Issue No. 2007/01
This EU Pharma & Life Sciences e-bulletin contains summaries of recent developments in European and Belgian pharma law.
Article 8(1) of Regulation (EC) n° 141/2000 on orphan medicinal products grants a ten year-period of market exclusivity for products designated as orphan drugs and authorized throughout the EU. However, Article 8(2) states that this period may be reduced to six years if it is established that the designation criteria are no longer being met by the end of the 5th year.
This draft guideline sets out the general principles and a two-step procedure which can lead to the reduction of the market exclusivity to six years. Comments can be sent to the Commission before May 7, 2006. The draft indicates that the review procedure, which is triggered by Member States, is “not intended to be systematic … on the contrary”. Member States should only inform the EMEA if they have sufficient indications that at least one of the designation criterion is no longer being met and “in that case they have to do so.” On this basis an assessment will be conducted by the Committee on Orphan Medicinal Products (COMP) and the Marketing Authorisation Holder will have an opportunity to submit its views and data in writing and possibly to participate in a hearing.
As far as the criteria relating to the significant benefit or the inexistence of a satisfactory method are concerned, the MAH may be requested to provide a critical review of its product including a bibliographical review and marketing studies, but it will not be required to generate new comparative data in relation to another treatment that has become available since the MA was granted.
Should the COMP consider that the initial designation criteria are still being complied with, it will adopt an opinion recommending that the period of market exclusivity should not be reduced.
Where the initial designation was based on prevalence and the COMP concludes that this criterion is no longer being met, it will assess the return on investment of the product and vice-versa. Should the COMP consider that a satisfactory method of treatment now exists, it will assess the significant benefit of the product. However, in the situation where the incentive was granted on the basis of a significant benefit and this criterion is no longer be fulfilled, “there would normally not be an alternative test available” unless a previous satisfactory method of treatment has disappeared.
Should the COMP consider that the alternative criterion is still being met, it will adopt an opinion recommending that the period of market exclusivity should not be reduced. In the contrary situation, the COMP “may recommend” that the period of market exclusivity should be reduced. The draft specifies that “relevant criteria for the COMP, on whether or not to recommend a reduction … are based notably on the extent to which a designation criterion is not fulfilled. For example in the case of prevalence, only slightly exceeding the threshold could lead the COMP to recommend upholding market exclusivity. Similarly, a barely sufficient return on investment may lead to the same conclusion.”
Regulation n° 1901/2006, adopted in December 2006, will, in the near future mandate the submission of paediatric studies for the registration of new products or of new developments for products benefiting from an SPC. Such studies will be conducted in compliance with an investigational plan. The main incentive for such additional works will be the granting of a 6-month extension of the SPC.
This draft guideline, which has been issued for external comments, is based on Article 10 of the Regulation n° 1901/2006 and addresses 3 main issues:
- The format and content of applications for agreement or the modification of a paediatric investigation plan, as well as requests for waiver and deferrals. This part notably provides guidance on significant therapeutic benefits, grounds for waiver etc.
- Compliance checks by the competent authorities: it is stated that “non-compliance with the requirement of Articles 7 and 8 of the paediatric regulation results in applications falling within the scope of those Articles being invalid”.
- Studies started before and completed after the
entry into force of the paediatric regulation: the granting of the
paediatric reward (IP incentive) in relation to these studies is subject
to the condition that they are considered to be significant. The draft
guideline provides a number of examples.
The Commission has recently announced its intention to strengthen and to rationalize the pharmacovigilance system, via both an improved implementation and the modification of the legal framework currently applicable. The documents can be found on http://ec.europa.eu/enterprise/pharmaceuticals/pharmacovigilance_acs/index.htm.
The planned improvements in implementation will notably include:
- The funding of safety studies as well as studies into the methodologies used to conduct pharmacovigilance.
- Addressing the different administrative practices.
- The strengthening of the EMEA’s coordinating role etc.
The changes to the legal framework will cover inter alia:
- The strengthening of the rules on transparency relating to pharmacovigilance data.
- The involvement of stakeholders (e.g. patient and healthcare professional groups) in processes such as reporting.
- The establishment of Good Vigilance Practices.
- The rationalisation and simplification of the reporting of suspected ADRs.
- Measures to prevent duplication of effort, while maintaining the current segregation of competences between the Member States and the EMEA.
- Clear legal requirements on conducting post-authorisation safety studies. etc.
The Commission's objective is to issue a proposal
The November 2005 version of Chapter 2 (Mutual
Recognition) has been updated and replaced by a new version of February
2007, which takes into account the accession of the new Member States.
As far as veterinary products are concerned, Chapter 1 (marketing
authorizations) has also been replaced by a new version of January 2007.
More than 7,000 active ingredients and intermediates used in the manufacture of pharmaceutical products already benefited from free trade, i.e. no customs duties, under the terms of the Pharma-GATT Agreement of 1994. However due to ongoing scientific developments, particularly in biotechnologies, a number of new products were not covered by the Agreement. The EU Member States, as well as the USA for instance, have recently adopted the third revision of this agreement, which basically adds around 1,300 substances to the list of products benefiting from free trade.
The Commission underlines in a press release that “the list of prefixes and suffixes, which can be used in combination with the names of the pharmaceuticals to describe their derivatives, has also been largely expanded and tidied up, making the system much clearer and more flexible” (see http://ec.europa.eu/trade/issues/global/medecine/pr120207_en.htm). The duty-free pharmaceuticals list will be available on the European Customs Inventory of Chemical Substances (ECICS).
This issue relates to the Novartis’ cyclosporine. Sandimmun was introduced in the early eighties while Neoral, which provides important therapeutic and other benefits for patients, was launched in the mid-nineties. Neoral has progressively replaced Sandimmun and became the standard treatment.
In 1999, a Royal Decree applicable at that time provided that the basis for the reimbursement of pharmaceutical products whose active ingredient has been reimbursed during 15 years should be reduced from %. Parallel measures were also taken regarding the price. Despite its added value, the reimbursement basis of Neoral was reduced in 1999 as cyclosporine (Sandimmun) has been reimbursed for more than 15 years. Novartis tried to obtain a summary judgment from the High Belgian Administrative Court, to suspend the MoH decision on the basis of urgency. This request was rejected in 2000 as the drastic conditions to obtain such a type of decision were not met.
During the action on the merits it was stressed that the Ministerial Decree reducing the reimbursement basis of Neoral was a unilateral administrative act, as it explicitly mentioned Neoral. Unilateral administrative acts are subject to a formal motivation and as this latter was lacking the argument was that the Decree should be annulled.
The Belgian Administrative Court considered that the decision of the competent authority to reimburse a specific product and to set the reimbursement condition is not only relevant for the pharmaceutical company concerned but also to all the patients that may use the product. It also considers that such an act cannot be qualified as a unilateral and individual administrative act taken by an administrative authority with the aim to produce legal effects toward the plaintive.
In a separate judgment the same Court also
considered that a similar price cut imposed to Sandimmun and Neoral
based on the circumstances that they both include the same active
ingredient does not constitute a breach of the principles of equal
treatment and non-discrimination despite the increased therapeutic value
of Neoral. It should be noted that if the power of the MoH to impose
price/reimbursement cuts have been expanded by recent legislative
measures, some derogations have also been introduced in case of added
therapeutic value (safety and/or efficacy).
In 2004 Belgium adopted measures “against abuses related to the promotion of pharmaceutical products” and Article 10 of the law of 25 March 1964 which was addressing the matter has been modified. The law has been made more specific particularly with respect to the prohibition of the granting by companies of financial or other rewards to doctors, hospitals, pharmacist and wholesalers, as well as examining control measures to be put in place.
The expenses incurred when doctors are invited to scientific events, seminars or conferences organized by pharmaceutical companies are not covered by the prohibition, provided that certain conditions are met. These conditions are as follows: the event should have an exclusively scientific character related to medical and pharmaceutical sciences, the cost borne by the company should be limited to the duration of the event, etc. In addition when such a conference involves an overnight stay, it is subject to a mandatory prior approval by the MoH or by an agreed organization. The alleged objective of this provision is mainly to control and avoid practices that could influence the prescription patterns of doctors.
At the time of the adoption of the new measure, a prior approval procedure was already included in the Code of Deontology of Pharma.Be, which mainly represents the innovative industry operating in Belgium. This code was binding for its member companies. However, this was no longer considered as fully appropriate, particularly as not all the companies operating in Belgium are members of Pharma.Be.
In this context, a non profit making organization, called MDEON, was created in 2006 with representative bodies from the R&D-based (Pharma.Be) and generic (FeBelgen) industries as well as the medical devices sector (Unamec), pharmacists and physicians. Industry represents less than one third of voting rights within the Board of MDEON.
MDEON adopted a Code of Conduct that has now entered into force on 1st January 2007 and was recognized by the MoH in February 2007 as the organization which will manage the system of prior approval. This will also imply that a representative of the MoH will participate in board meetings and will have access to the relevant documentation.
A number of detailed rules or recommendations are included, such as:
- In general at least 6 hours must be devoted to scientific activities – i.e. medical and pharmaceutical sciences -, with exceptions such as the time relating to transcontinental flights etc.
- Doctors can benefit from communication, tax and other trainings which may represent valuable events, but provided that most part of the event is still devoted to activities related to medical or pharmaceutical sciences.
- The organization or financial support of sport, leisure, cultural or gastronomic activities is not authorized.
- The time between the flight arrival/start of the conference or end of the conference/flight departure must be as short as possible. In the case of a stay extending to more than one day, the doctor will have to bear the flight expenses according to pre-defined criterion (pro rata).
- The organization of a European investigator’s meeting or advisory board in South Africa, for instance, are explicitly excluded, as is a meeting of Belgian doctors in the South of France, etc.
- Accompanying persons – spouses etc. – are allowed to participate in the trip at their own expense and the company cannot organize an alternative programme for them.
The procedure, including the justification and formalities, for obtaining the prior approval for events with one or more overnight stays is described in the Code of Conduct. The request should be submitted at least 15 working days before the event and the approval or refusal given by an internal body belonging to MDEON within 5 working days. The applicant can appeal against a decision of refusal. MDEON will inform the Belgian Medicine Agency of refusals, irregularities etc. It should be noted that the Law also includes potential criminal sanctions in case of violation of the Article 10.
It should be noted that approvals already granted by Pharma.Be to its members for events organized in 2007 are not subject to MDEON approval.
As far as events without overnight stay are concerned, the above principles remain applicable whenever relevant. The company can – but is not under the obligation to – notify MDEON of the event and provide certain related information and it can also ask MDEON'S opinion with respect to the event's conformity with the Code of Conduct – and the law. MDEON has no power to approve or to refuse the organization of such an event and the information provided to MDEON can, in principle, not be disclosed but will be used to develop further guidelines.
As far as post-marketing studies not covered by the Law on clinical trials are concerned, the Code of Conduct of Pharma.Be, which requires the prior approval by Pharma.Be, remains applicable to its member companies.
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