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The regulation of medicines in Australia
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Overview Whos checking your medicines?
Regulated medicine categories
Registered medicines
Over-the-counter medicine regulation
Generic medicines - bioavailability
Quality, safety and efficacy data
Australian Public Assessment Reports
Assessing and managing risk
Medicines scheduling
Lower risk medicine
Conditions for sup
Access to unauthor
medicines
Advertising medicin
Changing medicine
Other education mo
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Whos checking your medicines?
The organisation that has responsibility for the import, supply, or expmedicines in Australia is the Therapeutic Goods Administration
The Therapeutic Goods Act 1989 requires that products must be enttheAustralian Register of Therapeutic Goods (ARTG)
To make this happen a sponsor (usually the company that will supplymanufacture the product) must submit an application and pay fees toTGA
This presentation will take you through some of the critical things thedoes
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Regulated medicines include: Prescription medicines (including original
and generic brands)
Over-the-counter medicines (including
pharmacy, pharmacist only and
unscheduled medicines)
Complementary medicines
Vaccines
Blood, blood components and plasma
derivatives
All thesproducts regulated
the TGA
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Two broad categories of medicines
higher risk medicines that are registered on the AR
evaluated for quality, safety and efficacy
Product Information is approved by the TGA
Registeredmedicines:
lower risk medicines that are listed on the ARTG
contain pre-approved, low risk ingredients
can only make limited claims and cannot imply thuseful in the treatment or prevention of serious illn
Listedmedicines:
Approach is based on risk and, in the simplest terms, has two tiers:
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Registered medicines
Higher level of risk
- Al lprescription medicinesare registered
- Mostover-the-counter medicinesare
registered
- Somecomplementary medicinesare
registered
Registered medicines have an'AUST R' number
on the label and/or packaging
Prescription
(any medicine
requires a
prescription fro
a practitioner)
Complementar
(high dose calci
tablets from behcounter without
http://www.tga.gov.au/industry/pm.htmhttp://www.tga.gov.au/industry/otc.htmhttp://www.tga.gov.au/industry/cm.htmhttp://www.tga.gov.au/consumers/information-medicines-label.htmhttp://www.tga.gov.au/consumers/information-medicines-label.htmhttp://www.tga.gov.au/consumers/information-medicines-label.htmhttp://www.tga.gov.au/consumers/information-medicines-label.htmhttp://www.tga.gov.au/industry/cm.htmhttp://www.tga.gov.au/industry/otc.htmhttp://www.tga.gov.au/industry/pm.htm8/12/2019 The Regulation of Medicines in Australia
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Registering a new medicine
There is a large amount of
information to consider
It takes approximately 11
months to evaluate one new
higher risk prescription
medicine
Evaluation is undertaken by
scientists and clinicians
who look at data on:
Quality*
Safety and efficacy*
Process ofchecking and
communicatingwith applicant
1. Preparationand lodgement
2. Screening
3. Evaluation
4. D
*More information about what this means is provided later in the presentation
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Applications can be submitted in five application categories, each relates to different evaluation processe that corresponds to the lev
High risk
category
Over-the-counter medicine regulation
Preparation and Lodgement Screening Evaluation Decision
Low riskcategory Clones (identical productto existing approved)
Name variations
Flavour, fragrance or
colour variations
New patient
population
New indication
New active ing
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Bioequivalence refers to whether the genericmedicine releases the active ingredient into thebloodstream at the same rate and to the sameextent as the original medicine
Bioequivalence is demonstrated by conducting a
bioavailability study in which volunteers (usuallyhealthy) are given the original Australian medicineand, on a separate day, the generic medicine
Blood samples are taken at different times andthe rate and extent of absorption of the activeingredient into the blood is compared for thegeneric and original medicines
Bioavailabili ty studies data from app
Generic prescript ion medicines must be bioe
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Decisions are based on evidenceQuality data - supplied by the applicant
stability data
sterility data (if
applicable)
the impurity content
the composition of the
substance and theproduct
batch consistency
Evaluated by chemists, biochemists, microbiologists and
others working for the TGA
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Quality considerations
Batches of medicine should be the same European Union guidelines some with TGA annotations provide
on how to judge the quality of medicines
The official standards in Australia are:British PharmacopoeiaEuropean PharmacopoeiaUnited States Pharmacopoeia-National Formulary
Some (not all) EU guidelines are adopted by the TGA and may alsoone or more of the standards above
Drug substance: each batch should contain acceptable impurity lev
Drug product: each tablet should contain the same amount of activingredient
Stability studies must be conducted under conditions that represent
regions, because Australia contains significant populations in the tro
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Example of a container affecting qua
Epoetin alfa (erythropoietin) contained human serum albumin for stability
Proteins of human origin create a risk of human diseases, so the albuminwas replaced with a detergent, polysorbate, with TGA approval
Within months of the formulation change, there were reports of pure redcell aplasia* (PRCA; erythroblastopenia) in Australia (TGA), the EU,
Canada and Singapore
Determined that PRCA was associated with the new formulation, prefilledsyringes (not vials) and subcutaneous injection, but was not batch specific
Sponsor changed to using teflon-coated plungers in syringes (with TGAapproval) and PRCA dropped to previous low rate within the year.
*PRCA
severe a
absence
in the bo
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Decisions are based on evidenceSafety and efficacy data- supplied by the a
Pharmacology data
laboratory data
investigating efficacy
Pharmacokinetic data
Toxicology data
laboratory data
investigating safety
Mostly results of clinical
trials conducted by
pharmaceuticalcompanies and/or
hospitals or research
organisations, using
volunteers
Clinical data
Usually evaluated by a
medical doctor
TGA
Nonclinical data
Evaluated by toxicologists and
pharmaceutical chemists
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Safety information helps determine ris
Taking medicines involves risk European Union guidelines describe how studies should be des
obtain statistically valid safety information
Considers how valid the results of nonclinical studies in animals
increasing in vitro (e.g genomic assays) are by investigating:genotoxicity
organ toxicity
carcinogenicity
reproductive toxicity
Any safety concerns from clinical trials?
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Minimising infectious diseasesBovine spongiform encephalit is mad cow diseas
transmissible to humans
The TGA took regulatory action when this infectious d
emerged
Transmissible spongiform encephalitis (TSE) is a degenerative neuknown in humans as variant Creutzfeldt-Jakob disease (v
The brain tissue develops holes and takes on a sponge likeClinical features include psychiatric symptoms and neurolog
Australian cattle were unaffected, so Australia was in a position regulatory action in relation to medicines containing ingredients that
in order to protect human health
Normal brain
section
Affected brain
section
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First known protein adventitious a
Scientific dogma: all infectious diseases must involve nucleicacid (RNA or DNA) - multiplication occurs by replication
For TSE no nucleic acid is involved: prions are misfolded PrP
protein that can induce host PrP protein to undergoconformational change
PrPc(-helical conformation) changes to PrPsc (misfolded
protein sheet structure, resistant to proteinase digestion)
Normal sterilisation techniques including gamma and UVradiation have no effect on the protein
Regulatory control focused on restricting the source of bovine
material in medicines to countries known to be free from BSE
PrPc
normal
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Efficacy information helps determine
There must be evidence of clinical benefit European Union guidelines provide guidance on how to judge thefficacy of medicines
Could it work? nonclinical studies and animal studiesin vitro, such as receptor-binding
in vivo
Does it work? clinical trialsend points to judge clinical benefits need to be agreed
needs to be both clinically and statistically significant
placebo effect needs to be accounted for
Mechanism of actionsometimes informs safety information
sometimes informs drug interaction information
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History of paliperidoneUsing medicines in a new patient population
An application was made to the TGA to allow the use of the medicine paliperidadolescents aged 12-17 years old with schizophreniathis use was authoriseapproximately 10 countries, including the USA
Paliperidone and the related medicine risperidone are both used to treat sThe Australian Product Information states that paliperidone should not be
younger than 18 years and risperidone is lacking evidence in children witaged less than 15 years
The TGA was concerned about the design of the main clinical trial to support upaliperidone in Australian adolescents and asked the Advisory Committee on Medicines for advice
1
2
3
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See theAusPARfor more information.
The Advisory Committee on Prescription Medicines considered the studto support the proposed use in adolescents. The committee expressed sconcern about the design, duration, patient selection, screening and anamain clinical study
The TGA was also advised that different adverse events are associaeach of the two medicines. Risks include abnormal movement disordmetabolic syndrome, causing weight gain and diabetes
After receiving the TGA evaluation reports, overview and advice from thCommittee on Prescription Medicines, the application was withdrawn anProduct Information forpaliperidone still states that it should not be usedyounger than 18 years
Outcome for paliperidoneUsing medicines in a new patient population
4
5
6
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Find out more by reading an AusPAR!
AnAustralian PublicAssessment Report
provides information about
the evaluation of a
prescription medicine and
the considerations that led
the TGA to approve or not
approve an application to
register a prescription
medicineIncludes summaries of pharmacodynamic
pharmacokinetics, efficacy and safety, as
first and second round benefit-risk assess
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Assessing and managing riskWhat do we do?
Consider risks what are they?
Balance benefits with risks
Consider whether a medicine should be used in the
proposed population for the proposed indication
Use Product Information document as a riskmanagement tool
Consider other risk management tools
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Product Information documentA risk management tool
The document is approved by the TGA
The product is only authorised for specified
patient population for specified indications
All other use is off-label and the benefit-riskprofile has not been considered by the TGA
The precautions section gives details of some of
the risks involved
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Mesh
Example of PI as a risk management to
A fibrin sealant was already authorised for a number of indications
The application was to extend the indications to include fixingmeshes used in hernia repair operations
This submission consisted mostly of studies published in the
literature
When the fibrin sealant was used in nonclinical studies to fix amesh to the peritoneum, the mesh often did not stay in place
This information is now in the precautions section of the ProductInformation
Picture source: Anpo
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Planning for safety
A risk management plan states how safety concernswill be identified and mitigated. It is a required
component in the premarket authorisation process and
is also updated to cover the entire life of the product
It consists of:
an overview of the safety profile
a pharmacovigilance plan
a risk minimisation plan
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How can we control use?
A risk management plan might require thesponsor to:
Report on adverseevents
Develop educationalprogram
Limit supply toauthorisedprescribers
Keep a registry ofpatients
Automatically recruiton registry when
product isprescribed
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First medicine in class dapagliflozin
Diabetic foot infection
Selective and reversible inhibitor of th
co-transporter 2 (SGLT2), the majoglucose reabsorption in the
Used for the treatment of type 2 diabto diet and exercise
Long term benefits are likely to folloblood glucose levels in type 2
Safety concerns: renal impairmeninfections, genital infections, dehydra
Nonclinical studies did not indicate concerns. Bladder and breast cancer
considered by the TGA as unlikely
related, but this could not be
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Dapagliflozin conditions of registraNew class means limited relevant clin
in real world the TGA did not authmonotherapy because of safety recor
Authorised only for type 2 diaNot authorised in the moderately ren
(defined as: eGFR
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Medicines schedulingthe Poisons St Potentially dangerous drugs and chemicals are restricted to en
safe and effective use
Scheduling is the legal process used to achieve this
Scheduling decisions are made by a senior TGA medical office
account the advice of the Advisory Committee on Medicines Sc
The higher the number of the schedules, the more access is re
Scheduling is in legal terms a State matter, but all States now a
closely, or entirely, to the Poisons Standard, which is administe
Department of Health
Scheduling decisions are published on the TGA website
Remember: only registered medicines are scheduled
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Examples of scheduled medicine
Scheduleclassification
Type of medicine Example
Schedule 2 pharmacy only medicine large packet
paracetamol
Schedule 3 pharmacist only medicine topical thrush
treatmentsSchedule 4 prescription only medicine blood pressu
medications
Schedule 8 controlled drug S8 has
additional restrictions on the
storage and supply of medicines
strong uploa
painkillers
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Alprazolam belongs to a group ofmedicines called benzodiazepines
which are used to treat anxiety and
panic disorders.
Submissions to the TGA suggested
that Alprazolam should berescheduled from Schedule 4 to
Schedule 8 due to:
Rescheduling alprazolamIncreased morbidity and mortalit
possible increased
Rapid increase in use and evide
misuse
Concerns that the current pack sizfor indications
Evidence of misuse with
As of 1 February 2014, alprazolam will be a Schedule 8 controlled substance.
Jun
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Listed medicines
Lower level of risk
- Someover-the-counter medicinesare listed
- Mostcomplementary medicinesare listed
Listed medicines have an 'AUST L' numberon the
label Must NOT contain substances that are
scheduled in the Poisons Standard
Must contain pre-approved ingredients
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Regulating listed medicines premarke
Independent
expert advice maybe sought on newingredients
proposed for use inlisted medicines
Regulationcentres on the
safety of theingredients and
the consistency ofthe manufacturing
process;sponsors must
hold evidence tosupport the
claims
Only pre-approvedlow risk ingredients
may be used inlisted medicines
Listed medicines,
including mostcomplementarymedicines,
receive a lesserdegree of
checking thanhigher riskproducts
AR
uon
fee
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The TGA inspects and licenses manufacturing sites
in Australia and assesses sites overseas. This allows us
to enforce standards in relation to sterility and quality of the
ingredients used and the process followed.
Conditions for supplying low risk med
E
Fish oiltablets
Contains
pre-approved
low-risk ingredients
Does not claim or
imply it will be useful
in the treatment or
prevention of serious
illnesses
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Patients sometimes need special acc
Special AccessScheme (SAS)
Import and/or supply anunapproved therapeuticgood for a single patient ona case-by-case basis
Clinical Trial Exemption(CTX) and Clinical Trial
Notification (CTN)schemes
Access unapprovedmedicines throughparticipation in a clinicaltrial
Authorised P
Authorised prescprescribe a spectherapeutic goodthan once) to a with a particularmedical conditio
We help health professionals gain access to products that their pa
need, but which have not been approved for use in Australia.
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Advertising medIts important
The labelling, packaging
of what the medicine sho
are all regulated by the T
Advertising of prescriptio
consumers is illegal in A
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Changing medicine technologies1960s
Medicines wererelatively smallmolecules
Manufactured fromchemicals, such asaspirin, or were aproduct offermentation, such
as penicillin andcortisone
1970s Human plasma
started to be usedto provide productssuch as Factor VIIIfor haemophilia
1980s
Human proteinsproduced in bacteriausing recombinantDNA technology
Human insulinproduced - avoidedproblems of allergicreactions to animalinsulin
Human proteinsavailable: insulin,growth hormone
and interferon
1990s
More than ahundred protein
medicines wereproduced usingrecombinant DNAtechnology
Virus proteins couldbe produced withouthe actual virus andused as vaccines
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Protein/peptide medicines registered in
Medicine Disease state
Belimumab (Benlysta) Systemic lupus erythematosus
Peginterferon Alfa 2a (Pagasys) Hepatitis C
C 1 esterase inhibitor (Cinryze) Hereditary angioedema attacks
Velaglucerase alfa (Vpirv) Glucocerebrosidase deficiency (Gau
Afibercept (Eylea) Age related macular degenerationHuman fibrinogen and thrombin (Tachosil) Cardiovascular surgery
Adalimimab (new presentation - Humira) Arthritis, Crohns Disease
Insulin aspart (multidose Novorapid Fextouch) Diabetes
Eptacog alfa (NovoSeven RT) rFactor VIIa uncontrolled bleeding
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Regulation after product is on the mar
We have created a separate educational module on postmarket rwhich details what we do once products are in the supply chain. T
integral part of the regulatory system.
The module covers:
tools used in postmarket monitoring
signal investigation
recall actions
There are five other modules in this suite of educational material. T
accessed by the links on the next slide.
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Other education modules include
Introduction to the TGA
Biologicals
Medical devices
Postmarket monitoring
Good Manufacturing Practice
http://www.tga.gov.au/about/education.htm?fragment=students-introductionhttp://www.tga.gov.au/about/education.htm?fragment=students-biologicalshttp://www.tga.gov.au/about/education.htm?fragment=students-deviceshttp://www.tga.gov.au/about/education.htm?fragment=students-postmarkethttp://www.tga.gov.au/about/education.htm?fragment=students-manufacturinghttp://www.tga.gov.au/about/education.htm?fragment=students-manufacturinghttp://www.tga.gov.au/about/education.htm?fragment=students-postmarkethttp://www.tga.gov.au/about/education.htm?fragment=students-deviceshttp://www.tga.gov.au/about/education.htm?fragment=students-biologicalshttp://www.tga.gov.au/about/education.htm?fragment=students-introductionTop Related