, and hypoglycemia. More wrenching is that
antibiotic-related AEs were the most common drug class in children less
than five years of age that required ED evaluation.
Similar findings were reported by Jolivot et al. in 2016, in which 743 ICU
patient admissions were categorized into preventable AEs, unpreventable
AEs, and the control group.15 Similar to Shehab et al., Jolivot and
colleagues found that 23.3% of 743 consecutive ICU admissions were
due to an AE. Further, 13.7% of those AEs were preventable, and 9.6%
ICU admissions were due to unpreventable AEs. In total, 102/173
AE-related ICU admissions were preventable. The 102 preventable AE
related ICU admissions (59%) accounted for a total of 528 days of ICU
hospitalizations and an associated cost of €747,651.
Hence, the knowledge gap and the result is not surprising. This study
shows that predictable and known AEs can have a significant negative
impact on patients.
14
Shehab 17
Maniadakis
15
Jolivot 18
Costa
16
Kumar 19
Merigian
4 / MITIGATE DATA OVERLOAD WITH PROACTIVE PHARMACOVIGILANCE
NSAIDs are not the only class of drugs with AEs frequently seen in
medical literature. In 2017, Kumar et al. reported adverse events in
outpatients with mental disorders, including schizophrenia, bipolar disease,
and depression.16 Even at a fairly young mean age (32 years), more than
40% of patients reported sedation and 25% reported weight gain. While
sedation and weight gain seem to be small tradeoffs for disease control,
sedation and weight gain are common reasons that patients discontinue
mediation­­­–often without informing their health
care provider.
In the PV world, non-compliance is often reported as an AE. For example,
a report of a lack of drug effect or lack of efficacy can be the AE reported
when in reality, if you don’t take the drug as prescribed, it can’t be
expected to work. Or, non-compliance can result in the progression of
underlying diseases and sequelae. For example, a patient with diabetes
who does not adhere to their insulin regimen may report an AE of renal
impairment or loss of vision, a well-known sequelae of uncontrolled
diabetes. Anyone who has to fight with the big chain mailorder pharmacies
to get their drugs approved, much less delivered on time, understands that
non-compliance can be a complicated, multi-factorial problem.17,18,19
Can we really expect favorable outcomes when we do a poor job in
bridging the knowledge gap between pharmacovigilance data and clinical
treatment? Is this a knowledge gap or are we so overwhelmed by just
performing PV practices for compliance reasons that we lose sight of
what the data means to healthcare providers and patients and do not seek
meaningful ways to bridge that gap? We are clearly not learning or paying
attention to the data, not because we are lax, but because the volume
of data is overwhelming. Many investigators have looked at technology
solutions to ease this burden but to date, no one approach has proven to
be truly effective.20,21,22,23
Even with the decades of scientific and clinical awareness that AEs
drive poor clinical outcomes, interfere with other treatments, and
negatively impact disease progression, we still struggle with known
drug-drug interactions, underreporting, and drug-disease interactions.
Despite our wealth of knowledge, upwards of 30% of AEs are due to
known drug-drug interactions.24
By 2013, the drug realized more than $110M in revenue.26 It’s important
to note that this example of return on investment coming from early AE
data and astute PV awareness of the data.
There are multiple other examples in medical literature (see table on
the following page) demonstrating how adverse event (AE) profiles
(including off-label use or misuse) drive new indications for known
drugs, which as a result, helps increase ROI and positive patient
outcomes.27,28 Whether it be a new indication or a contraindication
leading to better outcomes, the examples provided below show the
value of AE data.

PV Return on Investment Challenges With Systems

All AE data holds value; how that value is determined takes an astute
scientific approach to surveillance. In 2001, the medical literature
began to include the results of a different approach to the treatment of
glaucoma and ocular hypertension. The class of drugs was relatively
new, and the mechanism of action increased the outflow of aqueous
humor and thus decrease intraocular pressure (IOP). For one of the first
times, unstable prostaglandin molecules (mediators released from the
COX pathway) were mimicked in stable molecular analogs: bimatoprost,
travoprost, and latanoprost.
One of the early AEs consistently emerging in these clinical trials
was increased eyelash length, thickness, and growth, notable after
one to four months of consistent use of the drug, not to mention the
effective decrease in IOP.25 By 2008, Allergan had an approved NDA for
(latanoprost) Latisse®, with a second indication for eyelash growth.
Looking at a PV system holistically, there are interconnected,
interdependent parts. Understanding how those individual parts function
independently, as well as their impact on the entire system, is important.
Breaking it out we have:
1. AE/PQC intake/capturing information
2. Storing the data and processing it (AE database)
3. Data surveillance (analysis and understanding what the data is
telling you)
4. Reporting (regulatory as ICSRs, aggregate, and sharing information
internally and externally with other stakeholders)
Subject matter experts work across or within the components. Supporting
the entire system are regulatory, compliance and quality, and technology
resources.

20
Nuckol 23
Ross 26
Allergan
21
Westphal 24
Iver 27
Alatawi
22
Correa 25
Easthopse 28
Bailie

MITIGATE DATA OVERLOAD WITH PROACTIVE PHARMACOVIGILANCE / 5

 The chart below illustrates that while drugs were initially approved for one indication, the post-marketing surveillance of AEs helped identity
secondary indications.

Secondary Indication
Drug Primary Indication Reference
from AE Data

Anti-platelet effect to decrease

the risk of coagulation for
Pyrexia, analgesic, prevention of MI, and other
Aspirin
rheumatoid arthritis cardiovascular events (lower
dose than for analgesia, i.e., 81
mg vs. 325 mg for analgesia)
Smith JB et al., 1971; Vane
et al., 1971; Bates and
Topol, 1989; Schrader BJ
and Berk SI, 1990

Hyperhidrosis, wrinkle Ghavimi et al., 2019, Munoz

Botulinum toxin Spasmodic dysphonia reduction, migraine, et al., 2019, Dima et al., 2019,
temporomandibular syndrome Whitcup 2019

Prevention/minimization
Kalil et al., 2008, Stratigos and
Isotretinoin Acne vulgaris of pigmentary
Katsambas, 2005
disorders, photoaging

Hypertension, Symptoms of stage

Beta-Blockers Neftel et al., 1982
cardiovascular disorders fright, migraine

6 / MITIGATE DATA OVERLOAD WITH PROACTIVE PHARMACOVIGILANCE

There are a host of factors that influence the value of each individual
component of the PV system. If one is not working optimally, the system
in its entirety will not work to its full potential to render the correct and
useful data. As an outcome, there could be a misleading interpretation
from the analysis of the PV data.
What can be done to minimize the old “garbage in = garbage out?” First,
we must identify and overcome/mitigate the challenges that impact each
component of the PV system. It is only then that we can move from a
reactive PV system to a proactive one.
How does a reactive PV versus proactive PV example look? We will
evaluate both approaches using hypothetical scenarios.
Reactive Pharmacovigilance
Company A launches a first-in-class drug/device combo biologic for the
treatment of psoriatic arthritis. The drug has a novel mechanism of action.
In clinical trials, the American College of Rheumatology response was
26 weeks. The drug is dispensed as a self-injectable to the patient after
the patient has undergone the proper screening and education for self-
administration.
The launch of the drug is complicated by the lack of support from
payers and providers due to the cost of the medication, even though the
clinical trial data overwhelmingly shows that in the majority of patients,
symptoms of disease and long-term sequelae are delayed. The payers
and providers are concerned that the high cost of the drug and its benefit
will be offset by a lack of patient compliance. Once-weekly dosing has
been shown to be a compliance challenge and compounding this particular
therapy is the ability of the patient to self-inject.
The early post-marketing period showed that a lack of drug effect was the
most-common AE reported (16-20 weeks post-launch) with more than
90% of all AEs reporting no change in clinical symptoms or resolution of
plaque size and number. Post-marketing data at 36 weeks showed 86%
of all AEs were lack of effect and disease progression despite Company A
ruling out product quality issues.
Company A continued to monitor the lack of effect and at 52 weeks
post-launch, 38% of patients who had begun therapy at launch had
discontinued the product. Notable AEs were not different from those
observed in clinical trials other than a higher percentage of patients who
complained of difficulty in the administration of the drug with the device,
stinging/localized irritation at the site of injection, and the continued
high reporting of lack of effect. PQC investigations using retain samples
did not show any differences in pH, rate of product administration or
other interactions between the product and the delivery device (i.e., no
secondary issues with drug/vehicle contact with syringe/needle and
storage method.
Company A is notified by the regulatory authority to engage in discussions
regarding the risk/benefit of the product, and there is no positive
movement for payer providers to cover the cost of the promising drug
from its clinical trial experience and early post-marketing experience.
Now that we’ve discussed a reactive pharmacovigilance approach, let’s
look at proactive pharmacovigilance.
MITIGATE DATA OVERLOAD WITH PROACTIVE PHARMACOVIGILANCE / 7
 Proactive Pharmacovigilance
Company A launches a first-in-class drug/device combo biologic for the
treatment of psoriatic arthritis. The drug has a novel mechanism of action.
In clinical trials, ACR response was 26 weeks. The drug is dispensed as
a self-injectable to the patient after the patient has undergone the proper
screening and education for self-administration.
The launch of the drug is complicated by the lack of support from payers
and providers due to the cost of the medication, concern for patient
compliance, even though the clinical trial data overwhelmingly shows that
in the majority of patients, symptoms of disease and long-term sequelae
are delayed. The payers and providers are concerned that the high cost of
the drug and its benefit will be offset by a lack of patient compliance.
The early post-marketing period showed that lack of drug effect was the
most-common AE reported, with greater than 90% of all AEs reporting no
change in joint pain and swelling or plaque size and number at 20 weeks
after therapy initiation.
Company A has a plan to mitigate the lack of efficacy after investigation
shows no PQC or issues with any of the batches/lots and testing of retained
samples. Company A believes its clinical data to be novel to treating
8 / MITIGATE DATA OVERLOAD WITH PROACTIVE PHARMACOVIGILANCE
psoriatic arthritis, understanding its data that showed in clinical trials patients
reported that the biggest challenge to compliance was remembering to self-
administer the injection once per week and negotiating the proper injection
technique due to joint involvement in the hands.
It quickly pivots and implements another branch of its medical information
call center as a patient-adherence and patient support program. With
regulatory authority knowledge, contact with key opinion leaders and
care providers, as well as an aggressive campaign targeted at psoriatic
arthritis patients, it offers patient support. Through that program,
patient adherence helps the individual patient understand the realistic
expectations of the therapeutic effect of the drug, resolve questions
on self-administration of a biologic injectable, and offer a separate
service to help with financial assistance in insurance coverage. For
those patients without healthcare coverage, it offers company-based
patient assistance programs.
The patient adherence program focuses on patients having a dedicated
nurse or pharmacist who knows the patient profile (dedicated patient
advocate). That healthcare professional calls or texts the patient the
day before their scheduled dose to remind them of the next day dosing,
anticipated common adverse events, and provides them a reminder that
they are “X” weeks in their therapeutic journey. Each patient is provided
a journal via a custom app on their smart device, which the dedicated
patient advocate assists them in recording their clinical symptoms,
including photos of plaque size and number, photos of affected joints,
and a simple numeric scale to record joint improvement. All photos and
data are standardized to help collect additional meaningful data and
support the patient. The data provided by the patient are summarized in
an easy to view graphic output for the patient to see their progress week
over week.
To assist with the known difficulties of home self-injection, a link is sent
for a video showing multiple approved methods of self-injection. The
patient advocate is also available for a live video chat with the patient to
assist if needed. On the day of dosing, the dedicated patient advocate
calls to ensure any difficulties in administration were addressed, checks on
the overall wellness of the patient and helps record their journal of clinical
symptoms.
By week 28 post-launch, the reports of lack of efficacy had decreased
from 90% to 68%, with 95% of all patients participating in the patient
adherence and support program. The drop-out percentage of patients from
therapy was less than seen in clinical trials.
All data relating to protected private information are handled as such and
passed to the pharmacovigilance group and the R&D group.
By week 35 post-launch, 50% of all patients report pain and stinging at the
injection site either through the patient adherence/assistance program or
through spontaneous AE reporting. A PQC investigation does not reveal any
trends in batch/lot number; however, the company receives approval for a
PASS trial to use a smaller gauge needle and to change the buffer in the
suspension to decrease stinging with injection.
The patient adherence and support program was offered with each
new prescription and all healthcare providers and pharmacists are provided
with materials to help enroll patients. At week 52 post-launch, 65% of patients
had a reduction in plaque size/number by 74% by skin surface area. For
patients with pre-treatment dactylitis and enthesitis prior to treatment, 71%
of patients scored their enthesitis as “0” and 89% with dactylitis now scored
their results as “0” by Maastricht Ankylosing Spondylitis Enthesitis (MASE).
MITIGATE DATA OVERLOAD WITH PROACTIVE PHARMACOVIGILANCE / 9
The top-reported AEs after week 52 of treatment included no
new safety concerns. The AEs reported included diarrhea, nausea,
headache, and increased incidence of minor upper respiratory infections.
The results of the PASS study were positive, with a decreased number
of injection site reactions (pain stinging) and the regulatory authority
approved the new formulation.
By week 35 post-launch, the payer providers were provided ongoing
anonymized data of the results of treatment and success from the patient
adherence/support programs. The new treatment was placed on the
formulary based on the results of proactive pharmacovigilance.
By week 65 post-launch, some patients requested bi-weekly calls in
lieu of emails and texts; 99% of all patients enrolled in the patient
adherence/support kept their therapy journal up to date and were 100%
compliant with treatment.
Summary: Why Proactive PV Can Work
Rather than reacting to the data, in the second hypothetical scenario,
Company A pivoted with ready-planned interventional PV practices at the
level of the intake system and took a patient-centric approach using smart
technology and dedicated patient advocates.
In the weeks following the implementation of patient adherence and
patient support programs (e.g., reminding patients of their next dose,
answering any questions or concerns), the rate of lack of drug effect and
the rate of disease progression decreased to a level comparable with that
reported in the pre-marketing clinical trials.
The patient assistance and adherence program is so successful that
Company A suffers no financial impact, and payers and providers are now
willing to cover the drug under their benefits. The novel treatment is so
successful that Company A begins to look at other immune-mediated
diseases in which its biologic could be as successful or other products
where PSP or PAP are beneficial. The data from the patient disease journals
was used as real-world data to change the device post-marketing to a
smaller needle and less buffer to decrease patient injection site reactions.
The second scenario is an example of proactive PV. It is only successful
if the data is digested and provided in real time. Are there technologies
available that allow such views of the PV data? Unequivocally, yes!
MITIGATE DATA OVERLOAD WITH PROACTIVE PHARMACOVIGILANCE / 10
 The Future of
Pharmacovigilance
How can you close the knowledge gap and move PV from a state of
reactive to proactive? While the presented earlier is merely an example,
it is based on real PV practices of a few forward-looking marketing
authorization holders. It takes some proactive planning and partnering to
spool-up a patient adherence and patient support program, but with the
right partner, you can be ready.
A holistic pharmacovigilance system is not just adverse event cases
entered into a database and endless line listings spit out for analysis. It
is an iterative process that begins with the first step in the PV system
and ends with the last feeding back to continuous improvement and
old-fashioned communication between healthcare providers, regulatory
authorities, and patients.
Many points exist where one touch can change reactive into proactive PV.
Proactive means early detection, implementation of quick remediation,
and actually changing the paradigm of the adverse event profile through
common sense touch with the care providers or the patients themselves
to enhance understanding of the drug, its use and set expectations based
on clinical data. Don’t forget about reviewing the AE profile in real time
to look for other potential indications from the AE profile such as
described earlier.
Technology plays a critical role in making this a reality. Do you have
the right analytics tools? Do you have the bandwidth to set up
real-time programs for patient support or adherence or partnerships
who can assist? Do you have the savvy scientific and clinical knowledge in
your organization?
11 / MITIGATE DATA OVERLOAD WITH PROACTIVE PHARMACOVIGILANCE
Remember the tenants of safety surveillance, but also the total risk
management system. Independent of product type, the continuous
surveillance of real-time data can make a difference.
Fit-for-Purpose Pharmacovigilance Analytics
Leveraging our deep pharmacovigilance, regulatory, operational and
technical expertise, we have created PV Hawk, an application that
enables Argus Safety users to watch and analyze the overwhelming
influx of PV data.
Download the PV Hawk Solution Sheet
Watch “Raise the Bar With Real-Time Pharmacovigilance
Surveillance,” a webinar that showcases PV Hawk
Meet the Author
Kari Blaho-Owens, Ph.D.
Director, Life Sciences
At Perficient, she leads a team that implements
fit-for-purpose technology solutions and provides
pharmacovigilance consulting. Kari Blaho-Owens received
her graduate degree in pharmacology and clinical therapeutics from LSU
Medical Center in New Orleans. She was a research director and clinical
toxicologist consultant in an inner-city emergency department at UT
College of Medicine and has spent much of her career in the life sciences
industry working for pharmaceutical and device companies, as well as
CROs. Kari also served as the global head of PV at a leading company. Kari
is also a peer reviewer for the DIA.
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