Regulation of Pharmaceuticals Briefing - Belgium

1) Which authority is responsible for overseeing the regulation of pharmaceuticals in Belgium?

The pharmaceutical sector in Belgium is regulated by the Belgian Federal Agency for Medicines and Health Products which is called Agence Fédérale des Médicaments et des Produits de Santé (AFMPS). The agency is also known by its Dutch name, Federaal Agentachap voor Geneesmiddelen en Gezondheidsproducten (FAGG). It is responsible for the quality, safety and efficacy of medicines (including homeopathic medicines, herbal medicines, pharmacy made and officinal preparations), health products, medical devices and accessories which are in clinical development as well as the raw materials for the preparation and production of medicines. AFMPS also ensures the quality, safety and efficacy of all operations involving blood, cells and tissues in Belgium.

AFMPS approves, registers and carries out pharmacovigilance for all new medication and health products in Belgium. The agency succeeded the Belgian Direction Générale des Médicaments du SPF Santé publique (DGM) as the new Competent Authority on 1 January 2007. It works together with health professionals and other competent authorities at the national and international level.

AFMPS’ functions are covered under the Law of 20 July 2006.

In terms of research and development AFMPS evaluates, approves, follows and controls requests for clinical trials for medicines and health products. The Agency also offers scientific advice.

AFMPS is in charge of evaluating all new requests for registration or marketing authorisation of a medicine or for requests to change existing registrations or marketing authorisations.

AFMPS is also responsible for vigilance which entails supervisory duties such as collecting information and monitoring adverse effects arising from medicines or health products.

AFMPS grants authorisations for production and distribution and checks that medicines and health products conform to current regulations concerning manufacture, distribution, delivery, import and export. It also controls pharmacists’ activities and combats illegal practices.

AFMPS also works to ensure that patients have access to all the relevant information they need in order for medicines and health products to be used rationally and safely. The Agency also regulates advertising for medicines and health products.

Reimbursement of pharmaceuticals in Belgium is governed by the Institut national d’assurance maladie-invalidité (INAMI) (Rijksinstituut voor ziekte- en invaliditeitsverzekering (RIZIV)) (National Institute for Health and Disability Insurance). The Ministry of Economic Affairs also plays a part in pharmaceutical pricing decisions but only in an advisory capacity.

Both AFMPS and INAMI are independent organisations which come under the responsibility of the Minister of Public Health and the Minister of Social Affairs, respectively.

2) How are adverse incidents reported and tracked and by whom eg doctors, manufacturers, users? To whom must adverse incidents be reported?

All adverse incidents relating to medicines used in Belgium should be reported to Le Centre Belge de Pharmacovigilance, the Belgian Centre of Pharmacovigilance (CBPH) for drugs for human use, which is part of the Agence Fédérale des Médicaments et des Produits de Santé (AFMPS) (the Federal Agency for Medicines and Health Products). The CBPH is responsible for compiling data concerning the adverse effects of medicines and coordinating the different tasks related to pharmacovigilance.

The main tasks of CBPH are as follows:

• collecting and evaluating periodic pharmacovigilance reports as well as individual reports received regarding undesirable reactions sent by healthcare professionals and marketing authorisation holders;
• collecting and evaluating reports about patient safety during clinical trials involving medicines authorised in Belgium;
• participating in European and international pharmacovigilance activities;
• distributing pharmacovigilance information to healthcare professionals and the general public;
• implementing proposed measures following evaluation of pharmacovigilance data,
• managing the renewal process for medicines authorised under the national procedure;
• carrying out pharmacovigilance inspections; and
• evaluating risk management plans and pharmacovigilance systems.

CBPH acts as the central collection point for all data regarding adverse incidents, while AFMPS acts in a supervisory capacity on the safety of drugs available in Belgium.

All suspected unexpected serious adverse reactions (SUSARs) should be reported by the public to their doctor, pharmacist, dentist, or healthcare professional who in turn should report all instances reported to them or discovered by them, to the CBPH via the “yellow form”. This is particularly the case for adverse effects for which no information has been found, if it is a serious adverse effect, even if the effect is well known, and if it is an adverse effect occurring in a child. Any supplementary information, which could prove important to the evaluation of the notification, should be added to the “yellow form” by the doctor or pharmacist, in collaboration with the patient. If further information is necessary, the CBPH will contact the patient’s doctor or pharmacist, who transmitted the notification to ask for the additional material.

The “yellow form” can be emailed to the CBPH via [email protected] or a hard copy sent to:

Agence Fédérale des Médicaments et des Produits de Santé (AFMPS)

Le Centre Belge de Pharmacovigilance

Eurostation building, block 2

Place Victor Horta 40, box 40

B-1060 Bruxelles

Belgium

SUSARs should be reported to the CBPH by authorisation holders within 15 days of receipt of being advised of a serious adverse effect, by healthcare professionals, clinical trial investigators, or by scientific publications. Authorisation holders must also send regular periodic safety update reports (PSUR’s) to the CBPH.

Clinical trial promoters and research centres conducting clinical studies are also obliged to inform the CBPH of all SUSARs which occur during clinical trials, whether they be for medicines which hold marketing authorisation or not. Clinical trial promoters must also send an annual safety report (ASR) to the CBPH regarding all serious adverse reactions that have taken place during the year.

If a drug has an undesirable effect which results in death, endangers life, requires hospitalisation or prolongs a stay in hospital, involves a disability or incapacity or causes an anomaly/congenital malformation in the patient, an adverse incident is judged to have taken place. In case of low-risk incidents the CBPH will contact the company responsible for marketing the drug in Belgium, pass on all information on the adverse incident and require them to investigate the claim and implement a policy to rectify the situation. In the case of high-risk incidents, CBPH takes sole control.

Pharmacovigilance data is evaluated by the CBPH along with a team of internal and external experts. Individual adverse effect reports (spontaneous reports and SUSARs) are evaluated on a weekly basis by a specific working group made up of pharmacists and doctors. Evaluation reports regarding periodic pharmacovigilance reports and marketing authorisation renewal files are submitted to a second specific working group for evaluation. The final opinion as to whether or not the measures suggested by the two working groups can be implemented is decided by the Commission for Medicines for Human Use.

Once an investigation into the adverse incident is complete there are several options open, eg:

• if necessary, the CBPH can decide, often in collaboration with the European Medicines Agency (EMEA), to make authorisation holders adapt the medication’s patient information leaflet, as well as requesting that the information contained in the “undesirable effects”, “special warnings and precautions for use”, “contraindications” sections of the summary of product characteristics (SPC) be modified.
• If the risks related to a particular drug out-weigh its benefits in treating a particular indication, the drug’s use can be limited. Marketing authorisation can also be temporarily suspended pending a thorough examination or withdrawn altogether following the decision of the Ministry of Public Health.
• If it appears, on the basis of notification, that the problem is one of quality, the CBPH can analyse the quality of the drug concerned and if required order the withdrawal of the relevant batches of those drugs from the market.
• If critical safety problems are detected, doctors and pharmacists are informed by means of an official statement on the AFMPS website, press release or circular. Authorisation holders can also be requested to send a ‘Dear Doctor’ letter to relevant healthcare professionals to inform them about the pharmacovigilance problem.

All important notification data, as well as evaluation results, are included in the Belgian database of the authorised medicines for human use. Furthermore the CBPH works closely with the Centre Belge d’Information Pharmacothérapeutique (CBIP), the Belgian Centre for Pharmacotherapeutic information, which publishes a monthly communiqué from the Pharmacovigilance Centre for healthcare professionals. This publishes all the updated news that has been received by the CBPH) or new data from specialist publications.

3) Which authority has the power to take pharmaceuticals off the market and how does it control the market?

Le Centre Belge de Pharmacovigilance, the Belgian Centre of Pharmacovigilance (CBPH) for drugs for human use, which is part of the Agence Fédérale des Médicaments et des Produits de Santé (AFMPS, the Federal Agency for Medicines and Health Products) has the power to limit the use of a particular drug for a particular indication if the risks related to its use out-weigh its benefits.

Marketing authorisation can be temporarily suspended pending a thorough examination or withdrawn altogether following the decision of the Ministry of Public Health.

4) What is the primary legal basis for pharmaceutical regulation in Belgium?

The main legal framework for pharmaceutical regulation in Belgium is the Medicines Act of 25 March 1964 and the Royal Decree of 14 December 2006.

The opening and transferring of public pharmacies is regulated under the Royal Decrees of the 10 November 1967 and 25 September 1974. Competition between pharmacists is covered under the Order of Pharmacists.

The statutory pricing of all pharmaceuticals marketed in Belgium is obligatory and is regulated by two Ministerial Decrees, dated 29 December 1989, which cover reimbursable and non-reimbursable pharmaceuticals.

Pharmaceutical reimbursement is regulated by the Law of 14 July 1994 which covers the legal framework and the Royal Decree of 21 December 2001 which covers the practical side of reimbursement.

The following legislation covers pharmaceutical regulation in Belgium:

• Royal Decree of 31 March 2009, in execution of article 6 of the Belgian Medicines Law of 14 April 2009, defines the conditions, timelines and rules of procedures for requests for national scientific and/or technical (eg regulatory) advice (STA).
• Royal Decree of 21 January 2009, appendices I-V on instructions for pharmacists.
• Law of 20 July 2006 relating to the creation and the operation of Agence Fédérale des Médicaments et des Produits de Santé (AFMPS), the Federal Agency for Medicines and Health Products.
• Royal Decree of 18 May 2006 modifying the Royal Decree of 30 June 2004 determining measurements of execution of the law of 7 May 2004 relating to the experiments on humans which relate to the clinical trials of drugs for human use.
• Ministerial Decree of 2 February 2005 on approval of laboratories covering analysis and control of drugs.
• Royal Decree of 30 June 2004 implementing the law of 7 May 2004 relating to experiments on humans with regard to clinical trials of drugs for human use.
• Law of 7 May 2004 relating to experiments on humans.
• Law of 19 March 2004 regulating substitution therapy.
• Royal Decree of 19 April 2001 regarding the importation of parallel drugs for human use and the distribution of parallel drugs for human and veterinary use.
• Royal Decree of 18 March 1999 relating to medical devices.
• Royal Decree of 15 July 1997 relating to active implantable medical devices. Modified by Royal decree of 21 January 2009.
• Royal decree of 7 April 1995 relating to information and advertising concerning drugs for human use (took effect 12 May 1995).
• Royal Decree of 20 July 1993 on fixing the reimbursement price of drugs concerned under article 13bis of the law of 25 March 1964 (took effect 31 July 1993).
• Royal Decree of 11 January 1993 fixing the conditions by which samples of drugs can be supplied.
• Royal Decree of 16 September 1985 concerning the standards and protocols applicable as regards to tests of drugs for human use (took effect 13 November 1985).
• Royal Decree of 3 July 1969 relating to the recording of drugs (came into effect 10 July 1969). Although this Decree was largely repealed by the Royal decree of 14 December 2006 relating to the drugs of human and veterinary use, the following provisions remain in force: article 25, ss 1st, 2, 3, 4, 4bis, 5, 6, 7, 8 and 9; article 26; and article 28bis, s 3, subparagraphs 3 and 4.
• Royal Decree of 22 September 1966 relating to the conditions and methods of recognition of laboratories analysing and controlling drugs (took effect 4 November 1966).
• Law of 25 March 1964 (took effect 17 April 1964) which included the list of non-therapeutic indications, appendices, explanatory notes and work methods covering ‘Compassionate Uses – Medical need Program’.
• Royal Decree of 6 June 1960 relating to manufacture and wholesale distribution of drugs and their dispensation (took effect 22 June 1960). This Decree was repealed by the Royal Decree of 14 December 2006 with regard to drugs for human and veterinary use, except for: article 48B which becomes article 34(a) of the Royal Decree of 31 May 1885 approving the new instructions for doctors, pharmacists and general storekeepers, given that in this article the words “of article 48” are replaced by the words “article 105 of the Royal Decree of 14 December relating to the drugs for human and veterinary use” and article 48, s 1st, subparagraph 4 which becomes article 34(b) of the above-mentioned Royal Decree of 31 May 1885, given that this provision is supplemented as follows: “The pharmacist of dispensary preserves these declarations of the doctor during 10 years.”
• Royal Decree of 31 May 1885 approving the new instructions for doctors, pharmacists and general storekeepers (took effect 19 June 1885). This decree was replaced for pharmacists and dispensary staff by the Royal Decree of 21 January 2009 bearing instructions for the pharmacists and dispensers.

5) Is there any other EU legislation that impacts medtech products in Belgium? What are the Belgian legal instruments that transpose these Directives?

European Directive 2001/20/EC was incorporated in Belgian national law by the Law of 7 May 2004 relating to experiments on humans.

6) Are any changes imminent to Belgium Regulations?

A new remuneration system for pharmacists is due to be implemented by 2010.

7) Are any other bodies involved in assessing the safety of pharmaceuticals in Belgium?

No.

8) Where are the Belgium Notified Bodies based and what products do they audit and against which annexes of the Directives?

APRAGAZ ASBL (NB 0029) and SGS Belgium NV (NB 1639) are the Notified Bodies which cover EU Directive 93/42/EEC Medical devices.

9) Who oversees the Notified Bodies?

Agence Fédérale des Médicaments et des Produits de Santé (AFMPS) (the Federal Agency for Medicines and Health Products) is responsible for overseeing the Notified Bodies in Belgium.

10) What is the legal basis in Belgium for the regulation of pharmaceutical products on the borderline with pharmaceuticals and of combinations of medical devices and pharmaceutical products?

The legal basis resides in EU legislation. If the product administers a medicinal product within the meaning of Council Directive 2001/83/EC, medicinal products, then the device part must meet the requirements of device legislation and the medicinal part will be governed by Directive 2001/83/EC.

Where the device and medicinal product form a single integral unit, intended exclusively for use in the given combination and which is not reusable, then that single-unit product is governed by Directive 2001/83/EC.

But where a device incorporates substances which, if used separately, may be considered to be a medicinal substance within the meaning of Directive 2001/83/EC, if the substances incorporated in the medical devices are liable to act upon the body with action ancillary to that of the device, the placing of the devices on the market is governed by the Medical Devices Directive but the safety, quality and usefulness of the substances must be verified by analogy with the appropriate methods specified in Council Directive 75/318/EEC of 20 May 1975 on the approximation of the laws of the Member States relating to analytical, pharmaco-toxicological and clinical standards and protocols in respect of the testing of proprietary medicinal products.

11) Do companies need to register in Belgium prior to marketing?

A company/applicant wishing to place a medicinal product on the Belgian market must obtain marketing authorisation (MA) from the Belgian Minister or an EU Marketing Authorisation as set out under the centralised procedure in Regulation (EEC) No 2309/93 and Regulation (EC) No 726/2004 on the authorisation and supervision of medicinal products and establishing a European Medicines Agency (EMEA Regulation. EMEA MA’s obtained under this centralised system are valid in all EU member States.

Specifically, in Belgium the procedure and conditions to obtain a MA are set out in the Royal Decree on the Registration of Medicinal Products of 3 July 1969.

An applicant must file a MA application with the Directorate General of Medicines, which includes: pharmaceutical and chemical data; pharmacological and toxicological test results and clinical trial results. Further information maybe requested during the review process from the applicant.

In special circumstances ie, subject to the performance of additional research a Marketing Authorisation maybe granted. However, it will be refused if: the medicinal products proves in normal usage to be harmful; if the applicant cannot prove its therapeutic efficacy or it is shown to be lacking or is insufficiently substantiated; or its qualitative and quantitative composition has not been declared. An MA will also be refused if support documentation does not comply with the relevant legal provisions outlined in the Royal Decree of 3 July 1969.

An MA can either be granted by the Belgian authorities or on the basis of a MA granted by another EU member state under the mutual recognition procedure (MRP).

A completed application is filed with the Directorate General of Medicines and then passed onto the secretariat of the Medicines Commission who organises for a scientific review to be carried out. Once complete, a report is submitted to the Minister by the Medicines Commission within 180 days of receipt of a complete application. If the report is acceptable the MA is granted by the Minister. If not, the 180-day period is suspended and the applicant is informed. The applicant then has two months to submit an additional dossier. If this deadline cannot be met the negative opinion becomes final.

If an additional dossier is submitted within the two month deadline, the Medicines Commission must submit to the Minister its final report who then has 210 days from the initial filing of the application to make a final decision.

In the case of a MRP application a decision should be made within 90 days of receipt of a complete application.

Under the Royal Decree of 3 July 1969 abriged applications are allowed based on EC provisions.

A list of MA fees is listed on the Directorate General of Medicines website - http://www.afigp.fgov.be.

12) Do manufacturers need to register high-risk and low-risk pharmaceuticals in Belgium prior to marketing?

Yes, see above.

13) Are there any additional forms that must be completed in Belgium by pharmaceutical manufacturers in terms of registration?

No.

14) Which laws regulate clinical trials in Belgium?

The following laws regulate clinical trials in Belgium:

• Law of 7 May 2004 relating to experiments on humans (as amended by Law of 27 December 2004).
• Law of 27 December 2005.
• Health law of 13 December 2006.
• Law of 27 April 2007.

The following Royal Decrees regulate clinical trials in Belgium:

• Royal Decree of 22 April 2007 fixing the fees to be paid in the framework of article 30, s 6 of the law of 7 May 2004 relating to experiments on humans.
• Royal Decree of 30 June 2004 determining the measures for carrying out the law of 7 May 2004 relating to experiments on humans concerning clinical trials of medicines for human use, modified by the Royal Decree of 18 May 2006.
• Royal Decree of 14 December 2006 concerning medicines for human or veterinary use, which replaces the law of 6 June 1960.

The following EU Directives regulate clinical trials in Belgium:

• EU Directive 2005/28/EC of 8 April 2005 laying down principles and detailed guidelines for good clinical practice as regards investigational medicinal products for human use, as well as the requirements for authorisation of the manufacturing or importation of such products.
• EU Directive 2003/94/EC of the Commission laying down principles and detailed guidelines for good manufacturing practice.
• EU Directive 2001/20/EC on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use.

The following Circulars relate to clinical trials in Belgium:

• Circular 472: for directors of hospitals and presidents of Ethics Committees, on the application of the Law of 7 May 2004 concerning experiments on humans, some clarifications for Ethics Committees and medical management. Circular 480 further clarifies Circular 472.
• Circular 460: quick notification (in 7/14 days) of individual reports about serious adverse reactions relating to registered or unregistered medicines to the Directorate-General of Medicines and to the main Ethics Committees.
• Circular 447: information in respect of submitting an application for an opinion or for authorisation to conduct a clinical trial.
• Circular 455: explanatory text relating to the Law of 7 May 2004 concerning experiments on humans.

15) What procedures must be followed by sponsors wishing to carry out clinical trials? Can you be more specific about how this works in practice in Belgium?

In order for a sponsor to carry out a clinical trial in Belgium they must submit an application to and receive a favourable opinion from one of the recognised Belgian Ethics Committees (a list of which can be viewed at:

http://www.fagg-afmps.be/en/binaries/comit%C3%A9s%20%C3%A9thique%20reconnus_tcm292-27289.xls). Based on the Ethics Committee’s opinion, if the Research and Development department of AFMPS (the Federal Agency for Medicines and Health Products) has not indicated any major insufficiency within the legal timeframe, approval is assumed.

Applications should be sent to:

Agence Fédérale des Médicaments et des Produits de Santé (AFMPS) Research and Development department

Eurostation II

8th Floor

Place Victor Horta 40, box 40

B-1060 Bruxelles

Belgium

email: [email protected]

Each application submitted to AFMPS’s R&D department must be accompanied by the payment of the appropriate fee. The fee for each complete application is €3,191; the fee for each modification thereafter is €286. Only one copy of each document contained in the application is required to be sent.

The validation process begins once AFMPS’s R&D department receives the application and proof of payment. For monocentric phase I clinical trials, the maximum time taken by AFMPS to give an opinion is 15 days, for all other clinical trials it is 28 days.

Information on how to request authorisation for a clinical trial is contained in “Detailed guidance for the request for authorisation of a clinical trial on a medicinal product for human use to the competent authorities, notification of substantial amendments and declaration of the end of the trial” published by the European Commission. Appendix 1 shows the information required by each member state. (it can be viewed at: http://www.fagg-afmps.be/en/binaries/CT%20application-2005-10_tcm292-27417.pdf).

The company requesting clinical trial approval must also seek a EudraCT number from the EU’s EudraCT database (http://eudract.emea.europa.eu).

Guidance documents relating to clinical trials include:

• Exploratory clinical trial: guidance: http://www.fagg-afmps.be/en/binaries/exploratory%20CTs-guidance_tcm292-27447.pdf
• Detailed guidance on the European clinical trials database: http://www.fagg-afmps.be/en/binaries/eudra-CT-EN_tcm292-27454.pdf
• Detailed guidance on the European Database of Suspected Unexpected Serious Adverse Reactions: http://www.fagg-afmps.be/en/binaries/eudravigilance-CT-EN_tcm292-27455.pdf
• Detailed guidance for the request for authorisation of a clinical trial on a medicinal product for human use: http://www.fagg-afmps.be/en/binaries/CT%20application-2005-10_tcm292-27417.pdf
• Detailed guidance on the application format and documentation to be submitted in an application for an Ethics Committee opinion: http://www.fagg-afmps.be/en/binaries/ethics%20committee%20application-EN_tcm292-27458.pdf
• Detailed guidance on the collection, verification and presentation of adverse reaction reports arising from clinical trials: http://www.fagg-afmps.be/en/binaries/adverse%20reaction%20reporting-EN_tcm292-27459.pdf
• Guidance on IMP’s and other medicinal products used in Clinical Trials: http://www.fagg-afmps.be/en/binaries/guidance-IMPs-med%20products-EN_tcm292-27460.pdf
• Draft guidance for consultation on “specific modalities” for non-commercial clinical trials referred to in Commission Directive 2005/28/EC laying down the principles and detailed guidelines for good clinical practice: http://www.fagg-afmps.be/en/binaries/draft-guidance-specific%20modalities-EN_tcm292-27461.pdf

16) What are the requirements concerning the reporting of adverse incidents during a clinical trial?

The legal basis for the reporting of adverse incidents which occur during a clinical trial being carried out in Belgium are set out in EU Directive 2001/20/EC in articles 11, 17 and 18.

Detailed guidance on the European Database of Suspected Unexpected Serious Adverse Reactions can be viewed at: http://www.fagg-afmps.be/en/binaries/eudravigilance-CT-EN_tcm292-27455.pdf while detailed guidance on the collection, verification and presentation of adverse reaction reports arising from clinical trials can be viewed at: http://www.fagg-afmps.be/en/binaries/adverse%20reaction%20reporting-EN_tcm292-27459.pdf.

17) How are products regulated in Belgium which are a combination of medical devices and advanced therapy medicinal products or are devices which contain non-viable human tissues?

The regulatory authority responsible for all medicinal products, including Advanced Therapy Medicinal Products (ATMPs), and for medical devices in Belgium is Agence Fédérale des Médicaments et des Produits de Santé (AFMPS), the Federal Agency for Medicines and Health Products. To place a medicinal product on the Belgian market, a manufacturer must submit to the European Medicines Agency (EMEA) (www.emea.europa.eu) an application for a centralised marketing authorisation (MA). The EMEA’s Committee for Advanced Therapies (CAT) is responsible for preparing a draft opinion on the quality, safety and efficacy of each ATMP for which a MA application is submitted. The CAT opinion is then submitted to the EMEA’s Committee for Medicinal Products for Human Use (CHMP) for final approval. Once granted, the marketing authorisation allows the product access to all EU countries. It is the responsibility of the AEMPS to monitor the activities of such products once on the market. The AEMPS is also the supervisory authority for manufacturers or importers of centrally authorised ATMPs. It is also the competent authority for ATMPs which are prepared and used under the hospital exemption.

An ATMP is a biological medicinal product which is either:

• a gene therapy medicinal product as defined in Part IV of Annex I to Directive 2001/83/EC;
• a somatic cell therapy medicinal product as defined in Part IV of Annex I to Directive 2001/83/EC; or
• a tissue engineered product as defined in Article 2 1(b) of the ATMP Regulation (1394/2007/EC).

The text of the EU’s ATMP Regulation (Regulation 1394/2007/EC), which regulates healthcare products containing human tissues or cells where the cells or tissues are viable and their action is primary, as well as gene and somatic cell therapy, was published in the Official Journal of the European Union on 13 November 2007 and came into force on 30 December 2008. This text essentially covers products that meet the definition of a medicinal product, but many are used in combination with medical devices.

The aim of Regulation 1394/2007/EC is to:

• improve patient access to safe and effective advanced therapy medicinal products (ATMPs) of good quality;
• provide a legal basis to promote development in the European biosciences industries; and
• harmonise market access in the EU by establishing a comprehensive regulatory framework which, includes the centralised procedure for marketing authorisations (MA) for ATMPs.

Under Regulation 1394/2007/EC, the definition of a medicinal product as defined in Article 1(2) of Directive 2001/83/EC has not changed but has been enhanced, clarifying how to deal with new and emerging technologies. The Regulation also clarifies that products containing viable cells or tissues must be regulated as medicinal products; and as ATMPs in particular.

In the case of combination products, manufacturers have to ensure that their products are in compliance with the national medical device regulations and the ATMP regulations, with the same type of rules applying as to which requirements take precedence as with drug/device combinations.

If an ATMP contains tissues or cells of human origin, the provisions of the Tissues and Cells Directive (2004/23/EC) apply. AFMPS is the competent authority for the Tissues and Cells Directive in Belgium. In cases where human tissues and cells are intended for human use and are not classified as medicinal products, the full provisions of the Tissues and Cells Directive (2004/23/EC) apply and cover donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells.

In cases where stem cells are to be used in a medicinal product, the donation, procurement, processing and testing of the cells are covered by the Tissues and Cells Directive (2004/23/EC). Other Directives that impact this area are:

• 2006/17/EC – Technical requirements for donation, procurement and testing of human tissues and cells; and
• 2006/86/EC – Traceability requirements, notification of SAEs and technical requirements for coding, processing, preservation, storage and distribution of human tissues and cells.

Manufacturers should also be aware that the drug authorities and European Medicines Agency (EMEA) are legally bound to examine the results of the notified body as far as an assessment of the device is concerned, and can seek a notified body assessment of the device element of the combination if one is not already available. In either case, there will be occasions when the notified body will be called upon to justify its decision in front of the drug authorities.

Manufacturers of any new ATMPs covered by the scope of the Regulation will have to meet its requirements as soon as the Regulation enters into force. But for manufacturers of tissue engineered products covered by the ATMP Regulation that are already on the market, they will have until December 2012 to obtain a new marketing licence for their products. This is one year longer than for manufacturers of cell and gene therapy products.

Work is now ongoing at the medical devices unit of the European Commission on the future regulation of medical products containing non-viable human tissues where the action of these tissues is ancillary. It is envisaged that these products will be regulated under the medical devices regulatory regime, although with requirements that reflect the level of risk inherent in these products.

Guidelines can be found on the EMEA Advanced Therapies webpage at:

http://www.emea.europa.eu/htms/human/mes/advancedtherapies.htm.

The Regulation, can be viewed at:

http://eurlex.europa.eu/LexUriServ/site/en/oj/2007/l_324/l_32420071210en01210137.pdf

Further information is also available from the European Commission’s Pharmaceutical website:

http://ec.europa.eu/enterprise/pharmaceuticals/advtherapies/advanced_en.htm.

18) How are nanomedicine devices regulated in Belgium?

Nanomedicine products are regulated according to the EU legislation that impacts the product sector in which the product falls. So the requirements of the pharmaceutical legislation would apply to any product which fell under the scope of the definition of a pharmaceutical. The same would apply to nanotech and drug/device combination products as with any other drug/device combination products.

The European Commission issued a code of conduct to govern research in this field in February 2008. This can be viewed at:

http://ec.europa.eu/nanotechnology/pdf/nanocode-rec_pe0894c_en.pdf.

19) Are there any other legal or guidance documents which impact the way pharmaceuticals are regulated or controlled in Belgium?

There are many additional aids and guidance documents on the way pharmaceuticals are regulated or controlled which are drafted at EU level, all of which can be found via the pharmaceuticals section of the European Commission’s Directorate General Industry and Enterprise website at:

http://ec.europa.eu/enterprise/pharmaceuticals/index_en.htm.

These texts do not have a legal status per se, but they provide a clear expectation of what is required, and any manufacturer which did not follow this guidance may be called upon, in the case of non-compliance or an incident, to explain why they did not follow these documents.

20) Are there any other important contact points within Belgium Competent Authority for pharmaceuticals?

A list of contacts for different departments at AFMPS (the Federal Agency for Medicines and Health Products) is available at:

http://www.fagg-afmps.be/en/contact/index.jsp

21) Which Belgian agencies are involved in giving approval so that a pharmaceutical product can benefit from reimbursement?

Reimbursement and pharmaceutical pricing is covered in Belgium under the legal framework of the Coordinated Law on the Mandatory Health Insurance of 14 July 1994, Article 35bis, and the Royal Decree of 21 December 2001 which forms the legal basis for the categories of reimbursement.

Pricing

The competent authority charged with establishing the maximum pharmaceutical price for all pharmaceuticals used in Belgium is the Ministry of Economic Affairs. Two pricing committees, one for reimbursed and one for non-reimbursed pharmaceuticals play an advisory role. Once the Minister of Economic Affairs has set the maximum price, the Reimbursement Committee (CTG) of the Institut national d’assurance maladie-invalidité (INAMI) (Also known as Rijksinstituut voor ziekte- en invaliditeitsverzekering (RIZIV)) (National Institute for Health and Disability Insurance) can open negotiations to determine reimbursement levels with pharmaceutical companies. These reimbursement levels are then passed onto the Minister of Social Affairs, who makes the final decision on reimbursement.

All pharmaceuticals in Belgium are subject to statutory pricing via the Ministry of Economic Affairs. There is no system of free pricing in Belgium.

A legal basis was established in 2006 for a new procedure based on “public tendering” principles, designed to modifiy reimbursement conditions for pharmaceuticals for budgetary reasons. In general, a pharmaceutical company is offered an indirect competitive benefit, via a lower co-payment for the patients for its pharmaceutical(s), offering, from the health insurance and patient perspective, the lowest cost for the treatment.

Currently, in Belgium all price decisions are made at the manufacturer level, with internal and external price referencing applied. External price referencing is applied for all pharmaceuticals. Internal price referencing is only used for those pharmaceuticals where a comparable product is marketed in Belgium.

For wholesale and pharmacy remuneration a fixed mark-up exists. In the case of wholesalers, this is statutorily fixed at 13.1% of the ex-factory price. In the case of pharmacies it is statutorily fixed at 31% of the wholesale price for (non-hospital) pharmacies and 22% for pharmaceuticals delivered in hospital pharmacies to non-hospitalised patients.

Value-added tax (VAT) of 6% is applied to all pharmaceuticals. There are no official discounts in Belgium.

In the case of ‘old pharmaceuticals’, regulated price cuts are applied for those which contain an active component that has been reimbursed for more than 12 years; these are reduced by 14% (ex-factory level). If the active component has been reimbursed for more than 15 years, the applied pharmacy retail price (PRP) and corresponding reimbursement basis is cut by 2.3% (ex-factory level)

Reimbursement

At the national level, the Institut national d’assurance maladie-invalidité (INAMI) (National Institute for Health and Disability Insurance) is responsible for the organisation of reimbursement of healthcare expenses and managing healthcare insurance in Belgium. At a local level, it is the responsibility of the sickness funds. All decisions concerning the scope of the health insurance are made at the national level in close collaboration with various organisations, ie the sickness funds, professional bodies of healthcare providers and the Government.

In order to obtain reimbursement, the pharmaceutical company that is responsible for the commercialisation of the relevant pharmaceutical on the Belgian market must submit an application to the Commission de Remboursement des Médicaments (Commissie Tegemoetkoming Geneesmiddelen) (CTG) (Commission for Reimbursement of Medicines) of INAMI. The Minister of Social Affairs is then responsible for deciding, based on information submitted by the Commission for Reimbursement of Medicines, whether or not the medicine should be added to the reimbursement list.

Under the Coordinated Law on the Mandatory Health Insurance of 14 July 1994, Article 35bis the review of reimbursement applications must take no more than 180 days, although this deadline may be extended if further information is requested. If a negative decision is not given within the 180 days, the application is deemed to be approved. This takes into account EU Directives covering the reimbursement procedure for pharmaceuticals of classes 1 (added therapeutic value), 2 (line extensions, without added therapeutic value) or 3 (generic). In the case of orphan drugs, and parallel-traded pharmaceuticals the reimbursement decision process should take at most 90 days.

The CTG reviews applications via the following criteria:

• product-specific (eg medical/therapeutic value, safety, lack of an alternative);
• economic (eg price, cost-effectiveness, reference price, impact on the budget);
• patient-specific (eg age, sex, chronic or terminal illness); and
• disease-specific (eg severity of illness, special medical needs).

A pharmaceutical company must also, in parallel, submit separate applications for price-setting to the Federal Public Service for Economy (decisions should take 90 days) and for reimbursement to the Reimbursement Committee (CTG). Although the maximum price of a pharmaceutical is set by the Minister of Economic Affairs, it is the Minister of Social Affairs who determines the reimbursement basis and the resulting applied pharmacy retail price (PRP).

All reimbursed pharmaceuticals are placed on a positive reimbursement list, which consists of different chapters. Each reimbursed pharmaceutical is attributed a reimbursement category which indicates to what extent the obligatory insurance is to reimburse the cost. This classification is not linked to price. The assignment of pharmaceuticals to these reimbursement categories (A, B, C, Cs or Cx) is done by the Minister of Social Affairs, based on CTG proposals. Pharmaceuticals in categories A, B and C are considered as “necessary” and are classified inaccordance to their specific medical and therapeutic importance.

The reference pricing system structure is set out in Royal Decree of 22 May 2001. Reference pricing is only applied to (off-patent) pharmaceuticals with generic alternatives (same active component). If a (cheaper) generic version of a reimbursed pharmaceutical is available containing the same active component(s) (same Anatomic Therapeutic Chemical (ATC) classification ATC 5) then the original pharmaceutical enters the reference price system. On entering the system, the reimbursement basis of the original pharmaceutical diminishes by 30% (of the ex-factory price); its applied pharmacy retail price (PRP) remains the same, however. The system also takes into account the active component (Anatomic Therapeutic Chemical (ATC) classification ATC 5) of the generic alternative. Pharmaceuticals which belong to ATC level 4 and contain at least one (reimbursed) generic pharmaceutical are subject to a higher maximum personal contribution. The aim is, whever possible, to encourage patients to switch to generic alternatives.

An extension of the reference price system was undertaken on 1 January 2007 to cover post-patent molecules without generic alternatives. Now, at the request of the CTG, the reference price system can be applied to these molecules.

The reference price system is reviewed every six months (on 1 January and on 1 July) by Institut national d’assurance maladie-invalidité (INAMI), the National Institute for Health and Disability Insurance.

In Belgium percentage co-payments are applied, which are limited to a percentage of the real cost, and limited to a “ceiling” fee.

The most important recent reimbursement-related cost-containment measures are is the lowering of out-of-pocket payments for category B (ATC 4 level group) and C (ATC 4 level group) in 2007. In May 2008 they were sustainably lowered again.

Under Royal Decree of 21 December 2001 class 1 pharmaceuticals included on the reimbursement list must undergo an individual review within 18 months to three years of being entered on the list. Individual reviews for other pharmaceutical classes are at the request of the Minister of Social Affairs or the CTG.

Reimbursement decisions are published on the web. Evaluation reports, drawn up by the CTG, are also published on the INAMI website at: http://www.inami.be.

22) Does the application procedure differ according to whether the product is intended for the ambulatory (out of hospital) or hospital settings?

The positive reimbursement list is valid for both the outpatient and the hospital sectors. When a pharmaceutical is used in a hospital there are no specific reimbursement conditions. However, specific financing systems and reimbursement (out-of-pocket payment) systems exist.

Hospitals receive a fixed sum for dispensed reimbursed pharmaceuticals dispensed during a patient’s stay, independent of the real expenditure for that patient. Hospitalised patients are charged a fixed daily rate for dispensed reimbursed pharmaceuticals, while non-reimbursed pharmaceuticals are charged in full.

In the case of pharmaceuticals used by out-patients the personal contribution is calculated according to the number of units of the pharmaceutical(s) the patient receives this is the same principle used in public pharmacies.

Each hospital draws up a list of pharmaceuticals (reimbursed/non-reimbursed) which are continuously available in the central hospital pharmacy, the so-called “hospital repertory”. In each hospital, the Repertory Commission decides on which pharmaceuticals should be listed in its repertory.

23) What is the procedure that new products need to follow to enter onto the Belgium Drug Listing of reimbursable pharmaceuticals for ambulatory care use?

In Belgium, the positive list of reimbursable pharmaceuticals is updated on a monthly basis, by means of Ministerial Decrees in which decisions on reimbursement (admission/modification/exclusion) of the preceding period are grouped. These decrees are drawn up by the administration of the Institut national d’assurance maladie-invalidité (INAMI) and formalised via decisions made by the Minister of Social Affairs.

Each month, the reference database is updated along with the reimbursement list and is available at http://www.inami.be for use by social insurance companies, hospitals and associations of pharmacists. Major reimbursement changes are also communicated via the website.

24) How is it possible to have new medical products recognised for reimbursement listing?

There have been no major changes to the reimbursement lists since the late 1990s.

25) What is the legal basis for pharmaceutical regulation of orphan drugs in Belgium?

European Commission Regulation (EC) No 141/2000:

(http://eur-lex.europa.eu/smartapi/cgi/sga_doc?smartapi!celexapi!prod!CELEXnumdoc&lg=en&numdoc=32000R0141&model=guichett), of 16 December 1999, on orphan medicinal products established the criteria for orphan designation in the EU and outlined incentives designed to encourage pharmaceutical companies to carry out research, development and marketing of medicines for rare diseases.

Regulation (EC) No 847/2000:

(http://eur-lex.europa.eu/pri/en/oj/dat/2000/l_103/l_10320000428en00050008.pdf) lays down provisions for implementing the criteria outlined in Regulation (EC) No 141/2000 and defines the concepts of “similar medicinal product” and “clinical superiority”.

The EU Committee on Orphan Medicinal Products (COMP) of the EMEA (www.emea.europa.eu/htms/general/contacts/COMP/COMP.html) is responsible for reviewing ‘orphan medicinal product designation’ applications and granting orphan drug status. Once achieved the drug enters onto the Community Register for Orphan Medicinal Products:

(http://ec.europa.eu/enterprise/pharmaceuticals/register/index.htm).

COMP also advises the European Commission on the establishment and development of EU orphan medicinal product policy, and assists the Commission in drawing up detailed guidelines and liaises internationally on matters relating to orphan medicinal products. However, each member state is still allowed to make its own decisions on the pricing and reimbursement of orphan drugs. So if a member state believes the impact of orphan drugs on their budget would be too high, they can restrict the reimbursement of new orphan drugs to specific groups of patients.

26) Useful Contacts

Agence Fédérale des Médicaments et des Produits de Santé (AFMPS) (the Federal Agency for Medicines and Health Products). (This is also know by its Dutch name: Federaal Agentachap voor Geneesmiddelen en Gezondheidsproducten (FAGG).

Eurostation building, block 2

Place Victor Horta, 40, box 40

B-1060 Bruxelles

Belgium

Tel: (general): [phone]

Email: [email protected]

Web: http://www.fagg-afmps.be/en

Centre Belge d’Information Pharmacothérapeutique (CBIP), (the Belgian Centre for Pharmacotherapeutic information)

c/o Heymans Instituut

De Pintelaan 185

9000 Gent

Belgium

Email: [email protected]

Web: http://www.cbip.be

Belgium Ministry of Public Health

SPF Santé Publique, Sécurité de la Chaîne Alimentaire et Environnement

Federal Public Service (FPS) Health, Food Chain Safety and Environment

Eurostation II

Place Victor Horta, 40 box 10

B-1060 Bruxelles

Belgium

Tel: [phone], Call Centre: [phone]

Email: [email protected]

Web: http://www.health.fgov.be/

Institut national d’assurance maladie-invalidité (INAMI) (Also known by its Dutch name: Rijksinstituut voor ziekte- en invaliditeitsverzekering (RIZIV)) (National Institute for Health and Disability Insurance)

Avenue de Tervueren 211

1150 Bruxelles

Belgium

Tel: [phone]

Email (general): [email protected]

Web: http://www.inami.fgov.be/fr/

Federale Overheidsdienst Volksgezondheid, Veiligheid van de Voedselketen en Leefmilieu; Diectoraat Generaal: Geneesmiddelen / Service public federal Santé publique, Sécurité de la Chaîne alimentaire et Environnement; Direction Générale: Médicaments

(Federal Public Service of Health, Food Chain Safety and Environment; Directorate General of Medicines)

Amazone Building (A)

Avenue Bischoffsheimlann, 33

B-1000 Bruxelles

Belgium

Tel: [phone]

Eurostation II, 8th Floor

Place Victor Horta, 40 box 10

B-1060 Bruxelles

Belgium

Tel: [phone]

Email: [email protected]

Web: http://www.afigp.fgov.be

Commissie Tegemoetkoming Geneesmiddelen / Commission de Remboursement des Médicaments (Commission for Reimbursement of Medicines)

Institut national d’assurance maladie-invalidité (INAMI) (Rijksinstituut voor ziekte- en invaliditeitsverzekering (RIZIV)) (National Institute for Health and Disability Insurance)

Avenue de Tervueren 211

1150 Bruxelles

Belgium

Tel: [phone]

Web: http://www.inami.fgov.be/fr/