The regulatory regimei Classification
The FAMHP plays an important role with regard to borderline decisions. It provides advice on product classification and assesses the correct regulatory classification of products when taking regulatory decisions, such as the granting or refusal of a marketing authorisation. In addition, the FAMHP operates a 'mixed commission' responsible for borderline reviews. The commission consists of representatives of the Federal Public Service of Public Health, the Federal Public Service for Economic Affairs, the Belgian food agency and the FAMHP itself. The commission reviews specific borderline aspects and provides an opinion to the Minister of Public Health, who takes a formal decision.
The FAMHP has issued a list of claims that are not considered medicinal, which helps in making borderline determinations based on the presentation of products. The claims are mainly relevant for determining the borderline between medicines and foods, and between medicines and cosmetics. Examples of non-medicinal product claims are statements suggesting that the products provide a soothing effect on the airways in the event of a sore throat, that they ensure regular bowel movements or that they prevent caries. Some of these claims are, however, subject to EU approval under the Nutrition and Health Claims Regulation for Foods. The Regulation takes precedence over the list. The mixed commission also issued guidance on the borderline between biocidal products, cosmetics and medicines, and on the classification of products containing Bach flowers.
Borderline determinations can also be made by the courts. This typically happens in criminal courts if the public prosecutor brings a criminal action for unlawful marketing of a product because, for instance, it is positioned as a cosmetic but in reality is an (unapproved) medicine; and by commercial courts in unfair trade practices litigation where, for instance, a competitor seeks an injunction against the marketing of a product as a food while, in reality, it is an (unapproved) medicine. Older case law is summarised in a ministerial circular of 1987.ii Non-clinical studies
The Act on the Protection of Animal Welfare of 14 August 1986 implements Directive 2010/63/EU into Belgian law from early 2013. The Act, combined with an implementing Royal Decree, permits research involving animals only in premises licensed by the Federal Public Service of Health, by appropriately qualified staff and in accordance with procedures designed to minimise animal pain and suffering. The facilities must also have an ethics committee and there is a federal ethics committee that can provide recommendations to the Federal Public Service.
The Royal Decree on Good Laboratory Practices (GLP) lays down the main GLP requirements. It applies to non-clinical testing of ingredients used in medicines, cosmetics, pesticides, veterinary medicines, food and feed additives, and industrial chemicals. The Decree requires that all animal studies be conducted in accordance with sound standards of GLP. These standards reflect the Organisation for Economic Co-operation and Development requirements.iii Clinical trials
The Act on Experiments on Humans of 2004 has a broad scope of application. It covers clinical trials with medicines and any other experiment that aims at 'the development of the knowledge that is proper to the exercise of healthcare professions' such as physicians, dentists, pharmacists, physiotherapists and nurses. It does not apply, however, to purely retrospective observational studies based on existing data. All experiments require scientific justification, a properly substantiated purpose, an acceptable level of risk and detriment for the subjects, an expected benefit that outweighs the possible risks, ethics committee approval and informed consent. Specific rules apply to clinical trials with medicines and, under the medical devices rules, to clinical trials with medical devices.
Sponsors of experiments are liable for damage suffered by subjects as a direct or indirect consequence of the experiment. The liability is not dependent on any fault or negligence and must be covered by an insurance policy. Subjects have a direct action against the insurance company. The liability regime sometimes raises complex questions, such as whether it extends to damage suffered by pregnant partners of trial subjects. A specific act regulates experiments on in vitro embryos.Medicines
The Act on Experiments on Humans of 2004 and the implementing Royal Decree contain specific provisions on clinical trials with medicines, which implement the EU Clinical Trials Directives 2001/20/EC and 2005/28/EC. Clinical trials of medicinal products in humans are generally only permitted if the FAMHP has granted a clinical trial authorisation and an ethics committee has issued a favourable opinion. Non-interventional trials, where the medicinal product is used within the scope of the marketing authorisation, in line with current medical practice and without additional diagnostic measures or controls, are subject to the general rules on experiments.
The new Law on Clinical Trials with Medicines for Human Use of 7 May 2017 was adopted in response to the adoption of the EU Regulation on clinical trials, which will repeal the current Directive 2001/20/EC once it becomes applicable (the precise date is yet to be determined and depends on the progress with the EU portal, but the current expectation is that the Regulation will apply as of mid-2019. See the European Union chapter of this publication). The scope of the new law is limited to clinical trials that are covered by the EU Regulation, and will therefore exist in parallel with the law of 7 May 2004, which has a broader scope. The law was implemented by the Royal Decree on Clinical Trials with Medicines for Human Use of 9 October 2017. Some aspects of the new law and of the new Royal Decree became applicable in November 2017. These relate, for instance, to the organisation of the competent authorities for ethics committees. Some of these rules have been updated in October 2018. The other provisions will start applying when the Regulation becomes applicable.
Approval process under the current rules: applicants for an approval must first have obtained an EudraCT number and must then submit the relevant application form and investigational medicinal product dossier (IMPD) to the FAMHP. The agency must react within 15 days for single-centre Phase I trials and within 28 days for other trials. In the absence of objections, the trial is deemed approved. For trials with gene or cell therapy medicines and with medicines that contain genetically modified organisms, longer periods apply and an express approval is required.
All investigational medicinal products must have been manufactured or imported by the holder of a manufacturer's authorisation in the European Economic Area (EEA). The manufacturer or importer must ensure that a qualified person has performed batch release of the products for clinical trial use, which is only possible if the product is in accordance with an appropriate standard of good manufacturing practice (GMP) and if the product conforms to the specifications in the IMPD.
Sponsors have reporting obligations for suspected unexpected serious adverse reactions, where applicable based on reports received regarding adverse events.Medical devices
Clinical investigations of medical devices are subject to the general rules on experiments and to specific provisions in the medical devices decrees. In addition to obtaining research ethics committee approval, the manufacturer must notify the FAMHP before the conduct of a clinical investigation involving a non-CE-marked medical device or a CE-marked device tested for another indication than covered by the CE-mark. For Class III devices and implantable or long-term invasive devices of Class IIa and IIb, the notification must be made 60 days before commencement of the trial, and the FAMHP can raise objections during that period. There are also obligations to report adverse events and reactions.
There is a different process for performance evaluation of a non-CE-marked in vitro diagnostic medical device (IVD). Manufacturers must draw up a declaration and follow the procedure set out in Annex VIII of the Royal Decree on IVDs, and must keep the documents available for inspection.iv Named-patient and compassionate use procedures for medicines
The Medicines Act and the 2006 Decree allow for different ways to make a medicine available outside the marketing authorisation system.
Magistral preparation: pharmacists can prepare medicines for an individual patient or a group of patients on the basis of a medical prescription. For certain types of products and under specific conditions, the preparation can be subcontracted to a licensed manufacturer. This allows a higher level of quality and GMP compliance.
Compassionate use: a non-approved medicine can be used under the compassionate use provisions laid down in Article 83 of Regulation (EC) No. 726/2004. Compassionate use programmes are defined in the Regulation as:
making a medicinal product belonging to the categories referred to in Article 3(1) and (2) [i.e., products covered by the centralised EU procedure] available for compassionate reasons to a group of patients with a chronically or seriously debilitating disease or whose disease is considered to be life-threatening, and who cannot be treated satisfactorily by an authorised medicinal product.
The product concerned must either be the subject of an application for a centralised marketing authorisation or must be undergoing clinical trials. The specific procedure to be followed in Belgium is set out in Article 106 of the 2006 Decree and was amended in 2014. The applicant must submit an application for a compassionate use programme to the FAMHP, which includes a review by an ethics committee. The Decree sets out what information is required in the application, including a standardised informed-consent form for the patient. The applicant must specify whether it requests the intervention of the compulsory health insurance for reimbursement purposes. The FAMHP forwards the application to the European Medicines Agency (EMA) and may request, in consultation with the EMA and the applicant, an opinion from the Committee for Medicinal Products for Human Use. The Minister of Health must adopt a decision on the compassionate use programme within 55 business days from the decision on the admissibility of the request, failing which, the decision is deemed positive. Decisions are published on the website of the FAMHP and are regularly reassessed. Under certain conditions and for certain diseases, products available under a compassionate use programme may benefit from (limited) reimbursement under the so-called 'early temporary reimbursement' regime (see Section III below).
In emergency situations, an unauthorised medicinal product can be used without requesting a compassionate use programme if a number of conditions are met, in particular:
- the urgency is motivated by the fact that a patient is in immediate risk of dying or that the risk from non-treatment is higher than the inherent risks of the treatment;
- informed consent was obtained from the patient;
- the medicinal product is not being used in clinical trials;
- it does not concern a medicinal product that does not need a registration or marketing authorisation;
- there is no other available treatment on the market, under hospital exemption or as a magistral preparation;
- there are no authorised products in other countries worldwide; and
- it is impossible to submit a request for a compassionate use programme.
While it is recommended to notify the FAMHP and the ethics committee of the site concerned, this is not a legal requirement to start the treatment. Treatment is provided under the responsibility of the healthcare professional and the entity arranging the supply.
Medical need: a medical need programme can be put in place by the marketing authorisation holder for an approved medicine but in an indication that is still under clinical development or regulatory review, or that is approved but for which the product is not yet marketed. The specific procedure is set out in Article 108 of the 2006 Decree and was amended in 2014. The procedure is somewhat similar to this for compassionate use programmes. The applicant must submit a request to the FAMHP, including the specified information. An opinion from an ethics committee is also required. The decision on the medical need programme is published on the FAMHP website. Under certain conditions and for certain diseases, products available under a medical need programme may benefit from (limited) reimbursement under the so-called 'early temporary reimbursement' regime (see Section III, below).
Imports: named-patient imports of medicines that have a marketing authorisation in the country of origin are allowed for patients who cannot be adequately treated with authorised and available medicines. This option is available for specific patients and for groups of patients, and the imports are made by a pharmacist.
In addition, the Medicines Act excludes specific products from the marketing authorisation requirement, including certain blood products, certain radiopharmaceuticals, and certain advanced therapies that are prepared in accordance with an individual prescription.v Pre-market clearance for medical devices
The Belgian rules on marketing authorisations for medicinal products and on CE-marking for medical devices closely follow the EU rules. The procedures are administered by the FAMHP.vi Regulatory incentivesMedicines
The Medicines Act and the 2006 Decree implement periods of eight years of regulatory data exclusivity (during which generic and biosimilar applicants cannot file) followed by two years of market protection (during which regulators may review generic or biosimilar applications, but generic or biosimilar manufacturers cannot launch) under Directive 2001/83/EC for products for which qualifying national applications were submitted after 30 October 2005. For complete free-standing applications submitted on or before that date, holders of Belgian marketing authorisations would benefit from 10 years of data exclusivity protection, during which generic applicants cannot file. These regulatory exclusivity periods begin when the product is first approved anywhere in the EEA, not necessarily in Belgium.
The additional data exclusivity provisions for 'orphan medicinal products' and for products with paediatric indications developed in accordance with an approved paediatric investigation plan under Regulation (EC) No. 141/2000 and Regulation (EC) No. 1901/2006 apply directly.
The Belgian Office for Intellectual Property is responsible for granting supplementary patent certificates for medicinal products that meet the criteria under Regulation (EC) No. 469/2009 and for the paediatric extensions. There is no patent linkage under Belgian law (i.e., no linkage between the regulatory approval process and patent expiry). The Medicines Act contains a Bolar provision, making it possible to perform any necessary trials for approval during the patent protection period.Medical devices
Belgian legislation does not provide specific regulatory exclusivity periods for medical devices. A device may be protected by a patent if it satisfies the requirements for patentability under the relevant rules.vii Post-approval controls
Post-approval controls over marketing authorisation holders for medicines and manufacturers of medical devices in Belgium closely mirror the EU requirements subject to the following of local requirements and procedures.viii Manufacturing controls
The substantive requirements governing the manufacture of medicinal products, including the need for a manufacturing or import authorisation, a qualified person and compliance with GMP, are discussed in the EU chapter.
The FAMHP regulates pharmaceutical manufacturing operations within Belgium and conducts inspections of manufacturing facilities pre-authorisation and periodically thereafter.
Changes to the manufacturing authorisation require variations to be submitted to the FAMHP.ix Advertising and promotionMedicines
Key principles on advertising are set out in the Medicines Act. They are supplemented by the 1995 Royal Decree on Information and Advertising for Medicines for Human Use and a 1993 Royal Decree on samples, which implement the EU advertising rules into Belgian law. These include the general requirements that advertising must not be misleading, and that it must be substantiated and accompanied by appropriate prescribing information. There is also a prohibition on pre-approval or off-label promotion of medicines, advertising of prescription-only medicines to the general public, and illegal inducements to prescribe (for further details on the latter, see Section V below). Some provisions go beyond what is required under EU law. Some forms of advertising media are prohibited (such as billboards or via telephone or SMS). Advertising to the public (of non-prescription drugs; advertising to the public is not allowed for prescription drugs) must be notified in advance to the FAMHP and, for radio and television advertising, prior approval must be obtained. This takes the form of a visa, granted by the Minister of Health, upon advice of the Control Commission of Medical Advertising.
The statutory scheme is supported by a self-regulatory system based on the pharma.be practice code. The code is enforced through an ethics commission within pharma.be. For non-interventional studies, the code also requires prior approval from the Visa Bureau of pharma.be. The visa procedure is intended to check compliance of the study with the legal and ethical requirements.
The rules restricting benefits to healthcare professionals, including a review of scientific meetings and hospitality, are discussed in Section V below.Medical devices
The rules on advertising for medical devices are much less elaborate. The key provision is that non-CE-marked medical devices cannot be promoted (subject to an exception for showing the devices at fairs with an indication that they are not yet in compliance with the rules). Advertising of implantable medical devices to the public is prohibited. Advertising of medical devices is also subject to general advertising rules, requiring that advertisements be substantiated, factual, balanced and not misleading.
The Belgian medical devices industry association beMedTech (formerly known as UNAMEC) operates a code of conduct that is enforced through an ethics commission. The rules restricting benefits to healthcare professionals, including a review of scientific meetings, and hospitality and disclosure requirements ('sunshine' rules), are discussed in Section V below.x Distributors and wholesalersMedicines
As under EU law, Article 12 ter of the Medicines Act provides that distributors of medicinal products must hold a wholesale distributor's authorisation and specific obligations are laid down in the 2006 Decree. In particular, wholesale distributors must operate appropriate facilities and staff under the supervision of an appropriately qualified responsible person. They must comply with good distribution practices and maintain appropriate batch records.
Wholesale distributors are also subject to supply obligations that are aimed at ensuring adequate availability of medicines throughout Belgium. These obligations have also been invoked by parallel exporters.
The FAMHP is responsible for issuing, suspending and revoking wholesale distributors' licences in Belgium. It conducts inspections before the grant of such a licence and periodically thereafter.Medical devices
Belgium operates a fairly closed distribution system of medical devices in that certain medical devices may only be sold to final users via public pharmacies, hospital pharmacies or dental clinics (the list is set out in Annex XIII.1 to the Royal Decree on Medical Devices). This may change in the near future (as we explain in Section VIII below).
In addition, distributors (and exporters) of certain medical devices need to notify their activities to the authorities. Some aspects of the notification system were changed recently, in an effort to simplify the procedure. The FAMHP and beMedTech also issued guidance on good distribution practices. Brokers must also register with the FAMHP. Since February 2015, distributors of certain medical devices (and hospitals) must put in place a 'contact point for materiovigilance', responsible for reporting incidents to the FAMHP. The requirements were updated in December 2017.xi Classification of productsMedicines
The Belgian rules on prescription status for medicines are based on the EU provisions.Medical devices
Some medical devices are subject to restrictions in the distribution chain (e.g., via pharmacists or dentists).xii Imports and exports
The Belgian regulations governing the import and export of medicinal products reflect those at the EU level.xiii Controlled substances
Belgium implemented the UN Single Convention on Narcotic Drugs 1961 and the UN Convention on Psychotropic Substances 1971, and has recently consolidated and updated its legislation. The licences for manufacturing, distributing, importing or exporting such substances are issued on a national basis by the FAMHP and are subject to renewal. As a rule, specific authorisations must be obtained for the import or export of narcotic or psychotropic substances. Close collaboration also exists with Luxembourg.xiv EnforcementMedicines
Breaches of the medicines rules are often investigated by inspectors of the FAMHP. They can result in administrative fines or a referral to the public prosecutor. The latter can propose a settlement or bring the case before the criminal courts. There are not many criminal court cases for infringement of the medicines rules.
Competitors or non-profit organisations can also bring cases before the commercial courts, typically with a request for an injunction.
Finally, enforcement through the self-regulatory system operated by pharma.be is possible.Medical devices
The enforcement mechanisms for medical devices are very similar to those for medicines.