John Skerritt, Theraputic Goods Administration - An update from the Medicines Regulator: Managing and Communicating Risk and Strengthening International Regulatory Convergence

John Skerritt, National Manager

Pharmaceutical Law Conference

May 2014

An update from the Medicines Regulator: Managing and Communicating Risk and Strengthening International Regulatory Convergence

Regulators don’t always get good press….

We need to be forward looking

Macquarie Dictionary definition doesn’t help

reg·u·la·tor (rgy-ltr)n “One, such as the member of a governmental regulatory agency, that ensures compliance with laws, regulations, and established rules”

The nature of medicines has changed… and their regulation has had to evolve too

Medicines use patterns have changed …and so must regulation

• Shift from short-term use of therapies (e.g. for infections) to

management of chronic disease with medicines

• Molecular targeting of cancers instead of using cytotoxic

agents

• Orphan drugs are becoming mainstream business

• Generics – focus on bioequivalence and manufacturing quality

• Biosimilars and biologicals – neither NCEs nor generics

• Reimbursement rather than registration often now seen as

the “real point of market access”

• Complexity from globalisation of medicines supply chains 3

Traditional clinical trials (drug vs placebo) assessed efficacy (whether the treatment works) and

safety but not effectiveness

i.e. “just” require new therapies to get over the bar

Clinical trial evidence requirements for medicines registration are evolving

• What endpoints to use ?

– Surrogate endpoints vs clinical outcomes (mortality/ disease incidence)

– Better use of patient-defined endpoints

– Ensuring populations in clinical trials are representative

• Benefit/ risk tolerance differs for different populations and individuals

• Personalised medicine – small patient groups

• Comparative effectiveness trials

– more closely reflect decisions on treatment in routine clinical practice

– compared with efficacy trials in narrow populations with few co-morbidities

• Adaptive trial designs using data gathered during the trial

• Can trial designs meet needs of both registration and reimbursement ?

The call for more “nimble” regulation

started with the HIV/AIDS crisis in the 1980s

Are regulators keeping up ?

• Emergence of biosimilars

• “Off-label” medicines prescribing

• Fast-track registration review and Adaptive licensing

• Getting decisions right

– Recall of medicines is hard solely on basis of poor efficacy (as

opposed to safety grounds)

‒ Medicines withdrawn/ highly restricted for safety reasons after being

licensed where suitable alternatives existed (Type 1 error)

– Failure to allow a beneficial medicine onto the market (Type 2 error)

• Recent international developments

7

Off label medicines prescribing • When a medicine is prescribed for an ‘indication’ or a patient

group that is not included in the approved product information

– may be because the patient group was too small to seek

registration and/or clinical trials did not include this patient group

• Not illegal, but puts responsibility on to the doctor to ensure that

prescribing is appropriate

– medicines are not eligible for PBS reimbursement and

– adverse event reporting may be incomplete

• A dilemma, since

– TGA cannot initiate registration of off-label indications and may be little

economic incentive for sponsor to do so, especially for generic drugs

– EMA program encourages registration, especially for paediatric indications

Biosimilars

• A follow-on version of a biological medicine already registered

– e.g. filgrastim (for neutopenia) and epoetin lambda (anaemia)

• TGA guidelines published late 2013

– www.tga.gov.au/industry/pm-argpm-biosimilars-00.htm

– treated as NCEs not generics for purposes of evaluation

– reference products, comparability studies and pharmacovigilance are key

– encourage prescription by name and close monitoring of patients starting a

product or switching

• Nomenclature – TGA follows WHO recommendations

– e.g. if a company registers a biosimilar for infliximab for autoimmune

diseases, the product uses the ABN infliximab sim-abcd

Fast track registration

• Full phase III trials usually but not always

been completed

• USFDA works closely with the sponsor in

advising on trial design requirements

• Some priority schemes in Europe and Japan

exist but they are less regularly used

• Both fast track and provisional schemes

MAY provide earlier access to cancer

medicines but they will less thoroughly tested

in patients

• Also creates dilemmas for setting suitable

reimbursement levels

Adaptive licensing – now being trialled in Europe

• Licensing of medicines prior to full

phase III trials subject to monitoring of

‘real-life’ effectiveness and safety

• A development plan is agreed to provide

information on risk versus benefit to enable

subsequent authorization

• Will it lead to lowered evidence

standards ?

• Who will be accountable if there is a

failure associated with a product ?

• Difficulties in withdrawing a medicine

once a patient cohort has been established

• Implications for reimbursement

Are regulators too conservative in the eyes of patients?

– Especially when prognosis is poor

or few effective treatments exist

– Patients are often prepared to take

greater risks than regulators

Natalizumab for Crohns disease/MS

– risk of progressive multifocal

leukoencephalopathy

Herceptin for metastatic breast cancer

– risk of cardiomyopathy

Thalidomide for inhibiting

angiogenesis in multiple myeloma

– risk of teratogenicity

Understanding patient perspectives hopefully we have come a long way from this ?

TGA market research and initiatives in response

• Extensive consumer surveys and focus groups conducted in 2013

• Established a Public Contact Team (call centre)

– Received 31,790 enquiries (11,229 from the general public) in 2013

• Website content/ social media on issues raised by focus groups, e.g.

‒ the role of the TGA

‒ the risk versus benefit approach we take to regulating higher (e.g.

prescription) - and lower-risk (e.g. herbal) medicines

‒ evaluation of generic medicines

‒ travelling with medicines

• ‘Translate’ service in TGA search engine for non-English speakers

• Developed teaching materials for universities on regulation

• Exhibition booths at non-mainstream conferences

Encouraging greater consumer reporting

of adverse medicines events at TGA

• Sponsor reporting of adverse events

compulsory but patient/ doctor reporting optional

• Why encourage reporting ? Real life / long term

drug use, co-morbidities

• Research project to explore consumers’ opinions

about experiencing, managing and reporting

adverse events will inform development of

awareness activities

• Web-based consumer reporting form and guide

released after usability testing with consumers

• Pharmacist dispensing software and training for

adverse event reporting

System for Australian Recall Actions

• Provides public access to information about

recall actions occurring since July 2012

• Searchable for recalls for product correction

and hazard alerts

• Recall actions are included on SARA two

working days after the decision to commence

recall action to allow time for the

sponsor/supplier/importer to distribute the

recall communication

• Consumer level recalls and recalls

involving implantable medical devices are

also published on the alerts page

Early warning system

Current and historical information on safety concerns

for medicines and devices that TGA has identified

Monitoring communications • early communications intended to highlight potential

safety concerns

• TGA aims to encourage further research and reporting to

provide more information as these concerns have not

been fully investigated

Alert communications • issued once a safety concern has been investigated

• provide advice on actions that may need to be taken by

health professionals and consumers

Medicines shortage information initiative

Collaboration between TGA, Medicines Australia and Generic Medicines

Industry Association in consultation with states and territories, health care

professional groups and the Consumers Health Forum

Comprises:

• Agreed Protocol (and guidance document) for classifying shortages

according to potential impact and advises on reporting processes

• A website to deliver information to health professionals and consumers

– temporary or permanent disruption to supply of prescription

medicines

– on anticipated, current and resolved shortages/discontinuations

through email and RSS feeds

• A communication and education strategy

• Operates in addition to the current responsibilities of TGA and industry

Why seek international regulatory

convergence?

• Medicines and device industries and supply

chains are global

• Avoid duplication of others’ efforts

• Access to pharmacovigilance data from

larger populations or different racial mixes

• Exchange of public and confidential safety

alerts and data

• Share best regulatory practices and

emerging policy thinking

• Development of new regulatory science

Multilateral medicines initiatives

• ICH (Intl Conference on Harmonisation of Technical

Requirements for Registration of Pharmaceuticals)

• PIC/S (Pharmaceutical Inspection Cooperation Scheme)

• International Generic Drug Regulators Pilot

• Heads of Agencies Consortium (Australia, Singapore,

Switzerland and Canada) and Australia-Canada Regulatory

Cooperation initiative – Manufacturing compliance and enforcement

– Generic medicines

– New chemical entities / orphan drugs

– Good review practices

– Risk communication methodology

– Secure portal for information exchange

– OTC medicines (Australia-Canada)

Constraints to work sharing /convergence Systemic issues

• Different risk appetites between regulators

• Inconsistent decisions reached yet based on identical evidence

• Codified processes in regulations limit flexibility of some regulators

• Differing financial models - cost-recovery vs government funding

• Differences in timing in receiving applications from industry

• Delays in receiving reports can outweigh benefits for industry

• Legal / confidentiality issues between regulators and with sponsors

• Confidence building , e.g. trusting reports from emerging regulators

• Incompatibility of IT and other systems between regulators

• Different languages and terminology in reports

Countries can have very different risk appetites

US and Europe can make different decisions

using the same data

Some examples from 2013

Approved by US FDA but banned or rejected in Europe

• Lorcaserin, Phentermine/topiramate for weight loss

• Mipomersen injectable cholesterol-lowering agent

Approved in Europe but not approved for these indications in the US

• Fluticasone/vilanterol inhaler for asthma

• Rivaroxaban for prevention of atherothrombotic events in acute

coronary syndrome

So who would Australia follow here ?

Constraints to work sharing /convergence Human issues

• Initial increase in cost and work with cooperation initiatives before they

are integrated into business as usual

• Limited benefits for big regulators

– In-house systems and attitudes long-established

– Workload implications for them in providing and explaining reports

– “FDA is not here to be the World’s regulator” FDA Commissioner

• Incompatibility of IT and other systems between regulators

• Staff may see their jobs as being under threat

• Differing priorities between regulators – e.g. some don’t regulate

generic medicines

The delicate issue of trust - use of reviews

by other regulators....

International Coalition of Medicines

Regulatory Agencies – formed Dec 2013

• First regulatory coalition at agency head level

– 23 countries plus EMA, EU and WHO

• Leverage/ strategic oversight of existing initiatives

• Initial priorities:

– Establish better Information sharing mechanisms

between regulators (e.g. IT systems, commercial

in confidence, united industry engagement)

– GMP Inspection worksharing

– Generic medicines convergence and worksharing

– Capacity building of emerging regulators

TGA approach to disclosure of

commercially confidential information (CCI) Following public consultation, the new

document covers:

• information that was classified as 'COMMERCIAL-

IN-CONFIDENCE' is now classified as 'For Official

Use Only‘

• criteria applied by the TGA in determining whether

information provided is commercially confidential

• the approach that TGA takes to the release of CCI

to the public, and underlying principles

Not a fundamental change in approach

Circumstances where release of official

information is permitted

TGA may release official information (including information provided by

a third party) in certain circumstances, such as:

– to the extent required by law or by lawful requirement of a government or

governmental body, authority or agency including in a review, audit or inquiry

– if required in connection with legal proceedings

– for purposes of public accountability, including disclosure on request to other

Government Agencies, and a request for information by Parliament or the Minister

– to allow the TGA to fulfil its statutory functions including release of information

necessary to ensure safe use of therapeutic goods (s61 of TG Act 1989)

– for exercise of Auditor-General, Ombudsman or Privacy Commissioner functions

• Whether the owner of information provided to the TGA regard particular

information as CCI is relevant but not determinative of its status

• Other than in the circumstances described above, TGA does not release

CCI except where we can justify it in the public interest and it is lawful

Sensitive information and privacy

The TGA remains bound by the Privacy Act 1988 in relation to

the collection, use and disclosure of personal information

• Any such information cannot be released by the TGA under

the Freedom of Information Act 1982 unless the person to whom it

relates has been consulted and has had the opportunity to make

submissions as to why it should not be released

• Other than in circumstances described above for release of official

information, TGA does not release to the public the identity of

individuals or companies that provide information to us

More information is at www.tga.gov.au

Conclusions

• Regulation approaches will continue to be reviewed and be cognisant

of the importance of public health and safety

• Greater international collaboration between regulators is critical

• Registration requirements and clinical trial designs are evolving

• Regulators are increasing their engagement with patient groups

• But high cost of many new medicines mean that reimbursement

rather than regulatory approval is trigger for access

• Options for faster regulatory approval for medicines being explored

internationally

• Importance of public communication and education on regulation

• Recent public consultation aimed to clarify, agree and document TGA

approach to disclosure of commercially confidential information