The Regulation of Medicines in Australia

8/12/2019 The Regulation of Medicines in Australia

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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
http://search-au.funnelback.com/s/search.html?collection=tga-artghttp://search-au.funnelback.com/s/search.html?collection=tga-artg


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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.htm


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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

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http://www.tga.gov.au/auspar/auspar-paliperidone-130520.htmhttp://www.tga.gov.au/auspar/auspar-paliperidone-130520.htmhttp://www.tga.gov.au/auspar/auspar-paliperidone-130520.htm


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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
http://www.tga.gov.au/industry/pm-auspar.htmhttp://www.tga.gov.au/industry/pm-auspar.htmhttp://www.tga.gov.au/industry/pm-auspar.htmhttp://www.tga.gov.au/industry/pm-auspar.htm


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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
http://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/industry/scheduling-poisons-standard.htmhttp://www.tga.gov.au/industry/scheduling-poisons-standard.htmhttp://www.tga.gov.au/consumers/information-medicines-label.htmhttp://www.tga.gov.au/industry/cm.htmhttp://www.tga.gov.au/industry/otc.htm


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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-introduction

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