Periodic safety update report

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A periodic safety update report (PSUR, regularly updated safety report , also PBRER, periodic benefit-risk evaluation report ) is a report to be drawn up by pharmaceutical companies at set intervals, which is used to update the risk-benefit assessment of drugs . Pharmaceutical companies are required by law to evaluate reports of side effects collected around the world and to check whether they result in measures for the safe use of a drug, i.e. whether further restrictions on use or additional side effects must be taken into account. The PSUR is subjected to an assessment by a pharmaceutical authority , which checks the content of the data submitted and evaluates the conclusions of the pharmaceutical company. If necessary, the product information texts , i.e. the summary of the product characteristics (corresponds to the product information ) and the package insert, will be amended accordingly.

PSURs are an instrument of the drug safety system in the European Union.

Legal basis

The legal basis for the establishment of an EU-wide pharmacovigilance system forms the Directive 2001/83 / EC of the European Parliament and of the Council on the Community code relating to medicinal products for human of 2001. Their revision in 2004 and from the implementation of EU pharmaceutical package resulting " Pharmacovigilance Directive ”(EU Directive 2010/84 / EU) had extensive effects on the monitoring of drug risks. They became legally binding through implementation in national drug laws. The regulations for veterinary medicinal products are based on Directive 2001/82 / EC. In Germany there is an obligation to submit a PSUR according to § 63d AMG . Regulation (EC) No. 726/2004 in the version amended by Regulation (EU) No. 1235/2010 forms the legal basis for centrally authorized medicinal products .

The procedures for the timely creation, submission to the competent authorities and assessment of PSURs and the implementation after completion are described in legal texts and guidelines of the EU.

In the international area, the safety reports are regulated as periodic benefit-risk evaluation reports (PBRER) via the ICH guideline E2C of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH).

content

A PSUR contains a cumulative representation of all data relevant for drug safety from the time a drug is approved. The focus is on the information since the last report. The content and structure of a PSUR are prescribed in detail.

In addition to administrative information on the drug or drugs, the authorization holder and an overview of reports submitted so far, the PSUR provides information on marketing data (sales volume, prescription volume) and scope of use. This is followed by information about safety-relevant measures taken up to the reference date (marketing restrictions, suspension or withdrawal of approvals, changes to dosage recommendations, contraindications, warnings, side effects and interactions). The PSUR then lists the adverse events spontaneously reported to the marketing authorization holder worldwide during the reporting period, cases reported by other authorities, case reports from clinical and non-interventional studies and information from the literature. This also includes data for areas of application and population groups that do not correspond to the approval. In addition to interval data, the cumulative data from the time of approval are also required. A main focus is on the current signal detection, i.e. the recognition of a possible causal relationship between the use of a drug and an event. The PSUR concludes with a scientific risk- benefit analysis for the approved areas of application of the drug ( Integrated Benefit-risk Analysis for Authorized Indications ) and, if necessary, contains suggestions for measures to improve drug safety ( conclusions and actions ).

Similar rules apply to veterinary medicinal products.

Submission to the authority

Unless otherwise regulated, PSURs must be submitted to the responsible pharmaceutical authorities every six months before and within the first two years after marketing, annually for the following two years and every three years thereafter. The submission dates are calculated from the date of approval of a drug in a member state.

For human medicinal products with the same active ingredients approved in several EU member states , the European Medicines Agency (EMA) publishes a list with EU-wide harmonized specifications on submission dates, reference dates for the reporting periods ( data lock point , DLP) and submission frequency, which is constantly being expanded (EURD- List). The submission frequency takes into account the potential risks of a drug. For substances that have been on the market for a long time and have already been well documented, PSURs usually only need to be created at long intervals. Generics , registered homeopathic and traditional herbal medicinal products , standard approvals and medicinal products approved based on “general medical use” are generally excluded from routine submission , unless the submission of a PSUR is expressly required. A PSUR is still mandatory for the drugs mentioned if the active substance is listed in the EURD list, which is the case for a number of substances. The authorities can also request or impose PSURs in individual cases (ad hoc request).

Official assessment

The PSURs submitted by the industry are evaluated by the competent pharmaceutical authorities with regard to new or changed risks and changes in the risk-benefit ratio of the medicinal products; if necessary, the authorities take appropriate measures.

Medicinal products for human use

With a comprehensive reform of European pharmacovigilance law, a standardized PSUR single assessment procedure (PSUSA) was introduced for human medicinal products in 2012 , which has been implemented gradually since then. It serves the EU-wide harmonization of drug characteristics while avoiding double assessments. The uniform individual evaluation procedure is binding for medicinal products that contain the same medicinal substance or the same medicinal substance combination and for which the reporting periods and submission dates have already been harmonized across the EU and are therefore included in the EURD list. It is irrelevant whether the approvals were obtained via central, decentralized or purely national approval procedures . The uniform assessment is carried out either by a member state authority appointed by the Member State Coordination Group (CMDh) or by a rapporteur appointed by the Pharmacovigilance Risk Assessment Committee (PRAC ) of the EMA . The evaluation process ends with the adoption of a recommendation by the pharmacovigilance committee. If it considers regulatory measures to minimize risk to be necessary, the Committee for Medicinal Products for Human Use or the CMDh will review the recommendation and communicate its position to the authorities with legal authority.

Until the full implementation of the EU individual assessment procedure, the procedure for the division of labor initiated in 2002 will continue to be practiced for drugs that are nationally approved in several member states ( PSUR worksharing procedure, WSP ), in which pharmaceutical companies can submit the PSUR to the authorities of the respective countries at the same time and a lead one Reference authority draws up an assessment report. Similar to the individual assessment procedure, there is also a list of harmonized reference dates for the division of labor procedure. It will be issued by the CMDh and will be replaced by the EURD list with the full implementation of the individual assessment procedure.

For drugs that are nationally approved in only one member state, the drug authority of that country is responsible.

Veterinary drugs

For veterinary medicinal products that are not authorized centrally, the national higher veterinary medicinal products authorities operate a procedure for the division of labor to assess PSURs. It was initiated in 2007 by the European Surveillance Strategy Group (ESS) of the veterinary drug authorities. Here, too, there is a list of harmonized reference dates, after which companies create the PSURs and submit them for evaluation.

activities

If a need for action with regard to drug safety has been identified in a PSUR procedure, the responsible authorities ( EU Commission or national drug authorities) take appropriate measures. They are based on the opinions of the relevant bodies (Committee for Medicinal Products for Human Use, CMDh, Committee for Medicinal Products for Veterinary Use). The following are possible:

Individual evidence

  1. ↑ Directive 2001/83 / EC of the European Parliament and of the Council on the creation of a Community code for medicinal products for human use
  2. ↑ EUDRALEX Volume 9, Pharmacovigilance
  3. ^ European Medicines Agency - Good pharmacovigilance practices
  4. ↑ Guideline on good pharmacovigilance practices (GVP) 3 Module VII - Periodic safety update report