Journal of the California Cannabis Research Medical
Approval as a Botanical Drug
By an FDA Consultant
I’ve never heard anyone at a drug company or FDA talk about medical marijuana,
but there’s a lot of useful experience with other botanicals.
The first step in qualifying a product for medicinal purposes, here or in any
other developed country, is to have a well-defined product, and this is where
most botanicals have difficulty. Even a botanical with a strong claim for homogeneity
(e.g., one made in huge, well-mixed batches, with some sort of convincing standards
to control batch-to-batch variation) would be suspect; it must contain many
chemical species, and it’s unlikely that all are useful or even benign.
Why not hold out for a better-defined preparation? Opium and digitalis leaf
were both important, but regulators and clinicians feel that they are on firmer
ground with morphine, codeine, digoxin, or digitoxin. It might have turned
out that morphine works only in the presence of codeine, and so on, but I don’t
know of any example where anything like that is the case.
There is no legal basis for FDA recognition of the differential cost of one
medication over another, so moderate difficulty in separating the components
of a botanical does not elicit any bankable official sympathy.
On the other hand, many so-called ‘pure’ substances are in fact racemic mixtures,
and there is only tepid interest in specificity at the enantiomer level. Even
returning to botanicals, the heterogeneity issue would be tractable if there
were solid proof of safety and efficacy, and if separation of the active components
appeared to be extraordinarily difficult. Suppose that a sponsor presented
data to that effect to FDA.
That’s the point at which the FDA would start to hear from outsiders in the
Administration and in drug companies. The Administration would be able to weigh
in first because an application before FDA is not publicly discussed until
an (optional) Advisory-Committee meeting, late in the course of review. Before
then, the Administration could quietly arrange that the application be rejected.
I would have regarded this possibility as far-fetched until this year, but
all things are possible with Bush.
The drug companies might chime in at an Advisory-Committee meeting, but it’s
hard to imagine a scenario in which things got that far. If it were agreed
that some easy-to-produce version of medical marijuana could be considered
by FDA, then its sponsor would face two problems, one much more serious than
The easy problem would be opposition from drug companies with competing products,
but aspirin has always held its own against the brand-name NSAIDs, and even
within the aspirin business, Bayer has made no serious attempt to drive the
cheaper brands from the field.
The more serious problem is that if marijuana were approved, then the original
sponsor would have no effective way of making any money from it. This is the
reason why newer uses of aspirin are rarely studied.
You ask if there are any significant differences between the FDA and the UK’s
Medicines and Healthcare products Regulatory Agency. The main difference is
that the FDA is much bigger, so FDA is the only drug-regulating agency in the
world able to look at raw data instead of working from the summaries provided
by academic experts. Also, there are at least a few deep thinkers at FDA, but
in my experience I came across only one at any other drug-regulating agency,
and she was from the German agency, not the UK.
Some other agencies (notably that of Australia) have arms that look at cost-effectiveness,
unlike FDA. Some (notably that of Germany) have arms that look at various folk
medicines (homeopathy, etc.) by different standards.
Another Indication for Sativex
GW Pharmaceuticals reported a favorable result in a phase
3 trial of Sativex involving 177 patients with severe cancer pain who
were not getting adequate relief from opiates. Sativex is a cannabis-plant
extract containing approximately equal concentrations of THC and CBD
(cannabidiol). Patients in the study continued taking morphine and
added either Sativex, a placebo, or another plant extract high in THC
(all sprayed into the mouth). Some 40% of the patients taking Sativex
reported pain reduction of 30% or more —significantly more relief than
the placebo or the high-THC extract provided.
The oft-repeated myth that Marinol (synthetic THC) contains the active ingredient
of marijuana is dispelled by this and other studies showing that CBD plays
a beneficial role.
GW’s application to market Sativex has been denied, to date, by the Medicines
and Healthcare products Regulatory Agency (MHRA, the UK equivalent of the FDA).
GW submitted data from clinical trials showing that Sativex reduced spasticity
in multiple sclerosis, but in Dec. ’04 the Committee on Safety of Medicines
(CSM), an advisory body to the MHRA, questioned the “clinical relevance” of
the reduced spasticity (its meaning to the patients, a fuzzy concept) and required
a confirmatory study.
GW is carrying out the extra study and also appealing the rejection of Sativex
to the Medicines Commission, the senior advisory body to the MHRA. Several
of the doctors who conducted the trials have expressed dismay. Derick Wade,
Professor in Neurological Rehabilitation, University of Oxford, an authority
on MS, said, “I have treated more than 60 patients in clinical trials with
Sativex. We have seen improvements in spasticity, and in other symptoms, usually
sustained for many months. For patients, relief of spasticity is, like relief
of pain, a substantial benefit in its own right. Many of those involved in
the studies had already tried all other available treatments and so I believe
Sativex is a valuable treatment option for people with MS whose spasticity
is not yet adequately controlled.”
Is GW Getting the Runaround?
Is GW Pharmaceutical getting the kind of runaround from British regulatory
authorities that Americans interested in developing cannabis-based medicines
get from NIDA, the DEA and HHS?
The British government would treat him fairly,
Guy assured us. He had no doubt about it.
GW founder Geoffrey Guy remarked our astonishment back in ’98 when
he said he’d been granted a license by the Home Office to grow cannabis,
develop extracts with different cannabinoid ratios, and test them in
clinical trials. The British government would treat him fairly, he
assured us. He had no doubt about it. There were hoops that had to
be jumped through —levels of purity and consistency to be achieved,
etc.— but he was a successful pharmaceutical entrepreneur and it was
With every passing day that GW fails to get approval to market Sativex, our
old cynicism is restored. The British government isn’t more enlightened than
our own, just more sophisticated.
Big Pharma swallowed the UK regulators whole in 1989 when Margaret Thacher
cut MHRA off from Department of Health funding and the drug companies undertook
to pay for the approval and regulation of their products.
Recently it was revealed that an influential psychiatrist named Stuart Montgomery,
a member of the Committee on Safety of Medicines, had advised Pfizer how to
rewrite its application for Zoloft (called “Lustral” in the UK) and held off
becoming a paid consultant until after the approval had gone through so he
wouldn’t be disqualified from voting. That level of coziness between the pharmaceutical
companies and the CSM is very ominous. The more influence Pfizer et al have
over the British regulators, the longer the runaround GW —and thousands of
MS patients— can expect.