Adis in-touch Pharmacovigilance, Issue 10 (free newsletter)

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Adis in-touch:
Pharmacovigilance
Issue 10

adis.com Adis in-touch: Pharmacovigilance – Issue 10
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Welcome to issue 10 of Adis in-touch
Pharmacovigilance
In this issue we hear from one of our licensing
managers, James Dunstan, who provides us with
some insights into the trends and challenges
of literature monitoring within pharmaceutical
companies.
Collaboration seems to be the key word in
pharmacovigilance at the moment as we see many
big players coming together to improve knowledge
and communication. One of our news items looks at
the collaboration between the US FDA and EMA and
the pharmacovigilance cluster they have established,
also involving Canadian and Japanese regulatory
authorities as observers.We also have details of a
joint training course being hosted by ISoP and the
UMC in June. Hopefully, this will be the first of many.
As always, we hope that you enjoy reading this issue
and we encourage you to get in touch with us if you
have any suggestions for future issues.
Kind regards
The Adis in-touch team
pharmacovigilance@adis.com
Can you help us?
We are currently running a short survey of
individuals involved in pharmacovigilance in
the Middle East. If you or any of your contacts
are based in this region, we invite you to
participate.The survey can be completed
online here and should take no more than
10–15 minutes to complete.

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Pharmacovigilance News
FDA and EMA pharmacovigilance collaboration strengthened
A new pharmacovigilance `cluster’has been set up by the FDA and the EMA. Monthly
teleconferences will take place allowing pharmacovigilance information to be exchanged
between the agencies in a more systematic and focused manner.This increased interaction is
intended to enhance the ability of the FDA and EMA to work swiftly on issues of medicine safety
and coordinate communication activities.
In the media release reporting the new pharmacovigilance cluster, Guido Rasi, the Executive
Director of the EMA, commented that“in an increasingly globalised pharmaceutical market,
collaboration between medicines’regulators is essential . . . Medicines’regulators are inter-
dependent: any action taken in one territory has repercussions on the rest of the world”.
Canadian and Japanese regulatory authorities will also participate in the pharmacovigilance
cluster meetings as observers.
Food and Drug Administration. FDA and European Medicines Agency strengthen collaboration in
pharmacovigilance area. Media Release: 19 Feb 2014. Available from URL http://www.fda.gov/

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Use of social media to meet FDA’s risk
communication requirement
A Sources Sought Notice was issued by the FDA seeking proposals from
small businesses to perform social media monitoring to inform and
evaluate FDA risk communications.
The contractor is expected to provide the FDA with the resources
needed to use social media to monitor the effectiveness of its ongoing
efforts for communicating about the risk and benefits of the products
that it regulates.
In particular, the contractor is expected to provide surveillance through
social media listening for early detection of adverse events and food-
borne illness. Analyses of social media that provide information on
consumer sentiment prior to FDA communication are also expected, as
well as social media analyses that depict changes in social media buzz
following such communications.The scope of work includes quarterly
surveillance reports related to specific FDA-regulated product classes,
social media buzz reports and a social media dashboard. Proposals had
to be submitted by 7 March 2014.
New EU rules on funding of reinforced
pharmacovigilance
A draft regulation aimed at ensuring the funding of reinforced
pharmacovigilance conducted at EU level has been approved by
the Permanent Representatives Committee in agreement with the
European Parliament.
According to the draft regulation, two types of fees will be charged
to marketing authorisation holders by the EMA. Fees to cover the
costs of pharmacovigilance assessment procedures vary from €19
500 per procedure for assessment of periodic safety update reports to
€179 000 as a standard fee for assessment in the context of referrals
initiated as a result of pharmacovigilance data.The second type of
fee is an annual flat-rate fee of €67 per pharmaceutical form.The draft
regulation still needs formal approval by the European Parliament at
plenary and by the Council of the EU.
FDA. Source Sought Notice: Use of Social Media to Inform and Evaluate FDA Risk
Communications. Internet Document : 3 Mar 2014. Available from: URL:
https://www.fbo.gov
Council of the European Union. Council confirms deal on the financing of reinforced
pharmacovigilance. Internet Document : [2 pages], 19 Feb 2014. Available from: URL:
http://www.consilium.europa.eu/uedocs/cms_Data/docs/pressdata/en/lsa/141076.pdf

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EMA publishes first risk management
plan summary
The first summary of a risk management plan (RMP) for a newly
authorised medicine has been published by the EMA.This summary,
for the radiopharmaceutical florbetaben (18F) [Neuraceq], details
what is known and not yet known about the product’s safety, and
what measures will be undertaken to prevent or minimise its risks.
The RMP summaries are‘a further step towards increased
transparency and public access to relevant information on
medicines’and‘one of the requirements of the new European
pharmacovigilance legislation’says the EMA.They are expected
to be accessed by stakeholders with a professional interest in
medicines, but will also be a useful resource for the general public.
The publishing of RMP summaries will be piloted for all newly
centrally authorised medicines during 2014, with RMP summaries for
previously authorised medicines produced at a later stage
EMA. European Medicines Agency publishes first summary of a risk-management plan for a medicine. Internet Document : 11 Mar 2014. Available from: URL:
http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2014/03/news_detail_002041.jsp&mid=WC0b01ac058004d5c1

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lamotrigine and levetiracetam. Hypersensitivity and skin reactions were
seen with the analgesic ibuprofen and the anticonvulsant lamotrigine.
Overall, 70% of the 741 suspect drugs had too few serious adverse event
reports in children (<2 reports) to allow evaluation. The antibiotics
amoxicillin and azithromycin, and the antiasthmatic albuterol are among
the most commonly prescribed drugs in children, yet they generated few
adverse event reports to FAERS.
Institute for Safe Medication Practices. QuarterWatch. ADVERSE DRUG EVENTS IN
CHILDREN UNDER AGE 18. Internet Document : [14 pages], 16 Jan 2014
Available from: URL: http://www.ismp.org/quarterwatch/pdfs/2013Q1-Kids-Special.pdf
Serious adverse events in children: 15 drugs
predominate
The latest QuarterWatch, published by the Institute of Safe Medication
Practices (ISMP), analyzed serious adverse events occurring during
normal medical use of drugs in children aged <18 years that were
reported to the FDA Adverse Event Reporting System (FAERS) in the five
year period between 2008 and 2012.The 16, 992 serious adverse event
reports analyzed represented 37% of the total reports.
Of the 741 suspect drugs in these serious reports in children, 15
drugs (2%) accounted for 41% of the reports.These most commonly
implicated drugs, in decreasing order of number of cases, were
infliximab, montelukast, somatropin, baclofen, isotretinoin,
methylphenidate, lamotrigine, lisdexamfetamine, aripiprazole,
ibuprofen, etanercept, atomoxetine, quetiapine, levetiracetam and
risperidone.
Psychiatric adverse events were prominent for 10 of the 15 drugs.
Suicidal behaviours, hallucinations or aggression were reported for the
three drugs (methylphenidate, lisdexamfetamine and atomoxetine)
prescribed for attention deficit hyperactivity disorder and the
antiasthmatic montelukast, while movement disorders, tics, weight
gain and sexual organ effects were reported for the three antipsychotic
drugs (aripiprazole, quetiapine and risperidone). Psychiatric events
also comprised ≥25% of reported adverse events for isotretinoin,

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Feature Articles
By Steve McMillan, Associate Editor for the Reactions portfolio
Two studies take a closer look at statin-related myalgia
Myalgia (muscle pain) is a well-known adverse event in statin
recipients. A search of Pharmacovigilance Insight identified 20 literature
reports, involving a total of 98 individual cases, regarding muscle pain
in patients receiving statins. However, two recently published studies
suggest that such adverse events may not always be attributable to
drug therapy.
A review of randomised, controlled trials recently published in the
European Journal of Preventive Cardiology, concludes that only a
minority of symptomatic adverse effects reported by patients on
statins are genuinely attributable to statin therapy.The reviewers found
that – while new-onset diabetes occurred at a significantly higher rate
in patients receiving statins compared with those receiving placebo –
myopathies, muscle aches, and fatigue were no more common in statin
recipients than placebo recipients. Read our summary of this review
article here.
In an article published in Annals of Internal Medicine, Canadian
researchers took eight patients meeting criteria for statin-related
myalgia and assigned them to individual n-of-1, placebo-controlled,
crossover trials.They found that, across all eight trials, there were no
statistically significant differences in measures of myalgia or pain when
patients were assigned to statin therapy or placebo. Following the
trials, five patients resumed statin therapy, and experienced positive
results in terms of improved low-density lipoprotein cholesterol levels
at a 10-month follow-up. Further details of the article are available here.
Macrolides and infantile hypertrophic pyloric stenosis
Antibiotic macrolides, such as erythromycin and azithromycin, are
commonly used for the treatment of gram-positive bacterial infections.
A Danish cohort study, recently published in the BMJ, shows that
Infants administered macrolides in the first two weeks of life have a
30-fold increased risk of infantile hypertrophic pyloric stenosis (IHPS),
a condition which involves hypertrophy and spasming of the pyloric
muscle – which can result in severe emesis and vomiting. We recently
reported this study in Reactions Weekly.The study also showed that
maternal use of macrolides during the first two weeks following birth
was associated with an increased risk of IHPS.
A search of Pharmacovigilance Insight identified five literature reports
that involved a total of seven cases of pyloric stenosis occurring
in infants. Four of these cases involved the use of erythromycin
(801124518, 800909776, 800506723), one involved the use of
erythromycin estolate (803086734), and two involved the use of
azithromycin (801061826). One article reported hypertrophic pyloric
stenosis in twin neonates who both received erythromycin within
the first two weeks of life; 801124518 whilst another article reported
pyloric stenosis in a 3-week old breastfed infant whose mother was
taking erythromycin (800506723)

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Featured content
In this section you will find a selection of articles that have been
recommended by our Editors.These are available to view on the
Springer platform via subscription or pay-per-view, unless otherwise
stated.
Pharmacovigilance for Children’s Sake
Star, K. & Edwards, I. R; Drug Safety. 37(2): 91-98, February 2014
Children are often excluded from premarketing clinical trials unless
the medicine is specifically developed for this population, limiting
access to age-specific information on dose recommendations, efficacy
and risks. Necessary therapy cannot be withheld from children, and
medicines are therefore used despite a lack of documented regulatory
support. In addition, healthcare personnel face an ongoing challenge
when treating this group, as continuous development in children
makes prescribing and administering age-suitable doses for individual
children difficult . Children are not only different from adults but differ
vastly within their own age group. Physical growth during childhood
is apparent to the eye, but less obvious is the ongoing maturation
of organ function important for drug disposition and action. In this
leading article published in Drug Safety, the authors consider these
and other issues that complicate safe medication use in pediatric
care, as well as current progress, and provide suggestions for building
knowledge within pediatric pharmacovigilance to be used to minimize
patient harm.

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EU’s New Pharmacovigilance Legislation: Considerations for
Biosimilars
Calvo, B. & Zuñiga, L.; Drug Safety. 37(1): 9-18, January 2014
As for any other medicine, the applicant of a biosimilar marketing
authorization must submit a risk-management plan, which should
take into account risks identified during product development, the
potential risks and how those risks will be addressed after authorization
of the product.
Recently, new European Pharmacovigilance legislation has been
implemented, ensuring proper risk management through the
recording of suspected adverse drug reactions and data collection
from all stakeholders.The new regulation entails a reduction of the
administrative burden on companies and regulatory agencies, as
obligations of the responsible parties are clearly established and
duplication of effort avoided.
This leading article, published in Drug Safety, analyzes the new
European Pharmacovigilance System requirements, with special
focus on those medicines requiring additional monitoring, such as
biosimilars, which are priorities for pharmacovigilance. Further, it
provides the new obligations to marketing authorization holders, such
as the continuous benefit–risk assessment.
A Framework for Assessing the EconomicValue of
Pharmacovigilance in Low- and Middle-Income Countries
Babigumira, J. B., Stergachis, A., Choi, H. L., Dodoo, A., Nwokike, J. &
Garrison Jr., L. P.; Drug Safety. 37(3): 127-134, March 2014
Pharmacovigilance (PV) programs are an essential component of
national healthcare systems.Well-functioning PV programs can
improve population health by identifying and reducing medicines-
related problems (MRPs). Many low- and middle-income countries lack
functional PV systems, but this deficiency has not been described in
terms of the potential economic value of strengthening PV systems.
In this article, recently published in Drug Safety, the authors propose
a framework for assessing the economic value of PV.They begin by
dividing national PV systems into four levels, representing increasing
levels of investment in PV capacity at the national or health facility
level for all available medicines, including vaccines.The proposed
framework can be used to estimate the costs of PV and outcomes
associated with PV and evidence generated using this could assist
policy makers, program managers, and donors in evaluating
investments that aim to increase the capacity and efficiency of national
and facility-level PV programs in low- and middle-income countries.

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Trends and regulatory changes
One significant regulatory trend that we have noticed is the slow shift
in countries accepting E2B format, leading to a more streamlined
delivery process.The AustralianTGA has now switched to E2B, while E2B
is already mandatory in Europe and Japan.The FDA is also suggesting
that it will also switch to E2B format. For our customers, this has meant
a change in processes: for customers who received ADR reports in email
format, often now receive reports in E2B, making it easier for them to
report to the authorities.
We have noticed that the Day Zero timeliness of ISCR reporting of
less than 7 days is becoming far more common.We have seen greater
pressure on pharmacovigilance departments to make sure that
submissions are more timely.This is showing up in audit comments
both when our customers have been audited as well as when we
ourselves have been involved as part of an audit.
ICSR searches
We have also noticed that a number of our customers are broadening
their ISCR search criteria to capture special circumstances due to their
interpretation of EMA guidelines.We have observed that the greater
scope of the searches is due to increased caution among a number of
our customers. I know one example of a Pharma company that has been
through an audit with the FDA where it was found that a number of
ISCRs had not been reported to the authority. Based on this, they had to
broaden the search criteria even though a narrower search appears to be
sufficient for other customers/other regulators.
Trends & Challenges in
Pharmacovigilance
Literature Monitoring
By James Dunstan, Licensing Manager for Springer
For the last year and a half I have had the pleasure of working with
pharmacovigilance professionals at a number of large and small
companies, mainly with our database product Pharmacovigilance
Insight (PVI) and Reactions Pharmacovigilance Service (RPS). During
this time I have gained some valuable insights into the trends and
challenges faced by our customers, and I will share these with you in
this update.

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Choice of database
We currently monitor all of the journals in two large bibliographic
databases (around 8,000 journals) as well as a number of information
sources such as conferences.We are noticing that mainly generic
companies are asking us to monitor just one database. One of the
companies has asked us to use separate search criteria for the US due to
different legislation requirements over there.
We maintain coverage of both databases to maximize the coverage of
journals – monitoring one of these databases may be sufficient for the
regulators, but we have taken a more cautious approach by monitoring
both.
We have also been asked about the advantages of Medline over
PubMed.The main reason is Medline’s indexing, which allows you to
search indexed terms or free-text terms, you can also search the indexed
terms, and therefore increases the likely number of hits. Some of the
articles on PubMed do not have any indexing terms or abstracts, so you
can only search for these types of articles by a free-text search for the
title of the article.This means that potentially relevant articles can be
easily missed.
PubMed does contain some additional sources that are not ever
covered by Medline (around 10% more), but the volume is small as
Medline is the largest subset of PubMed.The other types of articles on
PubMed are in-process and ahead of print, but these eventually end up
on Medline anyway, albeit at a later date.
Localisation
We have received a number of requests from our customers to monitor
the literature of journals that can’t be found in Medline or Embase.
These requests have become more frequent in the last 6 – 12 months.
We are unsure whether this is because of increased demands from
regulators or whether our customers would like to outsource more of
the local-literature monitoring.
There are several different ways of approaching local-language
monitoring and its challenges. One option is to use native-language
employees to translate or process these cases. However, in countries
where your company does not have a big presence, it may be
very difficult to find native speaking staff with the appropriate
pharmacovigilance training, particularly if you are including a multitude
of languages.
Another option is the use of online translation tools – I think that these
tools have a place in terms of an initial, very basic screening to assess for
key words, but are largely inadequate for reporting purposes.
Using a specialist translator is arguably the most expensive option and
there are questions about quality, cost and timeliness that need to be
taken into consideration.
For our PVI database and Reactions Pharmacovigilance Service, we
generally identify potential ISCRs based on the title of the article and a
basic screening with online tools. If we suspect that the article contains
an ICSR, we will get it translated by one of our network of translators.

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So there are pros and cons for each database. Since the FDA/EMA
guidelines suggest Medline (or Embase), we believe that the recall
rate is probably more important than the overall number of sources
covered. For our RPS service, we decided that we would use two
databases, as the overall number of journals covered is far greater
than one alone.
Off-label use
One of the key challenges we have come across is constructing
search to include off-label use. It is fairly straightforward to add the
term“off-label”into a search, but what about the cases where the
case report has no mention of being off-label use even though this is
clearly the case?There may also be the case where a drug is off-label
in the US but on-label in the EU or vice-versa.
Closer scrutiny from authorities
There was the famous example of the EMA conducting a year-long
review of a top-tier pharmaceutical company’s drug portfolio back in
2012. According to the FiercePharma news website, PRAC reviewed
safety data on this pharmaceutical company and discovered“80,000
uninvestigated adverse reaction reports from the US.The reports are
on a hodgepodge of drugs made by (large pharmaceutical company)
and include more the 15,000 reports of deaths.”
Examples like these show that the authorities have been scrutinizing
our customers much more closely.We have been involved in
a number of audits and have seen an increase in the need for
pharmaceutical companies to be more diligent in making sure all
relevant ISCRs are captured.
The challenge that arises out of this is striking a balance between
making the search criteria broad enough to identify relevant ISCRs
and narrow enough that you don’t have a deluge of articles that need
to be sifted through.We have one customer who was considering
expanding their search criteria for their 300+ drug portfolio.The result
was approximately 5,000 articles per week that would need to be sorted
through an analyst, taking approximately 83 hours per week (2 full-time
jobs) assuming each record was reviewed in an average of 1 minute. So
we had to review the benefits of expansion in relation to the cost and
come up with a solution somewhere in the middle.
If you have any questions, remarks or comments in relation to this
update, please do not hesitate to contact me directly.
This update was originally presented by James Dunstan during the 4th Annual
Pharmacovigilance & Risk Management Strategies Forum 2014.

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An introduction to Pharmacovigilance Insight
These sessions will provide an introduction to the database including an
overview of the content, how to run searches and set up alerts, and are
suitable for anyone using Pharmacovigilance Insight for the first time, or
needing a refresher to brush up on their database skills.
•• Thursday, May 8th 1.00 pm Central EuropeanTime (UTC/GMT +1)
•• Thursday, May 8th 1.00 pm Eastern StandardTime (UTC/GMT -5)
•• Alternatively, you can access a pre-recorded session here, which can
be viewed on-demand at a time that suits you!
Pharmacovigilance for Hospitals & Health
These sessions will look at how the database can be used within a
hospital or healthcare setting to identify previous cases of ADRs and
keep up to date with drug safety news.
•• Thursday, June 19th 9.30 am Central EuropeanTime (UTC/GMT +1)
•• Thursday, June 19th 3.30 pm Eastern StandardTime (UTC/GMT -5)
Pharmacovigilance Insight
Are you looking for a solution to help you with
adverse event literature monitoring?
We will be running a series of training sessions over the coming
months to demonstrate the benefits of using a database such as
Pharmacovigilance Insight within different industries.These sessions
are hosted online by our product and platform experts. All you need to
participate is an internet connection and access to a telephone.You will
be able to watch the presentation on your desktop and we will provide
you with a toll-free phone number to dial in should you wish to ask
questions during the session.
To register for any of these free training sessions simply click on the links
above and complete your details.

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Adis in-touch: Pharmacovigilance – Issue 10
Upcoming events
ISoPTraining Course: Proactive
Pharmacovigilance, Risk Management
and Pharmacovigilance in the Era of
Personalised Medicine
April 3-4, 2014
Zagreb, Croatia
Uppsala Monitoring Centre Research
Conference 2014“Risk:What risk?
Whose risk?”
May 22-23, 2014
Uppsala, Sweden
ISoP-UMCTraining Course:
Ensuring Safe Medicines: How
harminisation underpins international
pharmacovigilance
June 5-7, 2014
Manila, Philippines
14th ISoP Annual Meeting
October 19 - 22, 2014
Tianjin, China
30th International Conference on
Pharmacoepidemiology &Therapeutic
Risk Management
October 24 - 27, 2014
Taipei, China
A06462 | Images: page 1: Roel Smart/iStockphoto | page 5: fotolia

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