Presentation: Spotlight on prescription medicines reforms
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An overview of initiatives arising from the Review of Medicines and Medical Devices Regulation relevant to prescription medicines as well as orphan drugs and developments for eCTD and the new MedSearch app.
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Presentation: Spotlight on prescription medicines reforms
- 1. Spotlight on Prescription Medicines Reforms Priority Review, Provisional Approval and other reforms Adrian Bootes Assistant Secretary Prescription Medicine Authorisation Branch Medicines Regulation Division, TGA 2017 ARCS Annual Conference August 2017
- 2. 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 Under development, planned for first quarter of 2018 Prescription Medicines Reforms 1
- 3. Designation process • New designation step for Priority Review and Provisional Approval • Entry ticket to expedited pathways • Prior to the dossier submission for registration • Formal process to assess against the eligibility criteria • Validity of the designation will lapse after six months for Priority Review • Positive designation decisions will be published online • Designation decisions are appealable The electronic designation application form is now available and the first designation applications have been received. Prescription Medicines Reforms 2
- 4. Pre-submission meetings and submission phase • We strongly recommend discussion at pre-submission meeting before applying for Priority Review or Provisional Approval designation This will be important for any application with less than a full dossier, as it may be encouraged to consider the Provisional Approval pathway We can answer questions, but we cannot pre-suppose the designation outcome • Increased scrutiny during submission phase for all registration applications It will be important to use the correct ‘form’ • Whilst introducing more flexible pathways for sponsors, the standard pathway will be clearly defined as requiring a full data dossier, unless in exceptional circumstances Prescription Medicines Reforms 3
- 5. Eligibility Criteria • New prescription medicine or new indication • High level eligibility criteria for Priority Review and Provisional Approval Serious condition; and Major therapeutic advance; and Positive comparison against existing therapeutic goods Priority Review based on ‘substantial evidence’ Provisional Approval based on ‘promising evidence from early clinical data’ • Sponsors may apply for the Orphan designation prior to or simultaneously with a Priority Review or Provisional Approval designation application Prescription Medicines Reforms 4
- 6. Priority Review • Introduced 1 July 2017 through legislative change • TGA's Chief Medical Adviser to make designation decision within 20 working days • Flexible business processes to reduce the registration timeframes • Target total 150 working days consistent with international regulators • ‘Partnership’ with applicant and standard timeframes will apply if requirements for Priority Review are not met • Full registration in the Australian Register of Therapeutic Goods (ARTG) Prescription Medicines Reforms 5
- 7. Flexible registration process • An eCTD dossier will be required • Registration process will commence after dossier validated (no batching) • First and second round evaluation phases will be condensed • Rolling questions during the first round evaluation • Flexible arrangements for seeking expert advice • More resource intensive process cost recovered through new designation, application and evaluation fees Prescription Medicines Reforms 6
- 8. GMP requirements • Good Manufacturing Practice (GMP) licenses/clearances within the 150 working day target timeframe required • Entry requirements: – At designation Evidence of approved or submitted GMP clearance, certification or license tracking number for all manufacturing sites provided – At registration All fees paid and evidence lodged at dossier acceptance • Exit criteria – Priority Review may transition to the standard pathway if GMP requirements not met Prescription Medicines Reforms 7
- 9. Polling Questions What proportion of new chemical entities and new biological entities do you believe that you will submit via the Priority pathway over the next 12 months? – 0-10% – 10-20% – 20-30% – More than 30% – Not sure Prescription Medicines Reforms 8
- 10. Polling Questions What proportion of new indications do you believe that you will submit via the Priority pathway over the next 12 months? – 0-10% – 10-20% – 20-30% – More than 30% – Not sure Prescription Medicines Reforms 9
- 11. Implementation June • Amendments to the Therapeutic Goods Act changes passed on 19 June 2017 July • TGA started to accept notifications of the intent to file/lodge for Priority Review designation applications or requests for pre-designation meetings • The new Priority Review regulation came into effect (1 July) • TGA published Priority Review guidance prior to 1 July 2017 • TGA provides a new designation application e-form • TGA starts to accept Priority Review designation applications Aug/ Sep • First designation decisions under the Priority Review designation process are possible • Earliest opportunity to lodge Pre-submission Planning Form (PPF) with valid Priority Review designation • TGA starts to accept submissions for registration with valid Priority Review designation for priority evaluation Dec • Ongoing monitoring of the number of submitted designation applications and decision outcomes and the time from designation application lodgment to decision July 2018 • The impact of changes will be reviewed considering designation application numbers, designation outcomes and stakeholder feedback. The guidance material will be reviewed and updated if required 10
- 12. More information on our website https://www.tga.gov.au/priority-review-pathway-prescription- medicines Prescription Medicines Reforms 11
- 13. Provisional Approval Prescription Medicines Reforms 10
- 14. Provisional Approval Provisional Approval implementation scheduled for first quarter of 2018 (subject to legislative amendments) • Provisional registration of goods in the initial absence of full clinical data on safety and efficacy • Granted for specified time periods (2 years + up to 2 extensions of 1-2 years each) • Sponsors required to collect and submit further clinical data to demonstrate efficacy and safety for full registration • Enhanced post-market monitoring and surveillance • Subject to the provision of clear advice to consumers and healthcare professionals and any other conditions imposed by the TGA Prescription Medicines Reforms 10
- 15. Polling question For Provisional registration Companies when giving undertakings for a product in the (up to) 6 year period will fulfill: – all commitments – most commitments – all commitments but perhaps will need flexibility as trials develop for data sources – most commitments but some will not be completed due to other priorities Prescription Medicines Reforms 11
- 16. Outlook • Recent public consultation on implementation arrangements – Outcomes published on TGA website shortly – Stakeholder feedback informed proposed legislative amendments and business processes • Further targeted consultation with industry on draft guidance later in 2017 • Work closely with consumer and healthcare professional representatives to ensure messaging about the provisional status of medicines is appropriate Prescription Medicines Reforms 11
- 17. Orphan Drug Program Aims to provide an incentive to sponsors to bring medicines for a small population to market and make medicines available to patients who would not otherwise be able to access them. What’s changing? Why? • New criteria • Designation validity • Transition period • Two pathways • Documentation 1. To ensure that the correct medicines are being facilitated to be assessed free-of-charge 2. To ensure a more consistent proportion of medicines meet the Orphan criteria in the face of an increased ‘personalisation’ of medicines Applies to the Priority Review, Provisional Approval and standard pathways Prescription Medicines Reforms 16
- 18. 1. Standard Pathway Orphan Drug Program Criteria Incentive Designation validity Eligible application types Previous • ≤ 2,000 Australians OR not financially viable • No refusal to approve overseas for safety • 100% fee waiver for registration • Indefinite • A, B, C, D, F New • < 5/10,000 Australians OR not financially viable • No refusal to approve overseas for safety • Life threatening or seriously debilitating condition • Comparison against existing goods • Medical plausibility • 100% fee waiver for registration • 6 months + 6 months possible extension • A, B, C, F* Prescription Medicines Reforms 3
- 19. 2. New dosage form medicine pathway An orphan designation for a medicine that is a new dosage form: • Life-threatening or seriously debilitating condition • Not financially viable • No refusal to approve overseas • Comparison against existing goods Definition of new dosage form: • has the same chemical, biological or radiopharmaceutical active ingredient (or fixed combination of such ingredients) as another medicine that is included in the Register • has an indication in common with that other medicine • does not have the same dosage form as that other medicine Benefits small patient populations, e.g. paediatrics Prescription Medicines Reforms 18
- 20. Criteria comparison Priority review Standard orphan New dosage form medicine orphan Life threatening or seriously debilitating Comparison against existing therapeutic goods Major therapeutic advance Prevalence threshold OR Not financially viable Medical plausibility Prescription Medicines Reforms 19
- 21. Where we have landed – selected items Paediatric indications • Standard orphan drug pathway- paediatric indications will be considered eligible subsets where: – prevalence is met in relation to the whole of the disease – where the disease is different in, or specific to the paediatric subgroup • New dosage form medicines pathway- designed to benefit small patient populations, such as paediatrics Validity of designations • Priority review designations remain in force for a period of 6 months, OR when an effective section 23 application is lodged until the application is finally determined • Orphan drug designation will remain in force for a period of 6 months, OR When a 6 month extension of designation is approved for a period of 12 months • All existing Orphan designations prior to 1 July 2017 will expire on 1 July 2018. Impact of orphan designation on the PBAC process All enquiries regarding applications to the Pharmaceutical Benefits Advisory Committee should be directed to PBAC@health.gov.au Prescription Medicines Reforms 20
- 22. Orphan Drug Reform Implementation Plan July 2017 • The new orphan drug regulation came into effect 1 July 2017 • Orphan Drug guidance published • New designation application e-form available • Applications must be lodged using the new e-form • Applications required to be in the correct format and address new criteria and guidance Aug 2017 • First orphan drug designation decisions are possible under the new orphan drug regulation Dec 2017 • Ongoing monitoring of the number of applications, outcomes and timeliness of process Jul 2018 • Review impact of changes considering designation application numbers, outcomes and stakeholder feedback • Guidance material reviewed and updated if required • The validity of all orphan designations lodged prior to 1 July 2017 lapses Prescription Medicines Reforms 21
- 23. More information on our website https://www.tga.gov.au/orphan-drug-program-reforms Prescription Medicines Reforms 22
- 24. New e-form for minor variations • New electronic form available through TBS • Minor variations to prescription medicines Prescription Medicines Reforms 23
- 25. Reducing regulatory burden • Need for improvements to processes • Staged approach to improve the processing of minor variations • Number of minor variations received in 2016-2017 financial year Category Number 9D(1) 122 Category 3 1345 MEC 458 SAR 1232 SRR 707 Total 3864 Prescription Medicines Reforms 24
- 26. New electronic form One-stop shop • Consolidating six PDF forms into one electronic form • Reduced time and effort in making applications • Allows a real-time view of ARTG entries • More efficient processing of requests Launch • 18 sponsors were involved in testing • Progressive soft launch during July • Full launch 25 July 2017 • Paper forms will be turned off as an option by legal instrument in the near future. Prescription Medicines Reforms 25
- 28. Summary of changes and associated fees before you submit Fees Variation Group Legislative Fee item Fee* basis A new good with a new ARTG ID will be generated for the following goods based on the variation being made under this legislative basis: Correct an ARTG entry 9D(1) 2A(a) $1,625.00 Quality Information 9D(3) Product information (PI) 9D(2) 2CA $5,270.00 *Fees are for the 2016/2017 financial year Prescription Medicines Reforms
- 29. Next steps • Guidance updated and published - printable version and e-book • Request: sponsors pro-actively review errors and omissions in register entries via the form Prescription Medicines Reforms 28
- 30. Outlook – notifications process • A new notifications process for non-prescription medicines was launched in July 2017 • The new minor variations e-form is the first step in delivering a notification process for prescription medicines • Additional functionality to allow automatic processing of notifications will be implemented before the end of 2017 Prescription Medicines Reforms 29
- 31. More information Prescription Medicines Authorisation Branch Application Entry Team AET.application.entry.team@health.gov.au Prescription Medicines Reforms 30
- 32. Other activities 1. Revised committee structure and responsibilities – from 1 Jan 2017 2. Current state and future path of the electronic common technical document (eCTD) 3. Recent launch of the MedSearch app Prescription Medicines Reforms 31
- 33. Revised committee structure from 1 Jan 2017 Advisory Committee on Medicines (ACM) Advisory Committee on Prescription Medicines (ACPM) Advisory Committee on Non-Prescription Medicines (ACNM) Advisory Committee on the Safety of Medicines (ACSOM) Advisory Committee on Vaccines (ACV) Advisory Committee on Prescription Medicines (ACPM) (Functions related to vaccines) Advisory Committee on the Safety of Vaccines (ASCOV) Prescription Medicines Reforms 32
- 34. Current state and future path of eCTD Benefit: allows update of relevant dossier sections across multiple applications • Increasingly important with multiple sponsor applications in process, across multiple evaluation sections Current state: • Encouraged for ALL prescription medicines submissions • Mandatory for TGA’s ‘PPF-only’ Category 1, Priority Review, Provisional Approval (once implemented) • Now mandated by FDA, EMA, Health Canada • Increasingly used for internal TGA workflows Prescription Medicines Reforms 33
- 35. Current state and future path of eCTD Future path: • Expectation is a steady migration to eCTD (expected for Priority and where previous eCTD applications) • Direct upload capability for dossiers getting closer; only available for eCTD dossiers • An update to the eCTD specification primarily to accommodate Priority Review, Provisional Approval and allowed combinations of minor variations – Consultation later this year – Expected implementation early next calendar year Prescription Medicines Reforms 34
- 36. MedSearch™ The trusted source of medicine information in Australia • FREE app available from June 2017 • Consumer Medicine Information (CMI) or Product Information (PI) document • Sources directly from the Australian Register of Therapeutic Goods (ARTG) Prescription Medicines Reforms 35
- 37. MedSearch™ features Quickly access prescription medicine information from your phone: • Simply search the medicine name to find its CMI or PI • Favourites – bookmark medicine information in one place • Save medicine info documents and view them anytime • Share CMI/PI documents with family and carers Connects consumers, carers, doctors, nurses and pharmacists to trusted and current information about their prescription medicines Prescription Medicines Reforms 36
- 38. MedSearch™ Polling question Looking at the Medsearch App and its future: • The functionality is about right, and communications are at the right level • The functionality is about right, and should be rolled out in as many ways as possible • Functionality could be expanded, to provide other medicine communications to health care practitioners and patients/carers Prescription Medicines Reforms 37
Editor's Notes
- The key objective of the expedited pathways is to formalise the facilitation of earlier access to medicines that address unmet clinical needs for Australian consumers, without compromising our standards for safety, efficacy and quality. Review recommendations arose from the observation that Australia is out of step with overseas regulators (such as Japan, the USA and Europe). However, Australia has on occasion done this within existing legislation to address unmet clinical needs for Australian patients. In the case of Priority Review, medicines could come to market three months sooner and for Provisional Approval, as much as two years sooner than under the current framework. It is crucial to maintain the confidence of consumers and health professionals in TGA’s high standards for safety, efficacy and quality of prescription medicines following the introduction of these new pathways. The Senate showed much interest in this when they considered the legislation for Priority Review, so these aspects will likely be further strengthened in the legislation for Provisional Approval. These pathways will be mutual processes. We as a regulator will have additional expectations of sponsors at the pre-submission stage, during evaluation and in the case of Provisional, post-approval. For Provisional Approval, early data may be phase II data and some phase III available, or coming in future. I would like to emphasise that Priority is for a full data dossier, as it if is a standard application.
- The designation process will be an important step to provide us with a formal mechanism to determine whether a medicine is eligible for one of the expedited pathways. Timing If sponsors wish to apply for one of the expedited pathways, they will be encouraged to meet with the TGA 6-7 months prior to making their submission to register a prescription medicine. Resourcing Designation will also allow us to start lining up our resources so that we will be ready to commence evaluation as soon as the submission is received in the interests of a faster overall registration process. This step will help to ensure that the introduction of the expedited pathways does not unreasonably impact on our processes for the registration of other prescription medicines. The new pathways will be resource intensive for both the TGA and sponsors, so it is important that eligibility into the pathways is reserved for those medicines offering the greatest benefit to patients. We will also be introducing a new fee for the designation application to cost recover the work involved in this step
- Pre-submission meetings It will be crucial to discuss any applications with less than a full dossier, as we may encourage the sponsor to consider applying for Provisional Approval. The pre-submission meetings will assist in orienting TGA staff as to the medicine and the basis for the Priority or Provisional application. This meeting may also be used to canvas Orphan applications. It will allow us to start considering data that may be required. We can answer questions, but not questions so specific as to pre-suppose the designation outcome The Chief Medical Adviser (eligibility decision maker) may or may not be available for the pre-submission meeting, but senior staff from the clinical evaluation units will attend. Proposed ‘application provisions’ to increase scrutiny of all applications We will be proposing changes to the application provisions of the Act to clarify in the legislation how applications for evaluation of medicines may be made, and what a valid application looks like. These changes are not expected to result in changes to application forms, fees or procedures that sponsors will follow, but will provide greater clarity around application requirements and processes. Transparency We are considering increasing transparency of what applications (NCEs and EOIs) are currently under evaluation by the TGA.
- Seriousness = treatment, prevention or diagnosis of a life-threatening or seriously debilitating condition Comparison against existing therapeutic goods = either: (i) no therapeutic goods are included in the Register; or (ii) There is substantial evidence demonstrating that the medicine provides a significant improvement in the efficacy or safety compared to those goods included in the Register; Major therapeutic advance = there is substantial evidence [or promising evidence from early clinical data] demonstrating that the medicine provides a major therapeutic advance. Characteristics of TGA’s criteria All three of the eligibility criteria must be met The eligibility criteria have been designed so that a single application cannot be eligible for both Priority Review and Provisional Approval (priority is based on ‘substantial evidence’ of a complete data dossier; whereas provisional is based on ‘promising evidence’ from early data) We are trying to strike an appropriate balance between a formal regulatory framework to determine whether a medicine is eligible for one of the expedited pathways, while allowing flexibility for clinical judgement Whilst not wanting to be too prescriptive, considering our criteria and the performance of overseas regulators, we wish to target a rate of 1:5 to 1:10 applications. Designation rejections are appealable, but this is limited to the applicant only. However, an appeal must be made within 90 days and takes 60 days for consideration, so this may hold up evaluation via the standard pathway. Sections will have a system of peer review to ensure consistent in applying the eligibility criteria.
- Although the TGA has not had a formal Priority Review pathway since 2010, in circumstances where a medicine has been considered by the TGA to be a significant therapeutic advance or of critical importance to the Australian community (for example, in emergency situations), we have worked with relevant sponsors to facilitate early access to the new product (provided that it meets the TGA’s quality, safety and efficacy requirements). Introduction of the Priority Review pathway will formalise these processes and provide more certainty for TGA and sponsors. We will need a valid application and payment to initiate the 20 working days. Clinical sections will work up documentation for the CMA’s consideration. (By 23 August: some priority designation decisions will have been made – its likely that some will have been successful and some not). Meeting the Priority timeframe The Priority Review process will be more resource intensive for the TGA than the standard prescription medicines registration process. Assessment of Priority Review applications will be just as rigorous as any other TGA assessment process. In applying for the Priority Review pathway, sponsors will need to make a commitment to provide the TGA with all necessary information in a timely manner to be eligible for the designation and remain in the pathway. The average time for a standard submission registration process is targeted to be 220 days, and has averaged faster than this, so a sponsor should not feel substantially disadvantaged if their application is in the standard pathway. For both the standard and Priority Review pathways, our milestone dates are estimates only and for specific applications it may take longer to complete certain milestones for various reasons. For both pathways, the only binding statutory timeframe is completion within 255 working days.
- We believe with rolling questions, sponsors will have a view as to some of the issues raised by evaluators We will look to ensure a sufficient gap between the receipt of the full clinical evaluation report and the Delegate’s overview The cost-recovery element is estimated to be low, currently an approximate 5% increase in evaluation fees, and approximate 5% or $12,300 for the designation process. These fees will be reviews as we have more experience with the new pathways. Where we need expert advice, we may go to a scheduled meeting of the Advisory Committee for Medicines, or schedule an ad-hoc meeting between scheduled meetings when required.
- Please note in 2018 it is planned that the provisional approval pathway will be introduced. It will be key to remember that these are separate pathways and may not be combined.
- Provisional Approval will require changes to the Therapeutic Goods Act 1989 and to the regulations. The legislative chances are likely to be more comprehensive than those for Priority Review and Orphan Drug reforms. It the Senate continues its current thinking, it is likely that patient safety will be a key consideration for the passage of the legislative amendments. A Provisional Approval may be for an unregistered product or for a new indication of an already registered product. The 2-year lapsing provides a check-point, as we need to know that clinical trials and other data gathering are proceeding on track. The intention of the Provisional Approval pathway is that the sponsor will apply for full registration before the end of the maximum 6-year period. Options on receipt and consideration of an application for full registration may be: Continuation of provisional registration (up to a maximum period of six years) Transition of one or more indications of a provisional registration to full registration Restriction of the patient population/use of the provisional registration to a small group Removal of provisional registration and, where appropriate, continued access to the medicine for existing patients through the Special Access Scheme or as part of an Authorised Prescriber access.
- Designation fee is planned to be the same as for Priority (and waived if the Orphan designation is received for the same medicine and indication) Application and evaluation fees for Provisional Approval registration applications will be developed on a cost-recovery basis as we finalise our business processes Cost-recovery for future enhanced monitoring will be required and this will also be considered. Where we believe a standard dossier does not have sufficient data we will very strongly encourage withdrawal and re-submission in the Provisional Approval pathway.
- Designation fee is planned to be the same as for Priority (and waived if the Orphan designation is received for the same medicine and indication) Application and evaluation fees for Provisional Approval registration applications will be developed on a cost-recovery basis as we finalise our business processes Cost-recovery for future enhanced monitoring will be required and this will also be considered. Where we believe a standard dossier does not have sufficient data we will very strongly encourage withdrawal and re-submission in the Provisional Approval pathway.
- Note – this slide is animated and shows the new criteria underneath the previous criteria. Seriousness = treatment, prevention or diagnosis of a ;life-threatening or seriously debilitating condition; Comparison against existing therapeutic goods = either: (i) no therapeutic goods are included in the Register; or (ii) the medicine provides a significant improvement in the efficacy or safety (or for orphans a major contribution to patient care) compared to those goods included in the Register; Prevalence threshold = NMT 5/10,000 in Australia) currently ~12,000 Lack of financial viability = it is not likely that it would be financially viable for the sponsor to market the medicine in Australia unless the TGA application and evaluation fee were waived Medical plausibility = (1) the rationale for use of the medicine in the proposed orphan indication and (2) if the condition is a subset of a condition affecting a larger population, the medicine would not be effective for the larger population - This will be important for artificial slicing of indications by age or by biological mechanism etc. Characteristics of TGA’s criteria All relevant eligibility criteria must be met
- In the 2016 public consultation about half of all respondents supported the paediatric proposal , the other half did not. new dosage form medicine means a medicine that: (a) has the same chemical, biological or radiopharmaceutical active ingredient ( or fixed combination of such ingredients) as another medicine that is included in the Register; and (b) has an indication in common with that other medicine; and does not have the same dosage form as that other medicine Request for a more generous paediatric proposal Paediatric indications will be considered eligible subsets where: prevalence is met in relation to the whole of the disease where the disease is different in, or specific to the paediatric subgroup
- Why 6 months? The baseline of designations will change so re-designation is required.
- Where we have an orphan designation we may be more flexible with the requirement for an eCTD submission. However, if a submission has already been made for a product in eCTD format, we would expect the orphan (and other applications) to be in eCTD format.
- Not perfect on day 1! Page loading speed Reflecting the entries on the manufacturing database is still being worked on.
- A new notifications process for non-prescription medicines was launched in July 2017. Under the proposed notifications process, the sponsor notifies the TGA of the variation and the request is electronically validated allowing a computer program to inform the sponsor that the variation can be implemented. In comparison, all other variations must be assessed by the TGA. The new process attracts a lower fee and allows a sponsor to implement low risk changes more quickly than before. The first step for a new notification process for prescription medicines has been completed with the launch of a new e-form for all minor variations to prescription medicines. Additional functionality to allow automatic processing for notifications will be implemented before the end of 2017.
- From 1 January 2017, the TGA made changes to the structure of it’s committees as part of the MMDR Review. The ACMP, ACNM and ACSOM were consolidated to form the ACM The ACSOV and the functions of the ACPM were consolidated to form the ACV The Advisory Committee on Medicines (ACM) and Advisory Committee on Vaccines (ACV) provide independent medical and scientific advice related to the safety, quality and efficacy of medicines and vaccines respectively. Pre-market functions include advice related to the registration of new medicines and extension of indications. Post-market functions include advice related to the post-market safety matters. Committees membership comprised of experts with scientific and clinical expertise, as well as consumer health issues.