Pharmacovigilance in pharmaceutical companies: An overview.

Pharmacovigilance is responsible for monitoring the safety of medicines in normal clinical use and during clinical trials. In the light of the experience acquired and following an assessment by the Commission of the Union system of pharmacovigilance, it has become clear that it is necessary to take measures in order to improve the operation of Union law on the pharmacovigilance of medicinal products for human use. Regulation (EU) No 1235/2010 and Directive 2010/84/EU introduced new legislation on pharmacovigilance. The marketing authorization holder should be responsible for continuously monitoring the safety of its medicinal products for human use, for informing the authorities of any changes that might have an impact on the marketing authorization, and for ensuring that the product information is kept up-to-date. Marketing authorization holders (MAH) record all suspected adverse reactions occurring in the European Union or in the third countries, and which are brought to their attention spontaneously by the patients or their health care, or occurring in the context of post-authorization study. For all medicinal products is mandatory to maintain a pharmacovigilance system master file (PSMF). According to the Legislative Decree 219/2006 the MAH must submit to the competent authorities the information on suspected adverse reactions of a medicinal product, in form of a periodic safety update reports (PSURs).

INTRODUCTION

Pharmacovigilance (PV) is responsible for monitoring the safety of medicines in normal clinical use and during clinical trials. Its main aim is to minimize the risk related to drugs used and to maximize their benefits.[1]

According to the regulations of worldwide health agencies, pharmacovigilance units collect adverse events from all over the world that were caused or might have been caused by the use of a specific drug.[2]

Adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation participant who was administered a pharmaceutical product, which does not necessarily have a causal relationship with this treatment. A serious adverse event (SAE) is an AE that results in any of the following: Fatality; life-threatening symptoms; requires or prolongs hospitalization; disability or incapacity; a congenital anomaly or birth defect; a medically serious condition.[3]

An adverse drug reaction (ADR) is a negative side effect; it is a noxious and unintended reaction to a medicinal product. All noxious and unintended effects may be due to: The use of medicines according to the marketing authorization instructions; uses not complying with the wording marketing authorization: Unauthorized use of medication (off-label use), abuse, misuse, medication errors, overdose and adverse reactions associated with occupational exposure.[3]

The GVP (Guidelines on good pharmacovigilance practices; module VI) recommend tracking some “special situations”: Pregnancy and breast-feeding (is necessary to follow the outcome of the pregnancy and the development of the newborn); pediatric population or older [(or populations provided for in SPC (Summary of Product Characteristics)]; lack of therapeutic efficacy, a major failure of the product in the achievement of the pharmacological waiting for an approved indication (e.g., treatment failure, poor response, patient does not respond to medication, no results with the drug, etc.).[4]

Relevant legislation

The new legislation on pharmacovigilance is based on two new legislative acts:[5]

Regulation (EU) 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.

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 medicinal products for human use.

Objectives of the reform

The objectives of the reform are to promote and protect the public health by reducing the number and severity of ADRs and improving the use of medicines by:

Roles and responsibilities clear to all parties involved

Insurance of a European system robust and fast in making decisions necessary in the field of PV

Enhancing the participation of the patients and healthcare professionals

Improvement of communication systems on the decisions taken and their justification

Increased transparency

Better information on medicinal

Increase the efficiency of PV systems

Strengthening the European Network of PV

Strengthening systems of PV

Increased proactivity/programing of activities

Reduction of duplication of activities

The main tasks of the agency in the area of pharmacovigilance laid down in Regulation (EC) No 726/2004 should be maintained and further developed, in particular as regards the management of the union pharmacovigilance database and data-processing network (Eudravigilance database), the coordination of safety announcements by the member states and the provision to the public of information regarding the safety issues.

In order to allow all the competent authorities to receive and access simultaneously and share pharmacovigilance information for medicinal products for human use authorized in the union, the eudravigilance database should be maintained and strengthened as the single point for receiving such information. The database should be fully and permanently accessible to the member states, the agency and the commission, and accessible to an appropriate extent to the marketing authorization holders and the public.

Regulation (EU) No 1235/2010 and Directive 2010/84/EU introduced the concept of the pharmacovigilance system master file. In order to accurately reflect the pharmacovigilance system used by the marketing authorization holder, the pharmacovigilance system master file should contain the key information and documents covering all the aspects of pharmacovigilance activities, including the information on tasks that have been subcontracted. It should contribute to the appropriate planning and conduct of audits by the marketing authorization holder and the supervision of pharmacovigilance activities by the qualified person responsible for pharmacovigilance. At the same time, it should enable national competent authorities to verify the compliance concerning all the aspects of the system. The information contained in the pharmacovigilance system master file should be maintained so as to reflect any modifications that have been made and ensure easy accessibility and availability by the national competent authorities for the purpose of inspections.

Quality systems should form an integral part of the pharmacovigilance system. The minimum requirements for the quality system for the performance of pharmacovigilance activities should ensure that the marketing authorization holders, national competent authorities and the European medicines agency (EMA) establish an adequate and effective quality system, which provides for an effective monitoring of compliance and the accurate and proper documentation of all measures taken. They should also ensure that the marketing authorization holders, national competent authorities and EMA have at their disposal sufficient competent, appropriately qualified and trained staff. Adherence to a well-defined quality system should ensure that all pharmacovigilance activities are conducted in such a way that they are likely to produce the desired results or quality objectives for the fulfilment of pharmacovigilance tasks. As part of their quality system, national competent authorities and EMA should establish contact points to facilitate the interaction between national competent authorities, EMA, the Commission, the marketing authorization holders and the persons reporting the information on the risks of medicinal products, as referred to in the second subparagraph of Article 101(1) of Directive 2001/83/EC

Reporting by Italian marketing authorization holders (MAH)

It is necessary, from a public health perspective, to complement the data available at the time of authorization with additional data about the safety and, incertain cases, also about the efficacy of medicinal products for human use authorized in accordance with the Regulation (EC) No 726/2004. The commission should therefore be empowered to impose on the marketing authorization holder the obligation to conduct post-authorization studies on safety and on efficacy. It should be possible to impose that obligation at the time of granting the marketing authorization or later, and it should be a condition of the marketing authorization. Such studies may be aimed at collecting the data to enable the assessment of safety or efficacy of medicinal products for human use in everyday medical practice.[6]

The marketing authorization holder should be responsible for continuously monitoring the safety of its medicinal products for human use, for informing the authorities of any changes that might have an impact on the marketing authorization, and for ensuring that the product information is kept up-to-date. As medicinal products for human use could be used outside the terms of the marketing authorization, the marketing authorization holder's responsibilities should include providing all the available information, including the results of clinical trials or other studies, as well as reporting any use of the medicinal product which is outside the terms of the marketing authorization. It is also appropriate to ensure that all relevant information collected on the safety of the medicinal product for human use is taken into account when the marketing authorization is being renewed.[7]

It is essential that a strengthened system of pharmacovigilance not lead to the premature granting of marketing authorizations. However, some medicinal products for human use are authorized subject to additional monitoring. This includes all medicinal products for human use with a new active substance and biological medicinal products, including biosimilars, which are priorities for pharmacovigilance. Competent authorities may also require additional monitoring for specific medicinal products for human use that are subject to the obligation to conduct a post-authorization safety study or to conditions or restrictions with regard to the safe and effective use of the medicinal product that will be specified in the risk management plan. Risk management plans are normally required for new active substances, biosimilars and medicinal products for pediatric use and for medicinal products for human use involving a significant change in the marketing authorization, including a new manufacturing process of a biotechnologically-derived medicinal product. Medicinal products for human use subject to additional monitoring should be identified as such by a black symbol, which will be selected by the commission on the basis of a recommendation by the Pharmacovigilance Risk Assessment Committee, and an appropriate standardized explanatory sentence in the summary of product characteristics and in the package leaflet. The agency should keep an up-to-date, publicly available list of such medicinal products.[6]

MAH record all suspected adverse reactions occurring in the European Union or in the third countries, and which are brought to their attention spontaneously by the patients or their health care, or occurring in the context of post-authorization study. Also, ensure that those reports are accessible at a point only within the European Union. Holders of marketing authorizations take in consideration any reporting of suspected adverse reaction carried out by electronic means or by any other appropriate means, to patients and healthcare professionals.

With the exception of reports of suspected adverse reactions contained in the national network of pharmacovigilance, the MAH shall submit electronically to the eudravigilance database information on all suspected serious adverse reactions occurring in the European Union and in third countries, within 15 days following the day on which the holder concerned gained knowledge of the event. In addition, the MAH shall submit electronically to the Eudravigilance database information on all non-serious suspected adverse reactions that occur in the European Union within 90 days after the day on which the holder of the marketing authorizations concerned gained knowledge of the event.[5]

In summary, the MAH should:

Operate a pharmacovigilance system equivalent to the system of pharmacovigilance of AgenziaItaliana del Farmaco (AIFA).

Evaluate all scientific information, examine the ability to minimize and to prevent risks. To take the appropriate actions when required.

Perform regular quality control actions on its pharmacovigilance system. In case of deviations in the pharmacovigilance system the holders must record a note in the file reference and must implement an appropriate corrective action plan. Only after that the corrective actions have been fully implemented, the note may be removed.

Appoint a qualified person responsible for pharmacovigilance in possession of a degree in the health sector and with proven experience in all aspects of pharmacovigilance. The qualified person resides and carries out its activities in the European Union and he is responsible for establishing and the management of the pharmacovigilance system.

Maintain and make available on request a file reference of the pharmacovigilance system.

Implement a system of risk management for any medicine.

Monitor the outcome of measures to reduce risks to a minimum under the plan of risk management.

Make updates to the system of risk management and monitoring pharmacovigilance data, in order to determine whether there are new risks or change thereof or the benefit/risk ratio of medicines.

The AIFA may request to appoint a contact person at national level for pharmacovigilance questions. The contact person for pharmacovigilance or in his absence a qualified person shall register to the national pharmacovigilance.

For products approved prior to July, 21 2012 had not been required a system of risk management. The MAH, who submitted a marketing authorization application before July, 21 2012 (or July, 2 2012 for centralized products), were not obliged to submit, as part of the application for marketing authorization, the risk management plan also in case it was obtained after July, 21 2012 (or July, 2 2012 for centralized products). All applications for marketing authorizations pending benefited from the same exemption. For products that were approved after July, 21 2012 (or July, 2 2012 for centralized products) it was required to submit a risk management plan describing the system of risk management.[8]

For all medicinal products is mandatory to maintain a pharmacovigilance system master file (PSMF). The obligation to maintain and to indicate the location of a PSMF, applies to all medicinal products for which the marketing authorization was obtained before 2 or 21 July 2012, or an application was submitted before 2 or 21 July 2012.

When the holders want to make a public release on pharmacovigilance information related the use of a medicinal product shall promptly inform AIFA, competent national authorities of the other Member States, EMA and European Commission. The MAH must ensure that the information is presented to the public in an objective and not misleading way.

According to the Legislative Decree 219/2006 the MAH must submit to the competent authorities the information on suspected adverse reactions of a medicinal product, in form of a periodic safety update reports (PSURs). The PSUR was designed to be a stand-alone document that allows a periodic but comprehensive assessment of the worldwide safety data of a marketed drug or biological product. The PSUR can be an important source for the identification of new safety signals, a means of determining changes in the benefit-risk profile, an effective means of risk communication to regulatory authorities and an indicator for the need for risk management initiatives, as well as a tracking mechanism monitoring the effectiveness of such initiatives. For these reasons, the PSUR can be an important pharmacovigilance tool.[9] PSURs should be sent electronically to archive according to section 25a of Regulation (EC) No. 726/2004. This requirement shall apply twelve months after the EMA has established and announced the features of the archive. Until the EMA will not be able to provide the agreed upon functionalities for storage of periodic safety update reports, the holders of the marketing authorizations submit the periodic safety update reports to all member states in which the medicinal product has been authorized. For marketing authorizations granted after July 21, 2012, the frequency of PSURs submission is specified in the authorization. For marketing authorizations granted before 21 July 2012, the frequency of PSURs submission is not regulated by the authorization. In this case the frequency of PSURs submission can be:

At least every six months after authorization and until the placing on the market, if the product has not yet been placed on the market;

at least every six months during the first two years following the initial placing on the market and than once a year for the following two years, after that every three years if the product is being marketed.

The frequency of PSUR should be performed in a single evaluation in case of medicinal products authorized in several member states; all medicinal products containing the same active substance or the same combination of active substances; medicinal products for which has been fixed a date for the European Union. The harmonized frequency for the PSUR submission is made public by the EMA through the web portal of the European medicines. The holders of marketing authorizations shall submit an application for a variation of the marketing authorization. Any changes to the dates and frequency of submission of periodic safety update reports specified in authorization take effect six months after the date of publication on the European medicines web-portal.

CONCLUSION

Pharmacovigilance rules are necessary for the protection of public health in order to prevent, detect and assess adverse reactions to medicinal products for human use placed on the Union market, as the full safety profile of medicinal products for human use can be known only after they have been placed on the market. Pharmacovigilance activities cover the whole life-cycle management of medicinal products for human use in relation to safety. However, we must emphasize the importance of the pharmacovigilance as a continuation and completing of the analysis performed on medicines starting from the phase I studies, when the medication is administered for the first time in humans, and not only after their marketing authorization.