MEMORANDUM 29
Submitted by G W Pharmaceuticals Plc
(GW)
1. SUMMARY
1.1 GW Pharmaceuticals Plc (GW) is the company
licensed by the Home Office to conduct a unique pharmaceutical
research and development programme into the medicinal uses of
cannabis.
1.2 GW is currently conducting Phase III
clinical trials with a view to developing a portfolio of non-smoked,
cannabis-based prescription medicines for the treatment of a range
of conditions including the following:
— Peripheral neuropathy (Diabetes /
AIDS)
— Inflammatory bowel diseases
— Psychotic disorders (Schizophrenia)
— Epilepsy/movement disorders
1.3 GW produces natural whole plant extracts
from specific cannabis varieties and incorporates them into advanced
drug delivery technologies, such as sprays and inhalers. No synthetic
cannabinoids are used.
1.4 Government policy is that if these trials
are successful, and they lead to a medical preparation which is
approved by the Medicines Control Agency (MCA), the Government
is willing to amend the Misuse of Drugs Regulations to allow the
prescribing of such a medicine.
1.5 GW hopes to be in a position to submit
a confident application for regulatory approval to the MCA in
2003 with a view, subject to approval by the MCA, to the first
cannabis-based medicine being available to patients on prescription
shortly thereafter.
1.6 GW believes this approach represents
the best solution for patients likely to benefit from the medicinal
properties of cannabis but who wish to take a medicine approved
by the MCA on the grounds of quality, safety and efficacy.
1.7 GW believes that many patients will
wish to use a medicine which is legally prescribed, does not require
smoking, is of guaranteed quality and is available from their
doctor with medical supervision.
2. THE
CURRENT LEGAL
POSITION OF
CANNABIS-BASED
MEDICINES
2.1 In evidence to the House of Lords Select
Committee on Medicinal Cannabis in February 2001, the Home Office
set out the Government's policy on the medicinal use of cannabis
as follows: "If the clinical trials into cannabis are successful
and they do lead to a medical preparation which is approved by
the Medicines Control Agency, the Government is absolutely clear
that we are willing to amend the Misuse of Drugs Regulations to
allow the prescribing of such medicine . . . The changes could
then be made swiftly, by way of secondary legislation subject
to negative resolution, and would not be constrained by our obligations
under the UN Convention". (Pages 17 and 28, 2nd Report, Select
Committee on Science & Technology: "Therapeutic uses
of cannabis)".
2.2 In the same report Charles Clarke, MP
and Minister of State at the Home Office goes on to say, "It
is the medicine which would be made legal rather than general
use of cannabis, even by those who are affected by particular
conditions which they are seeking to resolve".
3. GW PHARMACEUTICALS
PLC
3.1 GW Pharmaceuticals (GW) was founded
in 1998 and listed on the Alternative Investment Market (AIM)
in June 2001. GW develops non-smoked prescription cannabis-based
medicines under Home Office licence for patients with Multiple
Sclerosis (MS), Spinal Cord Injury, Rheumatoid Arthritis, Peripheral
Neuropathy, Cancer Pain and other severe medical conditions for
which cannabis is believed to be beneficial.
3.2 GW is a full service pharmaceutical
company and as such maintains control over all aspects of the
development process: botanical research, cultivation, extraction,
formulation into drug delivery technologies, clinical trials and
regulatory affairs.
4. THE
CANNABINOIDS
Cannabinoids are a group of molecules found
only in the cannabis plant and the therapeutic effects reported
by patients who use cannabis are believed to result from the interaction
of the cannabinoids. Various cannabinoids have been shown to have
analgesic, anti-spasmodic, anti-convulsant, anti-tremor, anti-psychotic,
anti-inflammatory, anti-oxidant, anti-emetic and appetite-stimulant
properties and research is ongoing into neuroprotective and immunomodulatory
effects.
5. GW'S
CANNABIS-BASED
MEDICINES
5.1 To date GW has focused on two principal
cannabinoids: delta 9 Tetrahydrocannabinol (THC) and Cannabidiol
(CBD). A range of cannabis varieties have been selectively bred
to exhibit different ratios of these two cannabinoids because,
as GW's clinical trials have shown, different ratios of cannabinoids
have important different therapeutic benefits.
5.2 The cannabis plants are grown in a secure
glasshouse at a secret location in the UK under Home Office licence.
The glasshouse used is one of the most sophisticated computer-controlled
glasshouses in Europe, which enables GW to ensure that the plant
material grown is of sufficient quality and consistency to be
suitable for incorporation into pharmaceutical products. No chemicals
are used in the glasshouse with all pest control being by biological
means.
5.3 Modern extraction techniques utilised
by GW enable the company to extract the cannabinoids and other
plant constituents from specific plant varieties. These pharmaceutical
grade extracts are then incorporated into advanced drug delivery
technologies, such as sprays and inhalers. No synthetic cannabinoids
are used. GW's products undergo full pharmaceutical development
with a view to being approved as prescription medicines by medical
regulatory authorities, such as the Medicines Control Agency (MCA).
Preparations of various defined cannabinoid ratios have been extensively
analysed and formulated. Currently the most advanced products
use sub-lingual delivery (ie under the tongue), as a spray or
rapidly disolving tablet.
6. REGULATORY
REQUIREMENTS FOR
MEDICINES
To obtain regulatory approval for a prescription
medicine it must be demonstrated that the product meets the authorities'
requirements for quality, safety and efficacy. This requires lengthy,
extensive and costly pre-clinical (laboratory) and clinical research.
Each medicine must pass Phase I, II and III clinical trials, an
explanation of which is given in an Appendix.
7. STATUS
OF GW CLINICAL
TRIALS OF
CANNABIS-BASED
MEDICINES
7.1 Phase I: GW has completed 3 Phase I
clinical trials that have assessed 10 different drug forms and
involved 24 healthy subjects. These trials were used to establish
safe dosage regimen, tolerability and clinical pharmacology.
7.2 Phase II: After detailed submissions
by GW, the MCA approved progress from Phase I to Phase II trials
(which are used to assess the efficacy of medicines) in the following
conditions:
Relief of pain of neurological origin and defects
of neurological function in:
— Peripheral nerve injury
— Central nervous system damage
— Cerebral vascular accident
Relief of pain and inflammation in Rheumatoid
Arthritis
Relief of pain in brachial plexus injury
7.3 Phase II trials are ongoing at several
centres including Oxford, Guernsey, Great Yarmouth and London
and have involved over 125 patients to date, with the majority
suffering from multiple sclerosis. The Oxford trial operates under
a Clinical Trial Exemption or "CTX" (the approval required
for trials sponsored by a company) whilst Great Yarmouth and London
trials are carried out by independent physicians under a Doctor
and Dentist Exemption or "DDX". Data generated from
CTX trials can be used in the dossier submitted to the medical
regulatory authorities for approval to market a medicine whilst
in general data from DDX studies is used to support pivotal studies
sponsored by companies under CTX.
7.4 Phase III: The first pivotal Phase III
clinical trial of cannabis-based medicines is underway in Multiple
Sclerosis and the Phase III programme will expand into other centres
with a Phase III trial in cancer pain due to start shortly. The
number of patients involved in trials is therefore set to increase
more rapidly as the Phase III programme advances and Phase II
trials continue to explore new conditions. These larger Phase
III studies focus on target medical indications and will be used
in regulatory submissions to the MCA.
7.5 Long-term Safety Extension Studies:
Patients obtaining benefit in one or more symptoms during Phase
II or III trials become eligible to enter GW's long-term safety
extension studies which enables patients to continue to receive
medication and further safety and efficacy data to be collected.
Usually at the end of a clinical trial a pharmaceutical company
would continue to provide trial medication to patients who had
obtained benefit during the trial on a compassionate basis. However,
because GW's medicines are cannabis-based and because GW's licences
currently only permit the cultivation and supply of cannabis for
research purposes, patients can only continue to receive medication
as part of an approved clinical trial. This is also important
as it prevents patients who have obtained benefit from cannabis-based
medicines in the acute phase of the trial being tempted to purchase
cannabis illegally when they complete the trial.
7.6 As at the end of July 2001, of the first
53 patients entering the studies in three centres, two remained
in the acute phase of the study and 44 had completed this phase.
Of the 44 no fewer than 41 sustained sufficient beneficial response
to opt to continue on active treatment and enter the extension
phase. To date a total of over 125 patients have been involved
in all phases of GW's studies and, at the time of writing, over
60 patients have progressed to the extension study, out of a possible
maximum of 84 (some patients are still in the acute phase but
others are in trials which are not eligible for the extension
phase).
7.7 Although all patients must have obtained
medical benefit in the acute phase of the trial to become eligible
for the long-term study, it is notable that for some the benefit
obtained has been sufficient to transform their lives. This is
particularly encouraging because all patients involved in the
trials of cannabis-based medicines are those whose symptoms were
intractable in the face of all available standard therapy.
8. TRIAL
RESULTS
8.1 Safety: Following detailed submissions
to the MCA on the progress of patients in trials (amounting to
the equivalent of 20 patient years of data) the MCA has approved
the extended use of GW's THC- and CBD-containing cannabis-based
medicines from 12 to 24 months' treatment.
8.2 Adverse effects have been reported in
the trials but most of these seem to occur early in the treatment
periods and diminish as a suitable dose is arrived at by self-titration
(dose adjustment). Almost all of these effects have been transient,
of only mild or moderate intensity, and generally well tolerated
by the patients. In GW's trials most patients have been able to
self-titrate to a dose that achieves useful symptom relief without
the handicap of unwanted psychoactive effects that would interfere
with ordinary daily activities.
8.3 In accordance with accepted standards,
treatment-related adverse events in two patients have been classified
as serious because the patients involved were required to remain
in hospital overnight. In one event the patient experienced chest
pain, hyperventilation and distress (panic attack) and in the
other the patient experienced a vasovagal attack (fainting). Both
patients went on to make a full recovery within hours using standard
therapy and indeed one of the patients elected to proceed in the
trial and is still receiving active medication.
8.4 Efficacy: On 7 September 2001 GW publicly
presented data from Phase I and II trials of cannabis-based medicines
to the American Academy of Pain Management conference in Arlington,
Virginia. The data relates to the effects of different formulations
of cannabis-based medicines and placebo on patients suffering
principally from Multiple Sclerosis or Spinal Cord Injury. (The
data only relates to the patients for whom data has been processed.)
The highlights are as follows:
— Active treatments provide superior
benefit to placebo in key outcomes (pain, overall symptom relief,
sleep duration).
— The data show clear trends that support
the clinical improvements experienced by patients whose conditions
have been considered intractable in the face of standard therapy.
In some cases, the improvements have been sufficient to transform
lives.
— Of the first 53 patients entering
the studies in three centres, two remain in the acute phase of
the study and 44 have completed this phase. Of these, 41 sustained
a sufficiently beneficial response for them to opt to continue
on active treatment long term.
— The studies have generated over 20
patient-years of treatment. Adverse events have been predictable
and generally well tolerated.
— By careful self-titration (dose adjustment),
most patients are able to separate the thresholds for symptom
relief and intoxication, the "therapeutic window", so
enabling patients to obtain symptom relief without experiencing
the "high" associated with cannabis.
— Analysis of dosage levels over extended
periods shows no evidence of tolerance, thereby avoiding the requirement
for patients to progressively increase their dose.
8.5 Among the positive effects recorded
are relief of:
— Bladder-related symptoms
— Partial relief of tremor
— Improvements in quality and length
of sleep
— Improvements in mood and measures
of overall wellbeing
9. ADVANCED
DISPENSING TECHNOLOGIES
FOR CANNABIS-BASED
MEDICINES
9.1 GW is aware of the importance of preventing
cannabis-based medicines from being used other than as prescribed
by doctors. The Company has therefore established a separate research
and development programme to achieve this and is developing anti-diversionary
technology incorporating a range of mechanical and electronic
security features to achieve this. The device will record data
on the size and timing of doses that can then be downloaded to
the patient's doctor so enabling remote patient monitoring. The
device will be tamper-evident and tamper-proof and will require
a password before any medication is released. If the patient attempts
to take more medication in a given time period than was prescribed
by their doctor, the device will "lock-out" until the
correct time has elapsed. If stolen the device can also be locked-out
remotely.
10. INTERNATIONAL
PROGRESS
GW has received approval from Health Canada,
the Canadian medical regulatory authority, to conduct Phase II
trials and the first Canadian trial in MS began in Ottawa in August
2001. Clinical trials are also planned for Europe and the United
States and discussions have taken place with government representatives
or regulatory agencies from the US, Canada, France, Germany, Belgium
and the Netherlands.
11. HOME
OFFICE AND
MCA CO-OPERATION
Throughout the programme GW has worked closely
with the Home Office to ensure compliance with all regulatory
and legal requirements. The company is extremely grateful to the
Home Office for their valuable support and advice. In addition,
GW is also very grateful to the MCA who have provided helpful
advice and comment on GW's overall research plans.
12. TIMELINES
GW's Phase III clinical trials programme is
progressing well with the first trial underway and preparations
are going well for the next trials which are due to start shortly.
GW hopes to be in a position to submit a confident application
for regulatory approval to the MCA in 2003 with a view, subject
to approval by the MCA, to the first cannabis-based medicine being
available to patients on prescription shortly thereafter.
13. CONCLUSION
13.1 Cannabis is expected to help patients
suffering from a wide range of medical conditions, including those
related to neurogenic pain or dysfunction such as multiple sclerosis,
spinal cord injury, phantom limb pain and arachnoiditis and other
conditions without a neurological cause including osteoarthritis,
rheumatoid arthritis, AIDS, migraine, cancer pain, nausea and
epilepsy.
13.2 To date over 3,000 patients have contacted
GW asking to take part in clinical trials and, in a confidential
questionnaire, approximately a third reported having used illegal
cannabis for medicinal purposes. Patients expressed concern over
fear of prosecution, quality of material (fungal/chemical contamination,
variable potency), health risks of smoking, lack of medical supervision
and cost and difficulty of obtaining a regular, consistent supply.
13.3 GW is focused on making non-smoked
prescription cannabis-based medicines available to patients in
the shortest possible time. The company's programme has proceeded
at a considerable pace and to have started Phase III clinical
trials less than 30 months from the initial planting of the first
cannabis plants, marks remarkable progress by pharmaceutical industry
or other standards.
13.4 GW believes this approach still represents
the best solution for patients likely to benefit from the medicinal
properties of cannabis but who wish to take a medicine approved
by the MCA on the grounds of quality, safety and efficacy. We
believe that many patients will wish to use a medicine that is
legally prescribed, does not require smoking, is of guaranteed
quality and is available from their doctor with medical supervision.
However, before such a medicine can be made available the Government
would need to amend the Misuse of Drugs Regulations (as outlined
in paragraphs 2 and 2.1 of this document).
September 2001
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