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Successful Marketing of Medicinal and Cannabis-derived Products

• “, except for drogues et les conduites addictives) The Current Legal and Marketing delta 9-, and published an update of the legislation Situation in its esters and ethers, salts and the ( (CBD) le point sur la The (EU) is missing salts of the aforecited derivatives, législation) in June 2018. a harmonised law on medical and, and products containing them”. if appropriate, recreational use of Germany: cannabis. A high-leve l overview The Code of also With the amendment of the German of the national legal requirements lists exceptions (Article R. 5132-86-1) Drug Law in March 2017, the of some European countries on to the exclusions, e.g. for delta doors were opened for marketing of medicinal cannabis is provided 9-tetrahydrocannabinol used for products in Germany. below, thereby highlighting the the production of Marinol, which is The bases of the amendment were the differences within the EU. authorised as part of a Temporary Use definitions of cannabis in Annex I and III Exemption by name (Roquette Pflister, of the Narcotic Drug Law. M, 2019). After establishing a group of Denmark: experts, Temporary Specialized Scientific Annex I of the Narcotic Drug Law lists In December 2017, Denmark adopted Committee (CST), in September 2018, cannabis as a narcotic drug not being its legislation for a four-year medical analysing the use of medical cannabis in marketable, but defines exemptions: cannabis pilot project, allowing other European countries and results of for seeds, for specific certified varieties physicians to prescribe cannabis clinical trials and medical literature, the originating from European countries, the products which, until then, were not National Agency for Safety of Medicines content of THC may not be more than legal in Denmark (INCB-Report, 2018). and Health Products (ANSM) accepted 0.2%, and only for use as defined in With the implementation of the medicinal the proposal of CST to experimentally Annex III. Annex III defines exemptions cannabis pilot programme, cannabis allow medical use for certain defined for marketing and prescription of narcotic is legally available. Cultivation and indications, e.g. palliative situations or drugs to which cannabis was added production for medical use started with painful spasticity of . as: “Cannabis (Marihuana, plants and the introduction of a special development Follow-up shall be conducted via parts of plants belonging to the species plan, giving companies the ability to apply a patient register. ANSM started to of Cannabis) – based on state-controlled for a cultivation and handling licence to prepare, with the various government cultivation according to article 23 and produce cannabis for patients as well as departments concerned, technical 28 paragraph 1 of the Single Convention for export. Up to now licences have been arrangements necessary to establish on Narcotic Drugs from 1961, as well as given to two companies. the experimental phase. According to preparations approved and authorised information from Franceinfo, ANSM as finished medicinal products.” Since July 1, 2018, the Executive announced on January 22nd, 2020, the Order on Euphorizing Substances experiment on medical cannabis will Germany´s supervising authority has been amended. (content start in September 2020 and will include on medical cannabis is the “Cannabis- of tetrahydrocannabinol (THC) up to approximately 3000 patients; planned Agentur”. A tender on cultivation of 0.2%) does not fall under the definition time schedule of the experimental phase medical cannabis in July 2018 led to of an euphoriant substance. Depending is two years. signed contracts with three companies, on the products manufactured from for a total amount of 10,400 kg of hemp, rules on medicines, food and Another exception to the Code of cannabis, scheduled for a period of four food supplements need to be followed. Public Health is related to cannabis years. The first harvest is expected in the Denmark defines cannabidiol (CBD) free of narcotic properties (Article R. last quarter of 2020. as a pharmacological substance; 5132-86, II subsection 2) and describes only products with low concentration authorisation by ministerial order Cannabinoids, not being psychoactive, of CBD might be classified as food for culture, importation, exportation, e.g. the pure form of CBD, do not fall supplements. industrial, and commercial use. A under the Narcotic Drug Law. Careful ministerial order dated August 22, 1990 review on the production process is : defines the conditions for cannabis- considered since CBD extracts from In France, cannabis is regulated by the based non-narcotic requirements and the plant / parts of the plant might still Code of Public Health, including “narcotic allowed the manufacturing of liquids for contain psychoactive substances (e.g. substances”. Article R. 5132-86 lists the electronic cigarettes, cosmetic products, THC) and will then keep falling under kind of exclusions which are effective for: or capsules as legally acceptable the Narcotic Drug Law. In 2016, CBD • “cannabis, plant and resin, products (Roquette Pflister, M, 2019). Concerning was transferred to the list of prescription containing it, or those obtained from CBD products, MILDECA (Mission substances, without restriction to cannabis, plant or resin”; and, interministérielle de lutte contre les any strength, leading to necessary

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prescriptions for CBD products with a The Italian Competent Authority apply for assessment of their product medical claim. has the only licence to grow medical by the Health Products Regulatory cannabis in . To ensure patient Authority (HPRA) for suitability and CBD and food: since CBD-containing demand on medical cannabis, Italy inclusion to Schedule 1 as a specific products or CBD were not used as food or ran an additional tender in July 2019. controlled drug. When accepted, food ingredients before May 15th,1997, Import licensees of medical cannabis prescription via a registered medical these products are defined as novel food, are now issued to companies from the consultant is possible for patients according to the Novel Food Regulation and . who failed to respond to standard ((EC) 2015/2283), implemented on treatments for the following medical January 1st, 2018. The Higher Regional The Italian Legislation differentiates conditions: spasticity associated with Court of Hamm/Germany had already between two different categories of multiple sclerosis, intractable nausea & decided in 2016 (21.06.2016, Az.: 4 products: vomiting associated with Res 51/16), that the precondition for and severe, refractory (treatment- marketing of cannabis-based products, • products containing THC (controlled resistant) epilepsy. Currently only like CBD-oil, is the cultivation of plants substance) are considered as three cannabis-based products have with a THC content below 0.2%, from medicinal products only. been accepted. As part of the MACP, certified seeds only, for the purpose the Health Service Executive (HSE) of commercial and scientific use. With • products containing CBD without will keep a central register to record this decision cannabis-based products THC, or THC at very low levels, data including enrolled prescribers, containing CBD, with a TCH content are considered cosmetics, food anonymised patient identifiers and below 0.2%, like CBD-oil, were not supplements or medical devices. the products prescribed / supplied. marketable in Germany. Two other court Only extracts derived from cannabis The MACP is running on a pilot base decisions prohibited marketing of CBD sativa seeds are allowed for this for five years; further information can products, as these products are either category. be found at: Government of Ireland, defined as novel food and as such need a Medical Cannabis Access Program. marketing authorisation (administrative Medical products are prescribed as court of Düsseldorf 2019, 27.09.2019 - magistral preparation (non-renewable CBD as a pure substance, e.g. 16 L 2333/19 and Hannover, 18.11.2019, medical prescription on a "named manufactured synthetically, does not fall 15 B 3035/19) or contained THC contents patient" basis) and are considered under the Misuse of Drug legislation. CBD which were higher than the legal limit of ‘off-label', needing in addition an products produced from hemp (cannabis 0.2% (administrative court of Gießen, 11. authorised consent by the patient. sativa) via cold-pressing are legally November 2019, 4 L 3254/19.GI). Marketing as food or food supplement accepted due to low quantities of THC; is admitted only for products containing however, health claims are not accepted The use of cannabis in cosmetics is traces of THC below 0.2 mg/kg. Decree when selling as food supplements (further regulated by entry 306 of Annex II to dated November 4th, 2019 established information: Food Safety Authority Regulation 1223/2008. Narcotic drug maximum levels of THC in food and of Ireland). Products containing CBD substances are excluded from use in food supplements. For food supplement extracted via CO2-extraction fall under the cosmetics, thereby excluding cannabis. the limit is of 0.2 mg/kg (as sum of (-) Novel Food Regulation (EC) 2015/2283 This restriction is not applicable to the -trans-Δ9-THC and non-active precursor and require a market authorisation. use of hemp seed oil or synthetically (Δ9-THCA-A and Δ9-THCA-B)). For food produced cannabidiol; see Cosmetic use, Law n. 242 dated December 2nd, Netherlands: Ingredients database (Cosing database), 2016 set a maximum THC concentration In 2001, the Office of Medical Cannabis but still excludes plant-derived canna- in cultivated cannabis, which is 0.2% was established as the concerned bidiol. and, in any case must not exceed authority controlling cultivation and 0.6%, applicable to varieties listed in delivery of cannabis for medical Italy: the Common Catalog of varieties of and scientific purposes. Cannabis Decree 309/90 is the Law on Narcotic agricultural plants, following Article 17 is defined as soft drug (list II) and Drugs (governing psychotropic drugs of the Directive 2002/53/EC. underlies the Dutch Narcotic Act. and substances, prevention, treatment, Cultivation of cannabis started with and rehabilitation of the related states of Ireland: a first licence in 2003 to Bedrocan. drug ). Psychotropic substances Cannabis is listed in Schedule 1 of In 2019, the Netherlands developed are defined and divided into four tables the Misuse of Drugs Regulations plans for licensing a second company according to Article 14; cannabis is listed 1988, as amended. In 2019, Ireland for cultivation of medical cannabis in Table II (Table II and Table IV provide implemented the Misuse of Drugs to overcome the shortage of medical for minor penalties). (Prescription and control of supply of cannabis, the product in Europe. cannabis for medical use) Regulations From November 2015, the Italian 2019, to facilitate import, prescription Cannabis-based products carrying a Competent Authority took the respon- and supply of cannabis-based products, medical claim fall under the Medicinal sibility of supervising all companies that meet the requirements of the Product Act. Products containing CBD registered for cultivation, manufacture, regulations under the Medical Cannabis in combination with THC fall under the use, marketing and sale of psychotropic Access Program (MACP). The first Opium Act and require a prescription, substances. stage of the MACP is for companies to while products containing pure CBD do www.ipimediaworld.com INTERNATIONAL PHARMACEUTICAL INDUSTRY 25 Regulatory & Marketplace

not fall under the Opium Act but still (AEMPS) bans controlled dispensing these products still require a Home need a prescription (CIBG, June 2019). of cannabis flos and cannabis extracts Office Controlled Drug licence. for medical use, although authorisation The Dutch law is working with for the cultivation of cannabis plants A CBPM is defined as a medicinal exceptions to the drug law leading to for medical and scientific purposes are product or substance used in the CBD-based products legal for marketing, granted. The national legal background preparation of a medicinal product, in case they fulfill the following on narcotic drugs is laid down in Law which contains cannabis, cannabis resin, prerequisites: 17/1967, of April 8, implementing the cannabinol or a cannabinol derivative regulation on narcotic drugs according and are unlicensed products prescribed a) the amount of THC does not to the provisions of the 1961 United on a “named patient” basis. Cannabidiol exceed 0.05% Nations Single Convention. AEMPS lists (CBD) in its pure form does not fall b) the product should not bear a companies which received a license under the control of the MDR 2001. medical claim for controlled cultivation of medical A CBD product with a medical claim c) maximum daily use is not more cannabis being either exported to needs a marketing authorisation from than 160 mg CBD per day. entities authorised in the country the Medicines and Healthcare products of destination or which have been Regulatory Agency (MHRA). Authority advice from the Medicines previously authorised by the AEMPS Evaluation Board or Netherlands food (Autorizaciones vigentes emitidas por Following the MDR 2001 update and consumer product safety authority la AEMPS para el cultivo de plants de and the resultant mix of licensed and regarding product categorisation is cannabis, 13. De agosto de 2019). The unlicensed status of such medicines recommended (van Weren M, 2019). only authorised product which is on in the UK, the National Institute of market in Spain is Sativex, approved Health and Care Excellence (NICE) Portugal: in 2010. Expectation for the launch of published a guideline on November Medical cannabis has been legal in Epidiolex is during 2020 (Kanaval S., 11th, 2019 which covers prescribing of Portugal since 2018, with Law No. 2019). cannabis-based medicinal products for 33/2018 of 18 July, establishing the specific conditions. The NICE committee legal framework for use, preparations Since Spain has a strong tradition determined that the initial prescription and substances for medical purposes, in establishing Cannabis Social Clubs of such a product must be made by a including prescription and dispensation (CSC), medicinal users may have access specialist medical practitioner who in connected to a licence to cannabis by joining a CSC (Sanchez, should also have a special interest in from the National Authority for 2018). Regarding quality and safety the condition being treated. Products Medicines and Health Products, this is still an unsatisfactory situation: covered by the guideline include: CBMPs Infarmed. Cultivation of cannabis is relevant analysis to ensure the absence as set out by the UK Government in the under state control, and permission via of pesticides and other residues are not 2018 regulations, licensed products a state licence is needed. carried out and the concentration of THC with CBD (Sativex) and nabilone, active ingredients is unknown. plant-derived cannabinoids such as pure Amendment of Law 33/2018 in 2018 CBD and synthetic compounds identical classified CBD for medical use only, Marketing of products containing in structure to naturally occurring leading to availability of CBD-based cannabidiol was stopped almost cannabinoids (e.g. dronabinol). products only per prescription. Import of immediately, with CBD being defined as a cannabis or CBD needs an import licence novel food by the Novel Food Regulation Regulation 2 of the MDR 2001 to be issued by Infarmed. ((EC) 2015/2283), implemented since allows that some products may be January 1st, 2018. Supervising authorities considered exempt from control, in CBD as food and food supplement of the food market stopped marketing of limited circumstances. To market a CBD has been banned since 2018, due to the CBD products in Spain already in 2018. product containing cannabinoids (e.g. Novel Food regulation. Spain is lacking a national regulation for THC), it must meet all three limbs of cannabis to be used as food. the exemption definition. These specify Cosmetic products are legally that the controlled drug should not be regulated by Regulation (EC) No United Kingdom: designed for usage as a narcotic drug, 1223/2009, consultancy no. 15/CD/ Cannabis is a Class B controlled drug the controlled drug cannot be recovered 2013, Decree-Law no. 189/2008, in the UK, listed in Schedule 1 of the by readily applicable means, and limits September 24th prohibiting the use MDR 2001 and in the Misuse of Drugs the maximal amount of each component of narcotic substances. Consultation Designation Order 2015. However, in of controlled drug to one milligram per with Infarmed is recommended for 2018 so-called ‘cannabis-based products product or preparation. classification before marketing of a for medicinal use in humans’ (CBPM) product containing CBD as a non- were included in Schedule 2 of MDR Concerning food products, the Food psychogenic substance. 2001, allowing specialised physicians Standards Agency (FSA) clearly stated: to legally prescribe them to patients “Businesses need to submit, and have Spain: with unmet clinical needs without the fully validated, novel food authorisation Spain is still missing a legal regulation on pre-requirement for a Home Office applications by 31 March 2021. After this medical cannabis. The Spanish Agency licence. Nevertheless, companies date, only products for which the EFSA for Medicines and Medical Products wishing to supply, manufacture, etc. has a valid application will be allowed

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to remain on the market.” www.gesetze-im-internet.de/btmg_ 12. United Kingdom, legislation on narcotic 1981/ drugs: http://www.legislation.gov.uk/ Manufacturers of cannabis-based 5. Novel Food Regulation: https://eur-lex. uksi/2018/1055/made europa.eu/legal-content/EN/TXT/?uri= products should take the chance for CELEX:32015R2283 legal advice on product classification 6. Cosmetic Regulation N (EC) No 1223/ with the respective national authorities, 2009: https://ec.europa.eu/health/ on safe time to market, and to have their sites/health/files/endocrine_ products compliant with the individual disruptors/docs/cosmetic_1223_2009_ Barbara national legislations. regulation_en.pdf 7. Cosmetic ingredients database: https:// Siebertz ec.europa.eu/growth/sectors/ REFERENCES cosmetics/cosing_en Barbara Siebertz, Dr. rer. nat. 8. Italy, Decree 309/90: http://www.uni- graduated at the Albertus-Magnus- 1. International Control Board, cri.it/min.san.bollettino/altre/decree University of Cologne with a diploma Report 2018: https://www.incb.org/ 30990E.PDF incb/en/publications/annual-reports/ degree in Biology. She received her 9. Ireland, HPRA Legislaton: http://www. PHD and worked at the Max-Planck- annual-report-2018.html hpra.ie/ Institute for Plant Breeding Research 2. Code de la santé publique:https:// homepage/controlled-substances/ www.legifrance.gouv.fr/ controlled-substances/legislation in Cologne up to 1992. The topic of affichCodeArticle.do?idArticle= 10. Portugal, Law No. 33/2018 of 18 July: her thesis was the elucidation of a LEGIARTI000027516352&cidTexte= https://mgra.pt/en/ molecular regulatory mechanism LEGITEXT000006072665&dateTexte= legislacao_07-2018/ in wounded plants. In 1995 she 20130608 11. Spain, narcotic drug law: https://pharma- joined Sandoz Pharma in Basel in 3. Franceinfo: https://www.francetvinfo.fr/ boardroom.com/legal-articles/ the Department of Immunology, sante/drogue-/cannabis/ cannabinoid-drugs-medicinal- followed by an additional time of 4. Narcotic Drug Law, Germany: https:// cannabis-and-opioid-drugs-spain/ research at the Rheinisch-Westfälische Technische Hochschule in Aachen in the department of Pathological Biochemistry. In 1998 she joined Biofrontera Pharmaceuticals GmbH and started her activities in Regulatory Affairs activities. From 2013–2015 she was engaged in Regulatory Affairs studies at the University of Bonn and joined Sträter Life Science GmbH in 2015. Since 2018, she has worked as a consultant at PharmaLex and holds the position as Senior Manager, Regulatory Affairs and Special Projects.

Ute Hegener

Ute Hegener, Dipl. Biol. graduated at Heinrich-Heine-University of Düsseldorf with a diploma degree in Biology in the subject of elucidation of plant secondary metabolism by molecular biology methods. In 2003 she started her professional career with the development of a pharmaceutical wholesale company in Turkey for phytopharmaceutical products. In 2004 she joined Janssen-Cilag GmbH were she held different positions before starting in the Regulatory Affairs department at Janssen-Cilag GmbH. She then joined Axcount Generika (axicorp) GmbH in 2009, where she led the Regulatory, Quality Assurance and Scientific Affairs department until 2016. In her current position at PharmaLex she holds the position of Director, Regulatory Affairs.

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