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ARTICLE IN PRESS
YPHRS 2759 1–4
Pharmacological Research xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Pharmacological Research journal homepage: www.elsevier.com/locate/yphrs
1
Review
2
Ongoing pharmacovigilance on vaccines
3 4
Q1
Carmela Santuccio ∗ , Francesco Trotta, Patrizia Felicetti Italian Medicines Agency, Pharmacovigilance Office, 00187 Roma, Italy
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6 20
a r t i c l e
i n f o
a b s t r a c t
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Article history: Received 23 October 2014 Received in revised form 29 October 2014 Accepted 30 October 2014 Available online xxx
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Keywords: Vaccines Safety monitoring Surveillance Adverse drug reaction Pharmacovigilance
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Contents
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Vaccines represent a specific subgroup of drugs characterised by peculiar features that should be taken into account during adverse events surveillance. In this review, we analyse and discuss specific requirements of vaccine pharmacovigilance, including the needs of guarantee a safer use of vaccines and preserving public confidence in immunisation programmes. Key elements for the routine safety monitoring, new regulations and some available tools are taken into account. Finally, our experience in vaccine pharmacovigilance is shortly described. © 2014 Published by Elsevier Ltd.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Key elements for the routine vaccine safety monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The regulatory issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The tools . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Italian experience . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Introduction Vaccines undergo to a strict pharmacovigilance surveillance, aimed at evaluating safety profile and effectiveness. Vaccines have peculiar characteristics that should be taken into proper account during pharmacovigilance activity. Such characteristics include the decreasing frequency of preventable diseases, the potential of certain bacteria and virus to replace circulating strains and the importance of risk communication. Additional sources of concern are represented by the heterogeneity of stakeholders, which include subjects who stand against immunisation programmes for several reasons. All these aspects have an important effect on vaccine pharmacovigilance and may potentially affect the success of immunisation programmes.
The need of carrying out proper vaccine-vigilance programmes is well known [1–4] and the recent experience with pandemic flu vaccination highlighted the need to improve the pharmacovigilance system [5–7]. Several countries have identified a number of crucial features that should be strengthened for a more effective surveillance. These include risk-quantification, analysis of diseases burden, identification of subgroups of patients at higher risk for specific disease and improves the ability to generate timely data. The amelioration of approaches to communicate vaccine safety and efficacy, along with specific communication strategies for high-risk groups, represents another important goal to be reached. Finally, an increased collaboration at national and international level was also considered mandatory. Key elements for the routine vaccine safety monitoring
∗ Corresponding author at: Italian Medicines Agency, Via del Tritone 181, 00187 Rome, Italy. Tel.: +39 0659784365; fax: +39 0659784142. E-mail address: [email protected] (C. Santuccio).
Several issues should be considered in order to build up an efficacious routine monitoring of vaccine safety: (i) Vaccines are
http://dx.doi.org/10.1016/j.phrs.2014.10.011 1043-6618/© 2014 Published by Elsevier Ltd.
Please cite this article in press as: Santuccio C, et al. Ongoing pharmacovigilance on vaccines. Pharmacol Res (2014), http://dx.doi.org/10.1016/j.phrs.2014.10.011
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If new concerns on authorised products emerge, new legislation enables the Regulatory Authorities to require a Post-authorisation safety study defined as a study “. . ..conducted with the aim of identifying, characterising or quantifying a safety hazard, confirming the safety profile of the medicinal product, or of measuring the effectiveness of risk management measure” [13]. Furthermore, Regulatory Authorities can now require studies to assess efficacy or effectiveness of a drug/vaccine if evidence suggests that previous evaluations needs to be revised. Most of the above-mentioned provisions are not specific for vaccines. However, the new legislation affects also vaccine-vigilance and a dedicated GVP module has been recently published (Guideline on good pharmacovigilance practices. Product or population specific considerations I: vaccines for prophylaxis against infectious diseases [14]). This document is focused on vaccine-specific aspects that should be considered during pharmacovigilance activities for vaccines, such as the need to confirm the benefit–risk ratio of vaccination in a real-world setting by including different subgroups of patients than the ones enrolled in clinical trial. Additional, real-world data may include immunogenicity data to evaluate longterm protection or different vaccine schedules. Specific vaccine-related aspects are considered also in the RMP, which should include data on topic such as waning of immunity, co-administration with other vaccines, the “syndrome close resembling wild-type disease”, adverse events of special interest, monitoring of breakthrough infection cases, and reversion of the virulence in case of live attenuated vaccines.
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usually administrated to prevent diseases in healthy subjects, mainly children; (ii) A significant variability may exist within the same product because of manufacturing processes. This may result in differences between batches of the same vaccine. For this reason, current Good Pharmacovigilance Practices (GVP) require that reports of an adverse reaction include the batch of the vaccine involved. (iii) The surveillance of Adverse Event Following Immunisation (AEFI) is complex due to several reasons, including concomitant administration of different vaccines, difficulty in determining causal association and the needs of taking rapid and informed actions. For a quick decision-making process, a close collaboration among all the relevant stakeholders (regulatory authorities, public health authorities, healthcare professionals, academia, parents/citizens and vaccines manufacturers) is required. (iv) Risk communication represents a challenging issue and requires appropriate expertise in the era of the WEB 2.0, which allows access to medical information in absence of specific medical training. The failure in responding to online misinformation with an adequate and rapid official information may have significant effects on the compliance to immunisation programmes, resulting in outbreaks of vaccine-preventable infectious diseases. Several procedures could be adopted to improve vaccinevigilance and the public confidence in the vaccines, including developing adequate data-analysis tools, strengthening pharmacovigilance rules and increasing transparency in decision-making processes. The development of vaccine-vigilance is an ongoing process, and a large amount of work has already been done.
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The regulatory issues
The tools
A series of important regulatory changes in pharmacovigilance took place in Europe with introduction of new legislation (the Directive 2010/84/EU [8], the Regulation (EU) 1235/2010 [9], and the Regulation (EU) 520/2010 [10] and the release of Good Pharmacovigilance Practices [11] modules I to XVI). These new provisions were aimed at increasing patient’s health protection by sharing the amount of work among Member States, by saving resources, and by improving the efficacy of the actions taken. The main changes of the new legislation involved the collection and the analysis of all relevant information concerning medicines, regulatory process and communication with the stakeholders. One of the most important changes was the revision of the meaning of adverse reaction, which now includes also cases coming from abuse or misuse of drug, medication error, overdose and professional exposure. Other important changes were the specification of tools for ADR collection, signal detection and management as well as establishing the Pharmacovigilance Risk Assessment Committee. Regulation for manufacturer was also ameliorated by changing requirement for safety documents to be provided to Regulatory Authorities and by including the possibility from these latter to request legally bound post-authorisation studies. The Periodic Safety Update Report has now a new format and is called Periodic Benefit Risk Evaluation Report. It now presents and discusses both safety issues (including adverse reactions, signals and risks) and efficacy/effectiveness data, thus allowing an updated overall benefit/risk evaluation of each product. The new legislation extends the need of submitting the Risk Management Plan (RMP) for all new marketing authorisation applications. The RMP is a stand-alone document containing a detailed description of risk management system used by the Companies and is defined in the Directive as “a set of pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to a medicinal product, including the assessment of the effectiveness of those activities and interventions” [12].
The procedures for conducting routine signal detection have been established and described in a specific GVP module [15]. Signal is defined as an “. . .information that arises from one or multiple sources (including observations and experiments), which suggests a new potentially causal association, or a new aspect of a known association, between an intervention and an event or set of related events, either adverse or beneficial, that is judged to be of sufficient likelihood to justify verificatory action.” [15]. Despite the improvement in signal detection and management within the new legislation, it should be emphasised that this mechanism still relies on passive reporting systems. Vaccines safety surveillance has now evolved into a more efficacious a real time data monitoring, with an improved capability to investigate safety concerns and quantify risks. It is therefore expected that this system will adopt complementary active surveillance systems such as those based on large database of electronic medical records [16]. The use of such systems for monitoring vaccine safety will require the ability to link several sources of data, such as AEFI, hospital discharge databases and immunisation registers. The analytic power of these systems could be increased by analysing data from different countries though harmonised procedures and tools [17]. This would allow analysing rare adverse reactions that cannot be studied appropriately in a limited geographic area. An example of such experience is the Vaccine Adverse Event Surveillance & Communication (VAESCO) Consortium [18]. The VAESCO was founded by the European Centre of Disease Prevention and Control and includes heterogeneous partners such as regulatory and public health institutions, academia and companies. This consortium promoted the conduction of two EU-wide collaborative studies to investigate the risk of Guillain Barrè Syndrome and narcolepsy following pandemic vaccination [19,20]. The European Medicine Agency has recently transposed the need of promoting a pro-active approach to enhance safety surveillance for seasonal influenza vaccines into a specific guidance [21].
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This guidance now recognises that small clinical trials evaluating seasonal influenza vaccines immunogenicity are useless from an efficacy perspective [21]. The reason behind such change is that current scientific evidence suggests annual antigenic drift to have a little impact on the immunogenicity profile. Small clinical trials also suffer of limitations (including from a methodological perspective) in detecting safety issues such as reactogenicity and more frequent reactions [22]. The new European Medicine Agency Guidance now establishes that annual update trials will be no longer conducted and Companies will be required to submit to the Regulatory Authorities an enhanced surveillance plan including activity of active and passive pharmacovigilance surveillance, data mining or other activities requiring the use of electronic health record data. It has also been planned to make results of such surveillance available within one month from the beginning of seasonal immunisation programmes. For this reason, companies were invited to enhance collaboration with Public Health Authorities, possible in more than a single European region. Such need led to the institution of the Accelerated development of vaccine benefit–risk collaboration in Europe (ADVANCE) consortium [23]. The ADVANCE consortium is supported by the EU/EFPIA Innovative Medicines Initiative and it is finalised to develop “a pan-European framework for rapidly assessing and communicating the benefits and risks of vaccines” [23].
Italian experience In Italy, the Pharmacovigilance Office of the Italian Medicines Agency, AIFA, is in charge for post-marketing surveillance of drugs and vaccines. Reports of suspected adverse drug reactions are collected through the Italian Pharmacovigilance Network and included into a national database. These reports are transferred to international databases (The Eudravigilance and the Uppsala Monitoring Centre-World Health Organisation Vigibase). The Italian national database is reviewed regularly to check consistency and completeness of reports and to monitor signals of disproportionate reporting. In Italy, the number of reports of vaccine adverse reactions increased during the last ten years, from about 1800 in 2004 to more than 3700 in 2013. This increase was related to the introduction of new vaccines (e.g. the HPV vaccines) and to the improvements of the reporting system. Along with the increase of AEFI reports, the number of challenges and complexities to conduct the vaccines post marketing surveillance also increased and several procedures were implemented. A working group was established to analyse safety signal derived from national spontaneous reports concerning vaccines. This group is composed by delegates from AIFA, the Ministry of Health, the Italian National Institute for Health, the Regional Centres of Pharmacovigilance, and Public Health Authorities. Limits of the passive surveillance system have been largely acknowledged, and specific epidemiological studies are now frequently carried out to investigate and quantify emerging safety signals [24,25]. Along with passive surveillance, a number of active pharmacovigilance projects has been started, also involving parents of vaccinees. Efforts have been made to increase transparency and to make data on vaccine safety publicly available. In the 2009, AIFA published the first annual reports dedicated to vaccine postmarketing surveillance [26–28]. The annual report covers all the relevant events occurred, reporting results of analyses performed on reported AEFI and providing an update on active surveillance projects.
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During the last year, an AIFA working group dedicated to enhance vaccine safety and has been created to strength collaboration between different vaccine-vigilance figures [29]. Despite these improvements, the Italian vaccine-vigilance system still presents some weaknesses, including the absence of homogeneous data on vaccine uptake across the entire Country (data are often unavailable at individual level), the absence of links between different healthcare databases and the need to reinforce partnership and communication between different stakeholders. Vaccine Pharmacovigilance represents an uphill with new challenges to be faced. Current and future development of this field will allow enhancing vaccine safety and compliance to immunisation programmes. Conflict of interest The authors declare no conflict of interest. References [1] Ellenberg SS, Chen RT. The complicated task of monitoring vaccine safety. Public Health Report 1997;112:10–20. [2] Lankinen KS, Pastila S, Kilpi T, Nohynek H, Mäkelä PH, Olin P. Vaccinovigilance in Europe — need for timeliness, standardization and resources. Bull World Health Organ 2004;82:11. [3] Zanoni G, Berra P, Lucchi I, Ferro A, O’Flanagan D, Levy-Bruhl D, et al. Vaccine adverse event monitoring systems across the European Union countries: time for unifying efforts. Vaccine 2009;27:3376–84. [4] Definition and Application of terms for Vaccine Pharmacovigilance-report of CIOMS/WHO working group on Vaccine Pharmacovigilance-2011. [5] European Medicines Agency. CHMP recommendations for the pharmacovigilance plan as part of the risk management plan to be submitted with the marketing authorisation application for a pandemic influenza vaccine. Revision 1.1 adopted by CHMP on 24 September 2009. EMEA/359381/2009, http://www.ema.europa.eu/pdfs/human/pandemicinfluenza/35938109en.pdf. [6] Kurz X, Domergue F, Slattery J, Segec A, Szmigiel A, Hidalgo-Simon A. Safety monitoring of influenza A/H1N1 pandemic vaccines in EudraVigilance. Vaccine 2011;29:4378–87. [7] Hauquet G, Van Damme P, Brasseur D, De Cuyper X, Gregor S, Holmberg M, et al. Lesson learnt from pandemic A(H1N1) 2009 influenza vaccination. Highlights of a European workshop in Brussels (22 March 2010). Vaccine 2011;29:370–7. [8] Directive 2010/84/EU of the European parliament and of the council of 15 December 2010 amending, as regards pharmacovigilance, Directive 2001/83/EC on the Community code relating to the medicinal products for human use. [9] Regulation (EU) No 1235/2010 of the European parliament and of the council of 15 December 2010, amending, as regards pharmacovigilance of medicinal products for human use, Regulation (EC) No 726/2004 laying down Community procedures for the authorization and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency, and Regulation (EC) No 1394/2007 on advanced therapy medicinal products. [10] Commission implementing regulation (EU) No 520/2012 of 19 June 2012 on the performance of pharmacovigilance activities provided for in Regulation (EC) No 726/2004 of the European Parliament and of the Council and Directive 2001/83/EC of the European Parliament of the Council. [11] Good Pharmacovigilance Practices: http://www.ema.europa.eu/ema/index. jsp?curl=pages/regulation/document listing/docu ment listing 000345.jsp. [12] GVP module V Risk management systems: Http://www.ema.europa.eu/docs/ en GB/document library/Scientific guideline/2012/02/WC500123208.pdf. [13] GVP module VIII Pot-authorization safety studies: http://www.ema. europa.eu/docs/en GB/document library/Scientific guideline/2012/06/ WC500129137.pdf. [14] Guideline on good pharmacovigilance practices. Product or population specific considerations I: vaccines for prophylaxis against infectious diseases, http://www.ema.europa.eu/docs/en GB/document library/Scientific guideline/2013/12/WC500157839.pdf. [15] GVP module IX signal management: http://www.ema.europa.eu/docs/en GB/ document library/Scientific guideline/2012/06/WC500129138.pdf. [16] Huang YL, Moon J, Segal JB. A comparison of active adverse event surveillance systems worldwide. Drug Saf 2014;37:581–96. [17] Trifiro’ G, Coloma PM, Rijnbeek PR, Romio S, Mosseveld B, Weibel D, et al. Combining multiple healthcare databases for postmarketing drug and vaccines safety surveillance: why and how? J Intern Med 2014;275:551–61. [18] Vaccine adverse event surveillance & communication: http://vaesco.net/ vaesco/about-us.html. [19] Dieleman J, Romio S, Johansen K, Weibel D, Bonhoeffer J, Sturkemboom M, et al. Guillain-Barre syndrome and adjuvanted pandemic; influenza A (H1N1) 2009 vaccine: multinational case–control study in Europe. BMJ 2011;343:d3908. [20] Barker C, Snape DM. Pandemic influenza Ah1N1 vaccines and narcolepsy: vaccine safety surveillance in action. Lancetcom/Infect 2014;14:227–38.
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[21] Interim guidance on enhanced safety surveillance for seasonal influenza vaccines in the EU, http://www.ema.europa.eu/docs/en GB/document library/ 326 Scientific guideline/2014/04/WC500165492.pdf. 327 [22] Voordouw ACG, Beyer WE, Smith DJ, Sturkemboom MC, Stricker BH. Evaluation 328 of serological trials submitted for annual re-licensure of influenza vaccines to 329 regulatory authorities between 1992 and 2002. Vaccine 2009;28:392–7. 330 [23] Advance Project http://www.advance-vaccines.eu/. 331 Q2 [24] Menniti Ippolito F, et al. Vaccine effectiveness against severe laboratory332 confirmed influenza in children: results of two consecutive seasons in Italy. 333 Vaccine 2014;32:4466–70, http://dx.doi.org/10.1016/j.vaccine.2014.06.048. 334 Epub 2014 Jun 21. 335 [25] Galeotti F, Massari M, D’Alessandro R, Beghi E, Chiò A, Logroscino G, et al. ITANG study group. Risk of Guillain-Barré syndrome after 2010–2011 influenza 324 325
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[27]
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vaccination. Eur J Epidemiol 2013;28:433–44, http://dx.doi.org/10.1007/ s10654-013-9797-8. Epub 2013 Mar 31. Rapporto sulla sorveglianza postmarketing dei vaccini in Italia- anno 2009–2010, http://www.agenziafarmaco.gov.it/sites/default/files/rapporto vaccini 09 10 cop.pdf. Rapporto sulla sorveglianza postmarketing dei vaccini in Italia- anno 2011, http://www.agenziafarmaco.gov.it/it/content/rapporto-sulla-sorveglianzapostmarketing-dei-vaccini-italia-anno-2011. Rapporto sulla sorveglianza postmarketing dei vaccini in Italia- anno 2012, http://www.agenziafarmaco.gov.it/it/content/rapporto-sulla-sorveglianzapostmarketing-dei-vaccini-italia-anno-2012. Determinazione AIFA http://www.agenziafarmaco.gov.it/sites/default/files/ determina vaccinovigilanza.pdf.
Please cite this article in press as: Santuccio C, et al. Ongoing pharmacovigilance on vaccines. Pharmacol Res (2014), http://dx.doi.org/10.1016/j.phrs.2014.10.011
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ARTICLE IN PRESS
YPHRS 2759 1–4
Pharmacological Research xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Pharmacological Research journal homepage: www.elsevier.com/locate/yphrs
1
Review
2
Ongoing pharmacovigilance on vaccines
3 4
Q1
Carmela Santuccio ∗ , Francesco Trotta, Patrizia Felicetti Italian Medicines Agency, Pharmacovigilance Office, 00187 Roma, Italy
5
6 20
a r t i c l e
i n f o
a b s t r a c t
7 8 9 10 11 12
Article history: Received 23 October 2014 Received in revised form 29 October 2014 Accepted 30 October 2014 Available online xxx
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Keywords: Vaccines Safety monitoring Surveillance Adverse drug reaction Pharmacovigilance
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Contents
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Vaccines represent a specific subgroup of drugs characterised by peculiar features that should be taken into account during adverse events surveillance. In this review, we analyse and discuss specific requirements of vaccine pharmacovigilance, including the needs of guarantee a safer use of vaccines and preserving public confidence in immunisation programmes. Key elements for the routine safety monitoring, new regulations and some available tools are taken into account. Finally, our experience in vaccine pharmacovigilance is shortly described. © 2014 Published by Elsevier Ltd.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Key elements for the routine vaccine safety monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The regulatory issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The tools . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Italian experience . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Introduction Vaccines undergo to a strict pharmacovigilance surveillance, aimed at evaluating safety profile and effectiveness. Vaccines have peculiar characteristics that should be taken into proper account during pharmacovigilance activity. Such characteristics include the decreasing frequency of preventable diseases, the potential of certain bacteria and virus to replace circulating strains and the importance of risk communication. Additional sources of concern are represented by the heterogeneity of stakeholders, which include subjects who stand against immunisation programmes for several reasons. All these aspects have an important effect on vaccine pharmacovigilance and may potentially affect the success of immunisation programmes.
The need of carrying out proper vaccine-vigilance programmes is well known [1–4] and the recent experience with pandemic flu vaccination highlighted the need to improve the pharmacovigilance system [5–7]. Several countries have identified a number of crucial features that should be strengthened for a more effective surveillance. These include risk-quantification, analysis of diseases burden, identification of subgroups of patients at higher risk for specific disease and improves the ability to generate timely data. The amelioration of approaches to communicate vaccine safety and efficacy, along with specific communication strategies for high-risk groups, represents another important goal to be reached. Finally, an increased collaboration at national and international level was also considered mandatory. Key elements for the routine vaccine safety monitoring
∗ Corresponding author at: Italian Medicines Agency, Via del Tritone 181, 00187 Rome, Italy. Tel.: +39 0659784365; fax: +39 0659784142. E-mail address: [email protected] (C. Santuccio).
Several issues should be considered in order to build up an efficacious routine monitoring of vaccine safety: (i) Vaccines are
http://dx.doi.org/10.1016/j.phrs.2014.10.011 1043-6618/© 2014 Published by Elsevier Ltd.
Please cite this article in press as: Santuccio C, et al. Ongoing pharmacovigilance on vaccines. Pharmacol Res (2014), http://dx.doi.org/10.1016/j.phrs.2014.10.011
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If new concerns on authorised products emerge, new legislation enables the Regulatory Authorities to require a Post-authorisation safety study defined as a study “. . ..conducted with the aim of identifying, characterising or quantifying a safety hazard, confirming the safety profile of the medicinal product, or of measuring the effectiveness of risk management measure” [13]. Furthermore, Regulatory Authorities can now require studies to assess efficacy or effectiveness of a drug/vaccine if evidence suggests that previous evaluations needs to be revised. Most of the above-mentioned provisions are not specific for vaccines. However, the new legislation affects also vaccine-vigilance and a dedicated GVP module has been recently published (Guideline on good pharmacovigilance practices. Product or population specific considerations I: vaccines for prophylaxis against infectious diseases [14]). This document is focused on vaccine-specific aspects that should be considered during pharmacovigilance activities for vaccines, such as the need to confirm the benefit–risk ratio of vaccination in a real-world setting by including different subgroups of patients than the ones enrolled in clinical trial. Additional, real-world data may include immunogenicity data to evaluate longterm protection or different vaccine schedules. Specific vaccine-related aspects are considered also in the RMP, which should include data on topic such as waning of immunity, co-administration with other vaccines, the “syndrome close resembling wild-type disease”, adverse events of special interest, monitoring of breakthrough infection cases, and reversion of the virulence in case of live attenuated vaccines.
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usually administrated to prevent diseases in healthy subjects, mainly children; (ii) A significant variability may exist within the same product because of manufacturing processes. This may result in differences between batches of the same vaccine. For this reason, current Good Pharmacovigilance Practices (GVP) require that reports of an adverse reaction include the batch of the vaccine involved. (iii) The surveillance of Adverse Event Following Immunisation (AEFI) is complex due to several reasons, including concomitant administration of different vaccines, difficulty in determining causal association and the needs of taking rapid and informed actions. For a quick decision-making process, a close collaboration among all the relevant stakeholders (regulatory authorities, public health authorities, healthcare professionals, academia, parents/citizens and vaccines manufacturers) is required. (iv) Risk communication represents a challenging issue and requires appropriate expertise in the era of the WEB 2.0, which allows access to medical information in absence of specific medical training. The failure in responding to online misinformation with an adequate and rapid official information may have significant effects on the compliance to immunisation programmes, resulting in outbreaks of vaccine-preventable infectious diseases. Several procedures could be adopted to improve vaccinevigilance and the public confidence in the vaccines, including developing adequate data-analysis tools, strengthening pharmacovigilance rules and increasing transparency in decision-making processes. The development of vaccine-vigilance is an ongoing process, and a large amount of work has already been done.
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The regulatory issues
The tools
A series of important regulatory changes in pharmacovigilance took place in Europe with introduction of new legislation (the Directive 2010/84/EU [8], the Regulation (EU) 1235/2010 [9], and the Regulation (EU) 520/2010 [10] and the release of Good Pharmacovigilance Practices [11] modules I to XVI). These new provisions were aimed at increasing patient’s health protection by sharing the amount of work among Member States, by saving resources, and by improving the efficacy of the actions taken. The main changes of the new legislation involved the collection and the analysis of all relevant information concerning medicines, regulatory process and communication with the stakeholders. One of the most important changes was the revision of the meaning of adverse reaction, which now includes also cases coming from abuse or misuse of drug, medication error, overdose and professional exposure. Other important changes were the specification of tools for ADR collection, signal detection and management as well as establishing the Pharmacovigilance Risk Assessment Committee. Regulation for manufacturer was also ameliorated by changing requirement for safety documents to be provided to Regulatory Authorities and by including the possibility from these latter to request legally bound post-authorisation studies. The Periodic Safety Update Report has now a new format and is called Periodic Benefit Risk Evaluation Report. It now presents and discusses both safety issues (including adverse reactions, signals and risks) and efficacy/effectiveness data, thus allowing an updated overall benefit/risk evaluation of each product. The new legislation extends the need of submitting the Risk Management Plan (RMP) for all new marketing authorisation applications. The RMP is a stand-alone document containing a detailed description of risk management system used by the Companies and is defined in the Directive as “a set of pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to a medicinal product, including the assessment of the effectiveness of those activities and interventions” [12].
The procedures for conducting routine signal detection have been established and described in a specific GVP module [15]. Signal is defined as an “. . .information that arises from one or multiple sources (including observations and experiments), which suggests a new potentially causal association, or a new aspect of a known association, between an intervention and an event or set of related events, either adverse or beneficial, that is judged to be of sufficient likelihood to justify verificatory action.” [15]. Despite the improvement in signal detection and management within the new legislation, it should be emphasised that this mechanism still relies on passive reporting systems. Vaccines safety surveillance has now evolved into a more efficacious a real time data monitoring, with an improved capability to investigate safety concerns and quantify risks. It is therefore expected that this system will adopt complementary active surveillance systems such as those based on large database of electronic medical records [16]. The use of such systems for monitoring vaccine safety will require the ability to link several sources of data, such as AEFI, hospital discharge databases and immunisation registers. The analytic power of these systems could be increased by analysing data from different countries though harmonised procedures and tools [17]. This would allow analysing rare adverse reactions that cannot be studied appropriately in a limited geographic area. An example of such experience is the Vaccine Adverse Event Surveillance & Communication (VAESCO) Consortium [18]. The VAESCO was founded by the European Centre of Disease Prevention and Control and includes heterogeneous partners such as regulatory and public health institutions, academia and companies. This consortium promoted the conduction of two EU-wide collaborative studies to investigate the risk of Guillain Barrè Syndrome and narcolepsy following pandemic vaccination [19,20]. The European Medicine Agency has recently transposed the need of promoting a pro-active approach to enhance safety surveillance for seasonal influenza vaccines into a specific guidance [21].
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This guidance now recognises that small clinical trials evaluating seasonal influenza vaccines immunogenicity are useless from an efficacy perspective [21]. The reason behind such change is that current scientific evidence suggests annual antigenic drift to have a little impact on the immunogenicity profile. Small clinical trials also suffer of limitations (including from a methodological perspective) in detecting safety issues such as reactogenicity and more frequent reactions [22]. The new European Medicine Agency Guidance now establishes that annual update trials will be no longer conducted and Companies will be required to submit to the Regulatory Authorities an enhanced surveillance plan including activity of active and passive pharmacovigilance surveillance, data mining or other activities requiring the use of electronic health record data. It has also been planned to make results of such surveillance available within one month from the beginning of seasonal immunisation programmes. For this reason, companies were invited to enhance collaboration with Public Health Authorities, possible in more than a single European region. Such need led to the institution of the Accelerated development of vaccine benefit–risk collaboration in Europe (ADVANCE) consortium [23]. The ADVANCE consortium is supported by the EU/EFPIA Innovative Medicines Initiative and it is finalised to develop “a pan-European framework for rapidly assessing and communicating the benefits and risks of vaccines” [23].
Italian experience In Italy, the Pharmacovigilance Office of the Italian Medicines Agency, AIFA, is in charge for post-marketing surveillance of drugs and vaccines. Reports of suspected adverse drug reactions are collected through the Italian Pharmacovigilance Network and included into a national database. These reports are transferred to international databases (The Eudravigilance and the Uppsala Monitoring Centre-World Health Organisation Vigibase). The Italian national database is reviewed regularly to check consistency and completeness of reports and to monitor signals of disproportionate reporting. In Italy, the number of reports of vaccine adverse reactions increased during the last ten years, from about 1800 in 2004 to more than 3700 in 2013. This increase was related to the introduction of new vaccines (e.g. the HPV vaccines) and to the improvements of the reporting system. Along with the increase of AEFI reports, the number of challenges and complexities to conduct the vaccines post marketing surveillance also increased and several procedures were implemented. A working group was established to analyse safety signal derived from national spontaneous reports concerning vaccines. This group is composed by delegates from AIFA, the Ministry of Health, the Italian National Institute for Health, the Regional Centres of Pharmacovigilance, and Public Health Authorities. Limits of the passive surveillance system have been largely acknowledged, and specific epidemiological studies are now frequently carried out to investigate and quantify emerging safety signals [24,25]. Along with passive surveillance, a number of active pharmacovigilance projects has been started, also involving parents of vaccinees. Efforts have been made to increase transparency and to make data on vaccine safety publicly available. In the 2009, AIFA published the first annual reports dedicated to vaccine postmarketing surveillance [26–28]. The annual report covers all the relevant events occurred, reporting results of analyses performed on reported AEFI and providing an update on active surveillance projects.
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During the last year, an AIFA working group dedicated to enhance vaccine safety and has been created to strength collaboration between different vaccine-vigilance figures [29]. Despite these improvements, the Italian vaccine-vigilance system still presents some weaknesses, including the absence of homogeneous data on vaccine uptake across the entire Country (data are often unavailable at individual level), the absence of links between different healthcare databases and the need to reinforce partnership and communication between different stakeholders. Vaccine Pharmacovigilance represents an uphill with new challenges to be faced. Current and future development of this field will allow enhancing vaccine safety and compliance to immunisation programmes. Conflict of interest The authors declare no conflict of interest. References [1] Ellenberg SS, Chen RT. The complicated task of monitoring vaccine safety. Public Health Report 1997;112:10–20. [2] Lankinen KS, Pastila S, Kilpi T, Nohynek H, Mäkelä PH, Olin P. Vaccinovigilance in Europe — need for timeliness, standardization and resources. Bull World Health Organ 2004;82:11. [3] Zanoni G, Berra P, Lucchi I, Ferro A, O’Flanagan D, Levy-Bruhl D, et al. Vaccine adverse event monitoring systems across the European Union countries: time for unifying efforts. Vaccine 2009;27:3376–84. [4] Definition and Application of terms for Vaccine Pharmacovigilance-report of CIOMS/WHO working group on Vaccine Pharmacovigilance-2011. [5] European Medicines Agency. CHMP recommendations for the pharmacovigilance plan as part of the risk management plan to be submitted with the marketing authorisation application for a pandemic influenza vaccine. Revision 1.1 adopted by CHMP on 24 September 2009. EMEA/359381/2009, http://www.ema.europa.eu/pdfs/human/pandemicinfluenza/35938109en.pdf. [6] Kurz X, Domergue F, Slattery J, Segec A, Szmigiel A, Hidalgo-Simon A. Safety monitoring of influenza A/H1N1 pandemic vaccines in EudraVigilance. Vaccine 2011;29:4378–87. [7] Hauquet G, Van Damme P, Brasseur D, De Cuyper X, Gregor S, Holmberg M, et al. Lesson learnt from pandemic A(H1N1) 2009 influenza vaccination. Highlights of a European workshop in Brussels (22 March 2010). Vaccine 2011;29:370–7. [8] Directive 2010/84/EU of the European parliament and of the council of 15 December 2010 amending, as regards pharmacovigilance, Directive 2001/83/EC on the Community code relating to the medicinal products for human use. [9] Regulation (EU) No 1235/2010 of the European parliament and of the council of 15 December 2010, amending, as regards pharmacovigilance of medicinal products for human use, Regulation (EC) No 726/2004 laying down Community procedures for the authorization and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency, and Regulation (EC) No 1394/2007 on advanced therapy medicinal products. [10] Commission implementing regulation (EU) No 520/2012 of 19 June 2012 on the performance of pharmacovigilance activities provided for in Regulation (EC) No 726/2004 of the European Parliament and of the Council and Directive 2001/83/EC of the European Parliament of the Council. [11] Good Pharmacovigilance Practices: http://www.ema.europa.eu/ema/index. jsp?curl=pages/regulation/document listing/docu ment listing 000345.jsp. [12] GVP module V Risk management systems: Http://www.ema.europa.eu/docs/ en GB/document library/Scientific guideline/2012/02/WC500123208.pdf. [13] GVP module VIII Pot-authorization safety studies: http://www.ema. europa.eu/docs/en GB/document library/Scientific guideline/2012/06/ WC500129137.pdf. [14] Guideline on good pharmacovigilance practices. Product or population specific considerations I: vaccines for prophylaxis against infectious diseases, http://www.ema.europa.eu/docs/en GB/document library/Scientific guideline/2013/12/WC500157839.pdf. [15] GVP module IX signal management: http://www.ema.europa.eu/docs/en GB/ document library/Scientific guideline/2012/06/WC500129138.pdf. [16] Huang YL, Moon J, Segal JB. A comparison of active adverse event surveillance systems worldwide. Drug Saf 2014;37:581–96. [17] Trifiro’ G, Coloma PM, Rijnbeek PR, Romio S, Mosseveld B, Weibel D, et al. Combining multiple healthcare databases for postmarketing drug and vaccines safety surveillance: why and how? J Intern Med 2014;275:551–61. [18] Vaccine adverse event surveillance & communication: http://vaesco.net/ vaesco/about-us.html. [19] Dieleman J, Romio S, Johansen K, Weibel D, Bonhoeffer J, Sturkemboom M, et al. Guillain-Barre syndrome and adjuvanted pandemic; influenza A (H1N1) 2009 vaccine: multinational case–control study in Europe. BMJ 2011;343:d3908. [20] Barker C, Snape DM. Pandemic influenza Ah1N1 vaccines and narcolepsy: vaccine safety surveillance in action. Lancetcom/Infect 2014;14:227–38.
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