TGA presentation: Permitted indications for listed medicines

Complementary medicines reforms to the sponsor education workshop given at Sydney, Melbourne, Brisbane, Canberra, November-December 2017

12 December 2017

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The Australian Government Department of Health (of which the TGA is a part) advises that (a) the presentation papers 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 presentation paper.

Presentation

  • Presented by: Michael Shum, Director, Complementary and OTC Medicines Branch
  • Presented at: Complementary medicine reforms information sessions
  • Presentation summary: This presentation gives an overview and update of the progress of the permitted indications reform and what it means for sponsors.

Transcript

Complementary medicines reforms sponsor education workshops

Michael Shum
Director, Complementary and OTC Medicines Branch
Medicines Regulation Division, TGA

Slide 1 - Recommendation 38: Permitted Indications

Recommendation 38

The Panel recommends that the TGA establishes the list of Permitted Indications, from which sponsors must exclusively draw, for listed medicinal products in the ARTG.

Government response

The Commonwealth accepts Recommendation 38, noting that implementation of the list of Permitted Indications will require legislative change and will be subject to consultation with consumers, sponsors and health professionals

Slide 2 - Objectives

The purpose of establishing the list of permitted indications is to:

  • ensure that listed medicines can only make low level indications that are suitable for medicines that do not undergo pre-market assessment
  • provide transparency for sponsors on what indications are suitable for listed medicines to help prevent inadvertent non-compliance
  • avoid consumers from being misled by inappropriate indications on listed medicine labels
  • These objectives need to be balanced to ensure flexibility for industry

Slide 3 - What does this mean for sponsors?

  • Sponsors listing a medicine on the ARTG will only be able to use indications from a permitted indications list
  • 'Free text' field will no longer be available
  • Sponsors must continue to hold supporting evidence for their medicine indications
  • There must not be inconsistency between the indications that are listed in the Register and on the label
  • 3 year transition period for existing listed medicines

Slide 4 - Legislative overview

Slide 5 - Legislative framework

  • Medicines, including complementary medicines, are regulated under the Therapeutic Goods Act 1989 (the Act)
    • TheActsetsout the legal requirements for the import, export, manufacture and supply oftherapeutic goodsin Australia
    • The Act is supported by the Regulations,and various legislative instruments (e.g. Orders and Determinations)which provide further details of matters covered by the Act
  • Introductionof the permitted indications reform requires a number of legislative andregulatory changes and new legislative instruments

Slide 6 - Legislative changes for permitted indications

Application and certification changes

  • Introduce new requirement for medicines that are listed under 26A must only make permitted indications
  • Indications on the label and in the Register must be consistent

Establishing the list of permitted indications

  • Enables the Minister to determine
    • a list of 'permitted indications' or
    • a list of 'non-permitted indications'
    • Application procedures and criteria for new indications

Slide 7 - Legislative changes for permitted indications

  • Consequential amendments
    • Conditions of listing
    • Cancellation provisions
  • Transitional arrangements for existing products
    • All existing products to be re-listed
    • Provisions to ensure that sponsors can maintain continuous legal supply

Slide 8 - Transition arrangements

  • From 1 January 2018, all new listed medicines must select permitted indications (free text will be turned-off)
  • Sponsors of existing listed medicines will be required to transition their existing indications to 'permitted indications' by 31 December 2020:
    • AUST L numbers will not change (where 'grouping' applies)
    • Fee waiver if indications changed by 30 June 2019
  • Listed medicines that do not transition to permitted indications will be cancelled from the ARTG from 1 January 2021

Slide 9 - Transition arrangements – product changes

  • During the transition period, any product that is the subject to changes that amount to it being a separate and distinct good under the Act must transition at the time of making the change
  • These include changes to:
    • active ingredient or quantity of active ingredient
    • dosage form
    • product name
    • excipients
    • indications
  • Other product changes (9D variations) will not be required to transition at the time of the change

Slide 10 - What if my indication is not on the permitted list?

  • Before the end of the 3 year transition period, sponsors will be required to either:
    1. transition to 'permitted indications' by selecting appropriate indications from the list
    2. apply to add a new indication to the list and then apply to list their product; or
    3. if the medicine has higher-level indications, apply to list their medicine through the new assessed list medicine pathway

Slide 11 - Regulation amendments

This diagram illustrating the regulation amendments for eligibility medicines to be entered on the different parts of the Register.

Slide 12 - Establishing the list of permitted indications

  • The list of permitted indications will be made as a legislative instrument containing:
    • a comprehensive list of low risk indications that must be used to list a medicine in the ARTG
    • 'requirements' relating to the use of indications
      • including general rules for how permitted indications are entered in the register and used on medicine labels

Slide 13 - What is a permitted indication?

  • A permitted indication describes a therapeutic use for a listed medicine
  • Therapeutic use for listed medicines means use in, or in connection with, 'influencing, inhibiting or modifying a physiological process in persons'
  • Indications can be:
    • specific (e.g. refer to a named non-serious condition); or
    • non-specific (e.g. general health maintenance)

Slide 14 - Permitted indications – structure

  • Permitted indications have a consistent structure and terminology to describe the therapeutic uses that are appropriate for listed medicines
  • All permitted indications contain an 'action' and a 'target'

Action qualifier E.g 'help' plus Action E.g 'relieve' plus target qualifier E.g 'mild' plus target E.g 'dry skin'

E.g. Help to maintain/support healthy joints

Slide 15 - Non-indication statements and claims

  • Statements that do not describe a therapeutic use will not be included in the permitted indication list, for example:
    • Marketing statements
      • e.g.: 'Fast action formula'
    • Claims of effectiveness
      • e.g.: 'Improves by 10%' or 'Water resistant'
    • Structure, function, and/or mechanism of action statements
      • e.g.: 'Calcium is a natural component of bone'.
        • In some cases you may need to ensure you have chosen a related permitted indication

Slide 16 - Non-indication statements and claims

  • Non-indication statements are not required to be included on the ARTG in order to be used on product labels or other promotional material
  • However, you must certify that you hold information or evidence to support any statement/claim included on your medicine label
  • Your medicine may be cancelled from the ARTG if you hold incomplete or insufficient evidence to support all claims made for your product

Slide 17 - Criteria for permitted indications

  • Permitted indications meet the criteria for low-level indications:
    • health enhancement, e.g.  'May reduce fatigue'
    • health maintenance, e.g. 'Helps support healthy joints'
    • prevention of dietary deficiency, e.g. &'May prevent calcium deficiency'
    • a non serious form of a disease or ailment etc., e.g. 'Helps decrease/ reduce/relieve symptoms of common cold'
    • These are conditions that are self-diagnosable or self-manageable

An exception to these criteria will be made for indications linked to substance-based restricted representation approvals (folic acid, calcium and vitamin D)

Slide 18 -

Requirements – Type of evidence
'General' indications Can be supported by either scientific evidence or a tradition of use, e.g. "Relieve dry skin"
Traditional indications Include traditional terms that may be applicable across multiple traditional paradigms, e.g. "cholagogue", "alterative" "adaptogen" and must be support by a tradition of use.
Traditional Chinese Medicine indications Contain TCM specific terminology and must be supported by evidence of TCM use, e.g. "Increase Qi flow"
Traditional Ayuvedic Medicine indications Contain Ayuvedic specific terminology and must be support by specific evidence of use, e.g. "Balance Vata
Scientific indications Must be supported by scientific evidence only, e.g. "Helps maintain/support bone mass/density"

Traditional medicines must include a traditional use qualifier in the ARTG and on the product label

Slide 19 - Specific requirements for permitted indications

  • There will  be requirements relating to the use of certain indications in a listed medicine
  • The requirements may specify circumstances when an indication can or cannot be used or specify conditions that must be met. For example, requirements may:
    • Require a warning statement to be included on product labels, e.g.: 'If symptoms persist consult your healthcare practitioner (or words to that effect)'
    • Specify a vulnerable population for which the indication is not suitable, e.g.: 'Not suitable for use in children under the age of 12 months'
    • Require that the presentation of the medicine must not refer to or imply a serious form of a disease

Slide 20 - Permitted indications - Examples

The legislation will allow for cancellation of a medicine from the ARTG if the requirements relating to the use of the permitted indication are not complied with

Slide 21 - Indications catalogue

  • All listed medicine indication information and associated restrictions will also be available in an online database
  • Updates to the online database will be made to match updates to the Permissible Indications Determination
  • Ability to conduct searches using indication information such as; key words, phrases, evidence requirement or body part/system

Slide 22 - How to use permitted indications in your listing application

Slide 23 - How to select permitted indications for your medicine

  • Step 1: Review the evidence that you hold for your permitted indications
  • Step 2: Select a 'core' permitted indications (action and target only)
  • Step 3: Select qualifying terms to align indications with the evidence you hold for your medicine.
  • Step 4: Ensure that the medicine label is compliant with all necessary regulatory requirements

Slide 24 - Step 1: Review the evidence for your medicine

  • Sponsor must hold evidence for all indications and claims
  • Best practice to review your evidence to make sure they supported your indications
  • Evidence Guidelines provide guidance on:
    • Types of indications and evidence sources
    • Assessing relevance, quality and credibility
    • Obtaining, recording and presenting evidence

Slide 25 - Step 1: Review the evidence for your medicine

  • We will make minor modifications to the Evidence Guidelines for Listed Medicines prior to the permitted indication reform coming into effect
  • We are planning a complete review of the evidence guidelines next year

Slide 26 - Step 2: Selecting a core permitted indication

  • ELF will allow you to search for and add permitted indications into your ARTG entry
    • Evidence Requirement, e.g.: Scientific or tradition of use
    • Key word / phrase, e.g.: 'cough' or 'itchy'
    • Body system / part, e.g.: 'Body - ear' or 'Gastrointestinal - Bowel'
    • Indication Code, eg: BDEYH-S-MS

Slide 27 - Step 3: Selecting evidence qualifiers

  • You will be able to select appropriate evidence qualifiers to make a permitted indication more specific and align with the evidence you hold for your medicine
  • If a qualifier is included on the Register, it must be included on your product label

Slide 28 - Step 3: Selecting evidence qualifiers

Screen image of step 3: Selecting evidence qualifiers

Qualifiers will be included in the ELF code tables not in the permitted indications list

Slide 29 - Step 4: Including indications on medicine label

Indications will not have to be included 'word for word' on your label or advertising material:

  • the intent and meaning of the indication must not change
    • i.e. the same therapeutic action and target

For example:
ARTG indication: 'Maintain/support gastrointestinal health'
Label indication - same meaning: 'Maintains healthy gut'
Label indication - different meaning: 'Maintain healthy intestinal flora'

Slide 30 - Step 4: Including indications on medicine labels

The permitted indications list will contain 'primary' indications referring to diseases or conditions and indications referring to general symptoms

For example:

Helps decrease/ reduce/relieve symptoms of common cold

  • Helps decrease/reduce /relieve cough
  • Helps decrease/reduce /relieve watery eyes
  • Helps decrease/reduce /relieve nose

These symptoms can be linked to 'symptoms of common cold'

These indications can be combined on the product label to form a simple sentence, e.g.: 'Relieve symptoms of common cold such as cough, runny nose and itchy eyes'

Slide 31 - Step 4: Including indications on medicine label

  • Some indications will have mandatory qualifiers or required warning statements
  • Where these are specified in the permitted indications determination, they must also be included on your medicine label.

For example:

Indication Specific requirement relating to the use of the indication in the medicine
Decrease/reduce/relieve symptoms of mild arthritis/mild osteoarthritis

Label statement: 'If symptoms persist consult your healthcare practitioner (or words to that effect)'

Must be qualified by 'mild'

Must not be for serious forms of arthritis e.g. rheumatoid arthritis, juvenile arthritis, debilitating osteoarthritis

Slide 32 - Summary – Using permitted indications

Applications are required to select a ‘core’ permitted indication from the permitted indications list and align with traditional or specific use.

Slide 33 - Listed Medicines Compliance Framework

This flowchart illustrates the framework for Medicines Compliance with the ARTG.
The medicines maybe selected for review or assesed randomly by 

  1. Pre-approved ingredients
  2. Good manufacturing practice (GMP)
  3. Permitted indications

If fully compliant the medicines may be:

  • Medicine listed on ARTG
  • Post-market Compliance review

If non-compliant:

  • Cancelled from ARTG

Slide 34 - Post market compliance review outcomes

  • Where we identify a compliance issue we can:
    • Issue a proposal to cancel notice
      • sponsor is given a reasonable opportunity to correct the issue
    • Cancel the product immediately
  • Medicines making indications not covered by the permitted indications would be cancelled immediately
    • In general, we will work with you to bring your product back into compliance

Slide 35 - How to apply for new permitted indications

Slide 36 - Applying for a new permitted indication

  • After 1 January, an application form will be available for new permitted indications to be added to the list
    • A fee of $1000 will apply
  • Evidence to support a proposed indication will not be evaluated by the TGA. However, applications will be assessed against the legislated criteria 
  • The permitted indication list is likely to be updated on a quarterly basis, as is the process for new ingredients

Slide 37 - Agreed criteria for new permitted indications

  1. Must be a therapeutic indication (describe a therapeutic use)
  2. Must be a low level indication
  3. Must be capable of complying with the Advertising Code when included on promotional materials
  4. Must be consistent with the treatment paradigm (scientific/ tradition of use)

Slide 38/39 - Is it a low-level indication?

Is it a low-level indication?
Criterion What this means Examples
Health maintenance Normal physiological effects of substances in; growth, development and normal functions of the body

Maintain eye health

Maintain healthy liver function

Support healthy connective tissue / joints

Health enhancement Beneficial effects of substances on the physiological and /or psychological state of the body;
  • above and beyond normal growth, development and functions of the body

Improve immune system defence

Promote bowel regularity

Digestive stimulant

Prevention or alleviation of a dietary deficiency

Prevention of mild dietary deficiency

(not prevention of diseases resulting from severe deficiency)

Helps prevent dietary calcium deficiency

Helps prevent dietary vitamin B12 deficiency

A non-serious disease, ailment, defect or injury Those low risk conditions that are non-serious and self manageable.

May be related to;

  • reduction in risk/frequency/duration
  • relief
  • management or improvement in quality of life

…without resolution of the underlying non-serious disease, ailment, defect, condition or injury.

Relieve joint stiffness associated with mild osteoarthritis

Relieve symptoms of common colds

Relieve menstrual cramps

Relieve dry skin associated with mild eczema

Slide 40 - Indications NOT suitable for permitted indications list

The indication, must not:

  • refer to, or imply, the prevention or cure of any form of a disease, ailment, defect or injury
  • contain a prohibited representation
  • contain a restricted representation
  • be specified in a non-permitted indications list (if made)

Slide 41 - What is a prohibited representation?

Under the Therapeutic Goods Advertising Code 2015, a prohibited representation is defined as:

  1. any representation regarding abortifacient action; or
  2. any representation regarding the treatment, cure or prevention of the following diseases:
  • Neoplastic (i.e. cancer)
  • Sexually Transmitted Diseases (STD)
  • HIV AIDS and/or HCV; or
  • Mental illness (e.g. depression, anxiety, low mood)

Slide 42 - What is a restricted representation?

A restricted representation is serious form of a disease, condition, ailment or defect included in Table 1, Appendix 6 Part 2 of the Therapeutic Goods Advertising Code 2015

For example:

  • Cardiovascular diseases
  • Diseases of joint, bone, collagen, and rheumatic disease
  • Diseases of the eye or ear likely to lead to blindness or deafness
  • Diseases of the liver, biliary system or pancreas
  • Endocrine diseases and conditions including diabetes and prostatic disease
  • Gastrointestinal diseases or disorders
  • Infectious diseases

Slide 43 - What is a serious form?

Serious', means those diseases, conditions, ailments or defects that are generally accepted:

  • not to be appropriate to be diagnosed and/or treated without consulting a suitably qualified healthcare professional, and/or
  • to be beyond the ability of the average consumer to evaluate accurately and to treat safely without supervision by a qualified healthcare professional

Slide 44 - Other considerations

  • Must be capable of complying with the Advertising Code when included on promotional materials:
    • must not be likely to mislead consumers (e.g. improves the IQ of your unborn child)
    • can't imply the medicine is infallible, unfailing, magical, miraculous or that is certain or guaranteed to cure
    • must not state or imply that the product is effective in all cases of the condition
  • Must be consistent with the treatment paradigm (scientific/ tradition of use)

Slide 45 - Further information

  • New guidelines:
    • 'Permitted indications for listed medicines guidelines'
    • Update to the 'Evidence Guidelines for Listed Medicines'
  • New permitted indications webpage
    • Frequently asked questions page
    • Permitted indications factsheets
  • Contact us

Slide 46 - Development of the permitted indications list

Slide 47 - Development of the permitted indications list

  • The list of permitted indications has been developed in consultation with stakeholders based on agreed criteria
  • Draft list is based on industry submissions to previous consultations and refined following stakeholder feedback
  • Targeted consultation on the list also included stakeholders concerned with traditional paradigms, such as TCMs

Slide 48 - Development of the permitted indications list

  • Draft list published on TGA website in July 2017
  • Stakeholders were able to provide TGA with feedback on the list and propose new indications free of charge
  • New indications proposed after this time will incur a fee
  • Comment period closed on 1 October 2017 to enable the drafting and publication of the legislative instrument
    • More than 3000 proposals for additional indications
    • More than 900 proposals for additional qualifiers
  • We are still in the process of reviewing the comments received

Slide 49 - Issues arising from comment period

1. Indications covered by advertising exemptions for restricted representations

  • Restricted representations will require assessment through the new assessed listed medicines pathway.
  • Exception: Indications with substance based restricted representation approvals, for folate (neural tube defect), calcium and vitamin D (osteoporosis) will be included in the permitted indications list, based on a safe history if use, and an established evidence base

2. Biomarker indications e.g. cholesterol, blood glucose, blood pressure

  • Only low level biomarker claims are included in the permitted list – e.g. 'Maintain cholesterol health'
  • Higher level indications are indicators of serious disease – these may be assessed through the new listing pathway – e.g. 'Maintain within the normal range….'

Slide 50 - Issues arising from comment period

3. Inclusion/non inclusion of vulnerable populations as evidence qualifiers

  • E.g. pregnancy, foetal development, infants
  • Potential safety concern if these population groups are used as population qualifiers for any indication

4. Use of the term 'medically diagnosed'

  • Included for a limited number of conditions
  • Requests to include other conditions e.g. benign prostatic hypertrophy, tinnitus
    • Only appropriate for a person to self-manage and assess the symptoms of their condition after an initial diagnosis has been made

Slide 51 - Issues arising from comment period

5. Use of mild and mild/moderate qualifiers

  • 'Mild' is used to ensure that indications do not refer to a serious condition
  • Comments that mild qualifier is unnecessary for some indications e.g. stress and migraine
  • Requests 'mild to moderate' to beacceptable for certain indications e.g. mild to moderate osteoarthritis, mild to moderate temporomandibular joint pain

Indications for diseases or conditions of moderate severity may be appropriate for the new assessed listed medicine pathway

Slide 52 - Issues arising from comment period

6. Requirement for sunscreen indications to be compliant with new guidelines

  • All listed medicines will be required to transition to permitted indications
  • Only indications compliant with ARGS will be included in the list
  • Previously grandfathered sunscreens will have to comply with new ARGS

7. Clarification required of when function/ mechanistic claims can be used

  • If you wish to use a structure/function claim on your label that implies a therapeutic use you should enter an appropriate permitted in the Register
    • Label statement: 'Source of calcium. Calcium strengthens bones'.
    • ARTG indication: 'Maintains/supports bone strength'

Slide 53 - Issues arising from comment period

8. Inclusion /removal of cosmetic claims

  • Clarification required for distinction between cosmetic claims and therapeutic indications
    • Are they for health enhancement?

9. Inclusion of cellular level indications

  • Concern expressed that there is lack of evidence to support cellular level indications
  • Are the suitable for listed medicines and/or meaningful to consumers? More general indications are often available
  • Do they describe a therapeutic use?

Slide 54 - Issues arising from comment period

10. Inclusion of TCM and Ayurvedic specific terminology

  • Concern that these are not understandable for average consumer
  • However, if not included, general indications are not meaningful to consumers and practitioners familiar with these traditional paradigms
  • Concern combinations of indications can imply serious conditions
    • 1000 additional TCM indications proposed
    • We will seek expert advice to assist us determine if  these are appropriate for listed medicines

Slide 55 - Questions?

Visit the Complementary Medicine Reform page on the TGA website

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