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Question
grace
The National Drugs and Poisons Scheduling Committe (NDPSC) have now recognised the therapeutic benefits of cannabinoids and scheduled a botanical extract of Cannabis sativa which includes the cannabinoids listed below as a new Schedule 8 entry in a buccal spray. (Sativex)
http://www.tga.gov.au/ndpsc/index.htm
Schedule 8 – New entry
NABIXIMOLS (botanical extract of Cannabis sativa which includes the following cannabinoids: tetrahydrocannabinol, cannabidiol, cannabinol, cannabigerol, cannabichromene, cannabidiolic acid, tetrahydrocannabinolic acid, tetrahydrocannabivarol, and cannabidivarol, where tetrahydrocannabinol and cannabidiol (in approximately equal proportions) comprise not less than 90 per cent of the total cannabinoid content) in a buccal spray for human therapeutic use.
Appendix D, Paragraph 3 – New entry
NABIXIMOLS.
Appendix K – New entry
National Drugs and Poisons Schedule Committee
Record of Reasons of Meeting 57 - October 2009
11. OTHER OUTSTANDING MATTERS FROM PREVIOUS MEETINGS
11.1 NABIXIMOLS – A SPECIFIC EXTRACT OF CANNABIS SATIVA
PURPOSE
The Committee considered the scheduling of nabiximols.
BACKGROUND
Cannabidiol (CBD) is a cannabinoid found in Cannabis sativa. CBD was reputed to have analgesic, anticonvulsant, muscle relaxant, anxiolytic, neuroprotective, anti-oxidant and anti-psychotic activity. CBD was not specifically scheduled.
Delta-9-tetrahydrocannabinol (THC) is the main psychoactive substance found in Cannabis sativa.
At the November 1994 meeting, the Committee agreed to a XXXXX recommendation to schedule THC for therapeutic use in Schedule 8, with additional controls through a listing in Appendix D, paragraph 3 i.e. requiring authorisation by the Secretary of the Department of Health and Ageing under section 19 of the Therapeutic Goods Act 1989.
At the February 1995 meeting, the Committee added an Appendix K
listing because of sedative effects. At the August 1995 meeting, the SUSDP references to delta-9-tetrahydrocannabinol were replaced with the International Non-proprietary Name ‘dronabinol’.
Nabiximols (a specific extract of Cannabis sativa)
In recent years, CBD has been under investigation, in combination with THC, for use as an adjunctive analgesic treatment in multiple sclerosis (MS). In 2005, Canadian authorities approved the marketing of XXXXX, a THC+CBD buccal spray for MS patients to alleviate neuropathic pain and spasticity.
At the February 2009 meeting, the Committee noted that there had been enquiries to jurisdictions regarding the availability of a THC+CBD preparation (XXXXX). The Committee noted that there had been approvals for THC+CBD through the TGA’s Special Access Scheme (SAS) but it had been difficult for jurisdictions to also approve access given the unclear scheduling status of CBD. The Committee decided to gazette consideration of CBD for therapeutic use for the June 2009 meeting (noting that the THC component was captured by the dronabinol Schedule 8 entry).
At the June 2009 meeting, the Committee noted that the THC+CBD formulation also had small amounts of other cannabinoids that were also likely to be captured by the Schedule 9 cannabis entry. Hence the problem that certain jurisdictions could not allow access to Schedule 9 substances for medical purposes, regardless of SAS approval, would remain.
Members agreed that it was appropriate to allow access to this specific THC+CBD preparation and suggested that a pragmatic approach would be to create a Schedule 8 entry that was specific to this formulation, noting that this would also remove any possibility of the entry allowing inappropriate access to cannabis-type substances.
Members therefore agreed to gazette for consideration at the October 2009 meeting a new Schedule 8 entry for this specific Cannabis sativa extract, together with a listing in Appendix D, paragraph 3.
Following the June 2009 meeting, it was established that the US Adopted Names Council had designated ‘nabiximols’ as the approved non-proprietary name for an extract of Cannabis sativa containing, as major components, THC+CBD, and as minorcomponents, related cannabinoids and non-cannabinoid components alpha- and trans- caryophyllenes i.e. the specific THC+CBD formulation considered appropriate for inclusion in Schedule 8 by the June 2009 meeting.
DISCUSSION - SUBMISSIONS
The Committee noted that no pre-meeting submissions were received.
June 2009 Minutes
The Committee recalled the following from Members’ discussion at the June 2009 meeting:
• Certain jurisdictions could not allow access to Schedule 9 substances for medical purposes. Therefore, in the absence of a Schedule 8 (or lower) listing, access could not be granted by these State and Territory health authorities.
• The Committee agreed that efficacy was a primary consideration, given that this treatment had yet to be assessed by the TGA. While overseas clinical trial data were reassuring, it was noted that no trials have taken place in Australia as yet. This may be partly due to the current Schedule 9 status of this therapy.
Members also recalled the following regarding findings by the UK’s Medicines and Healthcare products Regulatory Agency (MHRA):
• Partly evaluated nabiximols in 2007 but the application was withdrawn before the evaluation was complete. The MHRA, in a December 2007 Public Information Report, noted that the evidence of efficacy was not considered to be sufficient at the time. Key issues that the MHRA stated need to be resolved included:
- The magnitude of the estimated treatment effect on the self-reported measure of spasticity in trials was small in the overall patient population.
- The applicant had presented post-hoc analyses supporting an argument that non responders could be identified in a four week therapeutic trial, and that the mean treatment effect in the remaining patients who would continue to receive treatment, would be clinically significant. This approach was welcomed.
However, it had not been prospectively investigated whether the effect calculated in thepost-hoc analysis could be translated into a pre-specified meaningful benefit for the patient. There was a lack of clinical data investigating such conditions of use, as no therapeutic trial followed by exclusion of non-responders was used in the pivotal trials.
- Further clinical data were necessary to investigate the effectiveness of the
proposed four week therapeutic trial in identifying responders and excluding non- responders, and to clarify the magnitude and clinical relevance of the efficacy achieved in the subgroup of patients who continue to be treated with nabiximols following a successful therapeutic trial.
The pivotal clinical trial data should clarify the potential efficacy benefits in a subgroup of patients against the potential risks to a larger number of patients of a four week therapeutic trial of nabiximols.
- MS was a chronic disorder and there was a lack of evidence of maintenance of efficacy with long-term treatment.
- The pattern of CNS side effects such as sedation was highly suggestive that some unbinding was possible. This issue still needed to be considered in the overall evidence of efficacy. The smaller the differences between active and placebo, the greater was the concern that a relevant contribution of that apparent difference may not be real if a source of bias existed. If a compelling treatment effect could be shown it might be concluded that the possibility of unbinding might not represent a major concern.
Members additionally recalled the following from the June 2009 meeting regarding new 2009 studies announced by XXXXX:
• In February 2009, XXXXX announced positive results from a placebo-controlled randomized withdrawal study of nabiximols in patients with spasticity due to MS.
This study:
- was intended to assess the maintenance of spasticity relief in patients who remain on nabiximols versus those who switch to placebo;
- was performed following guidance from the MHRA and, according to XXXXX, provided evidence of long term efficacy;
- evaluated 36 MS patients with spasticity who had previously been taking
nabiximols on prescription where mean duration of prior nabiximols prescription use was 3.6 years;
- patients were randomized to nabiximols or placebo for 4 weeks in a double-blinded manner and patients were not permitted to adjust their dose;
- the prospectively defined primary efficacy endpoint - the time to treatment failure - was statistically significantly in favour (p=0.013);
- the difference between nabiximols and placebo was also significant for the patient global impression of change (p=0.017) and the carer functional-ability global impression of change (p=0.001) meaning that the carer recognised that the patient’s spasticity became worse when they stopped taking nabiximols – providing independent verification of the primary endpoint;
- there was no evidence of a withdrawal syndrome, despite a very prolonged period on the medicine and, overall, there was a similar frequency and severity of adverse events in both the nabiximols and placebo groups, with more than 85 per cent of such events being deemed mild or moderate.
• In March 2009, XXXXX announced preliminary results from a pivotal Phase III
double-blind randomised placebo-controlled study in patients with spasticity due to MS, who have achieved inadequate spasticity relief with existing therapies. This study:
- was requested by the MHRA in order to gain approval in this indication XXXXX;
- used an enriched design whereby 573 patients initially received nabiximols for 4 weeks in a single blind manner (Phase A), following which nabiximols responders (n=241) were randomized to continue on nabiximols or switch to placebo for a further 12 weeks in a double-blinded manner (Phase
and during the randomized period, patients were not permitted to adjust their dose;
- the prospectively defined primary efficacy endpoint of the study – the difference between the mean change in spasticity severity of nabiximols vs. placebo in Phase B - was highly statistically significantly in favour of nabiximols (p=0.0002);
- the difference between nabiximols and placebo was also significant for a number of secondary endpoints in that 74 per cent of nabiximols patients achieved an improvement of greater than 30 per cent in their spasticity score over the entire study versus 51 per cent on placebo (p=0.0003);
- in addition, statistically significant improvements were also seen in spasm frequency (p=0.005), sleep disturbance (p<0.0001), patient global impression of change (p=0.023), and physician global impression of change (p=0.005).
Members also recalled the following from pre-meeting submissions considered at the June 2009 meeting:
• XXXXX.
• XXXXX indicated that it had no objection to rescheduling CBD to Schedule 8.
Noted that such products were available in Canada, New Zealand and the United Kingdom as an adjunctive treatment for the symptomatic relief of neuropathic pain in adult patients suffering from MS as well as an adjunctive analgesic treatment in adult patients with advanced cancer. The submission reiterated that this combination increased clinical efficacy while reducing adverse effects (adverse effects were judged to be mild to moderate) and showed no evidence of tolerance. It was also noted that current scheduling was a barrier for jurisdictions to allow access through the SAS.
• XXXXX suggested that before rescheduling, the Committee needed to be certain there was convincing data available that supported the therapeutic efficacy of CBD.
It was noted that, presently, there was evidence for its role in neuropathic pain and other neurological disorders but most data appeared to be based on animal experiments. It was further suggested that, should down-scheduling occur, the use should be limited to classes of physicians who are authorised to prescribe it under State and Territory poisons legislation.
DISCUSSION – RELEVANT MATTERS UNDER 52E
The Committee agreed that the relevant matters under section 52E(1) included (
risks and benefits, (f) the need for access and (g) the potential for abuse.
Members acknowledged that there was a substantial degree of controversy regarding a therapeutic role for cannabis extracts. However, Members agreed that it was important to clarify that the matter before the Committee at this time was a proposal to consider appropriate scheduling for nabiximols. It was the regulator’s role, not the Committee’s, to approve particular products for use in Australia.
With regard to the current confusion as to whether jurisdictions could allow access to a nabiximols product that had been given a SAS approval, some Members reiterated that it was appropriate that this uncertainty be resolved so that jurisdictions could allow restricted access. The Committee generally agreed that this uncertainty could be clarified by creating a new parent entry in Schedule 8 for nabiximols.
Members also agreed, however, that this entry would need to be supplemented with additional controls.
A Member therefore proposed that, in addition to a Schedule 8 listing, and in line with current controls on dronabinol, nabiximols could be listed under Appendix D, paragraph 3 i.e. requiring authorisation by the Secretary of the Department of Health and Ageing under section 19 of the Therapeutic Goods Act 1989.
A Member opposed this suggestion, noting that a section 19 authorisation would require, amongst other conditions, approval by an ethics committee.
The Member contended that this would inappropriately add to the workload of such committees. Several Members were also concerned that an Appendix D, paragraph 3 listing would impact on possible clinical trials of nabiximols. The Committee generally agreed, however, that including
nabiximols in Appendix D, paragraph 3 was appropriate, particularly noting that:
• Without an Appendix D, paragraph 3 entry (i.e. just a Schedule 8 listing) the SAS access would include the broader access through SAS Category A (which does not require prior approval, just notification after the fact to supply to seriously ill patients). Members agreed that access without a prior approval process was inappropriate for nabiximols at this time.
• It was necessary to have safe guards in place to make it clear that the Committee was allowing tightly restricted access to nabiximols only, this was to in no way be extended to other cannabis extracts.
• An Appendix D, paragraph 3 listing did not prohibit use for clinical trials, but would permit use only by an authorised prescriber.
The Committee also noted that Appendix D, paragraph 3 was subject to an editorial consideration under item 21.1.4
A Member suggested that, in addition to an Appendix D, paragraph 3 entry, the Schedule 8 nabiximols entry needed to be more restrictive in order to remove any possibility of allowing inappropriate access to cannabis-type substances.
The Member argued that the entry should clearly state that nabiximols was a very specific combination of cannabinoids.
The Committee agreed that this was appropriate. The Committee also agreed that the Schedule 8 entry should limit the allowed presentation to buccal sprays as this would further reinforce the very restricted scope of this entry and would require any new presentation to be brought to the attention of the Committee.
The Committee also considered whether to limit the Schedule 8 entry to a single indication – MS. Several Members noted, however, that there were ongoing trials for using nabiximols for other indications, including the treatment of unresponsive cancer pain.
A Member noted that any issue of indications etc., would be addressed by the regulator through the conditions imposed by the Appendix D, paragraph 3 entry.
The Committee agreed to not restrict the Schedule 8 nabiximols entry by indication.
Members additionally agreed that it would be appropriate to include nabiximols in Appendix K due to sedating effects as noted in the Health Canada PI (www.doctordeluca.com/Library/AddictionMeds/SativexProductMonograph05.pdf).
Members also agreed that the SUSDP index would need to clarify to stakeholders that the scheduling of tetrahydrocannabinols and dronabinol may fall under the nabiximols entry.
RESOLUTION 2009/57 - 17
The Committee decided to create a new entry for nabiximols, including a list of cannabinoids present, in the form of a buccal spray for human therapeutic use, in Schedule 8. The Committee further decided:
• To create a new entry in Appendix D, paragraph 3 for nabiximols.
• To create a new entry in Appendix K for nabiximols.
• To create cross references in the index from tetrahydrocannabinols and dronabinol to nabiximols.
Schedule 8 – New entry
NABIXIMOLS (botanical extract of Cannabis sativa which includes the following cannabinoids: tetrahydrocannabinol, cannabidiol, cannabinol, cannabigerol, cannabichromene, cannabidiolic acid, tetrahydrocannabinolic acid, tetrahydrocannabivarol, and cannabidivarol, where tetrahydrocannabinol and cannabidiol (in approximately equal proportions) comprise not less than 90 per cent of the total cannabinoid content) in a buccal spray for human therapeutic use.
Appendix D, Paragraph 3 – New entry
NABIXIMOLS.
Appendix K – New entry
Nabiximols
NDPSC___Record_of_Reasons.pdf
NDPSC___Outcome_of_October_Meeting.pdf
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