Tag Archives: pharmacovigilance

EMA Publish for Questions and answers on practical translation measures for the implementation of the pharmacovigilance legislation

This Question and Answer (Q&A) document provides practical considerations concerning the initial phases of operation of the new pharmacovigilance legislation (Regulation (EU) No 1235/2010 and Directive 2010/84/EU). The Q&A applies to all medicinal products for human use regardless of the route of authorisation. Any specificities depending on the route of authorisation (i.e. centralised procedure versus mutual recognition/decentralised procedure and purely national procedure) are highlighted when appropriate.

For further details, please view the document below.

EMA Publish Concept Paper on Key Aspects for the use of Pharmacogenomic Methodologies in the Pharmacovigilance Evaluation of Medicinal Products

There is large variability in the response to drug therapy – in terms of both efficacy and safety. Some of the variation is related to inherited or non-inherited characteristics of the genome, i.e. genetic variations or activation/suppression of genome functions. These genetic variations may relate to drug disposition (pharmacokinetics) or drug action (pharmacodynamics). Consequently, there may be subsets of patients with a different benefit/risk profile.
Some genomic biomarkers may predict drug exposure or the risk status of a patient related to adverse drug reactions (ADRs). Genomic factors may play a role in the pathogenesis of both predictable and unpredictable ADRs as well as in clinical progression of diseases.

For further details, please view the document below.

DMA publishes concept paper on bio similars containing proteins

In the current EMA guideline on similar biological medicinal products containing biotechnology derived proteins as active substances, nonclinical and clinical issues lays down the requirements of such products to determine its similarity to one another. This guidance came into effect in June 2006, however since then several by a similar products have come to the market and the number of guidance is in this area has increased significantly and the regulatory framework is becoming wider.

The EMA considers it necessary to update these guidance and bring together a number of issues into a single document. In order to tackle the complex issues that are arising. And to allow for the WHO guidelines on evaluation of similar biotherapeutic products. And also to be compliant with the Three R principals (replacement, reduction and refinement) with regard to the use of animal experiments.

excerpt from concept paper

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The Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues (EMEA/CHMP/BMWP/42832/2005) lays down the  nonclinical and clinical requirements for a biological medicinal product  claiming to be similar to another one already marketed. This guideline came into effect in June 2006. Since then several biosimilar products
have come into the EU market, the number of scientific advices given by the CHMP on the development of biosimilar products has increased significantly and the regulatory framework is becoming wider, e.g. the draft guideline of the biosimilar monoclonal antibodies is being finalised. .An increasing number of biosimilar products are under development, especially biosimilar monoclonal antibodies. The development of more complex biosimilar medicinal products is challenging, and several issues in the development are under re-evaluation. These include the selection of relevant species for
non-clinical studies, need for clinical equivalence studies and other issues of the design of the pivotal clinical studies, role of biomarkers, amount of immunogenicity data needed, and the possibility to
extrapolate to other indications. The WHO Guidelines on Evaluation of Similar Biotherapeutic Products with detailed recommendations on clinical development were published in October 2009. In addition,
the EMA is emphasizing the need to follow the 3 R principles (replacement, reduction and refinement) with regard to the use of animal experiments. All these factors suggest revising the current guideline.

EMA release concept paper on Pharmacovigilance and implementation

The European commission is seeking views from the public and industry on a concept paper dealing with the implementation of measures for performance activities related to safety monitoring of medicines. The paper is open for consultation until 7 November and provide technical details of the European medicines agency (EMA) marketing authorisation holders need to apply to their businesses.

excerpt from release

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The European Commission is seeking views from the public on a concept papericon link external EMA release concept paper on Pharmacovigilance and implementation on implementing measures for the performance of activities related to the safety monitoring of medicines.

The paper, which is open for consultation until 7 November 2011, provides technical details that the European Medicines Agency, medicines regulatory authorities in European Union (EU) Member States and marketing-authorisation holders will need to apply when implementing the new pharmacovigilance legislation.

The document provides details on:

  • pharmacovigilance system master files;
  • the quality system for the performance of pharmacovigilance activities;
  • the use of internationally agreed terminology, formats and standards;
  • monitoring data in the EudraVigilance database;
  • the electronic transmission of suspected adverse reactions;
  • electronic periodic safety update reports and risk-management plans;
  • post-authorisation safety studies.

The Agency and representatives from Member States provided technical expertise to help with the preparation of this document.

The concept paper is available to download from the European Commission’s pages on pharmacovigilanceicon link external EMA release concept paper on Pharmacovigilance and implementation. All comments on the paper should be sent directly to the Commission.

This consultation process is a key step in the implementation of the pharmacovigilance legislation. The Agency is working closely with the European Commission, as well as national medicines regulatory authorities, patients, healthcare professionals and pharmaceutical companies, to ensure the effective implementation of the new legislation.

The launch of this consultation is in line with the target in the implementation plan for the new legislation.

 

EMA Publish Concept Paper on Bio-Similar products containing Active Proteins: Clinical and Non-Clinical

EMA Publish Concept Paper on Bio-Similar products containing Active Proteins: Clinical and Non-Clinical

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The Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues (EMEA/CHMP/BMWP/42832/2005) lays down the  nonclinical and clinical requirements for a biological medicinal product claiming to be similar to another one already marketed. This guideline came into effect in June 2006. Since then several biosimilar  products have come into the EU market, the number of scientific advices given by the CHMP on the development of biosimilar products has increased significantly and the regulatory framework is becoming wider, e.g. the draft guideline of the biosimilar monoclonal antibodies is being finalised.

An increasing number of biosimilar products are under development, especially biosimilar monoclonal antibodies. The development of more complex biosimilar medicinal products is challenging, and several issues in the development are under re-evaluation. These include the selection of relevant species for non-clinical studies, need for clinical equivalence studies and other issues of the design of the pivotal clinical studies, role of biomarkers, amount of immunogenicity data needed, and the possibility to extrapolate to other indications. The WHO Guidelines on Evaluation of Similar Biotherapeutic Products with detailed recommendations on clinical development were published in October 2009. In addition, the EMA is emphasizing the need to follow the 3 R principles (replacement, reduction and refinement) with regard to the use of animal experiments. All these factors suggest revising the current guideline.



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EMA Announces Pharmacoepidemiology and Pharmacovigilance (ENCePP) Information Day

EMA Announces Pharmacoepidemiology and Pharmacovigilance (ENCePP) Information Day

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This information day is benefitting all pharmaceutical industry staff, in particular those responsible for risk management plans and post-authorisation studies (e.g. pharmacovigilance, pharmacoepidemiology and regulatory affairs) and academics, regulators, editors of medical journals, funding bodies and other professionals specialising in the field of observational research.


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EMA Announce Meeting on Excellence in Pharmacovigilance in Clinical Trials and Post Marketing

EMA Announce Meeting on Excellence in Pharmacovigilance in Clinical Trials and Post Marketing

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This course is designed to provide a firm grounding in key aspects of global clinical pre- and post-marketing safety.


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EMA Announce Meeting on Pharmacoepidemiology and Pharmacovigilance

EMA Announce Meeting on Pharmacoepidemiology and Pharmacovigilance

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European Network of Centres for Pharmacoepidemiology and Pharmacovigilance plenary meeting. 23/11/2011 – 23/11/2011

The 8th plenary meeting of the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) is being held on 23 November 2011. The plenary is the meeting of representatives from research centres and data providers included in the ENCePP database of research resources. Registration by invitation only. Registration open until 16/11/2011. Places limited.



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EudraVigilance Information Day

EudraVigilance Information Day

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10/05/2011 – 10/05/2011

The EudraVigilance Information Day is providing a forum for medicines regulatory authorities, marketing authorisation holders and sponsors of clinical trials to gain updates on the new legislation in pharmacovigilance, the key activities of the EudraVigilance Expert Working Group in line with their work programme for 2011 and recent developments in international standardisation activities in pharmacovigilance. Registration open until 9 May 2011. Places limited.

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EMA Announce EudraVigilance Information Day

EMA Announce EudraVigilance Information Day

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The information day will address the following areas: Changes in the EU regulatory environment in relation to clinical trials; The new pharmaceutical legislation and the impact on the conduct of pharmacovigilance in the EU; The new data quality management in EudraVigilance and impact on stakeholders; Practical implementation questions from stakeholders with focus on electronic reporting of ICSRs and pharmacovigilance. Panel discussions will provide the opportunity for extensive Q&As with the speakers, chairpersons and Programme Committee members.

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EMA VICH Data Elements for Submission of Adverse Event Reports (AERS)

EMA VICH Data Elements for Submission of Adverse Event Reports (AERS).

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Pharmacovigilance of veterinary medicinal products (VMPs) is important to guarantee the continued safety and efficacy of VMPs in use. The objective of this guidance document is to standardise the data for submission of adverse events relating to VMPs. A consistent set of data will contribute to a harmonised approach for the detection and investigation of adverse effects of marketed VMPs and thus help to increase public and animal health.

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EMA VICH Guideline on Controlled List of Terms

EMA VICH Guideline on Controlled List of Terms

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To assess the safety and efficacy of veterinary medicinal products, the use of controlled lists of terms is important in order to assure consistency, as well as to allow comparison between products and across product classes. The data fields that require controlled lists of terms have been identified in VICH GL42 “Data Elements for Submission of Adverse Event Reports”. Regulatory authorities and industry have partnered in the development of the lists and a maintenance procedure (through the ad-hoc Controlled Lists of Terms Implementation Task Force from June 2008 to February 2009). The lists have been developed by making use of existing lists from regulatory authorities (RA) and industry. The controlled lists of terms provide a level of discrimination sufficient to record, search and categorize for trending. The lists have standardized groupings of terms, of a manageable size but with sufficient detail to allow standardised input and analysis. The controlled lists are made accessible via the VICH
Secretariat Website (http://www.vichsec.org/) and RA websites. For the data fields that use controlled lists of terms, user systems can, to facilitate reporting or inputting,
use a subset of terms listed in GL30 that are considered relevant to the region and to the products involved. However, when receiving reports electronically, that are compliant with the relevant VICH guidelines, all systems must be capable of importing and storing the full report, including all standard terms and codes, without loss of information.

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EMA Guideline on Pharmacovigilance of Veterinary Medicinal Products

EMA Guideline on Pharmacovigilance of Veterinary Medicinal Products

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The objective of this guideline is to provide standards to construct a single electronic message to transmit GL42 contents to all regions.
The need to transfer and disseminate information quickly, accurately and easily between Regulatory Authorities (RA) and Marketing Authorization Holders (MAH) on a worldwide scope is especially pertinent to the notification and assimilation of information for pharmacovigilance. Whereas the definition of the pharmacovigilance information has been established within GL24, GL30 and GL42, this guideline defines the electronic standards for transfer of data. In order to allow for electronic exchange of this information between stakeholders, further specification of the field descriptors and their relationships, including agreement on format of the electronic message is essential.

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EMA, The European Drug Regulator, Announce ENCePP Information Day

EMA, The European Drug Regulator, Announce ENCePP Information Day

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26/11/2010

De Vere Venues, Canary Wharf, London

European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP)

This event will introduce ENCePP and the concept of ENCePP studies to a wider audience. It will also include future developments and presentations on new legislation for post-authorisation studies and other EMA activities in the field of pharmacoepidemiology. The ENCePP information day is targeted primarily towards pharmaceutical industry staff responsible for risk management plans and post-authorisation studies, as well as other interested professionals including academics, regulatory, editors of medical journals and other professionals specialising in the field of observational research.

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EMA, the European Drug Regulator, Publishes Draft Guidance on Detection and Management of Duplicate Individual Cases and Individual Case Safety Reports (ICSRs)

EMA, the European Drug Regulator, Publishes Draft Guidance on Detection and Management of Duplicate Individual Cases and Individual Case Safety Reports (ICSRs).

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Duplicate cases can pose significant problems for analysing signals arising from pharmacovigilance databases, both artificially inflating and masking signals of disproportionate reporting. The current reporting rules guarantee duplicate reporting.
Databases should be routinely screened to detect and eliminate duplicate cases. This guideline proposes methods for detecting, confirming and managing duplicate cases suitable for organisations receiving pharmacovigilance data in various different formats.

Volume 9A of The Rules Governing Medicinal Products in the European Union – Guidelines on Pharmacovigilance for Medicinal Products for Human Use1 and Volume 10 of The Rules Governing Medicinal Products in the EU2 provide detailed guidance on the reporting of suspected (unexpected) serious adverse reactions in compliance with the legal provisions laid dawn in Regulation (EC) No 726/2004, Directive 2001/83/EC as amended and Directive 2001/20/EC.
Guidance is also provided for situations where individual cases might be reported by different senders e.g. where a MAH is aware that a healthcare professional has reported an adverse reaction to one of the medicinal products, for which he holds a marketing authorisation, to the Competent Authority of a Member State. Volume 9A states that the MAH should still report the adverse reaction, informing the Competent Authority that the report may be a duplicate of a previous report. In this situation, it is essential for the MAH to provide all the available details including all case identification numbers allocated to the case, in order to aid identification of the duplicate.
Based on the current reporting rules and reporting practices, duplication of individual cases can occur. A duplicate refers to the same individual case reported by a primary source to describe suspected adverse reaction(s) related to the administration of one or more medicinal products to an individual patient at a particular point of time. This individual case may be reported by different senders, through different routes, whereby the case information may be handled differently by the processor of the case, which makes it difficult to identify the reported cases as duplicates. Case handling refers e.g. to coding practices, obtaining follow-up information and processing of personal data in line with EU Data Protection legislation.
Detection and handling of duplicates by National Competent Authorities (NCAs), Marketing Authorisation Holders (MAHs) and Sponsors of clinical trials (Sponsors) is an important element of good case management. The presence of duplicates in any pharmacovigilance system can create misleading signals and therefore impact on the safety monitoring and potential regulatory actions. How duplicates can impact on the identification of potential new safety issues can be illustrated by an example of duplication in the US FDA Adverse Events Reporting System (AERS) database. In an evaluation of quinine-induced thrombocytopenia, FDA researchers identified 20% of 141 reports as duplicates.3 Norèn et al.4 highlighted that since commonly used data-mining procedures may highlight associations with as few as three reports, one or two duplicates may severely affect their utility.

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Drug Regulators Publish Reflection Paper – Development of Similar Interferon Alfa

The Drug Regulator, EMEA, has published Guidance on developing Generic Interferon Alfa

The EMEA, published a reflection paper on the Non-Clinical and Clinical Development of Similar Medicinal Products Containing Recombinant Interferon Alfa.  in 2007, and has re-published the document on their website again.

This reflection paper lays down considerations on the non-clinical and clinical development of recombinant Interferon alfa-containing medicinal products claiming to be similar to another such product already authorised. Human interferon-alfa 2a or 2b are well-known and characterized proteins consisting of 165 amino acids. The non-glycosylated protein has a molecular weight of approx. 19,240 D. It contains two disulfide bonds, one between the cysteine residues 1 and 98, and the other between the cysteine residues 29 and 138. The sequence contains potential O-glycosylation sites. Physico-chemical and biological methods are available for characterisation of the proteins.

Recombinant Interferon Alfa 2a or 2b is approved in a wide variety of conditions such as viral hepatitis B and C, leukaemia, lymphoma, renal cell carcinoma and multiple myeloma. The sub-types Interferons alfa 2a and 2b have different clinical uses. IFN-alfa is used alone or in combination. Interferon alfa may have several pharmacodynamic effects. The relative importance of these effects in the different therapeutic indications is unknown. In general, interferon-alfa 2a or 2b use in oncology indications has reduced considerably and been superseded by other treatments.

Scope

This product specific reflection paper presents the current view of the CHMP on the non-clinical and clinical data for demonstration of comparability of two recombinant, on-pegylated, Interferon alfa containing medicinal products and should be read in conjunction with the requirements laid down in the EU Pharmaceutical legislation and other relevant CHMP guidelines (see References).

Non-Clinical Studies

Before initiating clinical development, non-clinical studies should be performed. These studies would be comparative in nature and designed to detect differences in the pharmaco-toxicological response between the similar Interferon alfa and the reference Interferon alfa and not just assess the response per se. The approach taken will need to be fully justified in the non-clinical overview.

Pharmacodynamics Studies

In order to compare differences in biological activity between the similar and the reference medicinal product, data from a number of comparative bioassays could be provided.

To support the comparability exercise for the sought clinical indications, the pharmacodynamic activity of the similar and the reference medicinal product could be quantitatively compared in an appropriate pharmacodynamic animal model, a suitable animal tumour model OR a suitable animal antiviral model.

Toxicological Studies

Data from at least one repeat dose toxicity study in a relevant species should be considered (for example, human Interferon alfa may show activity in the Syrian golden hamster). The study duration should be at least 4 weeks. Data on local tolerance in at least one species should be provided in accordance with the “Note for guidance on non-clinical local tolerance testing of medicinal products” (CPMP/SWP/2145/00).

Clinical Studies

Pharmacokinetic Studies

The pharmacokinetic properties of the similar and the reference medicinal product could be compared in single dose crossover studies using subcutaneous and intravenous administration in healthy volunteers. The recommended primary pharmacokinetic parameter is AUC and the secondary parameters are Cmax and T1/2 or CL/F.

Pharmacodynamic Studies

There are a number of PD markers, such as β2 microglobulin, neopterin and serum 2´, 5´-oligoadenylate synthetase activity, which are relevant to the interaction between Interferon -alfa and the immune system. The selected doses should be in the linear ascending part of the dose-response curve. Whereas the relative importance of these effects in the different therapeutic indications is unknown a comprehensive comparative evaluation of such markers following administration of test and reference products could provide useful supporting data.

Efficacy

Patient Population

The mechanism of action of interferon comprises of several different unrelated effects. Demonstration of similar efficacy between test and reference products is required. This could be performed in treatment-naïve patients with chronic hepatitis C (HCV) as delineated by the indication for the reference product. Other patient population(s) might be studied depending on the indications desired.

Study Design and Duration

A randomised, parallel group comparison against the reference product over at least 48 weeks is recommended. If possible, the study should be double-blind at least until data to complete the primary analysis have been generated. If this is not feasible, justification should be provided and efforts to reduce/eliminate bias should be clearly identified in the protocol.

Endpoints

Primary: Virologic response as measured by the proportion of patients with undetectable levels of HCV RNA by quantitative PCR at week 12. The assay used to measure HCV RNA and the cut-off applied should be justified. A 2-log decrease in viral load may be a co-primary endpoint. Secondary: virologic response at week 4 and end-of-treatment; sustained virologic response (24 weeks after completion of treatment); change in liver biochemistry including transaminase levels and morbidity.

Safety

Safety data should be collected from patients after repeated dosing in a comparative clinical trial over the treatment period plus 24 weeks of follow-up. The number of patients should be sufficient for the comparative evaluation of the adverse effect profile. Laboratory abnormalities for immune mediated disorders should be included. The safety profile should be similar to the reference products for the common adverse events (such as flu-like illness, alopecia, myalgia, leucopenia, anaemia and thrombocytopenia).

Immunogenicity

Comparative immunogenicity data (antibody levels) should be presented during the treatment period plus 24 weeks of follow-up according to the principles described in the “Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: nonclinical and clinical issues” (EMEA/CPMP/42832/05/) and the “Guideline on immunogenicity assessment of biotechnology-derived therapeutic proteins” (EMEA/CHMP/BMWP/14327/2006).

Extrapolation of Evidence

In principle extrapolation from one therapeutic indication to another is appropriate where the mechanism of action and/or the receptor are known to be the same as the condition(s) for which similarity in efficacy has been established. If indication(s) are sought, where the mechanism of action is not known to be the same, such extrapolation
should be adequately justified.

Pharamcovigilance Plans

Within the authorisation procedure the applicant should present a risk management programme/pharmacovigilance plan in accordance with current EU legislation and pharmacovigilance guidelines. Attention should be paid to immunogenicity and potentially rare and/or delayed serious adverse events, especially in patients undergoing chronic administration. Safety should be collected from patients representing all approved indications.

If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com