Low-dose CBD has been down-scheduled, but what does it mean?

Young-doctor-offering-pill

Low-dose CBD has been down-scheduled, but what does it mean?

The TGA recently released their Notice of interim decisions to amend (or not amend) the current Poisons Standard, and those in the medicinal cannabis industry were waiting with bated breath for the decisions relating to low-dose CBD.

Two proposals were submitted and have different results:

Proposal Result
Remove CBD from scheduled materials list altogether Rejected – CBD will not be excluded from the poisons standard.
Down-schedule low-dose CBD from Schedule 4 to Schedule 3. Accepted.

 

The majority of the TGA Committee was not convinced that there was sufficient evidence to relax all access controls on cannabidiol (both natural and synthetic) to the general sales levels. However, they were also not fully convinced that cannabidiol fully met the scheduling factors for Schedule 3 either.

Because of this, the Schedule 3 entry will come:

  • “with specified requirements”
  • “with additional supply requirements…to allow it to be provided by a pharmacist”.

Ahhh, government fine print…so what is this Schedule 3 category and what does the fine print say?

1. What is a Schedule 3 Poison?

Schedule 3 poisons are best summed up by a table provided by the TGA:

(Source: TGA Review on the safety of low dose cannabidiol)

Pharmacist-only medicines (also called “over the counter” or “OTC” medicines) are considered to be lower risk than prescription medicines, but they still require a certain level of scrutiny.

2. Where does low-dose CBD fit into this Schedule 3 category?

As mentioned before, there are limitations on low-dose CBD within this Schedule 3 category and they are best-summarised by an image from the interim decision document:

Ignoring the fact they misspelled cannabidiol (not cannabadiol), the main message boils down to:

Schedule 3 cannabidiol (CBD) cannot be supplied under the Special Access Scheme (SAS) and must be included (registered) on the Australian Register of Therapeutic Goods (ARTG).

There are also limitations for low-dose CBD products, namely:

  • the maximum dose is limited to 60 mg per day
  • products must be contained child-resistant packaging
  • product forms are limited to oral, oral mucosal, and sublingual formulations only (i.e. no vaping, no topicals, and as I’ve covered before: no cosmetics).

For the consumer, once the product passes all the checkpoints for product registration, it can be supplied to patients by a pharmacist without a prescription.

However, the interim decision also states that the TGA will “ensure that only products that have been approved for a specific indication appropriate under a Schedule 3 listing will be available without a prescription.”

Unfortunately for medical cannabis businesses, this means you will have to do all the heavy lifting and provide efficacy, safety, and quality assessment data for the product, for a particular medical condition, to enable the product approval.

3. How do I register low-dose CBD as an OTC medicine?

The TGA details the requirements that are in place for OTC medicines here. This includes links to the Australian regulatory guidelines for OTC medicines also known fondly as “ARGOM” (a.k.a. the OTC bible, hallelujah).

The TGA summarises the registration steps here, however, I’ve provided the high-level process below.

Step 1: Determine the correct OTC medicines category

OTC medicine applications are categorised according to risk. There are five risk levels for applications for new medicines (levels N1 to N5) and five risk levels for applications to make changes to existing medicines (levels CN to C4).

Each of these risk levels corresponds to an application category and a route to evaluation; applications in the lower risk levels require less supporting information than applications at higher risk levels.

In the interim report the delegate stated: “if a CBD product were to be registered as a Schedule 3 medicine, an application for product registration would include a full submission to support its intended use, including data relating to the efficacy for any indications for the product.”

Using this description and the OTC application placement question and answer tool, I’ve highlighted some pathways below that will depend on if the low-dose CBD product is an original registration (an originator) or a secondary registration (a generic drug).

Low-dose CBD as an originator

To find out where CBD would place on the OTC medicines category, I went down the TGA’s pathway as highlighted below:

Question Response
Is the product an OTC medicine? Yes
Is the application to register a new medicine or to make a change to an existing medicine? A new product (there is currently no low-dose CBD registered on the ARTG).
Is the active a new chemical entity? No. Cannabidiol is already listed on the TGA register as a chemical entity.
Does the medicine have the same:

  • quantity per dose of each of the active substances, and
  • dosage form, and
  • safety and efficacy properties, for example
    • directions for use
    • indications
    • target population

– as a fully evaluated approved OTC medicine? (ie. Is it a ‘generic’ medicine?)

No. The correct application level is N5.

 

The table below sums up the requirements for N5:

Category  N5
Definition An application for a new medicine that is an extension to a ‘Generic category’ medicine including:

  •  New therapeutic indications
  •  New strength
  •  New dosage form
  •  New directions
  •  New combination medicines
  •  Different patient population
  •  An application for a medicine containing a new chemical entity as an active ingredient.
Requirements Evaluation of both:

(More detail on the categorisation framework can be found here.)

NOTE: The registration under N5 may only need to occur ONCE as an “originator” drug. After that instance, any low-dose CBD products that fulfil similar characteristics can be registered as a “generic drug” instead.

Low-dose CBD as a generic drug

To continue my thought experiment and figure out where low-dose CBD would fit on the OTC medicines category once an originator had been registered, I went down the OTC application placement question and answer tool again. This time I ended up in two categories, depending on what I chose as my product characteristics:

Category N3 N4

Definition

New application for a ‘generic’ medicine other than those in levels N1, N2 or N4.

The medicine name does not include a risk associated with an umbrella branding segment that requires a higher level of assessment.

An application for a ‘generic’ medicine that:

  •  requires supporting safety and/or efficacy (clinical/toxicological) data or a justification for not providing the data. Examples of such applications are included below this table and/or
  •  has not previously been registered as an OTC medicine following down scheduling and /or
  •  includes a risk associated with an umbrella branding segment requiring a higher level of assessment.

Requirements

Does not entail evaluation of safety and efficacy data. Do not provide safety and efficacy data for applications at this level.

Requires full evaluation of Quality data (CTD module 3). However, in the circumstance where all quality aspects of the product are identical to a product which has previously been fully evaluated by the TGA, then you may provide an abbreviated module 3 dossier (including finished product specifications for the proposed product).

Requires evaluation of Quality data (CTD module 3).

However, in the circumstance where all quality aspects of the product are identical to a product which has previously been fully evaluated by the TGA, then you may provide an abbreviated module 3 dossier (including finished product specifications for the proposed product).

To register a generic drug, the only additional thing you may need to provide on top of the requirements detailled above is bioequivalence (or therapeutic equivalence) data to demonstrate that your drug performs the same way as the originator.

If there was an OTC monograph for low-dose CBD, the product would fall into an entirely different category and it would be a slightly easier process… but there isn’t, so moving on.

Step 2: Check guidelines, mandatory requirements and compile the dossier

This is where the Australian regulatory guidelines for OTC medicines (AGROM) becomes critical as a reference. The compilation of the product dossier is no small task and involves:

  • Including any patent registrations – CTD Module 1 – OTC medicines
  • Forming the Common Technical Documentation (CTD) which is split into different modules that have their own formatting and organisation requirements, the major ones being:
    • Quality module: covering the relevant chemical, pharmaceutical and biological data
    • Safety module: covering the relevant nonclinical (pharmaco-toxicological) data
    • Efficacy module: covering the relevant clinical study reports and data
  • Preparing a cover letter
  • Providing copies of all labeling, Product Information (PI), and Consumer Medicine Information (CMI) documents, where relevant.

For more information on setting up clinical trials to test safety and efficacy, we have a blog and an e-learning module to get you started.

Step 3: Provide valid evidence of GMP

You must have an active TGA GMP certificate for your manufacturing facility or have obtained GMP clearance for your overseas provider.

We have written extensively on GMP principles on our website here, and also have a specific blog on how to set about applying for a TGA GMP Manufacturing license for Medicinal Cannabis.

NOTE: For overseas providers, you should make sure the clearance is valid for at least 6 months (applicable for N3, N4, and N5 applications).

Step 4: Lodge your application

This proceeds via the TGA business services portal (of course you will have to pay fees because nothing in life is free). The target response time for applications is summarised in the TGA table below (more detail here):

4. Post-registration responsibilities

Unfortunately, the work doesn’t stop at product registration. GMP requires you to perform ongoing stability studies for your product so that, for example, if the shelf life changes, you update the product’s conditions of registration accordingly. Other things that could trigger a change include any:

  • Label changes
  • Formulation changes
  • Quality control changes
  • Changes to the medical condition being treated
  • Changes to directions for use

A ‘Change Table’ is included in the guidance Changing an OTC medicine: using the Changes Tables that provides details of changes that can be made and the information required to support a particular type of change.

Also, once a product is registered, you are required to take on pharmacovigilance monitoring for any unwanted and/or unanticipated side effects to ensure the ongoing safety profile of the product and safety of future patients.

If pharmacovigilance is a completely alien concept, we provide a document template pack and e-learning module.

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