Why have a Safety Database?

Safety databases should allow pharmaceutical companies to rapidly gather relevant information about the medicine or medicinal products in question. There will be information which needs to be supplied to regulatory authorities via statutory electronic reporting and the database must support this. The database must therefore be validated and acceptable to those regulatory authorities. In essence, the database must be entirely suitable to the task, in compliance with Part III of the relevant legislation, Volume 9A of The Rules Governing Medicinal Products in the European Union – Guidelines on Pharmacovigilance for Medicinal Products for Human Use ^[1]. Details of the database are assessed during the application stage for each MA, as they will form part of the DDPS ^[2]. To paint perhaps a more rapidly accessible picture here, the safety database is the tool used to help staff collate and analyse key drug safety data. One example could be any Adverse or Suspected Adverse Event Reports for one particular product. The database will be electronic but not ‘autonomous’: it will not perform tasks without key interaction by highly skilled staff, no matter which process is underway.

Signal Detection

A compliant, suitable Safety Database is able to process data related to signal detection. Signal detection essentially uses data to detect any new patterns or findings. These can be identified by analysing data tables according to principles of statistical disproportion. Upon detection the subsequent course will be variable but can involve action by the regulatory authorities.

Periodic Safety Update Reports Production (PSURs)

Any medicine or medicinal product granted an (EU) MA is legally required to become the subject of post-marketing Periodic Safety Update Reporting. PSURs are always more than an in-house assessment. Presented directly to regulatory authorities, as you might expect whenever drug safety is concerned, they will of course be subjected to an extremely thorough inspection of their contents. A comprehensive database will be able to process the required data in a manner which facilitates the production of PSURs in the appropriate format as far as those authorities are concerned. For example, modern databases integrate regionally-tailored support on regulations.

Statutory Electronic Reporting

Certain safety databases are able to incorporate functionality to file expedited and aggregate reports to regional regulatory authorities. Again, this would always take place with core staff input, rather than becoming any type of scenario where a computer simply somehow ‘spits out’ a report. Electronic reporting will be required within strict time deadlines and differing formats by differing authorities throughout the world. In the EU for example, expedited reporting is obligatory within 15 days of a spontaneous adverse drug reaction case report.

These are just some of the core functions of a suitable safety database, which make it easy to see why it’s one of the pillars of good quality drug safety monitoring. It may be web-based, but whatever the platform it will be electronic. It is not however necessary for pharmaceutical companies to purchase and install a dedicated ‘in-house’ safety database. Instead it is common to find them using commercially available fully compliant products introduced by external pharmacovigilance services firms, who simply provide them with the necessary ongoing support.

References:

1. EMEA. Volume 9A of The Rules Governing Medicinal Products in the European Union – Guidelines on Pharmacovigilance for Medicinal Products for Human Use. 2011. [ONLINE] Available at: http://ec.europa.eu/health/files/eudralex/vol-9/pdf/vol9a_09-2008_en.pdf. [Accessed 22 January 2011].

1. EMEA. Volume 9A of The Rules Governing Medicinal Products in the European Union – Guidelines on Pharmacovigilance for Medicinal Products for Human Use. 2011. Article 2.2.3 d [ONLINE] Available at: http://ec.europa.eu/health/files/eudralex/vol-9/pdf/vol9a_09-2008_en.pdf. [Accessed 22 January 2011].

In particular, Volume 9a of The Rules Governing Medicinal Products in the European Union [1] makes reference to compliance with ICH E2A by ensuring the ICSR contains a “case narrative”, meaning a comprehensive and complete medical description of the case. This should include [2]:

• Patient characteristics
• Diagnosis
• Therapy Details
• Medical History
• Narrative of Clinical events
• Known adverse reactions alongside the relevant outcome
• Results of laboratory tests along with the normal ranges
• “any other information that refutes or confirms an adverse reaction” [2]

As well as inclusion of component items, the report must follow the formatting guidelines as a matter of obligation rather than the regulators preference. Volume 9a is quite clear that this may require some of the information stipulated to be repeated [2]. The format must also apply when new information is added for follow-up reporting, which should be clearly delineated from the original case narrative.  Except to describe results of standard tests, abbreviations are to be avoided [2].

Pharmaceutical companies clearly have complex legal obligations in this area of drug safety monitoring. Many choose to outsource the compilation of ICSRs to external pharmacovigilance services providers for this very reason. Whilst there is a provision for times when information is not available in some circumstances, incorrectly submitted ICSRs are to be avoided at all costs. Many external providers offer a ‘complete’ service, processing the necessary data into the final format for compliant electronic submission. This can be of particular value to small to medium sized companies where it may sometimes be the case that not all available staff have current training and experience in the exacting requirements for both ICSR format and content.

References:

1. Volume 9A of The Rules Governing Medicinal Products in the European Union – Guidelines on Pharmacovigilance for Medicinal Products for Human Use. 2011. Part III, p.159-171 [ONLINE] Available at: http://ec.europa.eu/health/files/eudralex/vol-9/pdf/vol9a_09-2008_en.pdf. [Accessed 22 January 2011].
2. Volume 9A of The Rules Governing Medicinal Products in the European Union – Guidelines on Pharmacovigilance for Medicinal Products for Human Use. 2011. Part III, Article 5.1, p. 164. [ONLINE] Available at: http://ec.europa.eu/health/files/eudralex/vol-9/pdf/vol9a_09-2008_en.pdf. [Accessed 22 January 2011].

For the EU, it is mandatory for companies to submit a Risk Management Plan in accordance with a detailed template and guideline at the time of application for a Marketing Authorisation for most products. Plans also have to be submitted if new safety concerns are identified for a marketed product and all plans must be updated as circumstances change.

Thus companies are required to specify at the time of first marketing areas of safety about which they are currently uncertain and how they will resolve this uncertainty. They must also indicate what measures they will take to reduce known risks and how they will test whether these measures work.

The EU Risk Management Plan (EU-RMP) has 3 main elements. First, a detailed consideration of what is known about the safety of the product, based on pre-clinical and clinical studies. This “safety specification” considers identified risks and potential risks – the latter being areas of uncertainty regarding safety. It also specifies what the limitations of the clinical research program are and what important information about safety is currently missing. In the second component, the “pharmacovigilance plan”, the company must indicate how it proposes to resolve the uncertainties – what extra studies it will carry out after marketing to fill the important gaps in knowledge. The third component is the “risk minimization plan”. This states how the company proposes to reduce the severity or frequency of known adverse reactions. This may involve special communication programs, or educational exercises, or perhaps registration programs for patients, doctors or pharmacists, or other measures. The pharmacovigilance plan and risk minimization plan must include timelines for setting up the programs and milestones for their evaluation.

There are EU laws – regulations and directives – on the one hand, and national laws on the other. An EU regulation, when it comes into effect, is in force in all the Member States of the European Union. An EU directive, however, must first be enacted in national law in each EU Member State, within a specified time-frame. In addition to those national laws that promulgate the EU directives, there may also be national laws that concern pharmacovigilance.

The principal EU laws concerning pharmacovigilance are:

• Directive 2001/83, amended by Directive 2004/27. This concerns all medicinal products, although for pharmacovigilance it is most relevant to products authorised by the national, mutual recognition and decentralised procedures. The Member States are the licensing authorities in these procedures.
• Regulation 726/2004. This concerns centrally authorised products. The European Commission is the licensing authority for these products.
• Directive 2001/20. This is the Clinical Trials Directive and includes extensive coverage of pharmacovigilance for interventional clinical trials pre- and post-authorisation.

Guidelines

The EU laws make reference to guidelines drawn up by the European Commission which provide detail and interpretation. These guidelines are not considered to be voluntary – they are mandatory as far as companies are concerned. The guidelines are also directed at regulatory authorities, with detailed requirements for the way that they carry out pharmacovigilance as well. They comprise:

• Volume 9A of the Rules Governing Medicinal Products in the European Community – for post-authorisation pharmacovigilance
• Volume 10 of the Rules Governing Medicinal Products in the European Community. This applies to clinical trials pre- and post-authorisation and incorporates the guideline Detailed guidance on the collection, verification and presentation of adverse reaction reports arising from clinical trials on medicinal products for human use

In addition to these laws and regulatory guidelines, there are various voluntary guidelines. These are mostly generated by two organizations:

the Council for International Organizations of Medical Sciences (CIOMS)
the International Conference on Harmonization of Technical Requirements for the Registration of Pharmaceuticals (ICH).

CIOMS is a body set up under World Health Organization and UNESCO. It has developed a series of guidelines on pharmacovigilance, drawn up by a committee of volunteers from Industry, regulatory authorities, WHO and others. The main guidelines concern the international reporting form (CIOMS I); periodic safety update reports (CIOMS II); core data sheets (CIOMS III); benefit-risk assessments (CIOMS IV); practical issues in pharmacovigilance (CIOMS V); clinical trial safety data (CIOMS VI); and development safety update reports (CIOMS VII).

Whilst CIOMS guidelines are very influential they are not “official” regulatory guidelines, have no legal force and generally just provide a consensus on good practices and new methodologies.

ICH consists of representatives of the regulatory authorities in the EU, Japan and US, with representatives of the corresponding industry regional organizations and Health Canada and WHO as observers. ICH establishes guidelines applicable to the EU, US and Japan through a series of expert working groups. There is a stepwise development of the guidelines. At Step 4, there is consensus internationally and at Step 5, an agreement by the regulators that they will introduce the guidelines into legislation, although there may be some divergence when these are actually put into effect in the different regions.

The three areas covered by ICH guidelines are Efficacy, Safety and Multidisciplinary. Paradoxically, the “Efficacy” guidelines include clinical (human) safety, whereas the “Safety” guidelines concern only pre-clinical (animal toxicology) safety.

The main guidelines concerning pharmacovigilance are: