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Presentation: Medicinal cannabis evidence for efficacy clinical guidance development

TGA presentations: Industry information and consultation sessions on medicinal cannabis - Adelaide and Brisbane - July 2017

12 September 2017

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Presentation

  • Presented by: Tim Greenaway
  • Presented at: Industry information and consultation sessions on medicinal cannabis, Adelaide and Brisbane
  • Presentation date: July 2017
  • Presentation summary: Presentation providing an overview of the development of clinical guidance documents for the medicinal use of cannabis.

Transcript

Medicinal Cannabis Evidence for Efficacy Clinical Guidance Development

Tim Greenaway MBBS, FRACP, PhD, FAMA
Chief Medical Adviser
Health Products Regulation Group

Industry information and consultation sessions on medicinal cannabis, Adelaide and Brisbane, July 2017

Slide 1 - History

  • Use of cannabis as medicine is thousands of years old
  • Described in Chinese pharmacopeia Shennong Bencaojing (c 100 CE)
  • Used as an anaesthetic by Chinese surgeon Hua Tuo (c 140-208 CE)
  • Chinese term for anaesthesia means "cannabis intoxication"
  • Cannabis is one of the 50 fundamental herbs in traditional Chinese medicine

Slide 2 - However…

  • Cannabis contains >60 pharmacologically active cannabinoids
  • Usual pharmacokinetic, pharmacodynamic, bioavailability and toxicology studies lacking
  • GMP variable
  • Non-standardisation of extracts and dosage
  • Potential for harm, addiction and abuse

Slide 3 - Australian Advisory Council on the Medicinal Use of Cannabis and clinical review of evidence

  • Established in 2016
  • Chaired by Professor Jim Angus
  • To assist the Council, States and Territories and clinicians, DoH has commissioned academics from the Universities of NSW, Sydney and Queensland to review the evidence for the use of cannabinoids in palliative care, epilepsy, multiple sclerosis, chemotherapy-induced nausea and vomiting and chronic pain.

Slide 4 - Review activity and timelines

  1. October 2016-February 2017:
    • Analysis of critical reviews of evidence (5 conditions)
    • Review of existing clinical guidance documents and guideline development approaches
  2. February 2017:
    • Agreement on remaining systematic reviews to conduct
  3. Remainder 2017:
    • Conduct & publication of remaining systematic reviews
    • Drafts of clinical guidance for consultation

Slide 5 - Review team

  • Professor Louisa Degenhardt
  • Professor Michael Farrell
  • Professor Wayne Hall
  • Dr Megan Weier
  • Dr Suzanne Nielsen
  • Professor Jan Copeland
  • Professor Nicholas Buckley
  • Clinical experts:
    • Epilepsy - A/Professor Geoffrey Herkes
    • Palliative care - Professor Meera Agar; A/Professor Melanie Lovell (and later Professor Martin Meucke)
    • Pain - Dr Bridin Murnion
    • Nausea and vomiting - Professor Meera Agar
    • Multiple sclerosis - Dr John Pollard

Slide 6 - Literature search (1)

  • Multiple databases searched using specific search terms
    • Search strategy guided by specialist Librarian
  • Review protocols all registered to Prospero during initial search or early data extraction phase
  • Systematic reviews:
    • Priority to randomised controlled trials conducted since 1980
    • Also included observational studies, e.g. case reports, retrospective chart reviews, self-report surveys

Slide 7 - Literature search (2)

  • Two reviewers independently examined titles and abstracts for relevance, using Covidence Software
  • Relevant articles were obtained in full, and independently assessed by two reviewers for suitability for inclusion
  • Reasons for exclusion were documented in Covidence
  • Disagreements addressed and consensus reached

Slide 8 - Data assessment and extraction (1)

  • Two independent reviewers for all extraction
  • Cochrane Risk of Bias (RoB) tool
    • Original tool used for randomised trials - classified as low, medium or high risk of bias
    • Revised tool used for non-randomised studies - classified as low, moderate, serious or critical risk, or no information
  • GRADE methodological quality
    • Quality of empirical studies
  • Details of authors' disclosed funding and conflicts of interest reviewed

Slide 9 - Data assessment and extraction (2)

  • Study summary
    • Author, aims, publication type, study design, years of study, conditions examined, types of cannabinoids, risk of bias rating (randomised or non-randomised),GRADE rating, cannabinoid place on therapeutic hierarchy, funding and COIs
  • Intervention details
    • Conditions examined, age and gender range of participants, treatment duration, comparators used, cannabinoid used and dosage, pharmaceutical grading
  • Outcome
    • Outcomes measured as identified in review protocol (dichotomous or continuous outcome variables), comparator outcomes (if available), withdrawals, adverse events

Slide 10 - Findings

  • Epilepsy
  • Palliative Care

Slide 11 - Epilepsy

  • Study-level search - 383 articles
    • Clinical trials and observational studies
    • 314 articles excluded
    • 62 articles full text screening
    • 22 studies extracted
      • 5 randomised controlled trials (3 studies for meta-analysis)
      • 4 non-randomised clinical trials
      • 13 observational or self-report studies

Slide 12 - Outcomes - Epilepsy

  • Complete seizure freedom
  • 50% or greater reduction in seizure frequency (responder rate)
  • Quality of life outcomes
  • Withdrawals - adverse events or any reason
  • Adverse events
  • Serious adverse events

Slide 13

Study type N Cannabinoid examined (N) Pharmaceutical grade product (N) Comparator (N) GRADE range
RCT 5 CBD (3) Yes (2) No (1) Not stated (2) Placebo (5) 2-4
Open label clinical trial 4 CBD (4) Yes (4) None (4) 3
Observational 9 CBD (4); cannabis sativa (2); THC (2); CBD:THC (3) Yes (2); No (3); Not stated (2) None (100) 1-2
Self-report 4 CBD:THC (1); CBD only (2); Not reported (1) No (100) None (100) 1

GRADE scores:

  • 4 = high
  • 3 = moderate
  • 2 = low
  • 1/0 = very low

Slide 14 - Products and doses

Cannabinoid Commercial or pharma product names Dose range Delivery form and method
CBD Epidiolex; Rheem Oil RCT: 20mg/kg/day Observational: 2-50mg/kg/day Oral - capsule or oil
CBD:THC Charlotte's Web 1-28mg CBD/kg/day: 0.1-0.7 mg THC/kg/day Oral - oil
THC   0.07-0.14mg/kg/day Oral - oil or tincture
Cannabis sativa   0.5-8.0g/day Smoked, vaporised or drunk

Slide 15 - Complete seizure freedom

Studies Participants Pooled relative risk [95% CI] I2 Non-randomised studies Non-randomised participants Non-randomised studies pooled estimate [95%CI] I2
3 307 8.38 [2.02; 34.69]; p = 0.003 0.0 8 523 10% [5;16]; p =0.00 71.8

Slide 16 - 50% or greater reduction in seizure frequency

Studies Participants Pooled relative risk [95% CI] I2 Non-randomised studies Non-randomised participants Non-randomised studies pooled estimate [95%CI] I2
2 290 1.74 [1.24; 2.44]; p = 0.001 0.0 14 780 56% [40;72]; p = 0.00 94.9

Slide 17 - Quality of Life

Studies Participants Pooled relative risk [95% CI] I2 Non-randomised studies Non-randomised participants Non-randomised studies pooled estimate [95%CI] I2
2 274 1.73 [1.33; 2.26]; p = 0.000 0.0 8 214 38% [28;48]; p = 0.00 92.8

Slide 18 - Withdrawals

Studies Participants Pooled relative risk [95% CI] I2 Non-randomised studies Non-randomised participants Non-randomised studies pooled estimate [95%CI] I2
3 307 5.23 [1.87; 14.62]; p = .002 65.9 3 311 8% [2;12]; p = 0.00 0.0

Slide 19 - Adverse Events

Studies Participants Pooled relative risk [95% CI] I2 Non-randomised studies Non-randomised participants Non-randomised studies pooled estimate [95%CI] I2
3 307 1.28 [1.13; 1.44]; p = .001 0.0 10 504 46% [28;65]; p = 0.00 95.1

Slide 20 - Conclusions - Epilepsy

  • Limited RCTs indicate there may be therapeutic benefit of CBD in treating epilepsy and seizures – both seizure freedom and significant reduction in seizures
  • CBD relatively well tolerated; evidence for THC and CBD:THC products are all observational
  • Observational trials are positive, but many limited by lack of control and data on dosing
  • Safety issues: dosing, product concentrations, interactions with other medications, non-medically supervised delivery

Slide 21 - Original Article - Trial of Cannabidiol for drug-resistant seizures in the Dravet Syndrome

Orrin Devinsky, M.D., J. Helen Cross, Ph.D., F.R.C.P.C.H., Linda Laux, M.D., Eric Marsh, M.D., Ian Miller, M.D., Rima Nabbout, M.D., Ingrid E. Scheffer, M.B., B.S., Ph.D., Elizabeth A. Thiele, M.D., Ph.D., Stephen Wright, M.D., for the Cannabidiol in Dravet Syndrome Study Group.

N Engl J Med
Volume 376(21):2011-2020
May 25, 2017

Slide 22 - Screening, randomization, treatment period, and taper period

Slide 23 - Key baseline characteristics of the trial groups

Slide 24 - Primary efficacy end point of percentage change in convulsive-seizure frequency in each trial group

Slide 25 - Summary of Secondary End-Point Results during the Treatment Period (Intention-to-Treat Analysis Set)

Slide 26 - Adverse events occurring with a frequency of greater than 10% in either trial group, according to system organ class and preferred term

Slide 27 - Cannabidiol for drug-resistant seizures in Dravet Syndrome – Conclusions

Among children and young adults with the Dravet syndrome, a developmental disorder that is associated with treatment-resistant seizures, cannabidiol:

  • reduced the frequency of convulsive seizures, but
  • caused sleepiness and elevated liver enzymes in some patients

Slide 28 - Palliative Care

  • Insufficient quality systematic reviews or meta-analyses to conduct review of reviews
  • One recent systematic review and meta-analysis by Meucke et al. (2016)
    • Contacted author, agreement to update study-level review
    • No new studies identified since earlier review search
    • 9 studies, examining advanced tumour illness (N=5), HIV (N=3), and Alzheimer’s disease (N=1)

Slide 29 - Outcomes: Palliative Care

  • Change in pain intensity
  • Percentage of patients reporting a 30% reduction in pain
  • Other analgesic use
  • Functional status; physical functioning
  • Functional status; emotional functioning
  • Quality of life: Participant ratings of global improvements and satisfaction (including weight loss or gain)
  • Improvements in quality of sleep
  • Digestive discomfort measures (nausea, vomiting, appetite)
  • Adverse events

Slide 30

Study type N Cannabinoid examined (N) Pharmaceutical grade product (N) Comparator (N) GRADE range
RCT 6 THC (4); Dronabinol (2); THC:CBD (1); Nabiximols (1); OCE* (1) Yes (2) No (4) Placebo (6) 2-3
Double-blind randomized trial 1 Dronabinol (1) No (1) Active comparator (1); Placebo (1) 3
Cross-over study 1 Dronabinol (1)

Yes (1)

Placebo (1) 2
Randomized open-label study 1 Dronabinol (1)

Yes (1)

Active comparator (1) 1

GRADE scores:

  • 4 = high
  • 3 = moderate
  • 2 = low
  • 1/0 = very low

Slide 31 - >30% Pain reduction

Condition N Studies Effect estimate Author conclusion on effect
Cancer 2 0.07 [-0.0; 0.16]; p = 0.07 Trend towards favouring cannabinoids

Slide 32 - Appetite

Condition N Studies Effect estimate Author conclusion on effect
HIV/AIDS 1 0.57 [0.11; 1.03] p = 0.02 Cannabinoids significantly better than cannabinoids
Cancer 3 0.81 [-1.14; 2.75] p = 0.42 Not significantly different to placebo
Total 4 0.65 [-0.82; 2.12] p = 0.39 Not significantly different to placebo

Slide 33 - Nausea and Vomiting

Condition N Studies Effect estimate Author conclusion on effect
Cancer 1 0.21 [-0.10; 0.52] p = 0.19 Not significantly different to placebo
HIV/AIDS 1 0.20 [-0.15; 0.54] p = 0.26 Not significantly different to placebo
Total 2 0.20 [-0.03; 0.44] p = 0.09 Mixed, favours cannabinoids

Slide 34 - Conclusions: Palliative care

  • Low level of evidence for use of cannabinoids in cancer
    • Trend towards benefit in reducing pain and depressed mood
    • Megestrol acetate >Dronabinol in
      • increasing appetite, weight gain, and health-related quality of life
      • significantly better tolerability
  • Low level of evidence supporting use of cannabis in HIV palliative care
    • Greater weight gain and increase in appetite
    • Trend toward more symptoms of mental illness
  • Low level of evidence for use of cannabis in Alzheimer's disease
    • More weight gain and less negative affect for Dronabinol
    • Cross-over trials

Slide 35 - Aims of guidance documents

  • Overview of current evidence for use (based on review)
  • Working group consultation
  • Grade strength and quality of evidence
  • International approaches to condition
  • Products used and suggested dosing
  • Expected side effects, tolerance, and safety
  • Auditing outcomes

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