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

Overview

• Key requirements - Indications - Establishing efficacy

• Application process

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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

Assessed Listed medicines

AUST L(A)

• Pre-approved ingredients • GMPBUT 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 2

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 3

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 4

Indication risk classification 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

X

Lower risk Higher risk 5

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

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• 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

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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

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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

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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

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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 11

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 12

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 13

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 14

Standard application process Pre-submission

meeting Submission Screening Evaluation Decision Implementation

ebs.tga.gov.au

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Pre-submission • Check eligibility

‒ Ingredients

‒ Indications

‒ Mandatory requirements

‒ Evidence Guidelines

‒ Application category

• Pre-submission meeting 16

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.

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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

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Find out more https://www.tga.gov.au/assessed-listed-medicines

complementary.medicines@health.gov.au

Questions?

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