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TGA presentation: International Society of Pharmacovigilance, Training Course, 15-18 March 2018

Early access to medicines schemes: Local perspective

29 March 2018


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  • Presented by: Adrian Bootes
  • Presented at: International Society of Pharmacovigilance Training Course
  • Presentation date: March 15th - 18th 2018
  • Presentation summary: Overview of Australian expedited pathways


Early access to medicines schemes: Local perspective

Adrian Bootes
Assistant Secretary, Prescription Medicines Authorisation Branch

International Society of Pharmacovigilance
Training Course: March 15th - 18th 2018

Slide 1 - Presentation Overview

  • Overview of Australian expedited pathways
    • Priority review pathway
    • Provisional approval
  • Considerations for Implementation in Australia
  • Other options for access to medicines

Slide 2 - TGA expedited pathways

  • To facilitate earlier access to medicines that address unmet clinical needs for Australians, without compromising standards for safety, efficacy and quality.
  • Two new ‘expedited’ pathways for prescription medicines based on the government response to the recommendations of the MMDR review:
  • Priority Review of a complete data dossier within a reduced timeframe in certain circumstances

Implemented 1 July 2017

  • Provisional Approval on the basis of early data on safety and efficacy, where the immediate availability of the medicine outweighs the risk that more data is required

Likely to be implemented in the next few days

Slide 3 - Determination process

  • To use the pathways, a determination must be obtained before lodging a submission – "Entry ticket"
  • Formal process to assess against the eligibility criteria
  • Determinations lapse after 6 months
  • Ineligible determination decisions are appealable by the sponsor only

Slide 4 - Analysing the under-recovery

  • Early look at the data – Early assessment of benefit-risk (before the registration application is received)
  • Gives certainty of applications to both Sponsor  and TGA
  • Avoids outright rejection of indication/registration sought
  • Estimation of future work load
    • 7 /10 priority determinations are for anticancer medicines
  • Allows us to see if we have criteria right for public health reasons
  • Consistent and transparent process for assessing eligible medicines

Slide 5 - Determination Eligibility criteria

Determination Eligibility Criteria
Criterion Provisional Priority
New prescription or new indications medicine Yes Yes
Serious or life-threatening condition Yes Yes
Comparison  against registered therapeutic goods (excludes provisional registration) Yes – data preliminary Yes – data substantial
Major therapeutic advance Yes – data preliminary Yes – data substantial
Clinical study plan Yes No

Slide 6 - Determination administrative requirements

  • Must use eCTD format
    • Manage increased number of simultaneous applications
    • PI and CMI changes may be required – impact on other areas
  • For priority – resolve GMP early

Slide 7 - Pre-submission and submission process

Flowchart of the Pre-submission and submission process

Transcript for the image showing the pre-submission and submission process:

  1. Pre-submission meeting
    1. Go to step 2 or if standard Go to step 3
  2. Determination/Designation:
    • Priority Review,
    • Provisional Approval
    • Orphan Drugs
  3. Submission for registration include the following process:
    1. Standard
    2. Standard + orphan
    3. Priority
    4. Priority + orphan
    5. Provisional*
    6. Provisional* + orphan
    7. Provisional* + Priority

Slide 8 - Priority Review Process

This image shows the pathways to obtaining Priority Review Process.  This is broken in 3 groups: 1. by formal determination, 2. short and flexible registration and 3. full ARTG registration

Transcript for the priority review process involves:

✔ (EMA 150 days; FDA 120 days) ~3 months less than TGA standard target

The break down of the timeframe and process is:

  • 20 WD = Formal Determination (time limited)
  • 150 WD = Short & Flexible Registration Process
  • Full ARTG registration - established quality, safety & efficacy for the intended use

Note: New fee for determination increased fee for registration

Slide 9 - How do we consistently meet timelines?

  • Flexible business processes to reduce the subsequent registration timeframe
  • 'Partnership' with applicant, standard timeframes will apply if requirements for Priority Review are not met
  • The first and second round evaluation phases can be condensed
  • Rolling questions during the first round assessment process
    • Provides speed and re-assurance for the clinical evaluation
    • Gives an indication of emerging issues
  • Flexible arrangements for seeking expert advice

Slide 10 - How do we consistently meet timelines?

  • Intended to strike a balance between making decisions on the basis of promising data for the benefit of Australian patients, knowing that we need to proactively manage the risks of more unknowns about the efficacy and safety of these medicines
  • Provisional registration granted for specified time periods (2 years + up to 2 extensions, max 2 years each)
  • Intended only for those medicines where further confirmatory data is still being gathered.
  • Pathway subject to the provision of clear advice to consumers and healthcare professionals and any other conditions imposed by the TGA

Slide 11 - Overview of the Provisional Approval pathway

Flow chart on the overview of the provisional approval pathways: 1. Determination process, 2. Pre-market registration process, 3. Provisional registration period and 4. Transition to fully registered

Transcript for the overview of the provisional approval pathway/s:

  1. Determination process (3-6 months pre-dossier)
  2. Pre-market registration process (As quickly as possible (max. 255 working days))
  3. Provisional registration period (2 years initially (with the possibility of 2 extensions of 1-2 years each))
  4. Transition to fully registered (As quickly as possible (max. 255 working days))

Slide 12 - Considerations for Implementation in Australia

Slide 13 - Products approved via expedited pathways

New Active Substances (NAS)
Total NAS approvals 'Priority' 'Provisional'
EMA 28 5 (18%) accelerated 7 (25%) conditional
FDA 22 15 (68%) 6 (27%) accelerated
PMDA (Japan) 48 22 (46%) -
  • 1st Priority medicine registered on 30 January 2018
    • ✔ Alectinib (Alecensa), Extension of Indication
  • 2nd Priority medicine registered on 23 February 2018
    • ✔ Emicizumab (Hemlibra), New chemical entity

Slide 14 - Priority determinations

  • 14 Priority determinations received as of 28 February 2018
  • 10 (71%)  Priority determinations approved
    • 6 Extension of Indications (EOI) , 4 - New Chemical Entities (NCE)
    • 70%  anticancer pharmaceuticals
  • Rejection reasons – Failure to meet criteria
    • #3 – comparison against existing registered therapeutic goods
      • Criteria 3 challenging: Example Interferon for Melanoma but < 100 patients per year
    • # 4 – Major therapeutic advance

Slide 15 - Approval times: TGA Experience 2004-2018

TGA Experience 2004-2018
Product Name Pathway Year approved Working days
Cervarix Human Papillomavirus Vaccine Types 16 & 18 Standard with rolling submissions 2007 81
ADT Vaccine diptheria and tetanus vaccine Standard 2006 81
Isentress (Raltegravir) Standard p priority status 2008 82
Imbruvican (Ibrutinib) -140mg 2015 88
Panvax pandemic influenza vaccine Standard with rolling submission 2008 91
Gardasil (HPV recombinant vaccine) 2006 92
Opdivo-nivolumab Standard 2016 94
Alecensa (Alectinib) New Priority Pathway 2018 98
Lucentis (ranibizumab) Standard – priority status 2007 99
Alimta (pemetrexed ) Standard – priority status 2004 102
Hemlibra (emcizumab) New Priority Pathway 2018 104

Slide 16 - Safety Considerations

Screen capture of the JAMA article: 'Postmarket Safety Events Among Novel Therapeutics Approved by the US Food and Drug Administration Between 2001 and 2010'.

Source: Postmarket safety events among novel therapeutics approved by the US food and drug administration between 2001 and 2010.
JAMA. 2017 May 9;317(18):1854-1863. doi: 10.1001/jama.2017.5150.

  • 32% novel therapeutics affected by a post market safety issue
  • Accelerated and near-regulatory deadline approval statistically associated with higher events

Slide 17 - Safety Considerations – Priority pathway

  • Based on full data set
  • Additional pharmacovigilance issues not expected
  • Additional efficacy data not specified
  • May have up to 7 EOI for one New Chemical Entity (NCE) or New Biological Entity (NBE)
  • Safety signals may be from another therapeutic area
  • Does Faster review increase risk to patients?

Slide 18 - Safety Considerations – Priority pathway

  • Early data – could be NCE or NBE
    • Increased risk due to limited patient exposure
  • Early data for an EOI for already registered NCE/NBE
    • Increased risk if new dose or patient group
  • We will allow pre-specified updates to the dossier
      • Will this provides ability to deal with safety issues quickly?
      • Will this be enough to update PI and CMI?

Slide 19 - Safety Considerations – Priority pathway

  • New powers under the Act for provisionally registered medicines to:
    • reduce the class of persons for whom the medicine is suitable
    • to change the directions for use
    • to add a warning or precaution
    • change the Product Information related to the medicine
  • Gives delegates confidence to make a decision
  • Provides TGA ability to protect patients if unexpected problems occur

Slide 20 - Enhanced Vigilance Framework

  • Provisional medicines prioritised in enhanced vigilance framework
    • Black Triangle Scheme
    • PI Reformat
    • Inspection program
    • RMP Compliance Monitoring
    • Improved Adverse Event Management System (AEMS)

Screen capture of the TGA Australia tweet: Black Triangle will be seen on new medicine info from Jan 2018'

Source: Black Triangle will be seen on new medicine info from Jan 2018

Slide 21 - Confirmatory Trials

Screen capture of the New England Journal of Medicine article 'The Fate of FDA Postapproval Studies'

Source: The Fate of FDA Postapproval Studies.
Steven Woloshin, M.D., Lisa M. Schwartz, M.D., Brian White, B.A., and Thomas J. Moore, A.B.

Evaluated 614 requirements made in 2009-2010

  • 20% of studies had not been started after 5-6 years
  • 25% were still ongoing
  • 9% delayed, 16% on schedule
  • 54% completed as of 2015

Slide 22 - Confirmatory Trials: TGA approach

  • Provisional intended only for those medicines where further confirmatory data can be cullected
  • 2 year checkpoint to assess progress on clinical trial plan
    • Flexible approach needed as a smaller regulator
  • Requirement for Sponsor to have a clinical trial plan at determination stage
  • Planned trials to be fully accrued at determination stage
  • Other sources of real world data?

Slide 23 - Other Consideration: Quality & Outcomes

screen capture of Pub Med database showing the article ' Characteristics of pre-approval and post-approval studies for drugs granted accelerated approval by the US food and drug administration.'

Conclusion and Relevance: Amoung 22 drugs with 24 indications granted accelerated approval by the FDA in 2009-2013, efficacy was often confirmed in postapproval trials a minimum of 3 years after approval, although confirmatory trials and preapproval trials had similar design elements. including reliance on surrogate measures as outcomes.

Source: Characteristics of Preapproval and Postapproval Studies for Drugs Granted Accelerated Approval by the US Food and Drug Administration.
JAMA. 2017 Aug 15;318(7):626-636. doi: 10.1001/jama.2017.9415.

Slide 24 - Other Considerations: Communicating Risk

  • Standard wording in Consumer Medicine Information (CMI) & Product Information (PI)
  • Consumer and Health Professional Communication Plan
  • Improving Access to CMI
  • Reformating of CMI
  • Black Box warning
  • Promotion of provisional medicines – Industry may consider Medicines Australia Code of Conduct

screen capture of the Department of Health tweet ' Quick and easy PI and CMI with med search'

Source: Department of Health, #MedSearch app provide trsuted into for prescription

Slide 25 - Other Considerations

  • Standard wording in Consumer Medicine Information (CMI) & Product Information (PI)
  • Consumer and Health Professional Communication Plan
  • Improving Access to CMI
  • Reformating of CMI
  • Black Box warning
  • Promotion of provisional medicines – Industry may consider Medicines Australia Code of Conduct

screen image of the newpaper article titled: 'Malcom Turnball's Parliament gambit risks delaying access to life - saving drugs'

Source: Malcolm Turnbull's Parliament gambit risks delaying access to life-saving drugs

Slide 26 - Other options for Early access

Medicine applications/notifications
Medicine Applications approved / Notifications (Jul 2016 – June 2017)
Special Access Scheme 68,287
Clinical trials 705 (new trials)
Authorised Prescriber 764


  • Not commercially viable in Australia
  • Unproven therapy
  • Novel or new therapy
  • Travellers bringing products from overseas
  •  Compassionate Access
  • Pre- provisional registration
  • Lapse of provisional registration

Slide 27 - End of presentation

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