Registration instead of marketing authorisation
Many herbal medicinal products have been used in different European countries. These include plant extracts such as valerian, hawthorn, St. John’s wort, arnica and others. In some cases there is evidence that they have been used for centuries.
With Directive 2004/24/EC the European Commission has simplified market access for these medicinal products by implementing the traditional herbal registration (THR) scheme for medicinal products that have a tradition of use in Europe of at least 30 years. These products are considered to be of proven safety and efficacy without requiring additional evidence through clinical trials.
The manufacturer is, however, obliged to verify the quality of his medicinal product. He has to prove that active ingredients and manufacturing processes are in conformity with GMP guidelines. Suitable analytical procedures together with ongoing stability studies must be put in place. Information materials, such as the package leaflet (a still underestimated tool for promoting the safety of medicinal products) must be tested for readability. And of course the registration holder also has to ensure pharmacovigilance, namely that the safety of the marketed products is monitored.
Pharmacovigilance and quality assurance are, however, accompanied by fixed costs which are largely independent of the number of marketing authorisations/registrations held. And while small and medium-sized enterprises make for a large part of the registration holders, they typically hold a comparatively small portfolio of medicinal products each. Therefore, they frequently bring in external service providers so that they can profit from economies of scale and improve the cost structures for marketed products.
The Pharmacovigilance System
Working together with service providers often starts with the description of the pharmacovigilance system itself, which the registration holder has to put in place. EudraLex Volume 9a explains how such a system should be set up. The "Detailed Description of the Pharmacovigilance System" (DDPS) specified there is to be submitted with the registration application.
As pharmacovigilance systems have fundamental similarities, the setting up of a company’s own pharmacovigilance system is often outsourced to experienced service providers familiar with the formal requirements. It goes without saying that the DDPS must be specially tailored to the company in question and its structures and that the “bought-in” process descriptions must be practised, applied and regularly checked in-house.
Pharmacovigilance in practice
As soon as a product is brought to registration, the actual safety monitoring starts. The requirements apply for traditional registrations in exactly the same way as for conventional marketing authorisation procedures. The fact that, because of the registration prerequisites, traditional herbal medicinal products have a low risk profile is irrelevant, and no simplifications, as applied in the registration procedure, are provided for where pharmacovigilance is concerned.
In particular, holders of THRs are also subject to inspections by the relevant competent authority – with regard to conformity with GMP guidelines and meeting GDP requirements, but also with regard to their pharmacovigilance system. Under national legislation if the results are unsatisfactory or the requirements have not been met or a deadline has been missed, the authorities can impose sanctions accordingly.
The Qualified Person for Pharmacovigilance (QPPV) is responsible for continuous monitoring of medicines "as used in everyday practice" ; this person has already been mentioned in the DDPS. This person’s tasks include the establishment and maintenance of the pharmacovigilance system itself, the preparation of Adverse Drug Reaction (ADR) reports and Periodic Safety Update Reports (PSURs) and the correspondence with the competent authorities. The QPPV must be available round the clock. Arrangements for this person to be deputised, for holidays, illness or free time for example, must be submitted in writing.
These requirements pose financial and organisational challenges in particular for the small and medium-sized market participants. They therefore frequently use external assistance, which the European EudraLex Volume 9a (Part 1, Point 1.3) also explicitly allows: “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 (...)”. National laws and guidances in Europe also refer explicitly to this possibility. They do, however, also state that in such cases audits of the external contractual partner are recommended and that formal responsibility for the safety of medicinal products fundamentally remains with the pharmaceutical company.
Because of the long tradition, the safety profile of traditional herbal active ingredients is already well known and serious adverse events are extremely rare. In spite of this, traditional use is no guarantee of safety. It is perfectly possible that an individual product may contain risks. Therefore and because of the limited number of clinical trials available for most THRs, pharmacovigilance is particularly important.
In serious cases an adverse reaction is to be reported to the competent authorities within 15 days. Non-serious cases are included in the Periodic Safety Update Report (PSUR). The "EU Pharmaceutical Package" discussed by the European Parliament proposes that exclusively electronic reporting to the EMEA of both all serious and also all non-serious adverse reactions from the EU Member States should be obligatory for the marketing authorisation holder. In this case a reporting period of 90 days should apply.
No exceptional arrangements are currently planned for THR in the discussion. But for THR this will lead to a change in the way pharmacovigilance is processed, as so far only a small number of holders of traditional registrations have even familiarised themselves with the electronic EudraVigilance system, even where ADR reports are only accepted electronically, such as in Austria. The occurrence of a serious adverse reaction is too rare.
With it becoming obligatory to report even non-serious cases, this could change. It is likely that the already well-established procedures for having reports submitted by an appropriately trained and EudraVigilance-registered external service provider will become more widespread.
In particular for companies which are entering the medicinal product sector for the first time through THRs, training in how to handle spontaneous reports is very important even now. The reporting period runs from the time when, for example, the telephone switchboard receives a call about adverse reactions which have occurred, which meets the minimum criteria set (suspected product, suspected adverse event, identifiable patient, identifiable repoter (healthcare professional)). The employee must therefore be able to forward this data sufficiently quickly in order for the QPPV to obtain any information which is still missing, carry out an evaluation of the case and send the report to the authority within the reporting period. Pharmacovigilance training for all employees is therefore extremely important. It will become even more important if it becomes obligatory to also report non-serious cases, as described above.
Safety and quality
As serious adverse reactions occur comparatively rarely with traditional herbal medicinal products, in this market it is problems with pharmaceutical quality which take up most of the time when dealing with adverse events. Here the QPPV works closely with the Qualified Person who is responsible for the conformity of the finished product to GMP guidelines, as well as with other departments involved, such as production and distribution.
According to the Rapid Alert System (RAS), quality defects are divided into three categories (see Table 1). For the QPPV the categories with medicinal relevance are of importance, such as if wrong active ingredients or dosages of active ingredients reach the finished medicinal product in the manufacturing process. The QPPV then decides whether in fact there is a medicinal product risk, how serious it is and which steps need to be taken. These steps may range from adjusting the manufacturing and testing specifications to changing the description to recalling the product. If recall is decided upon, the following procedures must be considered:
- informing the competent supervisory authority
- blocking the material in question in the manufacturers’ and wholesalers’ warehouse
- recall from pharmacies
- recall of OTC medicinal products outside pharmacies
- if necessary, recall from hospitals and professional medical practices and recall of exported products
At regular intervals of 6, 12 or 36 months, registration holders "are expected to provide succinct summary information together with a critical evaluation of the risk-benefit relationship of the product in the light of new or changing information." Because of the proven tradition of use, on application by the registration holder a three-year PSUR interval is generally sufficient for THR. The authorities can, however, also order shorter submission intervals, as was the case with the British MHRA, for example, for Cimicifuga racemosa.
Writing a Periodic Safety Update Report (PSUR) has so far been a favoured discipline of external service providers. This is on the one hand because it would appear to be doubtful to justify the need for an in-house department for this task which only recurs at intervals and, on the other, because there is frequently the possibly of participation in a PSUR pool which offers considerable cost advantages.
The synergy effect is particularly clear from the regular literature searches and the resulting evaluation of published cases of Adverse Drug Reactions for around 1000 herbal and chemical-synthetic active ingredients, the PSUR qualifying dates of which are standardised nationally or Europe-wide. In Germany the pharmaceutical associations have already created participation models for central PSURs, some other countries are only just starting on this.
However, there are plans in the EU Pharmaceutical Package for generic, well-established use, traditional herbal products and some other with well-known safety profiles, to be exempted from the obligation to draw up PSURs. This simplification of the procedure should, however, be accompanied by the planned obligation mentioned above to carry out the electronic 90-day reporting of non-serious adverse reactions. In brief, in spite of the proposed alleviation, the EU Pharmaceutical Package is therefore introducing a considerable increase in the pharmacovigilance requirements for registration holders.
Pharmacovigilance for traditional herbal medicinal products is no different to the safety monitoring of conventional medicinal products with marketing authorisation. The long tradition of use does not lead to any simplifications of the procedure, apart from the PSUR period which is usually 36 months.
The discussed proposals from the EU Commission’s Pharmaceutical Package would apply for marketing authorisations and traditional registrations alike. Hence it is possible that the legal obligation of electronic reporting for non-serious adverse events could be introduced as early as 2011. Therefore it is now necessary to consider how this predicted increase in the workload of pharmacovigilance is to be handled.
External service providers and consultancy companies are already being used today, from the specialised GMP auditor, to case-by-case electronic ADR reporting, to the implementation of complete PV systems. This trend is expected to increase in future. Indeed small and medium-sized companies are able to benefit from the cost advantages of larger pharmacovigilance teams. Furthermore, if tried and tested experienced specialists of this kind are used, a higher level of quality is to be expected than if a "part-time QPPV" is used who is only responsible for one or a few registrations and is therefore unable to gain much in the way of practical experience.
As regards the planned amendments to the European Directives, specialised service providers can often also respond more quickly and offer timely solutions. In this respect, outsourcing is the pharmaceutical industry’s response to the continuous pressure to adapt in line with policy and the market.
TABLE 1: Classification of risk categories according to the Rapid Alert System
Class I: Potentially life-threatening or could cause a serious risk to health
- wrong product (label and contents are different products)
- wrong strength of active ingredient with serious medical consequences
- chemical contamination with serious medical consequences
- considerable mix-up with other products
Class II: Could cause illness or mistreatment
- mislabelling, e.g. wrong or missing text
- missing or incorrect product information
- chemical/physical contamination (e.g. cross-contamination, foreign bodies)
- different from the specifications (e.g. analysis, shelf-life, filled weight)
Class III: no significant hazard to health
- faulty packaging (e.g. wrong batch number or expiry date)
- faulty closure
- contamination, e.g. microbial spoilage, dirt or detritus, individual foreign components