Frequently asked questions on issues raised by industry in relation to permitted indications

The Evidence guidelines classifies indications as 'specific' and 'non-specific' to help sponsors determine the level of evidence required to support the use of an indication.

The indications included in Permissible Indications Determination are not categorised as 'specific' or 'non-specific' because the overall presentation of a medicine (including such things as the combination of indications, the product name and pictorials) needs to be considered to determine if indications are 'specific' or 'non-specific' for a particular medicine.

For example: An individual indication, 'Maintain digestive health' may be considered 'non-specific'. However, if this indication is linked with 'Helps decrease/reduce/relieve symptoms of mild gastritis' in the medicine's ARTG entry and on the medicine label, then it is likely that such an indication would be considered specific.

Sponsors need to assess the overall presentation of their medicine and refer to the Evidence Guidelines to determine the appropriate level of evidence required to support all of their medicine's indications.

In general, the TGA will not evaluate evidence to support the use of a proposed new indication or qualifier at the time of an application. A full evaluation of evidence occurs at the time of a compliance review, should this information be requested, and is reviewed in accordance with the Evidence Guidelines. However, consistent with TGA consideration of any other application, we may request further information to inform our decision.

Appendix 1 of the Permitted indications guidance is an assessment tool that shows what we consider when making a decision to accept or refuse an application for a new indication.

For example: In order for an indication to be considered not misleading as per the Therapeutic Goods Advertising Code (Question 8 of the Permitted indication assessment tool) the indication must be scientifically plausible or consistent with a documented tradition of use. If an initial assessment of an application raises questions about the scientific plausibility of an indication, the applicant will be required to provide a justification in order for the application to proceed.

Applications for new indication qualifiers may also be required to provide justification that the qualifier, when combined with a core permitted indication, is suitable for listed medicines.

For example: Indication qualifiers must not have the potential to increase the risk of an indication by referring to a vulnerable population.

For some applications to proceed, the sponsor may be required provide a justification that the:

• proposed new indication meets the criteria for permitted indications
• proposed new qualifier is appropriate for use with permitted indications in low risk listed medicines

While a justification may not be required for all applications, the provision of a justification at the time of application will expedite any approval process. A justification should:

• be a robust scientific explanation for the rationale behind the application for a new qualifier or indication
• make reference to, and be substantiated, by credible evidence and/or provide examples of evidence that would be held to support use of the proposed qualifier or indication.

If proposing a new indication or qualifier for a potentially vulnerable population such as pregnant women, infants or the elderly, it is expected that applicants address how the availability of the indication or qualifier presents a positive benefit: risk outcome in the context of the indications that are currently available. The justification may also include a consideration of the clinical need for the proposed indication and a discussion of the types of ingredients that may be used (and their suitability for use in the intended population).

For applications for new indication qualifiers, given the intent of using qualifiers for an indication is to align with the evidence a sponsor holds, the justification provided by an applicant should clearly outline how the proposed qualifier is necessary to align with the evidence held for a particular medicine. It should also outline why the existing available qualifiers are unsuitable.

For example: A proposed qualifier may be a gender specific population of athletes. A justification for this specific population may relate to potential differences in nutritional requirements for male and female subsets of athletes. This justification would demonstrate plausibility of the proposed qualifier and context of use, however, should also be supported by credible evidence substantiating these relevant differences.

Some permitted indications refer to multiple 'targets' as the terms are considered synonymous (or very similar) and would likely be supported by the same type of evidence (or evidence for one could be extrapolated to the other).

For example: The indication 'soothe/relieve mild skin burns/sunburns' includes the targets 'skin burns' and 'sun burns' as evidence that a medicine soothes sunburn is also likely to support use of the substance(s) to soothe a skin burn from other heat sources.

The therapeutic target terms included in a permitted indication (separated by "/") can be used interchangeably. This means that sponsors do not need to include all the targets on their label, rather they should only include the one they determine is most reflective of their evidence. If a sponsor has specific evidence that only supports one of the targets, they should provide a justification to this effect in their supportive evidence package.

Permitted indications can be qualified using the qualifying terms available in the Code Tables. This allows you to make a permitted indication more specific to align with the evidence you hold for your medicine.

Indications can be qualified either:

• Explicitly - by using an indication qualifier (which sponsors can select using the drop down lists in ELF) directly in relation to the indication entered in the ARTG, on the product label and advertising material. While this is optional, it is the recommended approach as it puts beyond doubt what the indications for the medicine are and will give sponsors confidence that there is consistency between the ARTG and the label/advertising.
• By implication - by including the qualifier in the overall product presentation, such as the name of the medicine and/or directions for use (for example, the name 'Women's Multivitamins' suggests the vitamins are formulated for women). Care needs to be taken here to ensure that:
  • the qualifier is available in the Code Tables
  • the overall presentation of the product is consistent with the ARTG entry
  • the product is consistent with the certifications made at the time of listing
  • the overall presentation of the medicine is not misleading

When applying to list a medicine, applicants are required to certify (under subparagraphs 26A(2)(fba)(i) and 26A(2)(fba)(ii) of the Act), that:

• any indication included on the medicine's label is 'covered by' the Permitted Indications Determination (the Determination); and
• each indication included on the medicine's label is also included in the medicine's entry in the Australian Register of Therapeutic goods (ARTG).

An indication will be taken to be 'covered by' the Determination, if the indication:

• is specified in the Determination (i.e. it is word for word); or
• is a more specific version of an indication specified in the Determination by use of indication qualifiers (from the TGA Code Tables) that specify use in a certain target population or for a particular time of use; or
• when used on the medicine label, the indication does not differ in intent or meaning from the indication specified in the determination and included in the medicine's ARTG entry.

Section 4(2) of the Permissible Indications Determination allows sponsors to modify a selected permitted indication to align it with the supporting evidence they hold for their medicine by using indication qualifiers in the Code Tables. Note that:

• sponsors must only use the indication qualifiers included in the Code Tables to qualify their medicine indications
• if a sponsor chooses to select an indication qualifier for use with any of the indications specified in the Determination, the combined indication and qualifier/s in the medicine's ARTG entry (the qualified indication) is the accepted indication for that medicine

No - the use of explicit qualifiers from the Code Tables (accessible via the TGA Business Services website) for each indication is optional for sponsors when they enter their medicine in the ARTG via the electronic listing facility (ELF).

However, it is important to note that the indications included in the ARTG (the accepted indications) must be consistent with those on the label or other advertising material [in accordance with the certification provisions in subparagraphs 26A(2)(fba)(i) and 26A(2)(fba)(ii) of the Act and the equivalent provision in section 9(d) of the Therapeutic Goods Advertising Code].

This means that:

• an indication must be qualified on medicine labels (or other advertising), either explicitly or by implication, if it is qualified in the ARTG entry
• an indication must not be qualified (explicitly or by implication) on a medicine label (or other advertising) if it is not qualified in the ARTG entry

Refer to 'Selecting indication qualifiers for your permitted indication' in the Permitted indications for listed medicines guidance for more information.

Indications on a label can be qualified explicitly by adding the population to the indication, or by implication (e.g. in the directions for use, product name or other aspects of the presentation of the product).

Sponsors need to take particular care when qualifying indications through the medicine name or directions for use to ensure that the target population on their label (and in other advertising) is consistent with the ARTG entry. For example, the product name should not be used to refer to a population group that is not available in the list of population qualifiers available in the Code Tables (unless the specific indication referring to the population, where available, is included in the medicine's ARTG entry e.g. foetal development), nor imply an indication that is not included in the Permitted Indications Determination.

Statements on the medicine label that suggest that the product has uses different from, or in addition to, the indications included in the ARTG entry (i.e. if a target population is specified or implied on the label or advertising that is not specified in the ARTG listing) would not comply with:

• the condition of listing (refer to paragraph 28(5)(ab) of the Act)
• the listing certifications
• the Advertising Code

Table 2 provides examples of population qualifiers on the label and in the ARTG entry.

The Evidence Guidelines state that, if a medicine indication is not directed towards a specific population sub-group (i.e. it is not qualified), the supporting evidence would need to be relevant to the general Australian population. That is, we would assume, and the sponsor must hold evidence to support, use of the medicine in:

• males and females
• that are generally healthy
• aged 18-65 years
• socio-culturally similar to the Australian population

As stated in the Evidence Guidelines, the health status of the study population should be representative of the target population for the medicine. The results from studies conducted in specific sub-populations are therefore not relevant to the general population.

For example: Clinical studies that only use females as the treatment group are not relevant to the general population.

If sponsors hold evidence to support the use of a medicine in the general Australian population, it would be optional to qualify the indications in the ARTG to refer to a sub-population within the general Australian adult population in order to differentiate their products in the market (e.g. Men's multi vitamin).

As stated in the Evidence Guidelines, extrapolation of results obtained from subjects outside the specific target population group (e.g. from a sub-population to the general population) is normally not accepted unless it can be appropriately justified. Therefore, if you only hold evidence referring to a specific sub-population that is not within the general adult population (for example: children or the elderly) specific qualifiers may be required to align the indications with the evidence held for a medicine. If sponsors do not qualify their indication when they only hold evidence for use of a medicine in a specific sub-population, rather than the general adult population, then the product may not comply with all regulatory requirements:

• the condition of listing (paragraph 28(6) of the Act)
• the listing certifications (paragraph 26A(2)(ja) of the Act); and
• may be considered misleading under the Advertising Code.

Examples of indications requiring population qualifiers are provided in Table 1.

If your medicine is indicated for population groups outside the general population, these need to be included in the ARTG for each indication.

Alternatively if the medicine's presentation, such as the medicine name, specifies a population e.g. 'Women's multivitamin', it is implicit that all indications for that medicine are indicated for that population and therefore do not need to be individually qualified. However, note that the product name should not be used to refer to a population group that is not available in the list of population qualifiers available in the Code Tables unless that population is specifically included in a permitted indication in the medicine's ARTG entry -refer to Q19.

No. Qualification, whether implicitly or explicitly, of an indication on the product label with a target population that is not available in the Code Tables has the effect of modifying the indication to be one that is not covered by the Determination. This qualified indication would not be compatible with the sponsor's certification under 26A(2)(fba)(i) of the Act.

Directions for use are critical to ensure the safe use of medicines for different target populations using the same medicine, or people using the same medicine for different purposes. As defined in section 3 of the Act, directions for use include information on:

• appropriate doses of the goods
• the method of administration or use of the goods
• the frequency and duration of treatment for each indication for the goods
• the use of the goods by persons of particular ages or those with particular medical conditions

Inclusion of directions for use on product labels is required by operation of the labelling orders. Sponsors are not required to enter directions for use in the ARTG.

Sponsors are not required to qualify their indications in the ARTG in order to provide directions for use for different population groups within the general Australian population (the default population) on their product label (e.g. in 'women', 'in adults', 'in men').

However, directions for use cannot specify a target population, directly or by implication, that is not consistent with the information included in the ARTG for the medicine.

For example: A medicine with an unqualified indication for health and wellbeing in the ARTG could not have directions of use for specific sub-populations such as: pregnant women; breastfeeding women; children; or elderly persons.

If sponsors do not qualify their indications in the ARTG (either through the product name or explicitly in relation to the indications) and the medicine label has directions of use for specific sub-populations that are not within the general Australian adult population (as described in the Evidence Guidelines, refer Q4), then the certification made under subparagraph 26A(2)(fba)(ii) of the Act may be incorrect.

If specific target populations are mentioned in the directions for use, sponsors are also required to hold evidence to support the use(s) in those populations. Table 3 provides examples of population qualifiers and directions for use on medicine labels.

No. Consistent with their low risk status, listed medicines may only use low level indications that should not lead to their unsafe or inappropriate use. Permitted indications have been assessed against a set of criteria and determined to be appropriate for listed medicines. As such, they only allow listed medicines to make indications for health maintenance and health enhancement or certain indications for non-serious, self-limiting conditions. It is assumed therefore that they are intended for use by generally healthy individuals from the general Australian (or 'default') population. Likewise, the list of available qualifiers in the Code Tables refers to specific sub-populations but not to diseased groups.

Therefore, generally speaking, the 'in healthy individuals' qualifier does not need to be used to preclude the use in unhealthy populations. However, this population qualifier is available if sponsors choose to use it.

Traditional indications must be qualified with the 'traditional context qualifier' in the ARTG entry and on the product label and in advertising [refer to paragraph 4(3)(e) of the Determination and the equivalent provision in section 23 of the Advertising Code].

If a medicine has a majority of traditional indications, then the medicine should be adequately qualified as being 'traditionally used' on the main medicine label, so that the presentation of the good is not misleading.

Table 4 provides examples of traditional qualifiers being used on a main label. All representations of the indications, on the label or in advertising, must be appropriately qualified to meet these requirements. This includes instances where the back panel list the indications in full but the main label only lists a brief summary of the indications. Consumers may not always read the full indications included on the back or side panel of the label.

Yes you can, for certain indications.

In general, permitted indications contain a single 'target' (e.g. a disease or symptom) and do not link general symptoms (e.g. 'relieves runny nose') to related conditions (e.g. 'relieves runny nose associated with common cold'). You can enter individual indications referring to symptoms and an indication referring to the symptoms of a disease or condition in your ARTG entry and then combine these on your medicine label, providing that the intent of the individual indications has not changed.

Certain indications can have other indications linked to them in ELF - these are called 'parent indications'. Parent indications are those that include the term 'symptoms of'. The indication code (indication codes are the TGA's unique identification number for indications and are viewable in TBS) of a parent indication ends in '- PR'

When a sponsor selects a parent indication in ELF, they are given the option to link symptom indications to it. However, parent indications can also be used as standalone indications.

Note that if a parent indication includes an indication qualifier (e.g. 'in adults') it is applicable to all indications linked under the parent indication.

Paragraph 4(3)(c) of the Determination allows sponsors to, on their product labels, vary the wording of indications entered in the ARTG (i.e. they don't have to be used word-for-word) and/or combine them into sentences. However:

• modifying/combining, must not result in the indications being different in meaning between the label and ARTG (i.e. the combined sentence must have the same targets and actions as that of the individual indications)
• the modified/combined indications must not infer or imply that a medicine is for the treatment of a serious disease/condition
• the modified/combined indications must not infer or imply that a medicine is for the prevention or cure of any disease/condition

An indication would have a different meaning if:

• it described a different therapeutic action or effect of a medicine - i.e. if 'reduce occurrence of' was replaced with 'prevents'
• it described a different physiological/psychological factor or process; or a different disease, ailment, defect or injury - i.e. if it referred to 'gastrointestinal pain' in place of 'gastrointestinal health'

Two combined indications would generally be considered to have the same intent and meaning if together they described a therapeutic action and target (a health benefit) that is consistent with the individual indications. If sponsors combine indications entered in the ARTG on their medicine label to give them a different meaning, then the certification made under paragraph 26A(2)(fba) of the Act may be incorrect. Table 5 provides example of combining indications.

Pregnant women are a particularly vulnerable population group who may be susceptible to being persuaded that a medicine is imperative for the optimal health of their unborn child. Given the vulnerability of this population group, the Code Tables do not include qualifiers for pregnancy and foetuses, as it is not appropriate for all permitted indications to be able to be directed for use in pregnant women.

Instead, there are specific indications for pregnancy and foetal development included in the Determination, for example: 'Maintain/support healthy pregnancy'; 'Maintain/support healthy foetal development'; 'Decrease/reduce/ relieve morning sickness'. All indications directed to pregnant women require the label statement: 'Advise your doctor of any medicine you take during pregnancy, particularly in your first trimester'.

Yes. However, the product name must not be used to specify a target population that is not available in the Code Tables unless that population is specifically included in a permitted indication in the medicine's ARTG entry.

If a product name includes the word pregnancy, all indications on the medicine label are, because of the product name, taken to be indicated for use in pregnant women. As such, only the specific permitted indications for pregnancy should be used, as it is not appropriate for any permitted indication to be able to be directed for use in pregnant women. For more information see Q.5 and Q18.

If you want to make pregnancy and foetal development indications not currently covered by the Permitted Indications Determination, you can apply for more specific pregnancy indications to be added to the Determination (using the 'Indication and Qualifier application' form via the TGA Business Services website ), noting that robust justification is expected as outlined in Q3. Alternatively, sponsors may be able to apply to enter their products in the ARTG via the assessed listed medicines or registration pathways.

Given the high probability of changing their intent, meaning and/or implying a disease or condition, it is not appropriate to combine indications for pregnancy with other permitted indications. However, it is possible that a medicine may have concurrent indications for different population groups. That is, you may have evidence that your medicine supports immune system health in women. You may also have other evidence that your medicine supports a healthy pregnancy. The medicine ARTG entry and label can include these separate indications concurrently (but not combined in a sentence).

Sponsors need to take particular care when using indications relating to pregnancy and foetal development with other permitted indications on their medicine label to ensure that the overall presentation of the medicine does not change the intent and/or meaning of the selected indications.

For example, if a sponsor selects 'Maintain/support healthy pregnancy' then any other indication included on the medicine label should be consistent with the maintenance of general health. There is a high probability that concurrent indications will have a different meaning if together they described a therapeutic action and target (a health benefit) for any disease or condition in pregnancy as this would not be consistent with the low risk status of listed medicines. Table 6 provides examples of using indications for pregnancy with other permitted indications.

If you want to make pregnancy and foetal development indications not currently covered by the Permitted Indications Determination you can apply for more specific pregnancy indications noting that robust justification is expected as outlined in Q3 above. Alternatively, sponsors may be able to apply to enter their products in the ARTG via the assessed listed medicines or registration pathways.

There has been some sponsor confusion that permitted indications are compliant with the advertising code and therefore approved for use in advertising. This is not the case - permitted indications have only been assessed to confirm they are suitable for listed medicines. One of the criteria for permitted indications is that the indication is capable of complying with the advertising requirements, including the Act and the Advertising Code when included on product labels and promotional materials. However, this does not mean that an advertisement containing the product's indications are compliant with the Advertising Code, as this requires consideration of the advertisement in its entirety and the likely consumer take out message - i.e. the likely impact of the advertisement on the reasonable consumer to whom the advertisement is directed.

Sponsors are responsible for ensuring that the overall presentation of their medicine [including interaction between, and acceptability of, indications as a group (see examples in Table 7), the label and any advertising used or provided to any other person for their use] is compliant with the labelling order, the advertising requirements in the Act, Regulations and the Advertising Code.

It is possible, for example, for permitted indications (which individually are low risk) to be combined to imply that a medicine is for the treatment of a serious disease which is not suitable for listed medicines. In these circumstances the certification made under paragraph 26A(2)(fe) of the Act that their medicine complies with the requirements set out in the Determination (that they must not imply treatment of serious diseases) would not be correct.

The required label statements for permitted indications relating to talking to a 'health professional', 'health practitioner' or a 'medical practitioner' have a specific intent and meaning:

• A health professional as defined in the Act, is any person belonging to certain health occupations such as medical practitioners, herbalists, naturopaths etc.
• A health practitioner as defined in the Act, is a person who, under a law of a State or internal Territory, is registered or licensed to practice certain health professions such as nursing, pharmacy etc. The label symptom statement relating to health practitioners have been intentionally specified in a small number of cases (e.g. for indications qualified by 'medically diagnosed') to avoid the indications being treated as restricted representations. Similarly, the statements for indications directed at pregnant women refer to health practitioner to reflect the potential vulnerability of this specific population group.
• A Medical practitioner is a person who is registered under the Health Practitioner Regulation National Law in the medical profession. For a small number of indications, sponsors must use the term medical practitioner (or words to the effect, e.g. doctor) on their label to reflect the more serious nature of the indication.

Care needs to be taken when including these statements on product labels to ensure that the intent and meaning of these statements is not changed.