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 1
Three pathways for complementary medicines Australian Register of Therapeutic Goods (ARTG) AUST L AUST L(A) AUST R Registered medicines Listed medicines Assessed Listed medicines • Pre-approved ingredients Pre-market evaluation for : No pre-market evaluation • GMP • Safety BUT BUT • Quality • Pre-approved ingredients Pre-market evaluation for: • Efficacy • GMP • Efficacy – Intermediate (& • Optional ‘claimer’ ??? • Permitted indications permitted) level indications • Optional ‘claimer’ Lower risk Higher risk 2
Key requirements Must draw exclusively from the permitted ingredients list. Ingredients must not be included Ingredients (or meet the criteria for inclusion) in a schedule to the Poisons Standard. Must comply with applicable standards and meet the PIC/S guide to GMP. Must not be of a Product & type required to be sterile. manufacturing quality 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 indications. Evidence of efficacy of the finished product submitted by the sponsor to support associated Evidence indications and claims. Pre-market assessment of efficacy evidence for all indications, and pre-market assessment Pre-market assessment of the product label. AUST L(A) number. Sponsors have the option to use a ‘claimer’ on product label and Presentation promotional material to indicate the product has been independently assessed. Products may be selected for random or targeted review to confirm applicant certifications Post-market compliance 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: Indications that are not appropriate for the list Indications that refer to the • health enhancement of permitted indications, but are not high level prevention, alleviation or cure of a • health maintenance indications. serious form of a disease, ailment or • prevention of dietary deficiency Intermediate level indications may refer to: injury (i.e. restricted representations). • a disease, ailment, defect or • the prevention, alleviation, or cure of a injury other than a serious form non-serious disease, ailment, defect or of those diseases. injury • restricted representations (i.e. a serious form of a disease). Lower risk Higher risk 4
X Indication risk classification Low level Intermediate level High level A low level indication must not: An intermediate level indication A high level indication must not: must not: • refer to, or imply, the prevention, • Contain a prohibited alleviation, or cure of any form of a • refer to the prevention, representation disease, ailment, defect or injury alleviation or cure of a restricted • contain a restricted representation representation (i.e. a serious • have been specified in a non-permitted form of disease) indications list • contain a prohibited • contain a prohibited representation representation Lower risk Higher risk 5
Examples of indications Low level indications (AUST L) Intermediate level indications AUST L(A) • Helps enhance exercise performance and • Prevents muscular cramps and spasms stamina • Prevents cold sores • Traditionally used in Chinese medicine to • Reduces symptoms of tinnitus disseminate Lung Qi • Alleviates mild dermatitis • Traditionally used in Western herbal medicine • Relieves rheumatoid arthritis symptoms, such as to improve digestion inflammation and pain • Helps maintain blood levels of Vitamin D • Relieves symptoms of gastroesophageal reflux • Aids/assists healthy red blood cell production disease • Relieves abdominal bloating and distention 6
• 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 7
Application categories L(A)1 L(A)2 L(A)3 Generic of TGA fully evaluated Products not covered by L(A)1 or AUST L(A) L(A)2 OR Products identical to existing i.e. AUST L(A) other than permitted Comparable Overseas Regulator new product requiring de novo differences (COR) report for efficacy. evaluation or a variation to an existing AUST L(A) Note: COR guidance currently under development 40 working days preliminary assessment 150 working days evaluation 45 working days evaluation 60 working days evaluation 8
Methods of establishing efficacy L(A)1 L(A)2 L(A)3 Access to reference Generics Method 1 medicine dossier • Meets biopharmaceutic and • clinical trials on the product pharmacokinetic study requirements Method 2A • Justification for use of particular • combined efficacy and bioavailability/bioequivalence ingredient combinations, including data to support product efficacy potential interactions Method 2B • combined efficacy and dissolution or in vivo COR • Full un-redacted COR evaluation pharmacokinetic studies to support product efficacy report 9
L(A)3 methods of establishing efficacy Method Suitable product type All product types including traditional, herbal, 1 probiotic and conventional medicines 2A Systemically acting isolated chemical substances Products with a compliant biowaiver or that do not 2B require biopharmaceutic studies or clinical efficacy studies 10
Method 1 Method 2A Method 2B (all types) (systemically acting isolated (biowaiver or not requiring Efficacy data chemical substances) biopharmaceutic studies) Full literature search ✓ ✓ ✓ ✓ Published studies or ✓ ✓ finished clinical study reports each active each active product ✓ Biopharmaceutic and ✓ X in vitro dissolution or PK studies pharmacokinetic not normally bioequivalence or comparative demonstrating in vivo release of evidence required dissolution actives All methods must provide justification of the use of the particular combination of Formulation ingredients, including potential interactions between ingredients 11 Refer to AUST L(A) Evidence guidelines – Table 5
Evidence hierarchy Category A Category B Category C Category D Double-blind, randomised, controlled Observational studies Non-systematic, generalised trials e.g. cohort and case reviews Traditional reference text (including cross-over control studies (including databases) trials) Publicised international Herbal monograph regulatory authority articles Evidence based reference Herbal pharmacopoeia text - scientific Comparative studies Systematic reviews (non-control) Materia medica Publicised international Scientific monographs regulatory authority articles (traditional only) 12 Refer to AUST L(A) Evidence guidelines – Table 6
Minimum evidence requirements Indication Primary (intermediate) Secondary (low level) Indication Scientific Scientific Traditional type Non-specific indications Non-specific indications Minimum of two sources from Minimum of two sources from Category D Category B or Category C to support the tradition of use Minimum of one from Category A Specific indications Specific indications OR Minimum of two sources from Category D Required Minimum of one from Category A evidence to support the tradition of use Minimum of two sources from OR Category B and one from PLUS Category C Minimum of one from Category B and Additional evidence from Category C or D two from Category C to support the specificity of the traditional indication 13 Refer to AUST L(A) Evidence guidelines – Table 7
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 Screening Submission Evaluation Decision Implementation meeting ebs.tga.gov.au 15
Pre-submission • Check eligibility ‒ Ingredients ‒ Indications ‒ Mandatory requirements ‒ Evidence Guidelines ‒ Application category • Pre-submission meeting 16
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