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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 PharmacovigilanceIn 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 teampharmacovigilance@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 NewsFDA 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 requirementA 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 pharmacovigilanceA 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 ArticlesBy 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 SakeStar, 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 BiosimilarsCalvo, 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 Economic Value of Pharmacovigilance in Low- and Middle-Income CountriesBabigumira, 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 Australian TGA 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 MonitoringBy 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 European Time (UTC/GMT +1)

• Thursday, May 8th 1.00 pm Eastern Standard Time (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 European Time (UTC/GMT +1)

• Thursday, June 19th 3.30 pm Eastern Standard Time (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 eventsISoP Training 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-UMC Training Course: Ensuring Safe Medicines: How harminisation underpins international pharmacovigilanceJune 5-7, 2014 Manila, Philippines

14th ISoP Annual MeetingOctober 19 - 22, 2014 Tianjin, China

30th International Conference on Pharmacoepidemiology & Therapeutic Risk ManagementOctober 24 - 27, 2014 Taipei, China

A06462 | Images: page 1: Roel Smart/iStockphoto | page 5: fotolia

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