the assessed listed medicines pathway
TRANSCRIPT
Complementary medicines reforms Sponsor Education Workshops
The assessed listed medicines pathway
Dr. Michael Gardner
Director, Complementary Medicines Evaluation Section
Complementary and OTC Medicines Branch
A new pathway for listing medicines
• Established under Recommendation 39 of the MMDR review.
• Three options by which sponsors may seek entry into the ARTG of complementary medicinal
products and other listed medicinal products for supply in Australia:
- Option 1: Listing in the ARTG following self-declaration by the sponsor of the safety, quality and
efficacy of the medicine (listed medicines).
- Option 2: Listing in the ARTG following self-declaration by the sponsor of the safety and quality of
the product, and following pre-market assessment of the efficacy of the product by the TGA.
- Option 3: Registration in the ARTG following full pre-market assessment of the product
(registered complementary medicines).
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2017 Sponsor Education Workshops
Key features
• A new product assessment pathway sitting between the existing Listed medicine (lower risk) and
Registered medicine (higher risk) pathways.
• Provides access to higher level indications than available in the Permitted Indications list, but which are still
appropriate for listed medicines (‘intermediate indications’).
• Sponsors self-certify the quality and safety of the product.
• TGA undertakes pre-market assessment of the efficacy of the finished product, and of the product label.
• Product has an AUSTL(A) number.
• Sponsors have the option to include a claimer that their product has undergone assessment by the TGA.
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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.
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, and pre-market assessment of the product
label by the TGA.
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
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Ineligible products
• Products that only have efficacy data associated with individual ingredients.
• Products that only have standard permitted indications.
• Products with indications based solely on evidence of traditional use, anecdotal evidence, or established
market presence (i.e. they must be supported by scientific evidence of efficacy).
• Products with high level indications or prohibited representations.
• Products with anticipated efficacy data only.
• Listed medicines that are assessed via a post-market compliance process.
• Sunscreens 4
What are intermediate level indications?
Must not refer to a prohibited representation
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Intermediate level indications
• Intermediate indications are generally more definitive and relate to more significant health conditions.
• May include references to prevention or alleviation of non-serious forms of a disease, condition, ailment,
defect or injury.
• May refer to restricted representations (serious conditions and diseases), and may make certain biomarker
claims.
• Examples of intermediate level indications include:
– Relieves insomnia
– Helps decrease high blood pressure
– Alleviates arthritis symptoms, such as inflammation and pain
– Relieves symptoms of benign prostatic hyperplasia
– Decreases LDL cholesterol levels
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Additional indications for assessed listed medicines?
• Although assessed listed medicines must have at least one intermediate indication, they can also use
secondary/ low-level indications.
• These are drawn from the list of standard permitted indications.
• May be scientific or traditional use, and may refer to efficacy of specific ingredients.
• Examples -
– Helps relieve mild dermatitis
– Ginseng is traditionally used in Chinese medicine to tonify qi (vital energy)
– Ingredients in this medicine have been traditionally used in Ayurvedic and Chinese medicine for relieving
symptoms of the common cold
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Establishing efficacy
• Efficacy studies focus on demonstrating statistically significant differences between intervention
groups in highly controlled (clinical) settings.
– Focus on minimising variation in order to establish a plausible cause-effect relationship between the
treatment and an effect.
– Cover aspects of the pharmacology and risks of a medicine, the meaningfulness of the benefits, and
the relevance of the effect for the wider population.
• Efficacy is not the same as effectiveness. Effectiveness is the extent of a beneficial effect under ‘real
world’ settings, and may be lower than efficacy due to impact of usage and socio-economic factors.
• Efficacy evidence can be provided as: (1) clinical trial data, (2) literature-based submission, or (3)
mixed application.
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Establishing efficacy
• Three approaches to demonstrating the efficacy of the proposed product.
* A biowaver is an acknowledgement that in vivo bioavailability and/or bioequivalence studies are unnecessary.
Method Requirements Use Product types
1 Clinical study on the product. New or published clinical trials on
the product itself.
All, including herbal substances,
traditionally used preparations etc.
2A Combination of efficacy data
on ingredients, and
biopharmaceutic studies on
the product.
Products that are
biophamaceutically equivalent to
existing / studied products.
Generics, modified release products.
2B Combination of efficacy data
on the ingredients and
pharmacokinetic data.
When a biowaver is appropriate or
when biopharmaceutic data is not
required.
Immediate release, highly permeable,
highly soluble products (BCS class I)
or products not absorbed (probiotics,
insoluble fibres etc.).
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Method requirements
Data type Method 1 Method 2A Method 2B
Body of
evidence
Full literature search report
on the product or formulation
Full literature search report on all
active ingredients and formulation
Full literature search report on
all active ingredients and
formulation.
Published
studies or
clinical reports
Efficacy evidence on the
finished product
Evidence for the efficacy of each
ingredient
Evidence for the efficacy of
each active ingredient.
Biopharmaceutic
&
pharmacokinetic
studies
N/A Bioavailability or bioequivalence data
for the product.
In vitro dissolution/ release
tests or pharmacokinetic (PK)
studies and validation of the
methods
Formulation Justification of the use of the
particular combination of
ingredients, including
potential interactions.
Justification of the use of the particular
combination of ingredients, including
potential interactions.
Justification of the use of the
particular combination of
ingredients, including
potential interactions.
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Determining the strength of evidence
• The level of evidence (type/ design, and quantity of consistent evidence)
• Evidence quality
• Statistical validity
• External validity (generalisability)
• Relevance of the evidence to the product and/ or indications
• Extent of evidence consistency
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Evidence sources and levels
• Certain sources of evidence provide higher quality information than others due to:
- design
- methodology
- degree to which sources of evidence have been limited
- level of review
• Certain types of studies are appropriate as support for both intermediate level indications and low level
indications, others are only appropriate for low level scientific or low level traditional use indications.
• The study type and quality, and the overall body of knowledge should be carefully considered in
evaluating evidence in supporting claims of efficacy.
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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
Pharmacopoeias Publicised International
Regulatory Authority
Articles – Traditional only
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How many studies of each type are required?
Indication Primary (intermediate) Secondary (low level)
Indication type Scientific Scientific Traditional
Required evidence
Minimum of one from Category A
OR
Minimum of two from Category B, AND
a minimum of one independent
sources from Category C
General indications:
Minimum of one from Category A
OR
Minimum of one from Category B,
AND a minimum of two
independent sources from
Category C
General indications:
Minimum of two independent
sources from Category D
OR
A minimum of one from
Category C
Supplementary
evidence
Specific indications:
Minimum of 1 from Category C to
support specific indications
(where relevant)
Specific indications:
Minimum 1 from Category D to
support indications (where
relevant)
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General • Must be compliant with Good Clinical Practice (GCP) guidelines
• Study population must be appropriate for the outcomes being tested
Sample • Intervention must be described at a level that would allow replication
• Inclusion/ exclusion criteria must be outlined
• The sample size should provide sufficient statistical power (> 80%)
Outcome(s) • Primary outcome described in advance
• Valid measures of the targeted effect must be used
• Adverse events or potential side-effects should be measured
Bias control • Appropriate controls
• Randomisation
• Appropriate blinding
Evidence standards
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Changes • Protocol violations and patient follow-up should be reported
• Missing data must be reported and handled appropriately
Analysis • Efficacy should be based on primary outcomes
• Intention-to-treat (ITT) population should be used
• Pre-test differences should be accounted for
Statistics • Statistical methods must be relevant and valid
• No serious negative effects on key outcomes
• The p-value (<0.05) and 95% confidence interval must reasonably exclude chance
• The 95% CI should only include significant results
• Outcomes should have clinical rather than merely statistical significance
Evidence standards
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Biopharmaceutic & pharmacokinetic studies
• Essential component of establishing efficacy.
• Demonstrate that medicines dissolve and release ingredients appropriately, and that the active ingredients
are absorbed and metabolised in a manner that allows them be efficacious.
• They also serve to ensure that undesirable effects such as dose-dumping, dose retention or in vivo
interactions do not either reduce the efficacy of the product or pose a risk to the consumer.
• Examples:
- zinc carnosine
- probiotics
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Biopharmaceutical & pharmacokinetic studies
• For assessed listed medicines, a variety of different types of pharmacokinetic studies are required in
addition to the reports/ papers.
• The types of data required depend on the nature of the product and the method used to establish efficacy.
Product type Method Data
New product, or product with efficacy on ingredients Method 2A Bioavailability
Generic, or pharmaceutically equivalent product Method 2A Bioequivalence
Generic product eligible for a compliant biowaver Method 2B Pharmacokinetic
Product not systemically or locally absorbed Method 2B Dissolution/ release
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Alignment of indications and evidence
Regardless of the quality or quantity of evidence, there must be suitable alignment between the
evidence and the indications and claims.
• The indication used on a product and the evidence supporting it must:
- refer to the same medicine or active ingredient(s)
- have the same meaning and intent
- refer to the same therapeutic action and the same context (e.g. the same target population)
- remain valid for the entire life cycle of the medicine.
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Alignment of indications and evidence Formulation and use • Medicine used in studies and proposed product should have the same ingredient(s),
dosage, dosage form, route of administration, and frequency and duration of use.
• Any differences must be justified through biopharmaceutic studies.
Duration of studies • Studies must be of an appropriate duration for the indication or claim (e.g. long-term health
benefit claim should be supported by long-term data).
Outcomes • Indications must not exaggerate the extent of the effects achieved in a study
• Indications must not suggest greater scientific certainty than the study is capable of providing
Context • Features controlled in trials may impact on the benefits in real use, and must be noted (e.g.
‘as part of a calorie controlled diet’).
Target population • Study population should be demographically similar to target population
• Indications should not generalise specific results, or transfer results to different groups than
used in studies.
Balance of evidence • Weight of evidence should be in agreement with the proposed indication
• Indication cannot be based on a study that is inconsistent with the body of knowledge
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Application categories
Category Description
L(A)1• Evaluation of a clone of an existing product, where the only difference is the name
and/or flavour, fragrance, printing ink or colour
L(A)2• An application for a new 'generic' medicine
• Evaluation of efficacy based on international evaluation reports
L(A)3
• Full de novo evaluation of efficacy.
• An application for a new medicine not covered by L(A)1 or L(A)2, or that is an
extension to an existing approved medicine, including new therapeutic indications,
strengths, or dosage form (i.e. major variations).
• The increasing levels correspond to the increasing complexity of applications, and consequently,
increasing data requirements, evaluation timeframes and fees.
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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:
- Cover letter
- CTD Module 1
- Module 5 Efficacy (clinical)
• 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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Transition arrangements
• Existing listed products with intermediate indications must transition to the new assessment pathway or,
alternatively, choose low level indications from the permitted indications list.
• Products with indications that refer to restricted representations must transition to the new pathway. The
evidence for the restricted representation will not be reassessed but must be supplied along with the
labels and evidence for other claims/ indications.
• Full application dossiers must be supplied. Standard application and evaluation fees apply.
• The transition must be completed by the end of the three year period. Products that have not transitioned
to permitted indications or the assessed listed medicines pathway will be cancelled from the ARTG.
• Three well-established ingredients (folic acid, calcium and vitamin D), have approved restricted
representations included in the permitted indications list on public health criteria. Products using these
representations are not required to transition, but sponsors have the option to transition them.
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Implementation phase
• It is proposed that the pathway be opened to all applicants as soon as the legislation comes into effect.
• Draft guidance will be made available on the TGA website as soon as possible.
• Full application and evaluation fees will be charged.
• TGA will work with sponsors during the application process to provide clarity around the evidence
requirements and appropriate indications.
• The first year of the programme will be used to test the suitability of the evidence guidelines and
timeframes.
• At the end of 2018, the TGA will publish a report on the outcomes of the implementation period and will
provide updated evidence guidance based on the feedback received.
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