The rapid spread of the novel coronavirus and disease COVID-19 as well as the drastic reac-tions of the affected countries mean a substantial intervention in global economies. In France, the ban on major events, the closure of schools and day nurseries and exit restrictions imme-diately put companies and their employees in crisis mode. The consequences of COVID-19 also and especially affect pharmaceutical and medical device companies, from which the population not only expects significant contributions to the fight against COVID-19, but which themselves had to set up an emergency management system practically overnight in order to maintain their business operations as far as possible.
For companies in the pharmaceutical and medical device industry, the current crisis mode raises a variety of legal and commercial questions. The authors provide a first overview of selected industry-specific issues in France.
Ongoing Clinical Trials (not related to COVID-19)
EU Level – The European Commission, the European Medicines Agency (EMA) and national Head of Medicines Agencies (HMA) published recommendations for sponsors on how to manage the conduct of clinical trials in the context of the coronavirus disease (COVID-19) pandemic (Guidance on the Management of Clinical Trials; Points to consider on Implications of COVID-19 on Methodological Aspects). The guidance notably provides information on changes and protocol deviations which may be needed in the conduct of clinical trials to deal with extraordinary situations and includes a harmonised set of recommendations, to ensure the utmost safety of trial participants across the European Union while preserving the quality of the data generated by the trials. In substance, sponsors are notably advised to identify de-viations related to the measures and individual decisions taken in relation to COVID-19, to record such protocol deviations and capture related reasons. They should also collect infor-mation related to pandemic-related measures and whether trial patients or trial conduct were affected, as well as the subpopulations of exposed / non-exposed, and infected / non-infected patients, which will be necessary to study the impact on the treatment effect. An analysis of the accumulating trial data should also be contemplated in order to “evaluate the implications on recruitment, loss of patients during the trial, ability to record data and ability to interpret the treatment effect in light of the pre-, during and post-pandemic measures phases”. A more thorough analysis may also be warranted and conducted by an independent Data Monitoring Committee (DMC).
Professor Raoult’s Early Tests – A clinical test was carried out on 24 patients at the teach-ing hospital of Marseille by Professor Raoult who presented his results on March 15, 2020. According to such clinical test, treatment with hydroxychloroquine would reduce COVID-19 patients’ viral load. Professor Raoult published a new study on 27 March 2020 conducted on 80 patients, which would confirm the efficiency of this treatment against COVID-19.
Many experts pointed out that Professor Raoult’s conclusions were premature. In particular, concerns were expressed with regard to (i) the conduct of these studies – e.g. absence of randomization and control group that would allow for comparison to determine whether the proposed treatment is the cause of the improvement, the obtaining of informed consent, the population tested (ii) potential conflicts of interests – e.g. one of the signatories of the publica-tion in the International Journal of Antimicrobial Agents is the journal’s editor-in-chief, (iii) communication around the results of the studies considered as misleading, deceptive and (iv) incidental effects of the wide publicity around hydroxychloroquine – e.g. it could compromise the enrolment to traditional clinical trials, as many patients would systematically request not to be provided other tested treatments / placebo.
Discovery Clinical Trial – A European clinical trial called “Discovery” was launched on 22 March 2020 at the initiative of the REACTing consortium (REsearch and ACTion targeting emerging infectious diseases) coordinated by the French National Institute of Health and Medical Research (INSERM), to evaluate treatments for COVID-19 (the “Trial”). This Euro-pean project is financed, for the French part, by the Ministries of Higher Education, Research and Innovation (MESRI) and Health and Solidarity (MSS). Its objective is to evaluate the effi-ciency and safety of four experimental therapeutic strategies including (i) remdesivir, (ii) lop-inavir and ritonavir, (iii) lopinavir, ritonavir and interferon beta and (iv) hydroxychloroquine. The Trial will include up to 3200 European patients with at least 800 hospitalized COVID-19 patients recruited in France. Allocation of patients to the various treatment modalities will be randomized, but patients and physicians will know which treatment is used (which is called an open trial). The data collected for the Trial will also contribute to the international clinical trial called “Solidarity” and launched under the auspices of the World Health Organization on 27 March 2020.
French Focus – In the coming weeks, the results of the Trial may lead to a Temporary Rec-ommendation for Use (RTU) in France, which gives the possibility to prescribe a drug outside its Marketing Authorization (MA) for a specific indication. RTUs are established by the Na-tional Agency for the Safety of Medicines and Health Products (ANSM) after information of the MA holder (in this case Sanofi-Aventis France) for a maximum period of three years, which is renewable. It is therefore quite possible that an RTU will be taken in the near future for hydroxychloroquine.
In the absence of a RTU, the prescription outside the MA is only authorized (i) in the absence of an alternative treatment benefiting from a MA or a temporary „cohort“ authorization for use (authorisation temporaire d’utilisation de cohort) (i.e. for a large number of patients), (ii) if the prescriber judges the prescription to be essential to improve the clinical condition of the pa-tient, and (iii) if the prescription takes into account scientific acquired data (article L5121-12-1 of the French Public Health Code (FPHC)). This last criterion is currently largely debated in France due to an absence of randomized controlled trial just like the tests conducted by Pro-fessor Raoult. When the criteria are meet, the prescriber is authorised, under his own respon-sibility, to prescribe outside the MA but is subject to a reinforced obligation to inform the pa-tient, has to justify his prescription in the patient’s medical record and must add the mention „Prescription outside marketing authorisation“ on the prescription.
Given the growing interest for the chloroquine molecule, the High Council of Public Health (Haut conseil de la santé publique) issued an opinion on 23 March 2020 – available here, and recalled that any prescriber must take into account the very limited state of current scientific knowledge and be aware that any doctor engages his responsibility when prescribing medi-cines for indications outside the scope of their MA and outside the framework of a clinical trial. The Council further recommended to use “a molecule with an expected antiviral effect (lopinavir ritonavir fixed combination, or even Remdesivir in the most severe cases) or, failing that, hydroxychloroquine” in case of serious symptoms.
The French Medicines Agency (ANSM) issued related recommendations on 30 March 2020 – available here. In conjunction with the regional pharmacovigilance centres, the ANSM has put in place enhanced monitoring of adverse reactions linked to the use of these treatments in the management of COVID-19, particularly when they are used outside clinical trials (chloro-quine, hydroxychloroquine, azithromycin, lopinavir/ritonavir, tocilizumab, colchicine).
In the EU – The EMA recalled on 1 April 2020 that the efficacy of Chloroquine and hy-droxychloroquine’s efficacy in treating COVID-19 is yet to be shown in studies and that “it is very important that patients and healthcare professionals only use chloroquine and hy-droxychloroquine for their authorised uses or as part of clinical trials or national emergency use programmes for the treatment of COVID-19” as such drugs can have serious side effects, especially at high doses or when combined with other medicines (available here).
Other On-going Clinical Trials – The EMA provides regular updates on treatments and vaccines against COVID-19 under development (update of 31 March 2020 available here).
Accelerated Market Access for Drugs to Treat COVID-19
EU Level – The pharmaceutical legislation provides for a number of procedures to ensure rapid market access for drugs in particularly sensitive cases. At EU level, there is in particular the PRIME system, the accelerated assessment and the granting of conditional approval. The above-mentioned EMA’s Guidance addresses the initiation of new clinical trials for treatments of COVID-19, and insists on the need for large, multinational trial protocols in line with the call of EMA’s human medicines committee (CHMP) for robust trial methodology in clinical trials for potential COVID-19 treatments or vaccines (Call to Pool Research Resources re. COVID-19 Treatments Clinical Trials). The EMA currently offers free scientific advice for the benefit of companies developing vaccines or therapeutics against COVID-19; developers of medi-cines or vaccines are invited to contact EMA as soon as possible with information about their proposed development by emailing email@example.com.
The EMA’s human medicines committee (CHMP) provided recommendations on compas-sionate use of remdesivir for COVID-19 on 3 April 2020 (available here). The aim of the CHMP’s recommendations for remdesivir is to ensure a common approach regarding the criteria and conditions of its use prior to authorisation of compassionate use programmes by Member States.
On a related topic, the European Commission called for startups and SMEs with technologies and innovations that could help in treating, testing, monitoring or other aspects of the Corona-virus outbreak to apply to a €164m round of funding from the European Innovation Council (the deadline for the first call’s applications was Friday 20 March 2020) (Call for Innovative Solutions to tackle Coronavirus Outbreak).
French Level – At the French level, the ANSM implemented accelerated procedures for the initial assessment of clinical trials authorization requests related to the management of the pandemic COVID-19 (Information re. ANSM Accelerated Procedures for Clinical Trials relat-ed to COVID-19). In order to ensure the proper follow-up of these dossiers, the ANSM rec-ommends contact to be made as soon as possible in order to prioritize the clinical trial, guide the evaluation and determine whether additional information is needed. Contact with the French Ministery of Health (DGOS) is also useful before finalization of the initial authorization procedure in order to anticipate the opening of the clinical trials centers.
Product Shortage – PPE
Simplification of the market entry – The market entry of PPE usually requires a – sometimes lengthy – conformity assessment procedure and CE marking. In order to adapt the supply of these products to the increasing demand as quickly as possible, the European Commission seeks to simplify the market entry for PPE and medical devices with its Rec-ommendation (EU) 2020/403 of 13 March 2020 – available here, to a considerable extent. In the Recommendation, the Commission requests the competent market surveillance authori-ties and notified bodies to take all available measures to provide immediate access to PPE and medical devices for healthcare professionals for the duration of the current health threat. Accordingly, PPE and medical devices may be placed on the market temporarily and in cer-tain circumstances even without CE marking.
Medical device companies should carefully consider and coordinate with the competent su-pervisory authorities and notified bodies whether their products are eligible for market access facilitation in line with the Commission Recommendation.
Limitation of exportation – The spread of COVID-19 has led to an extraordinarily high and further increasing demand for Personal Protective Equipment (PPE) or medical devices. In its Regulation (EU) 2020/402 of 14 March 2020 (Regulation) – available here, the European Commission acknowledges that „the current level of EU production and existing stocks will not be sufficient to meet demand within the Union„. In order to avoid shortages, the European Commission, via this text, has made exports of certain PPE subject to an authorisation since 15 March 2020: protective goggles and visors, face shields, oral and nasal protective equip-ment, protective clothing and gloves. Exports of such PPE products are now prohibited with-out authorization issued by the competent authorities of the Member State in which the ex-porter is established. Such Regulation enters into force on 15 March 2020, is applicable for six weeks and ceases to apply at the end of such period (e.g. 26 April 2020).
The new export restrictions are problematic for companies whose products fall within the scope of the Regulation and which are contractually obliged to supply these products to third countries. In this case, the company will have to assess whether an export license can be considered and, if not, what legal and other possibilities exist to deal with the export ban in the context of the business relationships concerned.
Import – On 3 April 2020, the European Commission approved requests from Member States and the UK to temporarily waive customs duties and VAT on the import of medical devices, and protective equipment, from third countries in order to help in the fight against coronavirus (press release available here).
Other Product Shortage
Paracetamol – In order to prevent stock shortage of certain medicines an order adopted on 23 March 2020 provides that the sale without a medical prescription of medicines composed exclusively of paracetamol is limited to two boxes for patients declaring symptoms such as fever or pain and one box in other cases. This restriction is applicable until 15 April 2020. In addition, online sales of medicines composed exclusively of paracetamol, ibuprofen and ace-tylsalicylic acid (aspirin) are suspended and no deadline is specified for this suspension.
Hydro-alcoholic gels – The French government called upon several actors from the French industry to manufacture and distribute hydro-alcoholic gels in order to prevent the risk of a country shortage amid the ongoing COVID-19 outbreak, and published several orders to authorize, by derogation, the temporary placing on the market and use of such products. The formulations, labelling, storage and batch release obligations are specified in the annexes of the order of 13 March 2020 (available here) and the order of 23 March 2020 (available here). The French government further tackled the increase of selling prices of hydro-alcoholic gels caused by the COVID-19 outbreak through the French Decree No. 2020-197 of 5 March 2020, replaced by the provisions of the French Decree No. 2020-293 of 23 March 2020 (available here). This Decree caps both wholesale and retail prices of hydro-alcoholic gels until 31 May 2020 (an order dated 5 April 2020, available here, however applies a multiplying factor for hydro-alcoholic gels manufactured by pharmacies).
The Directorate General for Risk Prevention (Direction Générale de la Prévention des Risques) published a FAQ on 1 April 2020 detailing the abovementioned derogatory authori-zations for the temporary placing on the market and use of hydro-alcoholic gels (available here).
Masks – In view of the shortages of protective masks available notably to health profession-als, the French government has decided to requisition existing and produced masks by a de-cree of 23 March 2020 (available here). According to such decree, the stocks of respiratory protection masks of types FFP2, FFP3, N95, N99, N100, P95, P99, P100, R95, R99 and R100 held by any legal entity under public or private law (i.e. including companies of the food industry); and stocks of anti-projection masks held by the companies that manufacture or distribute them are requisitioned until 31 May 2020. Besides, such masks produced between the publication of the first decree (e.g. 14 March 2020) and the date on which the state of health emergency ends shall be requisitioned for the same purposes.
Responding to a call from the Directorate General of Armaments (Direction Générale de l’Armement) to tackle the shortage linked to the Covid-19 epidemic, companies of the French textile industry adjusted their production machinery to produce protective masks. The sterili-sation sciences French organization (Société Française des Sciences de la Stérilisation) and the hospital hygiene French organization (Société Française d’Hygiène Hospitalière) have in this respect issued a joint opinion on the materials that could be used for these purposes and in particular on the sterilisation sheets and their specific indications (available here) in order for companies newly producing protection masks to have some guidelines at their disposal. Such provisions shall only apply to protection masks already present or produced on the French territory. The decree of 23 March 2020 mentioned above, has provided new provisions relat-ed to imported masks. According to the said decree, stocks of imported masks above a threshold of 5 million unites per quarter per company may give rise to a total or partial requisi-tion by order of the Minister for Health. Moreover, the silence kept by the Minister for Health more than 72 hours after receipt of an application for importation shall prevent requisition of a concerned imported stocks of masks.
Finally, the Directorate-General for Customs and Indirect Duties has established some measures to ensure the smooth import of masks – available here. As such, and until the end of the health crisis, masks may be imported without CE marking provided that the importer establishes that they comply with European standards or certain foreign standards recognised as equivalent, at the time of import.
Specialities containing the lopinavir/ritonavir combination or hydroxychloroquine – In order to ensure the appropriate and continuous supply of patients on the national territory, both in city pharmacies (pharmacies de ville) and in health establishments pharmacies (phar-macies à usage intérieur), a decree dated 25 March 2020 has suspended the export of speci-alities containing the lopinavir/ritonavir combination or hydroxychloroquine without longstop date. These provisions do not however apply to the supply of the French overseas regions and departments and to New Caledonia.
Other products. An online platform is also accessible at www.stopcovid19.fr to allow manu-facturers and distributors of essential products and equipment to distribute such essential products and equipment to health professionals and public institutions committed to the fight against COVID-19.
Loosening the conditions for reimbursement – A decree n° 2020-2027 adopted on 9 March 2020 (Telemedicine Decree) has loosen the requirements applicable to the reim-bursement of teleconsultation requested by any affected or potentially affected COVID-19 patients (COVID-19 Patients) until 30 April 2020. Under the usual legal framework, to be re-imbursable, the teleconsultation must be performed under specific conditions: it must be con-ducted within the mandatory care pathway (parcours de soin), and the physician must be a liberal doctor adhering to the national physician agreement who already knows the patient (i.e. a physical consultation must have been performed in the 12 months preceding the teleconsultation).
Pursuant to the Telemedicine Decree, teleconsultations requested by COVID-19 Patients will be reimbursed even if performed outside the mandatory care pathway (parcours de soin) and with a physician who does not know the patient. The preamble of the Telemedicine Decree recalls that teleconsultation can be performed by any technological means currently available for the transmission of videos (such as a dedicated place equipped with telemedicine devices but also secure site or application via a computer, tablet or smartphone, equipped with a webcam and connected to the internet).
Broadening the use of digital tools – An order dated March 19, 2020 completing the Tele-medicine Decree further allows health care professionals performing teleconsultations with COVID-19 Patients to use digital tools complying with the general policy on security of health information systems and regulations on the hosting of health data or, to deal with the COVID-19 crisis, any other digital tool. In addition, this order specifies that the monitoring of Covid-19 Patients by nurses can be performed with telemedicine tools (télésuivi). These provisions are applicable until May 31, 2020.
In view of the difficulties encountered by some patients who do not have the equipment ena-bling them to consult by video, the Ministry of Health and Statutory Health Insurance Services announced (decree is yet to be published), by way of derogation and only during the period of the epidemic and the containment, that it will accept to reimburse teleconsultations carried out only by telephone, at the same rate, than video teleconsultations in the following situations:
(i) patients residing in white areas (i.e. areas not covered by any mobile operator) or (ii) for the following patients who do not have access to a video tool, and including a smartphone : (a) COVID-19 Patients, (b) patients with long-term illness; and (c) patients aged 70 and older.
Please note that the French Ministry of Health recently issued practical guidelines with regard to the conduct of telemedicine acts with Covid-19 Patients (Guidelines on Teleconsultation; Guidelines on Telemonitoring with Covid-19 Patients). In addition, software companies provid-ing telemedicine tools for COVID-19 are encouraged to notify their teleconsultation, monitor-ing and document sharing solutions and their features to the French Ministry of Health and the French eHealth Agency, in order to assist health professionals in choosing the most adequate telemedicine software, depending on their needs.
Supply Chain of Medicinal Products
The increasing spread of COVID-19 poses a medium and long-term risk to the supply of me-dicinal products.
Pharmaceutical companies should keep an eye on the production networks and supply chains relevant to them and, where possible, ensure that they do not depend exclusively on individual suppliers. If there is a risk of a supply bottleneck in a specific case, e.g., due to a contract manufacturer having to reduce or discontinue its activities, pharmaceutical compa-nies should review their rights under the respective contracts in order to at least limit adverse commercial effects.
Regulatory Framework on Medical Devices
Postponement of the Application of the Medical Devices Regulation – Following the call of leading associations of the medical device industry for a moratorium with regard to the en-try in full application of the Medical Devices Regulation (MDR) expected on 26 May 2020, the European Commission has adopted on 3 April 2020 a proposal to postpone the entry into ap-plication of the new Medical Devices Regulation (MDR) for one year, in the light of COVID-19 situation, that is submitted to the European Parliament and the Council for approval (https://ec.europa.eu/commission/presscorner/detail/en/ip_20_589). Such proposal, if validat-ed, will not affect the date of application of the In Vitro Diagnostics Medical Devices Regula-tion, which becomes applicable from 26 May 2022.
Derogation from the normal conformity assessment procedures – The European Com-mission published on 3 April 2020 a guidance document confirming notably that “the public health crisis associated to the COVID-19 outbreak is to be considered justified circumstance” for Member States to authorize the placing on the market within the territory of the Member State concerned, of individual devices for which the conformity assessment procedures haven´t been carried out yet, in the interest of protection of health.
Deferred payment of rents as well as water, gas and electricity bills for smallest busi-nesses in difficulty;
A financial aid up to 1,500 euros for the most affected very small businesses, self-employed persons, liberal professions and micro-entrepreneurs;
A guarantee fund of 300 billion euros to secure bank loans, in order to ensure that companies have the necessary cash to continue their activity;
Support from the French State and the Banque de France (credit mediation) to nego-tiate a rescheduling of bank loans;
Maintaining employment through the simplified and strengthened partial unemploy-ment system;
Support from the Business Mediator to resolve a conflict with customers or suppliers;
Recognition by the French State and local authorities of Coronavirus as a case of force majeure for their public contracts (for all French State and local authorities con-tracts, late payment penalties will consequently not be applied).