This year has seen several changes and impending changes in the law affecting the conduct of clinical trials in Belgium. These are largely derived from the implementation of new EU legislation including the clinical trials directive and the amendments to the Community pharmaceutical code. Of particular interest is how the Belgian legislator has treated the liability of trials sponsors and the treatment of biologicals. The new “Bolar” exemption permitting trials of generics of in-patent drugs is also of particular significance, but one should also bear in mind the ability of those in drug development to rely on other existing exemptions in patent law in order to undertake trials of new agents falling within third party patents.
Belgium is a significant venue in Europe for the conduct of clinical trials. According to Belgian government statistics, for example, the second highest number of phase I studies per head of population is carried out in Belgium with the United Kingdom having the highest number. Reflecting this is the fact that the new Belgian law on experiments involving human subjects was passed on 7 May 2004, just after the 1 May deadline for implementation of European Parliament and Council Directive 2001/20/EC, better known as the clinical trials directive. To this end, the Belgian Royal Decree of 6 June 1960 relating to the manufacture, wholesale distribution and dispensing of medicinal products has also been amended.
To a large extent, the new law simply carries over the provisions of the directive. Readers will be well aware that this requires all studies to be undertaken in accordance with ICH GCP using investigational medicinal products produced in accordance with GMP In addition, all clinical trials will require prior authorisation by a governmental authority, which in Belgium is the Directorate-General of Medicinal Products of the Federal Public Service for Public Health, Food Safety and the Environment (DGMP) together with a positive opinion from a responsible local ethics committee. The DGMP will also be responsible for ensuring that GMP and GCP is complied with at manufacturing and trial sites. Trial subjects or their legal representatives must give their informed consent to participation in the trial having received specified information about the IMP and the trial. Finally, each clinical trial authorised must be entered into a central European database (“EudraCT”) and provision is made for serious adverse reactions to be reported to the DGMP, the responsible ethics committee and all concerned investigators and these are recorded by the DGMP, with such data entered on the central Eudravigilance database.
The Belgian Approach
The aim of a directive is to set minimum standards and leave member states to decide how to achieve this. Moreover, it is open to member states in their national legislation to deal with matters going beyond those required by the directive. With the new clinical trial law, the Belgian legislator has chosen to take this approach and so we will examine the peculiarities of implementation in Belgium since Directive in more detail.
The law applies to “experimentation”, which is defined as “every study, trial or investigation conducted in man with a view to developing biological or medical knowledge”. This appears to be broader than the definition of “clinical trial” set out in the directive and to which the directive’s requirements apply. In fact, the directive’s already comprehensive definition seems to cover the majority of situations that are encountered in reality and so the likelihood of this difference having practical consequences remains to be seen. It should also be noted that the law will not apply to trials for which at 1 May 2004 a positive ethics committee opinion had already been obtained.
Interestingly, the draft makes special provision for non-commercial trials, which is a trial the sponsor of which is a university, hospital, academic research institution or other authorised body, does not own a patent covering the drug under investigation and will retain any intellectual property in the results of the trial. In order to be qualified as non-commercial trial the sponsor may not be linked, directly or indirectly to the owner of the patent rights on the medicinal product. The sponsor of a non-commercial trial does not have to file certain quality data with the government authority when applying for authorisation in respect of a previously registered drug, does not have to pay any ethics committee fees and may be excused from certain labelling requirements. The draft law also provides that a patient cannot be involved in more than one phase I trial simultaneously. Most importantly, medicinal used in non-commercial trials may be reimbursed by INAMI under certain conditions (this does not apply to “commercial” trials, where products must be provided by the sponsor free of charge).
There is a provision in the implementing law that goes beyond the provisions of the directive as regards insurance and liability and this states as follows:
“Article 29 § 1 The sponsor is liable, even without fault, for damage to the participant and/or his successors connected directly or indirectly to the study; any contractual provision aimed at limiting this liability is void.
§ 2 The sponsor must prior to the study obtain insurance covering this liability as well as that of all those involved in the study regardless of the nature of the connection between those involved, the sponsor and the participant.”
We believe that it will impose on the trial sponsor a specific (and strict) liability for all events during the trial, whether or not within the control of the sponsor. This would be in addition to liability under the general law for example under the principles of negligence. Furthermore, “sponsor” is defined as “a person, a business, an institution or an entity responsible for the initiation, management and/or financing of a clinical study”. Notwithstanding any agreement with the commercial sponsor, a CRO could well fall within this definition. Consequently, a CRO managing a trial in Belgium would be well-advised to ensure that it obtains indemnities both from trial centres as regards claims arising from the centre’s or the investigator’s negligence or misconduct, but moreover from the “actual” sponsor covering any claims that may be brought against the CRO by study participants on the basis of the above article.
Criminal sanctions have also been introduced for failure to comply with the basic pre-conditions for undertaking a trial, such as a favourable ethics committee report, informed patient consent and appropriate insurance arrangements. Investigators and sponsors can be prohibited from conducting trials for certain periods of time if found to have committed such infringements.
The Authorisation Requirement
There are some fairly short time limits for both the competent ethics committee and the Directorate General of Medicinal Products to complete their respective reviews, with a period of 15 days applying in both cases to phase I trials and 28 days for all other trials. Once the trial is underway, the primary obligation lies with the ethics committee to monitor protocol compliance (the directive simply requires that this is done by the member state). Unfortunately and contrary to hopes raised during the legislative process, provisions have been introduced to the effect that a clinical study of any product falling within paragraph 1 of the Annexe to Regulation (EC) No. 726/2004 (that is, any medicinal products developed by means of one of the following biotechnological processes: recombinant DNA technology, controlled expression of genes coding for biologically active proteins in prokaryotes and eukaryotes including transformed mammalian cells or hybridoma and monoclonal antibody methods) must obtain a positive prior authorisation from the competent authority, rather having the benefit of a presumed authorisation where no objections are raised within the prescribed time-limits.
Finally, there is a circular from the Directorate-General setting out further guidance on the applications for authorisation. All the above texts are all available in French from the following website: http://afigp.fgov.be/ 
Impending Changes to Patent Law
Another fundamental issue to be considered primarily by the sponsor of a clinical trial, but with repercussions in addition for its CRO and trial centres is whether the conduct of the trial may be opposed by a third party asserting intellectual property rights covering some aspect of the IMP. The intellectual property in question, usually a patent or SPC, could relate to the basic composition of the active pharmaceutical ingredient, a method of synthesis, expression or purification, a particular formulation or medical use of a known compound. Whichever it is, the import, manufacture, storage and administration of such an IMP will generally be considered an infringing act under Article 27 § 1 of the Belgian Patent Act of 28 March 1984. In the absence of the patent owner’s consent to the trial, the person conducting the trial will have to rely on a specific exemption if he is to avoid liability for patent infringement; the purpose of the trial is irrelevant to determining whether an act is on the face of it an infringement.
Often these issues arise in the context of, for example, a bioequivalence study of a generic product. One of the recent amendments to EU Directive 2001/83 on the community code relating to medicinal products for human use provides that “conducting the necessary studies and trials with a view to the application of [the abridged procedure for obtaining a marketing authorisation for a generic medicinal product] and the consequential practical requirements shall not be regarded as contrary to patent rights or to supplementary protection certificates for medicinal products”. This is the so-called “Bolar” exemption introduced as part of the recent review of the whole regulation in the EU of medicinal products. It follows the lead of Japan and the United States which have had a similar provision in their patent law for the last 10 and 20 years respectively. The aim of the exemption will be to enable those wishing to market a generic medicinal product to place their product on the market immediately following patent expiry and expiry of the data and market exclusivity periods of eight and then two years respectively. The “Bolar” provision is currently set out in an EU directive and remains to be implemented in Belgium. It is not known how the Belgian government how will undertake this, although is understood that this will not be done until near the October 2005 deadline. It is also not known whether any conditions will need to be fulfilled in order to exercise the right or whether any limits will be imposed. In terms of the types of studies covered, guidance can already be obtained from the new medicinal products legislation, which defines what a generic medicinal product is. This makes clear, for example, that “The different salts, esters, ethers, isomers, mixtures of isomers, complexes or derivatives of an active substance shall be considered to be the same active substance, unless they differ significantly in properties with regard to safety and/or efficacy. … The various immediate-release oral pharmaceutical forms shall be considered to be one and the same pharmaceutical form. trials from the reference medicinal product's dossier shall not be provided” such that studies on such variations would be covered by the new exemption. From the intellectual property perspective at least, the provision is hoped to bring a degree of clarity and uniformity across the EU at least with regard to generics which was previously missing under the “experimental use” regime, which depending on the country allowed a widely-varying range of acts.
What about clinical studies that are not simply aimed at obtaining authorisation for some form of generic of an existing product? It seems to clear to us that the “Bolar” exemption supplements rather than replaces the experimental use exemption. In Belgium, this is contained in Article 28 § 1 (b) of the Patent Act which states that, “The rights conferred by a patent do not extend to: […] acts done for experimental purposes which relating to the subject-matter of the patented invention […]”. The scope of this has not been fully defined in case-law, although it has been accepted that it would not be an infringement to use the patented invention to “assess the merits of the [invention] and to discover its shortcomings and possible improvements”, but must not go beyond the realm of the experimental for a “disinterested purpose”. It is generally thought that the exemption is available to commercial organisations and is applicable to studies undertaken on a large scale. What matters is the aim of the experimentation and in particular whether one experiments “with” or experiments “on” the object of the patented invention. Commentators believe that it is perfectly legitimate to investigate the patented product or process itself in order to develop a new application of the patented product, for example new therapeutic effect, new dosing regime or new route of administration. On the other hand, the prevailing view seemed to be that studies aimed at obtained a marketing authorisation for a generic product was not producing any new knowledge or data and could not – under the old law – be undertaken without a licence from the patent owner.
It should be stressed however that there are no published decisions are available on the question of whether or to what extent clinical testing falls within this experimental use exemption and so these view are for simply to give some degree of guidance.
Finally, what about the transitional period pending full implementation in Belgium of the new “Bolar” clause? It could be possible to argue, given that the there is no actual case-law to the contrary, that the existing experimental use exemption should be interpreted consistently with the revised medicinal products legislation and so clinical studies of a generic product would fall within the current law. In any event, the “Bolar” exemption seems to go against the prevailing, restrictive view in Belgium and can only serve increase the popularity of Belgium as clinical study venue.
First published in Global Outsourcing Review.
 DGMP has offices at AMAZONE, Boulevard Bischoffsheim 33, 1000 Bruxelles, Tel.: + 32 2 227.55.00 and Fax: + 32 2 227.55.55 as well as at C.A.E. Vesalius, 3e étage Rue Montagne de l’Oratoire 20 / 3, 1010 Bruxelles, Tel.: + 32 2 210.45.11and Fax: + 32 2 210.49.35.
 The Royal Decree of 30 June 2004 relating to implementing measures concerning the Law of 7 May 2004. This measure also adopts into Belgian law the various detailed guidelines published by the European Commission
 A Royal Decree of 15 July 2004 has set the fees payable in respect of an application for an opinion or authorisation for the conduct of a clinical trial or study.
 Brussels, 11 May 1995, Ing.-Cons., 1995, p.254 – Fabricom Air Conditioning v. ABB Flakt AB & another.