The regulatory regime
Despite their supervision by the same national health agencies, medicines and medical devices are subject to two separate legal regimes. Medicines are governed by the provisions transposing the EU code relating to medicinal products for human use and cannot be tested, marketed or promoted without prior approval. Medical devices are subject to the provisions transposing into French law the CE marking requirement regime applicable throughout Europe, and harmonisation will be fostered by the direct application of Regulation (EU) 2017/745 of the European Parliament and of the Council on medical devices, and Regulation (EU) 2017/746 on in vitro diagnostic medical devices, both adopted on 5 April 2017, which will apply as from 26 May 2020 and 22 May 2022 respectively.
The adoption of these Regulations reinforces the trend towards increased similarity between both categories of products. In France, for instance, advertising material for medical devices has been mostly aligned with the prior-approval regime applicable to medicines. In addition, medicines and medical devices are subject to very similar processes in terms of pricing and reimbursement.i Classification
Rules and principles governing the classification of health products are broadly based on EU case law. For instance, the Administrative Supreme Court referred to the European Court of Justice the regulatory status of software assisting in the prescription of pharmaceutical products, which have been qualified as medical devices because of their aim. At the same time, French case law continues to broaden the scope of products falling within the definition of pharmaceutical products. This is the case for various food supplements claiming to have therapeutic effects or containing substances with therapeutic properties, and tiger balsam, the status of which is still not settled.
More recently, the Finance Bill for 2019 introduced the new category of hybrid medicines into the French regime. Like generics, hybrid medicines may be substituted for a reference medicine, but they are not similar to the originator product in terms of indications, dosage, pharmaceutical form or route of administration. The applicable conditions for substitution are therefore still pending, and these will be determined by a ministerial order. Hybrid status might notably concern medicinal products with a different form or packaging from the originator product.ii Non-clinical studies
The status of non-interventional studies conducted on human beings has been aligned with rules applicable to clinical trials, with some specificities. For instance, the ethics committee can give its opinion with only four members present, and the approval from the ANSM is not required.iii Clinical trials
Clinical trials for medicines and medical devices conducted in France must receive a prior opinion from an ethics committee and prior approval by the ANSM. In some cases, the ANSM can refuse to grant the approval. In a judgment dated 3 April 2015, an administrative court upheld one such refusal.
Decree No. 2016-1537 of 16 November 2016 significantly amended the regime applicable to clinical trials. Private sponsors must supply all the tested products free of charge to the healthcare centres hosting the healthcare professionals (HCPs) appointed as investigators and compensate for the costs and extra costs incurred in conducting the trial. For transparency reasons (particularly to avoid conflicts of interest that could arise between the ethics committees (ECs) and healthcare institutions) and to allow an appropriate assessment of the projects, the competent ECs are now designated on a lottery basis, from among those available and whose members have necessary skills in the project field under consideration. In addition, the requirements regarding reporting of adverse or unexpected events have been significantly strengthened, and can lead to the provisional suspension of the administration of the tested product in Phase I.
The ANSM initiated a pilot phase during which, on a voluntary basis, ECs, subject to the sponsor's acceptance, can implement EU Regulation No. 536/2014 on clinical trials. Following two years of implementation, the time frame for the review of applications is, on average, 68.9 days. In addition, to improve access to innovative therapies, and in anticipation of upcoming EU regulation of clinical trials, the ANSM set up, on an experimental basis, fast-track authorisations of clinical trials, which are likely to apply to both advanced therapies and new trial on known substances. Starting from 15 October 2018, this new experiment applies to all phases of clinical trials and aims to reduce the application review period from 60 to 25 days for clinical trials on known substances, and to 40 days for innovative treatments.
In 2014, the French government issued harmonised template agreements with the aim of accelerating the implementation of trials within French public hospitals. Decree No. 2016-1538 of 16 November 2016 broadens their application to any type of privately sponsored trial. The harmonised agreement is exclusive of any other agreement entered into in the framework of the same trial. It must therefore include the negotiations with the investigators, associations participating in the trial, etc. Moreover, when a trial involves several centres, the negotiation of financial aspects takes place between a single hospital and the sponsor; other centres will be bound by the same financial provisions. The aim is to be able to negotiate with the coordinating centre within a 45-day period. Hospitals receive financial incentives from public funds if they successfully implement the template. Moreover, sponsors might also provide for counterparts in return for the quality of the data collected, which correspond to former financial incentives related to the inclusion of patients. In 2015, 2,135 agreements had been entered into through this route with 91 healthcare institutions, whereas there were 3,117 agreements with 112 establishments in 2016.iv Named-patient and compassionate-use procedures
Named-patient and compassionate use procedures were significantly updated and strengthened by the Bertrand Law of 29 December 2011. A temporary authorisation for use (ATU) may be granted to treat severe or rare diseases for which no treatment has been authorised, if and when the treatment cannot be delayed.
When requested by the pharmaceutical company intending to market the product, an ATU will be granted if safety and efficacy are presumed and if a marketing authorisation has or will be applied for within a given time frame. When requested by a physician on a named-patient basis, an ATU will be granted if safety and efficacy are presumed, if the patient cannot be treated through a clinical trial, and if the product is either subject to a clinical trial or an application for marketing authorisation (even temporary), at least in a request form. The last of these conditions may be bypassed in a few specific cases, such as where there is a high probability of severe consequences for the patient without treatment. The Finance Bill for 2019 has opened up the possibility of obtaining an ATU for medicines that are already authorised for another indication where previously only medicines that had not been authorised were likely to be granted an ATU, for their first indication. Moreover, the Bill also provides that medicinal products authorised without a previous ATU but meeting the ATU criteria may be subject to a temporary reimbursement on that basis until final agreement on their reimbursement price, under conditions including the obligation to keep the product on the market for a certain length of time and at a price that may be set unilaterally by the CEPS.
Alongside these ATUs, the Bertrand Law has created a regulated scheme for off-label use, called temporary recommendation for use (RTU). A product may be prescribed off-label without any marketing authorisation or ATU, either because it is indispensable to the treatment of a patient, in light of the existing state of the art, or because it is permitted by an RTU issued by the ANSM. The conditions for granting RTUs are similar to those for ATUs, except that they are imposed on pharmaceutical companies by the authorities. In addition, the law amending social security funding for 2014 broadened the RTU regime to include cases where therapeutic alternatives might be available but not with the same active substance, dosage or pharmaceutical form. On 29 June 2016, the Administrative Supreme Court upheld this broadening of the RTU regime to cases where therapeutic alternatives are available, which had been challenged on the basis of, among other things, violation of Article 5 of Directive 2001/83/EC.
RTUs tend to get closer to standard marketing authorisations in several ways: first, they are issued for up to three years but can be indefinitely renewed (for example, an RTU was adopted for the medicinal product Avastin in 2015 and this was renewed for a new three-year period in September 2018); second, the Social Security Bill for 2018 has mirrored the pricing negotiation regime for the indications covered by an RTU, for which a distinct price can be agreed with the Pricing Committee (CEPS). The objective is clearly to encourage the use of the RTUs, despite the fact that they are deemed to cover exceptional circumstances.v Pre-market clearance
The procedures for the approval of commercial distribution of medicines and medical devices stem from EU regulations. There is a peculiarity in France arising from the concept of an exploitant of medicines. In addition to the requirement of a marketing authorisation, a medicine may only be marketed by an authorised marketing company, whose premises and operation have been inspected and authorised by the ANSM. The exploitant must either be the marketing authorisation holder, a third party appointed by the latter, or both. He or she must carry out the pharmaceutical activities connected with the sale, promotion and monitoring of the products, and only pharmacovigilance activities can be subcontracted as such. A head pharmacist is responsible for the control of all the pharmaceutical activities, such as pharmacovigilance processes and the compliance of promotional material with relevant laws.
Medical devices can be marketed in France provided they carry a CE marking. However, in addition, manufacturers located in France must notify the ANSM of the first marketing of their devices, as well as any commercialisation in France of implantable and Class III medical devices on French territory (pursuant to the classification of the Council Directive 93/42/EEC of 14 June 1993 concerning medical devices), and provide a copy of the instruction leaflet.vi Regulatory incentives
Data and market exclusivity rules in France follow EU regulations. However, there are some national peculiarities concerning the preservation of originators' intellectual property rights. First, originator companies must notify their rights to the ANSM for publication purposes. Second, such rights can also be notified to the CEPS, which undertakes, in principle, not to issue any reimbursement decision for generic products more than six months before the expiration of the originator's intellectual property rights. The CEPS cannot, however, prevent an at-risk launch scenario.
Increasingly, regulatory incentives tend to be developed at the pricing and reimbursement stage. Indeed, framework agreements entered into by the CEPS and the pharmaceutical and medical devices companies provide for pricing incentives or conditional pricing, subject to the conduct of additional studies to monitor the safety and efficacy of their products. The framework agreement between the CEPS and the pharmaceutical companies covering the period 2016–2019 also confirms the ability to agree on pay-for-performance schemes, but only in situations where the application of the usual pricing provision is not adequate. Moreover, the ministries supervising the CEPS stated that they intended pay-for-performance agreements to be limited to cases where the social security would not bear any risk, which de facto reduces the number of such innovative agreements.
In addition, the framework agreement speeds up the process for the determination of the price for the most innovative products, and provides for the discharge of mandatory rebates to innovative, orphan and paediatric drugs. Also, various provisions favour innovative paediatric indications, which are granted a one-year extension of guaranteed pricing (six years instead of five), as well as a guaranteed daily treatment cost not lower than for the adult dosage or the possibility of agreeing on a capped total turnover.
On another front, prescription of biosimilar medicines delivered in community pharmacies is incentivised by various means. First, healthcare institutions that have entered into an agreement with a Regional Health Agency will get an incentive corresponding to 20 per cent of the price difference between the biosimilar and the reference medicine in proportion to the biosimilar prescription rate. Moreover, since October 2018, certain healthcare institutions have been selected to trial alternative means of increasing the use of biosimilars alongside an increased incentive of up to 30 per cent.vii Post-approval controls
Following the French scandal concerning Poly Implant Prothèse (a company that produced breast prostheses), post-approval controls have been increased for medical devices. The ANSM can launch unannounced inspections to detect deviations from applicable technical standards, and impose fines or suspend the marketing of non-compliant products.
In the same way, post-approval controls over pharmaceutical products have improved quite significantly with the right of the ANSM to deliver marketing authorisations on a conditional basis, provided that the holder carries out safety or efficacy studies in real treatment conditions and in comparison with existing therapies within a given time frame. However, this route is very rarely used.
The inspection means should be optimised thanks to the agreement on mutual recognition on good manufacturing practice inspections entered into between the European Union and the United States; this agreement has become effective following the 1 March 2017 decision but remains in the transition phase until July 2019. EU Member States will now be able to use data from inspections carried out by the US Food and Drug Administration (FDA) and vice versa (France is one of the first of 20 EU Member States whose inspection methodology has been recognised as acceptable by the FDA).
Pharmacovigilance reporting obligations have also been broadened. For example, pharmaceutical companies must report to the European database EudraVigilance all suspected adverse effects within 15 days of obtaining knowledge any serious side effects and within 90 days of others. Moreover, as specified in the marketing authorisation, periodic safety update reports must be transmitted regularly to the European Medicines Agency.viii Manufacturing controls
Recurrent issues relating to the shortage of certain medicines, including those of high therapeutic value or without therapeutic equivalent, have given rise to several changes in the regulations.
Decree No. 2016-993 of 20 July 2016 obliges companies themselves to identify medicines with high therapeutic value, for which they must elaborate detailed alternative supply plans and organise emergency call centres to dispatch products in the event of an actual shortage. Any suspected shortage must be notified to the ANSM. In addition, pharmacists are allowed to import alternative products in the event of a shortage. Despite these measures, the ANSM registered 405 shortages in 2016. The French Senate published a report recommending implementing a new set of measures, including the creation of a national shortage management unit under the authority of the Prime Minister, or the purchase of medicine reserves for some patient populations.ix Advertising and promotion
Following the Bertrand Law of 29 December 2011 relating to the strengthening of the safety of medicines and health products, any kind of advertising and promotion of medicines and certain medical devices now requires prior approval from the ANSM.
Advertising and promotional materials for medicines must be submitted to the ANSM following a specific timetable determined by the ANSM: quarterly for advertising to HCPs, and during one of the eight weeks stipulated by the Director General of the ANSM for 2019 for advertising to the public. In the absence of a negative answer from the ANSM two months after the expiry date of each period determined by the ANSM for the receipt of proposed advertising, the advertising is deemed approved and will be valid for two years.
The approval process is the same for advertising and promotional materials for medical devices, except that submissions are not bound by the trimestral timetable.
In addition, the distribution of samples is now restricted to new medicines or for new indications within the first two years of their launch, and only in reply to a written request placed by an HCP.x Distributors and wholesalers
Wholesale activities have been affected by various measures aiming to address shortages of some key products. Wholesalers, who in France are entrusted with certain public service duties, must notify the ANSM of their geographical area of activity. In addition, the Public Health Code states that wholesalers must first distribute their products to meet the health needs in the notified geographical area before exporting them. As a result, pharmaceutical companies shall ensure an appropriate and continuous supply of products to any and all wholesalers, to enable them to comply with these duties.
The ANSM has audited compliance with wholesalers' requirements and has suspended several wholesale licences of distributors whose activity had deviated from the coverage of the French territory to the export of medicines.
Distribution in pharmacies has also been significantly affected by several changes, as outlined below.
First, medicines and medical devices fall within the pharmaceutical monopoly, namely only a pharmacy that has been granted an authorisation from a regional health agency (ARS), based on the number of residents within its market area, can sell those products to the public. Law No. 2014-344 of 17 March 2014 has removed contact lens solutions, pregnancy tests and ovulation predictors from the monopoly, allowing their distribution in grocery stores.xi Online sales
The transposition into French law of Directive No. 2011/62/EU on the sale of falsified medicines was rendered difficult by the classification of pharmaceutical products. Indeed, France first restricted online sales to a subcategory of non-prescription drugs, registered on the list of products available by direct access to the public. The Administrative Supreme Court annulled this provision on the grounds of non-compliance with the EU directive that envisaged online sales of any and all over-the-counter products. Consequently, all over-the-counter products are now available online.
More specifically, online sales of medicines are regulated by ordinance No. 2012-1427 of 19 December 2012. The obligations imposed on the functioning of online pharmacies are quite similar to those for brick-and-mortar pharmacies. An authorisation from the ARS is required. Pure players are not allowed as online pharmacies must rely on traditional brick-and-mortar ones. Two ministerial orders of 28 November 2016 set out good distribution practices for pharmacists, covering all types of situations, including online distribution, as well as the technical requirements for websites, aiming at ensuring the same level of confidentiality and safety as with physical distribution. The Administrative Supreme Court recently overruled some provisions of these two ministerial orders that were deemed a restriction on online pharmacies, in breach of EU law. For instance, the Court considered it not possible to ban any kind of promotion by online pharmacies, whereas this is not the case for bricks-and-mortar pharmacies.xii Imports and exports
Adopted on 26 January 2016 with a view to modernising the French health system, the Health Bill has introduced a prohibition on wholesalers exporting any medicine of high therapeutic value or without therapeutic equivalent. In addition, the Public Health Code states that other medicines may only be subject to export once national needs are covered; furthermore, it states that a trial or pilot scheme should be carried out whereby wholesalers would notify an independent third party of the volumes not distributed on the French territory. However, an order setting out the conditions for undertaking such a trial has never been published.xiii Controlled substances
Controlled substances are classified into three categories (narcotics, psychotropics, and drugs on controlled substance Lists I or II), depending on their level of danger. Registration is made by a ministerial decree, following the opinion of the ANSM when the substances are medicines. Drugs can receive a categorisation different from that of one of their compounds and, in the event of doubt or multiple categorisations, the stricter category will prevail.
Controlled substances in the form of active ingredients are subject to administrative requirements of traceability to track the precise volume used.
Drugs included on Lists I or II will be subject to specific requirements in terms of storage in separate and secured premises, labelling with a symbol for death, limited volume of product delivered and, concerning narcotics, use of secured prescriptions.xiv Enforcement
The enforcement of regulations relating to health products is the responsibility of several authorities. For instance, the ANSM is the main sanctioning authority with regard to health products. The ANSM's powers and sanctions have been strengthened by Ordinance No. 2016-966 of 15 July 2016 through a simplification of the scope of its activity. The Directorate General for Competition Policy, Consumer Affairs and Fraud Control is also entitled to sanction certain behaviours, such as infringements of the anti-kickback law.