TGA presentation: The assessed listed medicines pathway
Complementary medicines reforms to the sponsor education workshop given at Sydney, Melbourne, Brisbane, Canberra, November-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.
- Presented by: Dr. Michael Gardner, Director, Complementary Medicines Evaluation Section, Complementary and OTC Medicines Branch
- Presented at: Complementary medicine reforms information sessions
- Presentation date: November / December 2017
- Presentation summary: This presentation gives an overview and update of the progress of complementary medicine reforms.
Complementary medicines reforms sponsor education workshops
Dr. Michael Gardner
Director, Complementary Medicines Evaluation Section
Complementary and OTC Medicines Branch
Slide 1 - 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).
Slide 2 - 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.
Slide 3 - Key requirements
Ingredients Must draw exclusively from the permitted ingredients list. Ingredients must notbe included (or meet the criteria for inclusion) in a schedule to the PoisonsStandard. Product & manufacturing quality Must comply withapplicable standards and meet the PIC/S guide to GMP. Must not be of a typerequired to be sterile. Indications Product mustcontain at least one intermediate level indication which exceeds thepermitted indications list but are not high level indications. Evidence Evidence ofefficacy of the finished product submitted by the sponsor to supportassociated 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
Slide 4 - 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.
Slide 5 - What are intermediate level indications?
Listed medicines New pathway Registered medicines Low level indications
May refer to:
- Health enhancement
- Health maintenance
- Prevention/alleviation of dietary deficiency
- A health benefit for a non-serious disease orcondition (symptomatic relief)
E.g. maintain/support healthy bones
Intermediate level indications
May refer to:
- A health benefit for a serious disease (i.e.restricted representations)
- Prevention, alleviation or management of a non-serious disease orcondition (of a higher risk toconsumers than low level indications)
E.g. preventation of osteoporosis
High level indications
May refer to:
- cure of
of a serious form of a disease, aliment, defect orinjury (restricted reps)
Slide 6 - 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
Slide 7 - 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
Slide 8 - 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.
Slide 9 - Establishing efficacy
Method Requirements Use Product type 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.).
Slide 10 - Method requirements
Data type Menthod 1 Menthod 2A Menthod 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.
Slide 11 - 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
Slide 12 - Evidence sources and levels
- Certain sources of evidence provide higher quality information than others due to:
- 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.
Slide 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 Pharmacopoeias Publicised International Regulatory Authority Articles – Traditional only
Slide 14 - 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
Minimum of two from Category B, AND a minimum of one independent sources from Category C
Minimum of one from Category A
Minimum of one from Category B, AND a minimum of two independent sources from Category C
Minimum of two independent sources from Category D
A minimum of one from Category C
Supplementary evidence - Specific indications:
Minimum of 1 from Category C to support specific indications (where relevant)
Minimum 1 from Category D to support indications (where relevant)
Slide 15/16 - Evidence standards
- Must be compliant with Good Clinical Practice (GCP) guidelines
- Study population must be appropriate for the outcomes being tested
- 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%)
- Primary outcome described in advance
- Valid measures of the targeted effect must be used
- Adverse events or potential side-effects should be measured
- Appropriate controls
- Appropriate blinding
- Protocol violations and patient follow-up should be reported
- Missing data must be reported and handled appropriately
- Efficacy should be based on primary outcomes
- Intention-to-treat (ITT) population should be used
- Pre-test differences should be accounted for
- 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
Slide 17 - 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.
- zinc carnosine
Slide 18 - Biopharmaceutic & 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
Slide 19 - 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.
Slide 20 - 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
- 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
- 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’).
- 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
Slide 21 - 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
- An application for a new 'generic' medicine
- Evaluation of efficacy based on international evaluation reports
- 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.
Slide 22 - 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.
Slide 23 - 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.
Slide 24 - Transition arrangements
- 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.
Slide 25 - Questions
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