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Webinar recording: SME Assist - Permitted indications for listed medicines, March 2019
This recording is provided on the TGA's website solely for the purpose of indicating or suggesting what TGA representatives spoke about to the various conferences and seminars to which it relates. The papers are not legislative in nature and should not be taken to be statements of any law or policy in any way.
The Australian Government Department of Health (of which the TGA is a part) advises that (a) the recording should not be relied upon in any way as representing a comprehensive description of regulatory requirements, and (b) cannot guarantee, and assumes no legal liability or responsibility for, the accuracy, currency or completeness of the information contained in the recording.
Recording of online webinar
- Webinar date: March 2019
- Webinar summary: Help sponsors understand how to use permitted indications with their complementary medicine. This webinar is targeted at small to medium enterprises and any sponsor who is unfamiliar with the current permitted indication requirements.
Dr Adam Cook is here to my right. He's worked nationally and internationally for several years as a biomedical research scientist and previously at the TGA as a senior toxicologist, and he's now the director of the Listing compliance section within the Complementary medicines and over-the-counter medicines branch right here at TGA. I'll pass the camera to you. Thank you.
Dr Adam Cook Thanks Rachel. Hi everyone. Alright, so we're going to get straight into the presentation. Good afternoon everyone again, I'm really pleased to have the opportunity to talk to you about permitted indications for listed medicines.
Thanks Rachel. Hi everyone. Alright, so we're going to get straight into the presentation. Good afternoon everyone again, I'm really pleased to have the opportunity to talk to you about permitted indications for listed medicines.
Just to ensure we're all on the same page from the outset, I'd like to make sure that we all have the same understanding of what it is we're talking about when referring to an indication.
An indication is a statement that describes the therapeutic use of a medicine and, in the context of listed medicines, therapeutic use usually means in or in connection with influencing, inhibiting or modifying a physiological process in persons. This is defined in our governing legislation the Therapeutic Goods Act. So, it's that definition in particular that we turn our minds to.
We categorise indications in one of two ways in the case of listed medicines:
- Specific indications are those that refer to a named non-serious condition. So, for example, a reference to tonsillitis.
- Non-specific indications are those that refer to, for example, general health maintenance. In this example, there is no condition named. Rather, the indication refers to the overall health of the gastrointestinal tract.
Now importantly, marketing statements are not indications nor are claims of effectiveness or directions for use.
These statements don't describe a therapeutic benefit and you won't find them in the permitted indications list because they are considered to be claims.
So what is a permitted indication then?
A permitted indication is one that the TGA has already assessed as being suitable for use with listed medicines in terms of the particular wording. It means that they are low-risk.
They can refer to:
- health enhancement; for example, 'to enhance or promote skin health'
- health maintenance
- prevention of dietary deficiency
- or a non-serious form of a disease or ailment
Conditions, disease or ailments that are self-diagnosable or self-manageable are the ones that are permitted for use with listed of medicines. There have been some exceptions to this criterion for three indications linked to substance-based restricted representation approvals and they are for folic acid, calcium and vitamin D, and they appear in the permitted indications list.
Permitted indications have already commenced. The TGA has been very busy working on them for a couple of years now. They commenced on 6 March 2018.
Since this stage, the free-text field that was previously available for sponsors to formulate their own indications is no longer available for new medicines.
For existing products on the ARTG, there is a three-year transition period and that ends on 6 March 2021. So, sponsors of existing listed medicines will be required to transition their listing by this date.
Now importantly, any changes to indications on the listing that require you to transition, up until 6 September 2019, are free of charge. So, we do expect a lot of sponsors to be transitioning over the next few months to take advantage of that fee-free period.
If you think that a permitted indication has not been covered in the list and you'd like it to be included, sponsors can apply to have new indications considered for inclusion in the list of permitted indications. An application fee does apply and we do recommend that you check the current list thoroughly first because perhaps an indication that you're interested in is already covered by the list.
So where can you find this list of permitted indications? Well, it's actually contained in a legislative instrument which is called the Permissible Indications Determination. Only the indications in the Determination can be used when listing a medicine on the ARTG. It also includes requirements relating to the use of indications such as how they may be used on medicine labels.When applying to list a medicine, applicants are required to certify that under Section 26A of the Act that each indication entered in the Register is covered by the Permissible Indications Determination. They also certify that each indication included on the medicine label is covered by the Permissible Indications Determination. Lastly, they certify that each indication on the medicine label is also included on the ARTG entry.
So, what does it mean for an indication to be covered by the Permissible Indications Determination? Well, this means that:
- it is specified in the Determination
- tit is reproduced word-for-word on a label for example
- it is a more specific version of an indication that's in the Determination, but only through the use of optional qualifiers from the TGA Code Tables
- when used on the medicine label, the indication does not differ in intent or meaning. So, the indications on the label and the register need to be consistent in that way.
So, how can you ensure that all of the certifications are fulfilled and the indications are used in the appropriate way? Well, as shown here, there's a guidance document on permitted indications available that will help you understand the Determination and it also provides some examples. So, I encourage you to check out that document.
You can also browse and search the list of permitted indications on the TGA Business Services portal. You can search by evidence requirement. For example, indications that are for scientific or tradition of use evidence basis. You can search by keyword or a phrase or body system or part.
All medicines carry indications with varying restrictions and requirements attached.
High-risk medicines like those containing scheduled substances (so, those prescription medicines or over-the-counter medicines which carry an AUST R number) are fully evaluated for quality, safety and efficacy as part of an application process prior to them being registered on the ARTG.
Listed medicines are not pre-assessed by the TGA before they enter on the ARTG. Instead, they are monitored post-market. This is in line with their low risk. I should say that registered medicines are also monitored post-market but there's a very prominent role for post-market monitoring in the case of listed medicines.
Listed assessed medicines follow a similar pathway to listed medicines but they have more pre-market assessment by the TGA, notably for evidence supporting the claims made.
Permitted indications are intended for use with listed medicines to ensure that the indications for these low-risk medicines are worded correctly and do not reference serious conditions without pre-market assessment by the TGA. So, listed medicines can only use permitted indications. There is no other alternative. So, listed medicines always use those indications.
Listed assessed medicines may use permitted indications for their low-risk indications but they can also use free-text indications with our pre-approval.
Since registered medicines are rigorously assessed pre-market, permitted indications are not applied to them per se, although similar indications may be considered for use as part of the application process for those medicines.
Permitted indications actually follow a particular structure as I'm going to show here and they are composed of several elements:
- They have an action qualifier at the beginning. For example, 'Helps'.
- They may have an action. For example, 'reduce the occurrence of' or 'relieve'.
- They have a target qualifier. For example, 'symptoms of mild'.
- And finally, they have a target. For example, 'common cold' or 'skin burn'.
And so a permitted indication is made up of these elements.
Now permitted indications also come with certain obligations that you need to be aware of as a sponsor.
Here are some topics on the left that I'm going to go through to help you understand these obligations or these requirements. I just want to note that legislation allows for us to cancel medicines on the ARTG if the requirements are not met (requirements that are required to be met with the use of permitted indications).
So looking first at evidence.
Sponsors of listed medicines must hold evidence to support all the indications and claims for their medicines. The evidence must be related to the same medicine or active ingredients and have the same therapeutic action and context. So, for example, the same target population.
Permitted indications are suitable for listed medicines. This does not mean that we approve them for use with a given medicine. So, for whichever indication you decide to use as the sponsor, you'll need to have the relevant evidence that demonstrates efficacy in line with the indication. For instance, if the goods can relieve symptoms of a mild headache and you only have evidence to support that indication, you cannot use a permitted indication that suggests relief from migraines.
So, each indication will need supportive evidence relevant to your goods, and it's the evidence guidelines that provide guidance on:
- the types of indications and evidence sources
- how to assess relevance
- the quality and credibility of evidence
- obtaining, recording and presenting your evidence, which is important if your medicine is subject to a post-market compliance review
We regularly monitor listed medicines once they are on the market to assess whether they are compliant with regulatory obligations. Not having sufficient evidence for an indication is considered a breach of requirements and may be grounds for us to cancel your medicine from the ARTG.
The next topic is in regards to the ARTG.
This slide highlights an important point which is that permitted indications must be included on the ARTG entry for your goods. This means not just browsing the list and then applying them to the label or advertising of your goods, but actually recording them on the ARTG entry.
This is what it will appear like on the certificate of listing once that's been done successfully.
Failure to do so - that is, adding it properly to your ARTG entry – would also be considered a breach of regulatory obligations and potential grounds for cancellation of your good.
Thirdly, I'm going to talk to you about the use of qualifiers with indications. So, qualifiers help determine the focus of an indication to match the sponsor's evidence.
There are four main types of qualifiers that are available to use and these are shown in the TGA Code Tables. Most qualifiers are optional, but all require corresponding evidence.
If you add a qualifier that changes or narrows the scope of indication, the evidence should support the new scope.
Target population qualifiers specify a population sub-group that an indication applies to.
They can be optional but remember we would expect to see evidence that demonstrates the effect specifically in the population you choose. Only use a qualifier if you have the corresponding evidence to support the indication.
We have some examples here:
- If you only hold evidence in which a specific sub-population was studied – for example, children as seen here – the indication would need a qualifier.
- Without the population qualifier 'in children', we would assume the evidence that is held applies to generally healthy adults.
- The evidence seen here would be insufficient to support the indication without a qualifier as it specifically applies to children.
- But with the qualifier 'use in children', the evidence matches the qualifier.
If an indication is not directed to a specific population sub-group – that is, there is no qualifier – the supporting evidence would need to be relevant to the general Australian population.
Here we can see that the evidence is far more general and a qualifier is not required. A qualifier in healthy individuals could be used but it is not required. This is because, consistent with their low-risk status, listed medicines may only use low-level indications that will not lead to their unsafe or inappropriate use. It is assumed that they're intended for use by generally healthy individuals.
Now just a reminder that sponsors of listed medicines must hold evidence to support all indications and claims made for their medicine. It must be related to the same medicine active ingredients and have the same therapeutic action and target.
If it's not directed for a specific population sub-group, that is, if it's not qualified, the supporting evidence would need to be relevant to the general Australian population.
There are also some qualifiers for restricted populations.
Pregnant women are a vulnerable population 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 sub-group, there aren't population qualifiers available for pregnancy and foetuses, as it's not appropriate for all permitted indications to be able to be directed for use in pregnant women.
Allowing these groups to be selected for any or all of the core permitted indications is at odds with the low-risk nature of listed medicines. Instead, there are specific indications for pregnancy and foetal development. For example:
- 'Maintain support healthy pregnancy'
- 'Maintain/support healthy foetal development'
In these cases, the population is actually embedded within the core indication from the permitted indications list. Note that the use of these indications requires a specific warning statement too (I'll come back to that in a moment) that's stipulated in the Permissible Indications Determination.
The intent of the warning statements is that women should seek advice from their doctor when taking medicine during pregnancy. It's not to state that medicines should not be taken at all. Just a final note to remind you that you need to have relevant evidence to support these pregnancy/foetus indications. Using the indication in itself does not mean you don't need to hold evidence to back it up.
Another type of qualifier that's available to use is time of use qualifiers.
The time of use qualifier is an optional qualifier that indicates the time of therapeutic benefit for the medicine or the time of occurrence of a symptom. For example, 'Relieves muscle stiffness after exercise' ('after exercise' being the time of use qualifier) Remember though, that just like population qualifiers, don't use these qualifiers if you do not have corresponding evidence to support them.
Now, I think the final one I'm talking about today is traditional use, traditional context qualifiers.
Permitted indications can relate to specific traditional medicinal paradigms.
There are three traditional paradigms that you can select from using the appropriate traditional context qualifier:
- The traditional context is a mandatory qualifier for indications supported by evidence of a tradition of use. There are general traditional indications for a variety of paradigms. These must be supported by evidence of traditional use in a recognised paradigm outside modern conventional medicine. Indications can be used across different traditional paradigms. For example, 'blood cleanser' or 'purifier'.
- The list also specifically distinguishes Traditional Chinese Medicine (TCM) indications from the others. These must be supported by evidence of traditional use within traditional Chinese medicine and they use specific terminology within TCM. For example, 'Traditionally used in Chinese medicine to disseminate Lung Qi'.
- There is also a specific distinction for traditional Ayurvedic Medicine indications. These must be supported by evidence of traditional use within Ayurvedic medicine. For example, 'Traditionally used in Ayurvedic medicine to relieve aggravated Vata'.
Finally, it's important to note that if you do not apply a traditional context qualifier, then an indication is considered to be a scientific indication, and these must be supported by scientific evidence such as clinical studies or systematic reviews. So, an example of one of these is 'Help maintain/support bone mineralisation', which is taken to be a scientific indication.
Just a little bit about TCM indications.
There are quite specific ones here which are TCM pattern qualifiers. We recognise that some traditional paradigms have specific language with specific medicinal meaning attached to it. So, in this fourth type, we permit these pattern qualifiers. It's an optional qualifier for TCM medicines that specify the underlying pattern that causes the rise of the symptoms of the indication.
Remember that sponsors of listed medicines must hold evidence to support all the indications and claims including for the pattern qualifiers.
Moving on now to a bit about directions for use.
Directions for use are not required to be specified in a permitted indication. They're not a qualifier. They don't have to be recorded on the ARTG.
However, they cannot contradict an indication or existing qualifiers.
If your product is for use in generally healthy populations, you won't be able to include directions for use in relation to the elderly which are not encompassed by the default core indication. They can complement your existing qualifiers though. So, if your product is for use in women, your directions for use can reference women.
Alright, so now just a little bit about requirements.
I mentioned that these are specified in the Permissible Indications Determination and these can include label advisory statements. You must include these on your label where that's specified. For example, 'If symptoms persist, seek the advice of a healthcare professional' or words to that effect. If that's specified for an indication, then it must be included on the label. Failure to include these warning statements is a breach of requirements and your medicine may be cancelled from the ARTG if they're missing.
Some permitted indications also have presentation requirements; that is, overarching requirements to do with the presentation of the good. These are designed to ensure that, for example, the name of your goods or another indication doesn't contradict or lessen the impact of an important warning statement or message, or confuse the consumer as to the meaning of your permitted indication.
Let's look at an example from the Permissible Indications Determination. This is just a snapshot from one line in that Determination.
- You can see on the left the number. That's the number of the entry in the Determination.
- The next column shows the permitted indication itself – in this case, 'Relieve irritability'.
- We then have the type of evidence that can be used in the next column, scientific or traditional. Remember that which one you choose will have to be backed up by evidence where there's either option.
- And in the final column, you can see other requirements.
Here you can see that if you use the permitted indication 'Relieve irritability', you'll have to include a warning statement 'If symptoms persist…' on the label.
You can also see that the overall presentation of the goods cannot imply or reference mental illness disorders or issues. These requirements will apply to all advertising of the good including the label unless it is specified that the requirement only applies to the label.
Just a few words about proper use now of indications.
Many of the requirements just discussed are aimed at ensuring permitted indications are used correctly and do not present misleading information to the consumer. Often this relates to the overall presentation and advertising of a good.
We'll go through a few examples on how the indications can sometimes inadvertently be misused, thereby giving new or inappropriate meaning to a permitted indication and possibly causing a breach of regulatory requirements.
I should start by reiterating regulatory requirements.
The key focus of permitted indications is that they are specifically worded to not reference serious diseases, conditions or ailments.
As we've discussed, permitted indications are low-risk for use with low-risk listed medicines. So, a common error that occurs is modification of a permitted indication to imply or reference a serious disease, which may be a breach of the Advertising Code.
So, how could you reference or imply a serious condition?
Well, some permitted indications, if placed together or combined, can imply a serious condition. Here are some examples:
Let's look at this list of permitted indications which are all individually acceptable. They're available in the Permissible Indications Determination, and we'll assume that the sponsor has evidence for all of them also. However, when combined and used on the label or other advertising, they may imply that the medicine is for the treatment of post-natal depression, which is not suitable for listed medicines.
It's the sponsor's responsibility to make sure that they choose indications which are appropriate and be aware of misleading combinations.
Just some further words about the use of indications on label and advertising.
You have to be aware of how you write your permitted indications on your labels, websites and other advertising material.
They don't have to be included word for word on these materials, but the intent and meaning of the indication must not change. That is, they have to have the same therapeutic action and target. The overall presentation of your medicine must be consistent with the indications entered in the ARTG and compliant with the Advertising Code.
Just as we've discussed before, take care with the product name and the claims, graphics or other representations as these can all influence the original meaning of an indication.
Here's a really exaggerated example, but it does show the power of an image or a graphic in changing the meaning and intent of an otherwise simple indication.
Let's just take a look at another example.
On the ARTG, we have selected the permitted indication 'Maintains/supports gastrointestinal health'. This indication can be used word for word on a label or any other piece of advertising, obviously picking either 'support' or 'maintain'. But, as previously mentioned, the indications don't have to be used word for word.
Here we see two examples of how this permitted indication has been applied to a label. We have 'Maintains healthy gut' and we have 'Maintains healthy intestinal flora'.
The first has the same meaning and intent as the original indication, whereas the second one has a different meaning and intent to the one selected on the ARTG. We're starting to wonder if this means it will help our gut bacteria rather than our overall intestinal health.
And that brings us to the end of the presentation. I believe Rachel is going to pop up a survey for you now while we take a look at some of the questions you sent through, and I'll be back shortly.
End of slides
Dr Adam Cook: Hi everyone, I'm back.
I have with me here to help address some of your questions Nicholas from my section who's been a bit of a guide for me during today's session. So, I'm just looking across some of the questions and I think Nick is going to take me through them.
Nick (off screen): The first question that we've received today is about population qualifiers. The question is: If the evidence is on general adult population, do sponsors need to qualify? Could you elaborate a little bit on the population qualifiers?"
Dr Adam Cook: Sure. If the evidence held and the indication is relevant to the adult population, men and women, relevant to the Australian demographic, then the qualifier is not required to be used because that's our default expectation for the evidence that would be held.
Nick: Great. The next question we have is about relevance to the Australian population. The question is: "Can you elaborate on relevant to the Australian population? Does this mean that the research must be done in Australia?"
Dr Adam Cook: So, it doesn't mean that the research has to be done in Australia. But it does mean that the research has to be conducted in a population that's relevant demographically, ethnically to the Australian population. So, that may be performed abroad but depending on the indication made in maybe different scopes or types of populations that these studies are generated in and a sponsor who holds the evidence should have a clear ability to justify the transferability or relevance of their study population to the Australian population.
Nick: Great. The next question is again about qualifiers: "If a sponsor has the corresponding evidence for a qualifier but they don't put the qualifier on the ARTG record, is that an issue during a compliance review?" So, taking for example the example in the slides about children, if the evidence is in children but the qualifier wasn't included, would that be an issue? So, I assume just elaborate on the qualifiers generally.
Dr Adam Cook: Sure. So, in the absence of a qualifier, the indication is taken to be for the adult population said and relevant to the Australian population. If the evidence is related to children, then there'd be a mismatch between the evidence and the population that the indication is indicated for. So, the evidence always needs to match what is entered on the ARTG. It's just that in the case of males and females, healthy adults, that's our default expectation. So, it's not necessary to add a qualifier in that case.
Nick: The next question is about a warning statement: "For the warning statement 'If symptoms persist, seek the advice from a health professional', can a sponsor be more specific instead? For example, 'Consult a doctor if your problem persists'?"
Dr Adam Cook: So, the wording in the Determination is quite specific and we have given quite specific consideration to when we've indicated a particular type of health professional. Now, health professional is quite broad. So, as long as it's the same intent and meaning, that would be OK. What I would emphasise is that in some cases we've made the warning statement to be really quite specific about the type of health professional. And so that's really deliberate and should be followed by a sponsor.
Nick: And the next question: "If an indication is in the ARTG that has a corresponding label statement required and if we do not include that specific indication on the label, do we need to include the corresponding label statement on it?"
Dr Adam Cook: No. So, the warning statements are related to that indication. If they're not actually used (if an indication is not used on the label) then the warning statement would not be required. However, care should be taken to ensure that the presentation of the good doesn't in any way refer to that indication or population where it triggers a warning statement. So, I guess the simple answer is no. But it really depends on the context of the good. The sponsor would need to ensure themselves that the presentation of their good does not reference an indication that may have a label statement requirement.
Nick: And we have another question to do with qualifiers: "Can two types of qualifiers be applied to one permitted indication - for example, two population qualifiers – or does it have to be two different indications?"
Dr Adam Cook: The electronic listing facility doesn't permit multiple qualifiers to be added to one indication. To add more than one qualifier on the listing, the indication needs to be added a second time, for example. But then when it comes to the presentation of the good, obviously you don't have to repeat the indication another time. You can use both qualifiers. That's just a technical limitation of the listing facility where we're unable to provide the option to add multiple qualifiers simultaneously to one indication.
Nick: And along a similar vein again with qualifiers: "If there's a medicine that has a specific qualifier for a specific age group, do they need to define the age group in the population qualifier or can they just put in general 'children' and just have the qualifier for the broad child population?"
Dr Adam Cook: So, if the evidence is for a really narrow range of the population that's within a broader population entered on the ARTG, then that would be a mismatch with what's on the ARTG. So, the assumption is for children that the evidence is applicable to the children of all ages within that population. If the evidence is for a narrow window, then the sponsor would have to ensure themselves that it's applicable to all children. And that's something that the sponsor needs to ensure – that it's a criterion that they would be able to justify.
Nick: And one more question: "Some of the permitted listed indications specify only scientific evidence is accepted. However, if traditional evidence can be found for the indication, is this acceptable or is there a process to notify the TGA of that?"
Dr Adam Cook: Yeah, sure. So, we do have an application process to propose, or for sponsors to apply for, consideration of new indications to go on the list and on the Determination. So, if there is an indication that's present at the moment that is only indicated for scientific evidence, but an applicant thinks that there is a traditional evidence base, they apply to us for consideration of expansion of that to also be covered by traditional.
Rachel: Alright, thanks Adam.
Dr Adam Cook: You're welcome.
Rachel: Thank you everyone. We're going to wrap it up there. Thanks for your time.
Dr Adam Cook: You're welcome. Thanks to everyone.
Rachel: And thank you guys for your time and all the questions.
Today's presentation will be located on the TGA website (www.tga.gov.au, under the media room tab). You'll find it there within the coming weeks. Thank you all again.