Recommendation 39 of the Review of Medicines and Medical Devices Regulation (MMDR review) proposed the introduction of new pathway under which listed medicines can be assessed for efficacy.

1. An overview of the new regulatory pathway for listed
medicines – Assessed listed medicines
Ali Alaraji
Director (A/g), Complementary Medicines Evaluation Section
Complementary and OTC Medicines Branch
Medicines Regulation Division, TGA
ARCS
21 August 2018

2. Overview
• Key requirements
- Indications
- Establishing efficacy
• Application process

3. Three pathways for complementary medicines
Australian Register of Therapeutic Goods
(ARTG)
AUST L
Listed medicines
No pre-market evaluation
BUT
• Pre-approved ingredients
• GMP
• Permitted indications
AUST L(A)
Assessed Listed medicines
• Pre-approved ingredients
• GMP
BUT
Pre-market evaluation for:
• Efficacy – Intermediate (&
permitted) level indications
• Optional ‘claimer’
AUST R
Registered medicines
Pre-market evaluation for:
• Safety
• Quality
• Efficacy
• Optional ‘claimer’ ???
Lower risk Higher risk

4. Key requirements
Ingredients
Must draw exclusively from the permitted ingredients list. Ingredients must not be included
(or meet the criteria for inclusion) in a schedule to the Poisons Standard.
Product &
manufacturing quality
Must comply with applicable standards and meet the PIC/S guide to GMP. Must not be of a
type required to be sterile.
Indications
Product must contain at least one intermediate level indication which exceeds the
permitted indications list but are not high level indications. Can also have other low level
indications.
Evidence
Evidence of efficacy of the finished product submitted by the sponsor to support associated
indications and claims.
Pre-market assessment
Pre-market assessment of efficacy evidence for all indications, and pre-market assessment
of the product label.
Presentation
AUST L(A) number. Sponsors have the option to use a ‘claimer’ on product label and
promotional material to indicate the product has been independently assessed.
Post-market compliance
Products may be selected for random or targeted review to confirm applicant certifications
are correct. Efficacy evidence would not be routinely reassessed post-market

5. Indication risk classification ✓
Low level Intermediate level High level
A low level indication may refer to:
• health enhancement
• health maintenance
• prevention of dietary deficiency
• a disease, ailment, defect or
injury other than a serious form
of those diseases.
Indications that are not appropriate for the list
of permitted indications, but are not high level
indications.
Intermediate level indications may refer to:
• the prevention, alleviation, or cure of a
non-serious disease, ailment, defect or
injury
• restricted representations (i.e. a serious
form of a disease).
Indications that refer to the
prevention, alleviation or cure of a
serious form of a disease, ailment or
injury (i.e. restricted representations).
Lower risk Higher risk

6. Indication risk classification X
Low level Intermediate level High level
A low level indication must not:
• refer to, or imply, the prevention,
alleviation, or cure of any form of a
disease, ailment, defect or injury
• contain a restricted representation
• have been specified in a non-permitted
indications list
• contain a prohibited representation
An intermediate level indication
must not:
• refer to the prevention,
alleviation or cure of a restricted
representation (i.e. a serious
form of disease)
• contain a prohibited
representation
A high level indication must not:
• Contain a prohibited
representation
Lower risk Higher risk

7. Examples of indications
Low level indications (AUST L) Intermediate level indications AUST L(A)
• Helps enhance exercise performance and
stamina
• Traditionally used in Chinese medicine to
disseminate Lung Qi
• Traditionally used in Western herbal medicine
to improve digestion
• Helps maintain blood levels of Vitamin D
• Aids/assists healthy red blood cell production
• Relieves abdominal bloating and distention
• Prevents muscular cramps and spasms
• Prevents cold sores
• Reduces symptoms of tinnitus
• Alleviates mild dermatitis
• Relieves rheumatoid arthritis symptoms, such as
inflammation and pain
• Relieves symptoms of gastroesophageal reflux
disease

8. • Assessment of efficacy data will be based on the finished
product (rather than active ingredients in isolation) and
include a detailed evaluation of evidence to support all
indications and claims
• Only products supported by quality scientific evidence of
efficacy will be accepted for assessment through this
pathway
• Guidelines on the evidence requirements are available on
TGA website
First twelve months 'implementation phase‘ to review and refine the
evidence guidelines, administrative processes and timeframes

9. Application categories
L(A)1 L(A)2 L(A)3
Products identical to existing
AUST L(A) other than permitted
differences
Generic of TGA fully evaluated
AUST L(A)
OR
Comparable Overseas Regulator
(COR) report for efficacy.
Note: COR guidance currently under
development
Products not covered by L(A)1 or
L(A)2
i.e.
new product requiring de novo
evaluation or a variation to an
existing AUST L(A)
40 working days preliminary assessment
45 working days evaluation 60 working days evaluation 150 working days evaluation

10. Methods of establishing efficacy
L(A)1 L(A)2 L(A)3
Access to reference
medicine dossier
Generics
• Meets biopharmaceutic and
pharmacokinetic study requirements
• Justification for use of particular
ingredient combinations, including
potential interactions
COR
• Full un-redacted COR evaluation
report
Method 1
• clinical trials on the product
Method 2A
• combined efficacy and bioavailability/bioequivalence
data to support product efficacy
Method 2B
• combined efficacy and dissolution or in vivo
pharmacokinetic studies to support product efficacy

11. L(A)3 methods of establishing efficacy
Method Suitable product type
1
All product types including traditional, herbal,
probiotic and conventional medicines
2A Systemically acting isolated chemical substances
2B
Products with a compliant biowaiver or that do not
require biopharmaceutic studies or clinical efficacy
studies

12. Efficacy data
Method 1
(all types)
Method 2A
(systemically acting isolated
chemical substances)
Method 2B
(biowaiver or not requiring
biopharmaceutic studies)
Full literature search ✓ ✓ ✓
Published studies or
clinical study reports
✓
finished
product
✓
each active
✓
each active
Biopharmaceutic and
pharmacokinetic
evidence
X
not normally
required
✓
bioequivalence or comparative
dissolution
✓
in vitro dissolution or PK studies
demonstrating in vivo release of
actives
Formulation
All methods must provide justification of the use of the particular combination of
ingredients, including potential interactions between ingredients
Refer to AUST L(A) Evidence guidelines – Table 5

13. Evidence hierarchy
Category A Category B Category C Category D
Double-blind,
randomised, controlled
trials
(including cross-over
trials)
Observational studies
e.g. cohort and case
control studies
Non-systematic, generalised
reviews
(including databases)
Traditional reference text
Systematic reviews
Comparative studies
(non-control)
Publicised international
regulatory authority articles
Herbal monograph
Evidence based reference
text - scientific
Herbal pharmacopoeia
Scientific monographs
Materia medica
Publicised international
regulatory authority articles
(traditional only)
Refer to AUST L(A) Evidence guidelines – Table 6

14. Minimum evidence requirements
Indication Primary (intermediate) Secondary (low level)
Indication
type
Scientific Scientific Traditional
Required
evidence
Minimum of one from
Category A
OR
Minimum of two sources from
Category B and one from
Category C
Non-specific indications
Minimum of two sources from
Category B or Category C
Non-specific indications
Minimum of two sources from Category D
to support the tradition of use
Specific indications
Minimum of one from Category A
OR
Minimum of one from Category B and
two from Category C
Specific indications
Minimum of two sources from Category D
to support the tradition of use
PLUS
Additional evidence from Category C or D
to support the specificity of the traditional
indication
Refer to AUST L(A) Evidence guidelines – Table 7

15. Biopharmaceutic and pharmacokinetic studies
• Essential component of establishing efficacy
• Excipients effect bioavailability → efficacy and safety
e.g. 1968 phenytoin intoxication
• New / generic products - L(A)3 and L(A)2
• Guidance 15: Biopharmaceutic Studies
• Studies performed against innovator
• Some products may not require biopharmaceutic
studies
• Rapid effect claims

16. Standard application process
Pre-submission
meeting
Submission Screening Evaluation Decision Implementation
ebs.tga.gov.au

17. Pre-submission
• Check eligibility
‒ Ingredients
‒ Indications
‒ Mandatory requirements
‒ Evidence Guidelines
‒ Application category
• Pre-submission meeting

18. Dossier structure
• Dossier structure based on a simplified version of the Common Technical Document (CTD)
format.
• The following components are required for L(A)3 applications:
- CTD Module 1 (Administrative information e.g. cover letter, labels)
- Module 2 (overviews - summaries of Module 5 data)
- Module 5 (clinical data to support efficacy)
• This must include any valid justifications as to why any data may not be required.
• Minimum format requirements:
- Single text-searchable, bookmarked/ hyperlinked PDF document for each module
- CTD heading and numbering must be used in each module.

19. Evaluation
• Evaluation against:
– Mandatory requirements
– Evidence guidelines
– TGO 92 and Advertising Code (label)
• S31 request: opportunity to clarify questions/issues
– Clock will stop
• Timeframes based on level of de novo evaluation
required
• May seek advice from expert advisory committees

20. Find out more
https://www.tga.gov.au/assessed-listed-medicines
complementary.medicines@health.gov.au

21. Questions?