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Guidelines on the evidence required to support indications for listed complementary medicines

Who are these guidelines for?

These guidelines provide information for sponsors and applicants:

· on the type of evidence that is required to support indications for listed complementary medicines; and
· to help you understand your regulatory obligations in relation to holding evidence to support indications for your medicine.

How are complementary medicines regulated in Australia?

Therapeutic goods that are imported or manufactured for supply in Australia are required to be included in the Australian Register of Therapeutic Goods (ARTG) by the Therapeutic Goods Act 1989 (the Act) unless they are specifically exempted by the Therapeutic Goods Regulations 1990 (the Regulations).

Within the regulatory framework, complementary medicines are either listed or registered in the ARTG based on their ingredients and the indications made for the medicine. While some complementary medicines are registered, most are listed.

Listed medicines are considered ‘low risk’ medicines. The listing process allows for rapid market access for listed complementary medicines. Unlike registered medicines, the TGA does not evaluate listed medicines prior to inclusion in the ARTG.

Refer to the Australian regulatory guidelines for complementary medicines (ARGCM) for more information on the regulation of complementary medicines in Australia.

What are your regulatory obligations when you list a medicine on the ARTG?

Before you list a medicine in the ARTG, you must ensure that the medicine complies with all applicable regulatory requirements. When you apply to list your medicine via the online application portal1, you, as the sponsor of the medicine, must certify that the medicine meets the regulatory requirements of:

· Section 26A(2)(a)–(k) of the Act; and
· subsection 26A(3) of the Act if your medicine is manufactured outside Australia.
The range of regulatory requirements includes that:
· your medicine only contains ingredients permitted for listed medicines
· you hold evidence to support any indications and claims made about your medicine; and
· the presentation of your medicine is not unacceptable.

In relation to evidence for your medicine, Section 26A of the Act provides that you must:

· hold evidence to support your indications at the time the medicine was included in the ARTG
· retain that evidence at all times while the medicine remains listed; and
· provide that evidence to the TGA if requested to do so.

There are offences for making false statements in, or in connection with, a certification of any matter under subsection 26A(2) of the Act.

When will the TGA look at the evidence you hold for your medicine?

After listing in the ARTG, a proportion of listed complementary medicines are reviewed for compliance with the regulatory requirements. Your medicine may be selected for compliance review at any time after it is listed in the ARTG. For further information see Listed complementary medicine compliance reviews.

Briefly, a compliance review of a listed complementary medicine involves:

· assessing information about the product against the relevant legislative requirements, including, where relevant, the certifications given by the sponsor at the time the product was listed; and
· taking appropriate actions when a breach of the legislative requirements is identified.

If your medicine is selected for a compliance review, you will be required to provide necessary information to the TGA. Evidence provided to the TGA for an ‘evidence-based listing compliance review’ must be sufficient to address all relevant regulatory requirements.

The TGA may take regulatory action (including cancellation of the listing in accordance with section 30 of the Act), if it is found that any of the certifications (among other things) made at the time of listing were incorrect.

What are the types of evidence for listed medicines?

Evidence used to support indications for listed medicines is usually sourced from the available open literature, rather than from clinical trials specifically conducted with a particular medicine2.

Depending on the proposed indication, the evidence will be sourced from scientific literature or based on a history of traditional use.

What information do these guidelines contain?

The document is comprised of two parts:

Part A provides guidance on:

· the types of indications and evidence sources

· how to assess the relevance, quality and balance of scientific evidence

· how to assess the credibility and relevance of evidence of traditional use; and

· how to obtain, record and present the evidence that supports your indication/s.

Part B provides additional technical guidance:

· to help you assess the relevance, quality, outcomes and overall balance of currently available scientific evidence; and

· on the evidence required for indications relating to weight loss, biomarkers and nutritional supplementation.

Evidence package checklists are available on the TGA website to help you assess, record and present the available evidence for the indication/s for your medicine. Appendix 1 provides assistance for completing the checklists.

Part A: Evidence to support indications for listed complementary medicines

Indications for listed medicines

What is an indication?

In relation to therapeutic goods, the definition of ‘indications’ is provided in Section 3 of the Therapeutic Goods Act 1989 (the Act) as: ‘the specific therapeutic use/s of the goods’.

The indication of a medicine is its claimed purpose or health benefit, for example: ‘relieves coughs’.

What is not an indication?

Statements or claims which do not convey a specific therapeutic use such as references to the properties of the product or the packaging are not considered to be therapeutic indications. Some examples are:

· ‘contains 25% more’
· ‘new formula’; and
· ‘high in vitamin C’.

Indications must be included in the ARTG entry for a medicine, whereas other claims not related to therapeutic use are not required to be in the ARTG. However, sponsors must hold evidence to support both indications and other claims for their medicine.

Any statement you make in relation to the medicine, such as marketing claims, must be truthful, factual and not misleading. Refer to the Therapeutic Goods Advertising Code (TGAC) for details of advertising requirements.

What indications are suitable for use in listed medicines?

Consistent with their low risk, listed complementary medicines may only carry appropriate indications that will not lead to their unsafe or inappropriate use.

When listing a medicine, you must certify3 that the medicine is eligible for listing. To be eligible for listing (pursuant to Schedule 4 of the Therapeutic Goods Regulations 1990), the indications for the goods must not refer to the treatment of specified types of diseases, conditions, ailments or defects4.

In addition, to be included on the label, an indication must not refer to a serious form of those diseases, conditions, ailments or defects without prior approval by the TGA5. Serious forms include conditions which are generally accepted not to be diagnosed, treated or managed safely without the assistance of a qualified healthcare practitioner.

In general, an indication suitable for use in listed medicines:

· will describe a specific therapeutic use
· may refer to health maintenance and/or health enhancement
· may not refer to the treatment or cure of a disease, ailment, defect or injury; and
· may not refer to a serious form of a disease, ailment, defect or injury.

In specific circumstances, the TGA may allow indications for listed medicines to refer to serious forms of conditions (referred to as restricted representations) where it is considered in the public interest to do so. This can occur upon application by the sponsor for approval to use a restricted representation under s 42DK(1) of the Act.

Should a sponsor wish to make a high-level indication for their medicine, then the product is required to be registered and must undergo full pre-market evaluation by the TGA for quality, safety and efficacy.

What does an indication look like?

An indication must describe the specific therapeutic use(s) of the goods. An indication is made up of the components listed in Table 1.

Table 1: Components of an indication

What are the different types of indications?

Indications for listed medicines are either traditional or scientific, based on the type of evidence supporting the indication.

Traditional and scientific indications are further classified into ‘non-specific’ or ‘specific’ sub-types depending on the how the indication is phrased.

What are traditional indications?

Traditional indications belong to a recognised paradigm outside modern conventional medicine. Traditional medicine is an integral part of many cultures and includes a diverse range of health practices, approaches, knowledge sets and belief systems relating to medicines. Examples of traditional medicines include:

· Traditional Chinese Medicine (TCM)

· Aboriginal and Torres Strait Islander healing practices

· Ayurvedic medicine

· Western herbal medicine

· Homoeopathic medicine

· Aromatherapy; and

· other indigenous medicines.

Traditional indications must indicate that the health benefit is based on long-term use and experience in a specific traditional paradigm. As traditional indications are not based on scientific evidence, they cannot imply efficacy in a clinical setting.

Examples of traditional indications:

　　　　　‘Traditionally used in Chinese medicine to ‘resolve phlegm’ to relieve cough’.
　　　　　‘Traditionally used in Western herbal medicine to relieve nasal congestion’.
　　　　　‘Traditionally used in Homoeopathic medicine to improve appetite’.
　　　　　‘Traditionally used in Ayurvedic medicine to support healthy immune function’.

What if your traditional medicine includes multiple ingredients?

For medicines that have multiple active ingredients from the same traditional paradigm, indications can be linked to individual ingredients or relate to the entire medicine (if the indications for each ingredient are traditionally used for the same health benefit).

Example of a traditional indication for multiple ingredients from the same paradigm:

　　　　　‘The ingredients in this medicine are traditionally used in Western herbal medicine to maintain a healthy liver function’.

What if your medicine includes multiple ingredients from different traditional paradigms (‘multiple traditional paradigm medicine’)?

If all the active ingredients from the different traditional paradigms are traditionally used for the same health benefit, the indication/s can be applied to the whole medicine. Alternatively, an indication can be provided for each individual ingredient.

Example of a traditional indication for a ‘multiple traditional paradigm medicine’:

　　　　　‘Ingredients in this medicine have traditionally been used in Ayurvedic and Chinese medicine for relieving common cold symptoms’.

Example of individual indications for different ingredients in a ‘multiple traditional paradigm medicine’:

　　　　　‘Trichosanthis kirilowii (tian hua fen) is traditionally used in Chinese medicine to ‘clear and drain lung heat’ to help relieve chest congestion’ and
　　　　　‘Ocimum tenuiflorum is traditionally used in Ayurvedic medicine to help remove excess ‘kapha’ (mucus) from the lungs and nasal passages’.

What are scientific indications?

Scientific indications belong to conventional modern medicine and are supported by scientific literature, such as clinical studies or systematic reviews (refer to ‘Do you have scientific evidence?’).

Examples of scientific indications:

　　　　　‘Helps relieve common cold symptoms.’
　　　　　‘Helps maintain blood circulation to the peripheral areas of the body.’

　　　　　‘Assists in the management of mild acne pimples.’
　　　　　‘Helps support a healthy immune system.’

What if your medicine has a combination of traditional and scientific indications (‘cross evidence base medicine’)?

A medicine with a combination of scientific and traditional indications (a ‘cross evidence base’ medicine) requires scientific evidence to support the scientific indications and evidence of traditional use to support the traditional indications.

Example of indications for a medicine that has cross paradigm indications:

A medicine that contains Panax ginseng, Bacopa monnieri and folic acid may have the following indications (if supported by appropriate evidence):

　　　　　‘This medicine has been formulated from traditional and non-traditional ingredients, to help support a healthy memory, specifically:
　　　　　Panax ginseng is traditionally used in Chinese medicine to tonify qi (vital energy) and support memory in times of fatigue.
　　　　　Bacopa monnieri is traditionally used in Ayurvedic medicine to improve memory.
　　　　　Folic acid helps support cognitive function’.

What are the indication sub-types (specific or non-specific)?

Traditional or scientific indications can be further classified into two sub-types:

Sub-type 1: Non-specific (general indications)

Non-specific indications refer to general health and wellbeing, such as:
· health maintenance
· relief of symptoms not related to a named condition; and
· general vitamin, mineral or nutritional supplementation.

Sub-type 2: Specific indications

Specific indications refer to health benefits beyond general health and wellbeing, such as:

· health enhancement
· reduction of risk or frequency of a named condition or symptoms
· management or relief of symptoms linked to a named condition; and
· nutritional supplementation claims linked to a specific therapeutic benefit.

Whether using traditional or scientific indications, the specificity of your indication determines the level of evidence required to support your indication (refer to ‘What level of indication does your traditional evidence support?’ and ‘What level of indication does your scientific evidence support?’)

Tables 2a and 2b provide examples of specific and non-specific indication sub-types.

Evidence to support indications for listed medicines

The term ‘evidence’ refers to both information and evidence as described in paragraph 26A(2)(j) and subsection 28(6) of the Act.

As the sponsor of a listed medicine, you must hold evidence to support all the indications you make for your medicine at the time you list the medicine in the ARTG. The evidence you hold must adequately support all indications and demonstrate all claims made for the medicine are true, valid and not misleading. You must keep that evidence for the whole time the medicine remains listed and provide it to the TGA if requested to do so [as provided by subsection 26A(2)(j) and 28(6) of the Act].

What type of evidence do you have to support your indication?

Before deciding the indication/s for your medicine, you must determine the type of evidence you have on which to base the indication. That is, do you have evidence of traditional use or scientific evidence? And, is the evidence you hold supportive of a specific or non-specific indication?

Your evidence must:
· have the same meaning and intent as the proposed indication

· be related to the same medicine or active ingredient/s; and
· have the same therapeutic action and the same context, for example: the same target population or same traditional paradigm.

Where there are differences between the ingredient and reported therapeutic benefit, a justification will be required in your evidence package to address the discrepancy.

Do you have evidence of traditional use?

Traditional medicines are based on an extensive history of use, often measured over thousands of years. This history provides an accumulated repository of systematic observation and underpins the use of these medicines in a traditional setting. Usually when a medicine or a relevant ingredient in the medicine has been used over a long period of time its dosage and formulation have been refined by experience to maximise therapeutic effectiveness and minimise risk.

Evidence of traditional use for an indication needs to show that the medicine or the relevant ingredients in the medicine have a significant history of use in the specified tradition for the specified therapeutic purpose. You are required to hold documentary evidence that your medicine or its active ingredient has been used for at least three generations (at least 75 years) in the tradition it belongs to. This will establish that it belongs to that tradition and that there is an accumulated repository of observations in humans that underpins the use of the medicine.

For many traditional medicines there has been little quantifiable scientific research, scientific assessment or scrutiny undertaken on the medicine’s mode of action or effect. It is inappropriate to use evidence of traditional use to support a scientific claim of efficacy, a mechanism of action or an underlying physiological process, as these are required to be supported by scientific evidence.

If you have determined that the evidence you have is traditional, ‘What evidence do you need to support your traditional indication?’ provides guidance on compiling your evidence package.

Do you have scientific evidence?

Scientific evidence refers to quantifiable data and usually includes reports of clinical trials in humans, human epidemiological studies, animal studies and other cellular or pharmacological studies. Due to the quantifiable nature of scientific evidence, scientific indications can imply clinical efficacy where the indication is supported by such data.
Examples of scientific evidence include:

· systematic reviews
· reports of clinical studies
· peer-reviewed published review articles; and
· pharmacopoeias and monographs.

If you only have non-clinical studies, cellular or pharmacological studies, these alone are not considered sufficient evidence to support a scientific indication. However, such studies can be used to provide secondary support to human data.

If you have determined that the evidence you have is scientific, ‘What evidence do you need to support your scientific indication?’ provides guidance on compiling your evidence package.

Do you have a combination of scientific evidence and a history of traditional use (cross-evidence base medicine)?

It is possible for a listed medicine to have scientific and traditional indications where there is a combination of traditional and non-traditional ingredients (cross-evidence base medicine) with a similar therapeutic purpose. Also, it is possible that an ingredient in a cross-evidence base medicine may have evidence of traditional use that is also supported by current scientific literature (cross-evidence base ingredient).

Each scientific or traditional indication requires supportive evidence and the indications must indicate the evidence source (that is, traditional indications must include the traditional context of use).

If you have a combination of scientific and traditional evidence for your medicine, ‘Cross-evidence base medicine: What evidence do you need to support your medicine with a combination of traditional and scientific indications?’ provides guidance on compiling your evidence package.

How to source, assess, record and present evidence to support your indication

Before listing your complementary medicine, you should compile an evidence summary to support your traditional, scientific or ‘cross evidence base’ indications. Your evidence summary should show that you have conducted an objective, comprehensive, transparent and robust review of the literature relating to your indication. The resulting evidence you hold should be of high quality, credible and relevant to your medicine.

Evidence package checklists available on the TGA website help you sift through the available literature to identify what is appropriate evidence and exclude what is not. The checklists will assist you to collate and compile your evidence summary and determine which evidence items are credible, relevant and of high quality.

As a mechanism of establishing that you have the evidence to support your indications, you should consider completing the appropriate checklists for your medicine and associated indications, before listing your medicine on the ARTG. You should hold all the information contained within the checklists for your medicine and submit this information to the TGA when requested to do so.

During a compliance review of your medicine, the TGA may request the evidence you hold to support the indications you make for your medicine. At this time, you may include the appropriate checklists (or similar information) as part of your response to the TGA’s request for information. While presenting your information in the provided checklist format is not mandatory, submitting information in this format will help facilitate and expedite the compliance review process.

Diagram 2 provides a general flow chart on the steps for compiling your evidence package for your listed medicine. Detailed guidance on compiling traditional or scientific evidence packages is provided in:

· How to compile a summary of the evidence to support your traditional indication
· How to compile a summary of the evidence to support your scientific indication.