Presentation: An overview of the new regulatory pathway for ......An overview of the new regulatory...
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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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Questions?
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