1. Legal Requirements
The EudraLex Volume 9A incorporated the obligation to include a "Detailed Description of the Pharmacovigilance System" in every marketing authorisation application (module 1.8.1 of the licence documents; see Volume 9A part I, point 2.2.1). This should serve to document the fact that future Marketing Authorisation Holders have an effective safety system for their medicinal products in place, or –if they have not already done so– are able to establish such a system. At the same time, the EudraLex Volume 9A empowers the competent federal authority to conduct pharmacovigilance inspections in order to check the practice and content of the implemented system on site.
Whilst these sorts of formalities may seem less unusual for the Rx industry, they represent much more in the way of new ground for the OTC industry. It is much less common for these drugs to have serious adverse reactions. Nevertheless, the law requires small and medium-sized businesses with OTC products to meet the same standard as that which applies to large corporations in the Rx sector.
The current contents specified for the elements can be found in the European Commission's EudraLex Volume 9A which was finalised in March 2007. It applies to all medicinal products intended for human use which are registered in the Member States of the EU, as well as in Iceland, Liechtenstein and Norway – irrespective of the approval procedure (national, mutual recognition, decentral, central) and irrespective of the current approval status.
The purpose of the Detailed Description of the Pharmacovigilance System (DDPS) which is formalised in Volume 9A is to describe the actual safety-monitoring practice followed in the company. Therefore, the DDPS requirements can be interpreted as a requirement for daily PV practice in the company. In view of the complexity of the requirements and the resulting manpower requirements, businesses with a smaller number of marketing authorisations are at a disadvantage compared to their larger competitors when it comes to PV; the more marketing authorisations a company manages, the more experience it acquires, thus enhancing the quality and efficiency of its pharmacovigilance procedures. At the same time, there are synergy effects in terms of cost structures. Therefore, pharmaceutical companies producing low-risk medicinal products are turning increasingly to specialised PV service providers. This practice is permitted explicitly in Volume 9A (part 1, point 1.3): "A Marketing Authorisation Holder may transfer any or all of the pharmacovigilance tasks and functions, including the role of the QPPV, to another person(s) or organisation (...)". However, formal responsibility for the safety of the medicinal products remains with the pharmaceutical company.
2. Detailed Description of the Pharmacovigilance System
The DDPS contains the company-wide definition, independent of products and licences, of the working structures and processes established in the company for ensuring the safety of the medicinal product. This comprises, among other things, the areas of recording, processing and reporting suspected incidents of adverse drug reactions (ADRs) of medicinal products, compiling and reviewing Periodic Safety Update Reports (PSURs), signal detection, as well as emergency procedures within the company.
There is no uniform approach between regulatory authorities, regarding the scheme of the DDPS. In Germany, the Federal Institute for Drugs and Medical Devices permits pharmaceutical companies to submit this description once as a Pharmacovigilance Master File. Future applications for approvals then refer to this master file. The BfArM currently does not appear to regard amendments in the description of the PV system as a type II variation, as Volume 9A (part I, subsection 2.2.1) actually requires. If there are errors in the DDPS or if it is not submitted at all, an approval application will be rejected for formal reasons.
Paradoxically, this frequently affects those pharmaceutical companies which have a low-risk product portfolio and which, therefore, have had to contend less intensively with the problems, formal and otherwise, of pharmaceutical safety. Experienced service providers can provide these companies with assistance in implementing a PV system which meets requirements, including documentation.
Where relevant, the Marketing Authorisation Holder must provide a detailed description of the following components of its PV system (cf. Fig. 1), defining its cooperation with service providers:
2.1. Qualified Person Responsible for Pharmacovigilance
The Marketing Authorisation Holder is responsible for the safety of its products and must undertake to commission a Qualified Person for Pharmacovigilance (QPPV) to monitor the safety of medicinal products and to provide this person with the requisite resources to do so. The QPPV must, for instance, maintain an overview of safety profiles and precautions for the medicinal products or implement them in the first instance. He or she is, among other things, responsible for submitting reports of adverse drug reactions and PSURs, for periodic research through literature, for personnel training and acts as the central contact for the authorities. In short, the QPPV is responsible for ensuring that the PV system in the company conforms to current statutory regulations and is practised in full.
The EudraLex Volume 9A places great requirements on the QPPV (see Volume 9A (part 1, point 1.2.1) These requirements present a major financial and organisational challenge for small and medium-sized businesses because a QPPV has to be contactable around the clock. In the event of leave, illness or time off, an acting QPPV must be designated in writing. Therefore, as was previously the case with the former "travelling" control and production managers, industry companies frequently engage external support, this is also explicitly facilitated by Volume 9A. The external contracting partner must implement quality assurance and quality controls. It is recommended that the Marketing Authorisation Holder conduct audits.
The DDPS also contains a description of the organisational structure. It should include names, locations and internal contact details of the parts of the company which are responsible for PV, as well as a brief description of the activities conducted there. There should also be a diagram (organisation chart) depicting the structure of the organisation in order to illustrate the general outline within the company and in relation to external partners.
2.3. Documented Procedures
A flow chart should be generated for the DDPS, showing the central processing steps within the company for an incoming report of a suspected adverse drug reaction (cf. Fig. 2). An inspector from the regulatory authority or a commissioned external auditor should be able to refer to this organisational description and identify potential gaps or needless procedures in the PV processes. Product-specific additions, such as the exchange of safety-related data with a licensing partner, should be illustrated in an appendix.
Pursuant to Volume 9A, e.g. the following procedures should also be documented in a DDPS:
- QPPV's activities, arrangements for an acting QPPV
- Collection, evaluation and classification of Individual Case Safety Reports (ICSRs)
- Follow-ups on ICSRs
- Detection of duplicate reports
- Notification of 7 or 15-day ICSRs, compliance with deadlines, electronic reporting
- PSUR (preparation, quality control, submission)
- Literature research
- General PV (signal detection, benefit/risk assessment, communication with authorities, healthcare professionals etc. regarding safety-related changes to medicinal products)
- Dealing with safety risks resulting from product defects
- Emergency measures, dealing with queries from competent authorities
- Commitments towards competent authorities
- Working with databases
- Internal audits
Standard Operating Procedures
Standard Operating Procedures (SOPs) accompany the DDPS and must be listed. The SOPs should generally be made available within two days, on request from the competent authority . SOPs are binding global records used by a company to define the specific functions and tasks of all employees, as well as standardised processes.
The preparation and updating of SOPs and of accompanying process-specific descriptions are complex. Existing processes have to be controlled because it is imperative to ensure conformity with regulations requirements, in particular, but also to design work flows rationally. Experienced service providers with an "unbiased view" may identify scope for improvement more quickly.
Receipt of Spontaneous Reports
Processing reports of suspected cases of adverse drug reactions is a central issue of any PV system. All employees, from the switchboard to the field service to the Drug Safety department, should have a sound understanding of the company's standard procedures for taking receipt of PV-related information. Therefore, the relevant SOP has to show which information (minimum criteria) is to be recorded, how it is to be recorded (e.g. verbatim) and what is to be done with it (to be forwarded to the PV coordinator immediately). There should also be a cross-reference to a training SOP, which is used as a basis for training all the employees in question on how to process spontaneous reports.
Service providers can take receipt of spontaneous reports. As in other situations where tasks are outsourced, the Marketing Authorisation Holder takes on a certain dependence: If, for example, the receipt of spontaneous reports is contracted out to a call centre, the Marketing Authorisation Holder has to ensure that the personnel concerned receive training and perform audits to ensure that the call centre agents are trained in how to receive and pass on spontaneous reports. All the people who receive training should provide written confirmation that they have been trained.
Individual Case Safety Reports
Service providers may handle spontaneous reports instead of the Marketing Authorisation Holder. ICSRs represent an interesting yet sensitive area in the cooperation between pharmaceutical companies and external service providers. Pharmaceutical companies which do not operate an electronic reporting system of their own or which wish to set up a new system outsource this facility. At the same time, if suspected adverse drug reactions are encoded and evaluated by an independent third party, the utmost objectivity and commercial independence are guaranteed. However, spontaneous reports are frequently received directly by the company, a contracted call centre or via another source. Therefore, the SOP's description of the interfaces between the sources and the processors of PV-related data is particularly important when service providers are engaged on multiple levels.
Periodic Safety Update Reports
Preparing a PSUR is where external service providers come into their own. Since researching literature and preparing PSURs primarily take place not on a single product-related basis, but based on the active ingredient, synergy effects arise here. The synergy potential stems from the harmonisation of the birth dates for what are now well over 1,000 active ingredients at national and European level.
Whether the decisive factor is having an opportunity to participate in PSUR compilation service projects for known active ingredients or whether keeping the workload in check is what matters, Marketing Authorisation Holders frequently contract out the preparation of PSURs to specialised service providers. In the case of small and medium-sized businesses with a smaller number of approvals in particular, it makes sense, given the high cost burden involved, not to set up a separate department just to prepare PSURs which have to be compiled every 6, 12 or 36 months. In this case, there should be an SOP for PSUR preparation, clearly showing who supplies the requisite approval-related data, reports of adverse drug reactions, sales figures and, where relevant, study data, and when. Does the service provider also undertake the research of literature? How is compliance with the timescale regulated? These points must also be defined in the SOP.
The pharmaceutical company should maintain a system, normally a validated database, for ensuring that any adverse drug reactions reported to the pharmaceutical company can be recorded, classified and, where necessary, retrieved worldwide. The aim is to handle and store data in such a way that it cannot be lost or falsified and to enable changes to be traced (audit trail). There is no structure prescribed for the recording system, although data protection regulations must be complied with when handling (patients') personal details.
In case of external database solutions, the allocation of responsibilities between the company and the IT service provider must be clearly defined in the description of the PV system. In addition to the structure of the database and data back-up, attention must also be paid to standards for reporting adverse drug reactions, EudraVigilance registration, updating and validation.
Alternatively, traditional paper-based recording can also be used in businesses which experience few reports of adverse drug reactions. In that case, however, the DDPS or the accompanying SOPs should contain notes explaining the procedures for the systematic processing and documentation of adverse drug reactions and how they are reported. It is important to remember, for example, that even where medicinal products are only approved nationally for example in Germany, (suspected) serious and unexpected adverse drug reactions experienced in non-EU member states still have to be reported electronically to the EMEA's EudraVigilance database by specially trained personnel. Where necessary, this may also be contracted out to PV service providers.
2.5. Contractual Arrangements
The points to be disclosed in the DDPS also include contractual agreements with people or businesses relating to pharmacovigilance. This, for example, may take the form of co-marketing contracts which include a contractual provision on reporting spontaneous incidents. Contracts with PV service providers, such as for the task of the QPPV, for electronic reporting, for maintaining databases, researching literature or preparing PSURs, also come under this. The authorities expect a brief description of the nature of these agreements with the relevant assignment of responsibilities.
2.6. Training courses
Records must be kept of the initial and further training of the personnel who are assigned PV activities. Jobs descriptions, CVs, training documentations, as well as any tests on the training material must be archived.
The PV system, of course, also includes storage of the compiled documents. The DDPS should show where and how this is done, and, if relevant, indicate the name and address of the service provider commissioned to do this. There is no period of time stipulated for document retention e.g. in Germany. The legal position is similar in the UK, although the UK authority MHRA recommends that "pharmacovigilance records should be kept indefinitely" . Archive planning should be designed on a suitably long-term basis.
2.8. Quality Management System
A brief description of the quality management system should also be submitted. It is particularly important to define the responsibilities. Special attention should be given to the quality assurance of the PV system, as well as to auditing external service providers.
2.9. Supporting Documentation
Supporting documentation can be added to the DDPS, confirming that the PV system is in correct working order and, if relevant, providing information about changes or revisions to the system. This additional information may be particularly important for assessments or inspections.
3. Pharmacovigilance Inspections
Since EudraLex Volume 9A came into effect, the EMEA and the national competent authorities have had the power to inspect the PV systems of pharmaceutical companies in situ. Increasing use is being made of this option. Volume 9A outlines certain requirements on the basis of which inspections are conducted . A competent regional authority may also participate in the inspection.
About two months' notice is generally given for a routine inspection. As a general rule, the company being audited must submit the DDPS and various additional documents to the authority no later than 14 days before the date of the audit. This includes "more detailed information for example about the product range, the SOPs, about further training documentation or further facilities." There is an overview on the documents which are routinely required available to download from the BfArM, although this overview does not claim to be complete.
The pharmaceutical company will be given an opportunity to demonstrate its PV system during any inspection, which generally takes one or few day(s). Furthermore, the inspectors shall examine individual elements, such as the recording, processing and quality of incident reports, the data-acquisition system or the job descriptions of employees who are involved in the creation of PV documents.
Following the inspection, the company shall receive a draft of the inspection report with identified problems upon which to comment. National law allows the authorities to impose sanctions if the results are unsatisfactory. In any event, the costs of an inspection shall be borne by the pharmaceutical company. In Germany, fees for inspections conducted by the BfArM are calculated on the basis of the German Medicines Acts Regulations on Costs, which have yet to be revised.
Audits by internal or by experienced external auditors are helpful in preparing for official PV inspections. External audits conducted from an outside perspective enables companies to see how they match up the ideal situation generally required by the authorities. However, where scope for improvement is discovered, this can rarely be incorporated at short notice into an existing system without causing some disruption to the smooth running of the system, ahead of official inspections. Therefore, routine audits are advisable.
External service providers and consultants may be involved in virtually any pharmacovigilance process. The services they offer are being continuously refined. There is now a wide array of highly skilled services available on the market, including auditing, commissions to submit electronic reports of suspected adverse drug reactions to the EMEA, the provision of Qualified Persons for Pharmacovigilance and the implementation of complete PV systems. Professional associations are also very active in this area.
Some companies outsource all their PV tasks so as to ensure that they instantly have a fully functioning PV system. Others only bring in service providers who perform special tasks to reduce peak loads or avail of external expertise to ensure compliance with changing legal requirements.
The possible disadvantages identified in outsourcing are a potential dependence on external third parties or upon the reliability of their work. It should be noted that there is no fundamental difference between a contractual commitment to a service provider and being committed to (changing) employees through employment contracts. At any rate, the advantage of outsourcing is continued quality assurance by engaging the services of highly specialised, experienced PV teams.
Specialised service providers can often respond to changes in the law more quickly, offering suitably adapted solutions soon afterwards. In this regard, outsourcing also represents an effective and consistent response by the pharmaceutical industry to the continuous pressure exterted by international regulations on safety issues.
 EudraLex Volume 9A, Pharmacovigilance for Medicinal Products for Human Use (version April 2007)
 Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM), „Mitteilung zur Einreichung von Unterlagen gemäß § 22 Abs. 2 Nr. 5 und Nr. 6 AMG (Pharmakovigilanz- und Risikomanagement-System; qualifizierte Person für Pharmakovigilanz)“ vom 9. 1. 2007
 EudraLex Volume 9A, S. 23
 Medicines and Healthcare Products Regulatory Agency (MHRA), „Frequently asked questions for Good Pharmacovigilance Practice“ vom 5. 3. 2007
 Kroth, Elmar, „Pharmakovigilanz − BfArM präzisiert Anforderungen an die Pharmakovigilanz-Inspektionen“, Pharm. Ind. 69, Nr. 3, 311−312 (2007)
 Bornern, Mechthild et al., „Pharmakovigilanz − Fimeninternes Pharmakovigilanz-System im Rahmen des Antrags zur Arzneimittelzulassung / Vorschlag zur Erstellung einer Systembeschreibung“, Pharm. Ind. 68, Nr. 10, 1160−1166 (2006)
 Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM), „Mitteilung zu Pharmakovigilanz-Inspektionen“ vom 15. 1. 2007