The ENVI Committee in the European Parliament has begun discussing the issue of pharmacovigliance following the release of the Commission proposed Directive as part of the Pharmaceutical Package in November 2008. On 1 September 2009 Günter Verheugen, Commissioner for Enterprise and Industry presented the Pharmaceutical Package to the ENVI Committee.
Regulation 726/2004 and Directive 2001/83/EC were introduced to strengthen the EU pharmacovigilance system with the overall objective to promote public health. The amendments will clearly define the roles and responsibilities of different actors. In addition, they will help increase transparency and communication on medicines in order to increase the patient’s understanding and build trust and between patients and health care professionals. Another goal is to develop a collection of data about safety of medicines.
The Rapporteur on pharmacovigilance for the ENVI Committee is:
Linda McAvan (S&D)
The Shadow Rapporteurs are:
Pilar Ayuso (EPP),
Antoniya Parvanova (ALDE),
Michail Tremopoulos (Greens),
Marina Yannakoudakis (ECR), and
Jiri Mastalka (GUE).
The ITRE and IMCO Committees also have Rapporteurs on the issue who are respectively Michèle Rivasi (Greens) and Claude Turmes (Greens).
Pharmacovigliance in the EU
In the EU, new medicines are licensed to be sold on the European market (“market authorisation”) by the Community-wide European Medicines Agency (EMEA) and by Member States’ own drug regulatory agencies (“competent authorities”). The EMEA handles market authorisation applications for medicines seeking a licence for more than one European country. Medicines to be marketed in only one European country apply for authorisation from that Member State.
To gain a market authorisation, a newly developed medicine must demonstrate efficacy, safety and quality in clinical trials, and demonstrate a favourable benefit to risk ratio. The evaluation of medicines prior to marketing authorization only provides a general idea of their adverse effects, because the medicines have been tested for a limited time on a selected sample of clinical trials participants (volunteers and patients). Some adverse drug reactions (ADRs) only arise after long-term use in a larger population, sometimes under unique circumstances or in the presence of co-existing treatments.
The role of pharmacovigilance is to obtain further knowledge of adverse effects that arise after a medicine is marketed in order to limit the harm to patients and consumers. Pharmacovigilance entails medicines safety monitoring, in which the safety of patients is the top priority. The system is largely driven by spontaneous reporting of suspected adverse drug reactions by healthcare professionals and (in some countries) patients to drug regulatory authorities and/or pharmaceutical companies. Pharmacovigilance systems must be carefully attuned to the patients’ experience in order to detect unexpected, idiosyncratic, or rare adverse drug reactions that have the potential to be very serious.
The WHO- World Health Organisation (2002) defines pharmacovigilance as “the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem”.
Adverse drug reactions can be serious and the human and financial costs of the adverse effects of medicines are high. Adverse effects are responsible for at least 5% of hospital admissions and the 5th ranking cause of hospital deaths according to the European Commission. [[Examples from recent years include rofecoxib (Vioxx°) with fatal cardiovascular events, selective serotonin reuptake inhibitor antidepressants (fluoxetine (Prozac°), paroxetine (Deroxat°/ Seroxat°) and others) and rimonabant (Acomplia°) with increased suicide risk, olanzapine (Zyprexa°) with diabetes and metabolic disorders, and rosiglitazone (Avandia°) with fatal cardiac disorders.]] The WHO Uppsala Monitoring Centre estimates that 4% to 5% of marketed medicines are withdrawn due to safety concerns. On occasions, alerts from ADRs are not acted on quick enough and patients experience exacerbated adverse effects. Recent examples include rofecoxib (Vioxx®), a painkiller with cardiovascular side effects in 2004 and rimonabant (Accomplia®) an anti-obesity drug with psychiatric side effects in 2008.
Some ADRs are already known to health care professionals and can generally be managed by a clinician e.g. by closely monitoring the therapy, adjusting and reducing doses, switching to different medicines with the same effect (for example, using blood pressure lowering medicines from a different pharmacological class) or treating the side effect (for example, by using laxatives for constipation caused by morphine).
Periodic Safety Update Reports (PSURs) are used to re-evaluate safety post-marketing and are prepared by the drug companies to be deliver to the drug regulatory authorities.
The Proposed Pharmacovigilance Directive and Regulation
The EU proposal includes a centralised pharmacovigliance system that makes greater use of risk management systems. According to the proposal, it is proposed that a marketing authorisation can be granted provided that post-authorisation studies are to be conducted (this condition has to be stated in the risk management plan). [[ Proposed article 22a of the Directive and article 10a of the Regulation. But every time the health authorities want to ask for a risk management system or]] post-authorisation study to be carried out, they will need to seek the opinion of the producer before confirming their request.[[proposed articles 22a and 104a of the Directive]][[ There are no plans however to provide public access to the health authorities’ detailed requests or the drug companies’ responses that influence the confirmation and final content of these requests. Yet these documents are extremely informative, as illustrated by the US experience with paediatric studies
for which requests are publicly accessible on the FDA website, accompanied by the modifications requested by the pharmaceutical companies.]]
The Commission proposes to support a central pharmacovigilance database, based around the existing Eudravigilance database, which would potentially allow better detection and analysis of rare adverse events through its increased size, and avoid duplicate analysis by multiple national authorities.
The Commission proposes that pharmaceutical companies receive healthcare professionals’and patients’ adverse drug reaction reports. [[proposed article 107(1) and (2)]] Companies will be responsible for sending these reports to “a single point within the Community“ [[proposed article 107(1)]] (i.e. Eudravigilance database). This arrangement provides an opportunity for drug companies to manipulate the data before independent analysis.
It is also proposed that Member States may hand over the “follow up of such [PSUR] reports” to drug companies. [[proposed article 107(4)]] In this case, pharmaceutical companies would be both defendant and jury charged with assessing the change, if any, in their product’s risk-benefit balance. The subcontracting of data interpretation to drug companies is a major limitation in the current pharmacovigilance system. Enlarging these subcontracting arrangements would further endanger patients by stripping the health authority of their authority, expertise, credibility and autonomy. [[proposed article 107b which stipulates that the “scientific evaluation of the risk-benefit balance of the medicinal product“ be produced by pharmaceutical companies in their periodic safety update reports (PSURs)]]
The directive requests that Member States establish web-based reporting portals through their competent authorities, and make it possible for patients as well as healthcare professionals to report ADRs. The directive asks Member States to encourage healthcare professionals to report ADRs and suggests that Member States create powers to compel healthcare professionals to report event, if this is felt necessary.
A new Pharmacovigilance Risk Assessment Advisory Committee (PRAAC) would be established in the EMEA, reporting to the Committee on the Use of Medicinal Products in Humans (CHMP). CHMP is responsible for the initial risk assessment of a new medicine and the decision to grant or refuse a marketing authorisation. The current EU Commission’s proposal foresees that a European Pharmacovigilance
Risk Assessment Advisory Committee (PRAAC) will replace the Pharmacovigilance Working Party, [[proposed amendment to article 27 of the Directive and to article 56(1)(aa) of the Regulation]] reviewing safety concerns of marketed medicines without the authority or resources to enact their recommendations. The only real advance of the proposed PRAAC is that, as part of the EU pharmacovigilance procedures, the PRAAC would be able to organise public hearings, which would enhance transparency. [[proposed article 107k(2) of the Directive]]
The proposal allows for the EMEA to request a post-marketing safety study be undertaken by the pharmaceutical company in response to concerns about a medicine, with submission of an abstract and full report to the EMEA.
The centralisation of pharmacovigilance activity would also include streamlining PSURs, so that pharmaceutical companies produce a central report for the EMEA, rather than multiple reports (covering variable time periods). The frequency of PSURs, which can be contested by the pharmaceutical companies, is variable and determined by that which is “appropriate” to the drug’s risk profile.[[ proposed article 107c(6) point (c)]] Moreover, PSURs will no longer be required for longstanding products considered to have been in “well-established medicinal use” (for at least 10 years within the Community).[[ proposed article 107b(3)]]
The legislation is less prescriptive around the specifications of pharmaceutical company pharmacovigilance systems (currently set for the lifespan of a product as part of the marketing authorisation application).
The directive widens the definitions of reportable adverse events to include those which result from medication errors, overdoses, uses outside the product license and illicit use, rather than those simply occurring during routine licensed use.
The directive also changes the requirements for Summaries of Product Characteristics (SPCs or SmPC) – the detailed prescribing advice for each medicine – and the requirements for the package inserts of information for patients. For both these items, the directive would add a box of key information for safe use of the product.
Cost Impact
The pharmacovigilance amendments are predicted to reduce costs for industry and increase costs for the regulators, but doesn’t build on previous legislative changes further to the pharmaceutical review, which included provisions that pharmacovigilance activities should be funded through public funds. It is suggested that these costs are recouped by way of fees from industry.
For more information on Pharmacovigilance —-
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