SOR/2016-106: Regulations Amending the Food and Drug Regulations (Parts G and J — Lefetamine, AH-7921, MT-45 and W-18)
REGISTRATION OF FEDERAL REGULATION - VIA OIC DATABASE, PRIOR TO PART II OF THE GAZETTE
May 20, 2016
REGULATORY IMPACT ANALYSIS STATEMENT (This statement is not part of the Regulations and the Order.) Issues The non-medical use of pharmaceuticals such as opioid analgesics has emerged as one of North America’s leading public health and safety concerns. Canadians are the second highest per capita users of prescription opioid drugs in the world. Opioids are a highly addictive class of drugs and ava... (Click for more)
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Published on May 20, 2016
SOR/2016-106: Regulations Amending the Food and Drug Regulations (Parts G and J — Lefetamine, AH-7921, MT-45 and W-18)
REGULATORY IMPACT ANALYSIS STATEMENT (This statement is not part of the Regulations and the Order.) Issues The non-medical use of pharmaceuticals such as opioid analgesics has emerged as one of North America’s leading public health and safety concerns. Canadians are the second highest per capita users of prescription opioid drugs in the world. Opioids are a highly addictive class of drugs and available data shows an overall high degree of harms, intoxication and deaths attributed to opioids. Although most opioids are listed in Schedule I to the Controlled Drugs and Substances Act (CDSA), the synthetic opioids AH-7921, MT-45 and W-18 are not currently controlled under the CDSA. They have no known use apart from scientific research and are considered new psychoactive substances (NPS), also known by terms such as “designer drugs” or “research chemicals.” AH-7921 Reported adverse effects from AH-7921 include hypertension, tachycardia and seizures. (see footnote 2) Fifteen deaths have been associated with AH-7921 in Europe, one in the United States (U.S.) (see footnote 3) and one in Canada. (see footnote 4) In March 2015, the United Nations Commission on Narcotic Drugs (CND) voted in favour of controlling AH-7921, under Schedule I to the Single Convention on Narcotic Drugs, 1961 (the 1961 Convention). As a signatory, Canada is obliged to impose controls on this substance. MT-45 The clinical symptoms reported from non-fatal intoxications of MT-45 include respiratory depression, unconsciousness, paraesthesia, balance and vision disturbances. Persistent hearing loss has also been associated with its use. (see footnote 5) Twenty-eight deaths have been associated with MT-45 in Europe and two deaths in the U.S. (see footnote 6) In March 2016, the CND voted in favour of controlling MT-45 under Schedule I to the 1961 Convention. As with AH-7921, Canada is obliged to impose controls on this substance. W-18 Available evidence suggests that W-18 is an extremely potent analgesic, with one pain test on mice showing W-18 to be potentially up to 10 000 times more active an analgesic than morphine. (see footnote 7) This suggests a potential severe risk for overdose. Risks associated with AH-7921, MT-45 and W-18 can be further elevated because of a lack of data about toxicity, bioavailability, tolerance, half-life and onset of effects, which can lead users to rely on self-reported experiences and other information from user web forums, which may be inaccurate. These substances have similar abuse potential to other opioids already controlled under the CDSA, but they are not currently subject to the same controls. Isomers and derivatives of lefetamine The chemical structure of MT-45 is related to that of lefetamine, a stimulant with analgesic effects. Lefetamine combines amphetamine-like properties with opioid-like effects, but it has lower dependence potential or abuse liability compared to other psychotropic substances. As a result, lefetamine is controlled under Schedule III to the CDSA and Part I of the schedule to Part G of the Food and Drug Regulations (FDR). Lefetamine was scheduled in 2003, in accordance with the requirements of the United Nations (UN) Convention on Psychotropic Substances, 1971. In order to ensure that the isomers, derivatives and salts of isomers and derivatives of lefetamine are captured under Schedule III to the CDSA and are not unintentionally captured under Schedule I as analogues of MT-45, the entry for lefetamine under Schedule III must be amended to include its isomers, derivatives and salts of its isomers and derivatives, and these substances must be specifically excluded under the entry for MT-45 in Schedule I. Background The CDSA provides a legislative framework for the control of substances that can alter mental processes and that may cause harm to the health of an individual or to society when diverted or misused. Currently, over 300 such substances are expressly listed in schedules I to IV to the CDSA. AH-7921 AH-7921 is a synthetic opioid developed in 1974 as a potential analgesic, but never marketed commercially. Animal research indicates that it is comparable to morphine in terms of pain-relief potency and withdrawal effects, (see footnote 8) but it has stronger effects on respiratory depression. In 2012, AH-7921 appeared on the recreational drug market internationally and in Canada, promoted by internet retailers as a “research chemical.” Although Health Canada has not identified any Canadian businesses currently supplying AH-7921 to the Canadian market and has not found the substance offered on retail Web sites based in Canada, it is available to Canadians through international internet retailers. MT-45 MT-45 is a synthetic opioid developed in the mid-1970s as part of a research project aimed at developing compounds with analgesic, anti-tussive and anti-inflammatory effects. Animal research indicates that MT-45 is comparable to morphine in terms of pain-relief and withdrawal effects. However, studies suggest that MT-45 preparations are more toxic than morphine. MT-45 began to be marketed as a “research chemical” and used recreationally in Europe in 2013 and in Canada in 2014. Diphenidine (DEP), methoxphenidine (MXP), ephenidine (NEDPA) and isophenidine (NPDPA) are analogues of MT-45 and form part of a class of dissociative drugs called diarylethylamines. (see footnote 9) DEP and MXP were first made available for sale on Canadian Web sites in 2014 and NEDPA, in 2015. MT-45, DEP, MXP and NEDPA are currently sold in Canada. Health Canada has identified four Canadian chemical research and distribution companies that sell one or more of these substances. Of these four companies only one is currently licensed to conduct activities (e.g. sell, import, export) with controlled substances in Canada. W-18 Another synthetic opioid, W-18, was developed in the early 1980s. Although initially developed for its analgesic potential, there are no published studies or case reports regarding legitimate uses for W-18. W-18 was found in samples seized by Canadian law enforcement authorities in 2015 that included counterfeit tablets that had W-18 as the only active ingredient, but were made to appear like prescription oxycodone tablets. W-18 is currently available in Canada. Health Canada has identified one Canadian company that sells W-18 for research purposes as part of its overall product catalogue. W-18 is also available to Canadians through international internet retailers. In 2014, W-18 was added to the European Monitoring Centre for Drugs and Drug Addiction’s list of NPS which highlights substances that may pose a public health threat and are comparable to substances controlled internationally under the UN drug control conventions. Objective The objective of these scheduling amendments is to protect the health and safety of Canadians by imposing controls on AH-7921, MT-45, W-18 and related substances, and also to fulfill Canada’s international obligations to control AH-7921 and MT-45 under the 1961 Convention. Description The Order The Order will add new entries to Schedule I to the CDSA for AH-7921 (and its salts, isomers and salts of isomers), as well as for MT-45 and W-18 (and their salts, derivatives, isomers, analogues, and salts of derivatives, isomers and analogues). These related substances are also known to have psychoactive effects so they are being scheduled along with their parent substance. In the interest of clarity, four analogues of MT-45 (DEP, MXP, NEDPA and NPDPA) will also be specifically listed under the entry for MT-45. The Order will also add the isomers, derivatives and salts of isomers and derivatives of lefetamine to Schedule III to the CDSA, where lefetamine and its salts are already controlled, and specifically exclude these substances under the entry for MT-45 in Schedule I to the CDSA. This will have the effect of ensuring that these substances are not unintentionally captured under the entry for MT-45 in Schedule I. For substances listed in Schedule I and Schedule III to the CDSA, the Act prohibits activities such as possession, production, trafficking, possession for purpose of trafficking, importation, exportation and possession for the purpose of exporting these substances, unless authorized under regulations or by an exemption under the CDSA. The Regulations The Regulations add AH-7921 (and its salts, isomers and salts of isomers) and MT-45 and W-18 (and their salts, derivatives, isomers, analogues, and salts of derivatives, isomers and analogues) to Part I of the schedule to Part J of the FDR to allow for research uses as well as the manufacture and sale of test kits containing these substances. DEP, MXP, NEDPA and NPDPA will also be specifically listed under the entry for MT-45 in Part I of the schedule to Part J of the FDR. The Regulations will also add the isomers, derivatives and salts of isomers and derivatives of lefetamine to Part I of the schedule to Part G of the FDR. This will allow for activities with these substances in accordance with the regulatory requirements. Persons intending to conduct certain activities (e.g. selling, importing or exporting) with AH-7921, MT-45, W-18 or their related substances must apply for a licence or for an amendment to their existing licence to obtain authorization to conduct activities with these substances under Part J of the FDR, subject to certain exceptions. In addition, persons who have a licence must obtain an import and/or export permit if they intend to import and/or export these substances. Researchers affiliated with institutions engaged in research on drugs intending to use AH-7921, MT-45, W-18 or their related substances for research purposes must, depending on their circumstances, obtain an authorization from Health Canada under Part J of the FDR, become a licensed dealer under Part J of the FDR, or obtain an exemption under the CDSA, to obtain, possess and use these substances. “One-for-One” Rule These amendments may result in administrative costs to four Canadian businesses, should they wish to continue selling one or more of these substances. The company which is already a licensed dealer would need to apply for an amendment to its existing licence (one hour to complete), while the remaining three companies would need to apply for a new licence (approximately three hours to complete). These businesses may also incur additional administrative costs associated with submitting permit applications (30 minutes per application) if they decide to import or export these substances. Although the number of import/export permits varies by company, a conservative approach has been taken and it is assumed that businesses may require up to as many as 20 permits per year. The administrative costs are calculated using an average cost of $41.60 per hour, based on the assumption that an employee in the natural and applied sciences field would be filling out these forms. In accordance with the Red Tape Reduction Regulations, the administrative burden to businesses, assuming they will have activities with the substances, was calculated over 10 years and discounted using a rate of 7%. The present value (2012) of the total annualized incremental administrative cost to these businesses is estimated to be $1,715 or approximately $428 per business. Since the amendments will result in administrative burden, the “One-for-One” Rule applies and they are considered an “IN” under the Rule. The estimated cost will be offset by an equivalent reduction in the administrative credits available within the health portfolio. Small business lens Four Canadian chemical companies have been identified as selling one or more of the synthetic opioids, MT-45 or W-18, or their analogues, one of which is a small business. In order to meet the compliance and administrative requirements, the total incremental cost over 10 years in present value for these four stakeholders is estimated to be $147,672. As this cost is under one million dollars annually, the small business lens does not apply. Nevertheless, given the principles of the small business lens, Health Canada has considered whether any flexibility could be provided. However, administrative activities such as applying for a licence and/or import/export permits, submitting criminal record checks, establishing proper education credentials of personnel responsible for supervising the activities with controlled substances, and record keeping are essential for the proper administration of the regulatory regime. Compliance actions such as licence application/renewal and the installation of proper physical security measures for controlled substances are also essential for public security and health. Therefore, providing any flexibility in terms of reductions in these requirements would weaken the regulatory regime and could negatively impact public health. As a result, no flexible option is proposed. Consultation Health Canada published two separate Notice to Interested Parties (NTIP) in the Canada Gazette, Part I, to notify stakeholders and the general public regarding these scheduling amendments. The NTIP (http://gazette.gc.ca/rp-pr/p1/2015/2015-08-01/html/notice-avis-eng.html#nb3) with respect to AH-7921 and MT-45 was published on August 1, 2015, and the NTIP (http://www.gazette.gc.ca/rp-pr/p1/2016/2016-02-13/html/notice-avis-eng.html#nl3) with respect to W-18 was published on February 13, 2016. There were five stakeholder responses as a result of these consultations. One stakeholder expressed concern that controlling AH-7921 and MT-45 might negatively affect legitimate research on these substances. In response, AH-7921, MT-45, W-18 and related substances are being added to Part I of the schedule to Part J of the FDR to allow access for legitimate research activities. Four stakeholders expressed support for the control of W-18 and related substances. World Trade Organization Technical Barriers to Trade notifications were also posted for AH-7921 and MT-45 in August 2015 and for W-18 in February 2016. No comments were received as a result of either of these notifications. Rationale AH-7921, MT-45 and W-18 are all synthetic opioids and are not known to be used for any legitimate industrial or medical purpose. Their pain-relief potency and withdrawal effects have been compared to morphine, a controlled substance under Schedule I to the CDSA. Based on user reports, many of the effects of these substances appear to resemble those of classic opioids. Reports indicate that these substances are being sold and used recreationally in Europe as well as the U.S. and Canada, as substitutes for controlled opioids. There are also reports of intoxications and deaths linked to these substances. Substantial risks are associated with these substances due to lack of data regarding toxicity, bioavailability, tolerance, half-life and onset of effects. Both AH-7921 and MT-45 have been added to Schedule I, one of the most restrictive schedules in the 1961 Convention. (see footnote 10) The main features of the control provisions that apply to substances in this schedule include the need for a licensing system, obligation to keep detailed record of any transactions with these substances and access limited to medical and scientific purposes. Adding AH-7921, MT-45, W-18 and related substances to Schedule I to the CDSA is intended to impose controls on these high risk opioids. Listing these substances to the schedule to Part J of the FDR ensures that access is possible for legitimate scientific and research uses. These amendments also allow Canada to meet its international obligations under the 1961 Convention. Costs These regulatory initiatives may result in costs to stakeholders (one licensed and three non-licensed businesses) in order to comply with the regulatory requirements. In the event that they want to continue activities with the scheduled substances, they would need to become licensed dealers or obtain an amendment to their existing licence. The non-licensed businesses would also incur associated incremental costs, including the costs to prepare the appropriate application package and to put in place adequate security measures, as per regulatory requirements. These costs would include paying fees, acquiring and installing security apparatus, if not already in place, and any additional monitoring costs. The approach that has been used to calculate overall costs reflects the maximum costs that could be incurred. For example, it assumes that all non-licensed businesses would seek to become licensed dealers and would have to complete all of the requirements outlined above in order to do so. It is estimated that the present value of the total costs of these amendments would amount to $147,672 over a 10-year period, using a 7% discount rate, or an annualized cost of $21,025. A search of scientific publications dating back to the early 1970s suggests that there is no recent or on-going research with respect to AH-7921, MT-45 or W-18 in Canada. Nevertheless, should there be research institutions that want to access these substances for research purposes, they could submit an application for authorization under Part J of the FDR. There would be a small administrative burden associated with such actions as completing the form and keeping records for a period of two years. This cost has not been estimated, because no impacted research institutions have been identified. No incremental cost is expected to be incurred by the government. Any contraventions of the CDSA and its regulations regarding AH-7921, MT-45 and W-18 would be dealt with through existing compliance activities of Health Canada and/or law enforcement activities. Benefits This scheduling initiative is expected to result in benefits to Canadians. The recreational use of these substances can result in a range of fatal and non-fatal negative health effects. The fact that these substances are currently accessible over the Internet poses health and safety risks to Canadians. Further, individuals may be tempted to experiment with these substances, mistakenly believing that they are safer than controlled opioids. Controlling these substances will also enable law enforcement agencies to take action against illicit activities involving these substances. Implementation, enforcement and service standards As part of the implementation of the amendments, Health Canada will notify stakeholders of the changes to schedules I and III to the CDSA and to the schedules to Part G and J of the FDR. Information will also be provided on Health Canada’s Web site. These regulatory amendments will come into force 180 days after the date of publication. This delay in coming into force will provide sufficient time for affected stakeholders to apply for a licence, licence amendment, authorization or exemption, as required. At that time, Health Canada will be responsible for authorizing activities with these substances and for monitoring compliance with regulatory requirements. Federal, provincial and local law enforcement agencies are responsible for taking enforcement action in response to contraventions of the CDSA. Under the CDSA, a range of penalties apply to the offences associated with the substances covered by this initiative. For certain offences associated with AH-7921, MT-45, W-18 and their related substances listed in Schedule I to the CDSA, there is a maximum penalty of life imprisonment (mandatory minimum penalties of one, two or three years may apply if certain conditions are met). For certain offences associated with lefetamine and related substances listed in Schedule III to the CDSA, there is a maximum penalty of up to 10 years of imprisonment if the offence is prosecuted by indictment or up to 18 months of imprisonment if the offence is prosecuted by summary conviction. No incremental cost is expected to be incurred by the government. There are no additional service standards other than those that already exist for issuing licences and permits under the CDSA. Contact Denis Arsenault Healthy Environments and Consumer Safety Branch Health Canada Main Statistics Canada Building 150 Tunney’s Pasture Driveway Ottawa, Ontario K1A 0K9 Email: OCS_regulatorypolicy-BSC_ [email protected] Footnote a S.C. 2015, c. 22, s. 4(1) Footnote b S.C. 1996, c. 19 Footnote 1 C.R.C., c. 870 Footnote 2 European Monitoring Centre for Drugs and Drug Addiction. AH-7921: Report on the risk assessment of AH-7921 in the framework of the Council Decision on new psychoactive substances. 2015. p. 8. Footnote 3 World Health Organization. AH-7921 Critical Review Report (Geneva, June 2014), p. 13-14. Footnote 4 The death occurred in Alberta in 2013. Although AH-7921 was detected in a second death in Canada in 2015, it was not identified as the cause of death. Information provided by the members of the Canadian Centre on Substance Abuse (CCSA)-led, Canadian Community Epidemiology Network on Drug Use (CCENDU) on February 25, 2015. Footnote 5 A. Helanger, M. Backberg and O. Beck. MT-45, a new psychoactive substance associated with hearing loss and unconsciousness. Clinical Toxicology (2014), 52, p. 902. Footnote 6 World Health Organization. MT-45 Critical Review Report (Geneva, November 2015), p. 14. Footnote 7 The comparison was based on a standard measure of analgesic action for morphine (0.0000037 mg/kg for W-18 versus 0.038 mg/kg for morphine). Footnote 8 Brittain RT, Kellett DN, Neat ML, Stables R. Proceedings: Anti-nociceptive effects in N-substituted cyclohexylmethylbenzamides. Br J Pharmacol 1973 Sep; 49(1):158P-9P. Footnote 9 User reports indicate strong dissociative effects with MXP and with DEP and have reported other symptoms including tachycardia, hyperthermia and hospitalization due to seizures. Footnote 10 Schedules of substances range from most restrictive to least restrictive, in this order: Schedule IV, Schedule I, Schedule II, Schedule III.
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