© Crown copyright 2005
Safeguarding public health
Review of Unlicensed Medicines
MHRA meetings with
interested parties
March 2011
Title: RUM progress report
© Crown copyright 2005
Purpose of meeting
• To explore with interested parties latest thinking on ideas on reform developed by the RUM Steering Group
• Reflects responses to earlier consultation; also our understanding of the Coalition’s regulatory agenda
• Aim is to test out current thinking before revising and/or firming up proposals for formal consultation later in 2011
• Looking for help in teasing out regulatory impact
Health Warning! • Specific ideas for reform presented are ideas for exploration and
don’t necessarily represent official policy of MHRA or any others represented on RUM Steering Group
Title: RUM progress report
© Crown copyright 2005
Review of unlicensed medicines
Remit: Review UK use of the derogation
permitted in Art 5.1 of Directive 2001/83/EC
Coverage: UK “Specials” and associated
import notification scheme
RUM Steering Group: MHRA, Health Departments,
NPSA, PASA
Timetable
2007 Review set up:
Feb 2008 Concept paper
May 2009 Interim Report
Late 2009 / early 2010 updating proposal in light of responses to consultation
Late 2010 to date – update in light of Coalition’s regulatory agenda
Title: RUM progress report
© Crown copyright 2005
Aims
Prescribers able to take professional responsibility to supply unlicensed medicines to meet special needs
Improve public health protection
Clear responsibility/accountability for protecting patient safety and rights
Meet Better Regulation principles: proportionality, targeting, consistency, transparency and accountability
Arrangements to complement not undermine licensing of medicines
Title: RUM progress report
© Crown copyright 2005
Where are we now?
Proposals largely unchanged from earlier consultation
Quality and manufacturing standards applying to Specials
Strengthen pharmacovigilance
Advertising
Proposals changed since last consultation
Patient information
- Greater responsibility on healthcare professional to exercise judgement
Proposal for structural reform of notification system covering both domestic manufacture and imports
- Ideas for improved streamlining
Title: RUM progress report
© Crown copyright 2005
Proposals largely unchanged………
Title: RUM progress report
© Crown copyright 2005
Quality & Manufacturing
Feedback
Support for quality standards Support for development of BP monographs Some concerns about application of standards to low
volume products; impact on small manufacturers
Proposed approach Develop further guidance on application of GMP to
these products Continue programme of developing BP monographs
for unlicensed medicines
Title: RUM progress report
© Crown copyright 2005
BP Monographs for Unlicensed Medicines
The publication of a BP monograph provided a legally binding enforceable quality standard for unlicensed medicines
Unlicensed Medicines in the BP- Supplementary chapter (non-mandatory)- General monograph (compliance mandatory)- Product monographs (compliance mandatory)
Title: RUM progress report
© Crown copyright 2005
Supplementary Chapters
Chapter V Introduction Legal requirements Ethical consideration and guidance Labelling Standards for preparation and manufacture
Chapter V.a Preservative-free unlicensed medicines
Chapter V.b Bioequivalence of oral suspension
Chapter V.c (Draft for 2011 edition) Storage and shelf lives for unlicensed medicines
Chapter V.d (Draft for 2011 edition) Formulations for Extemporaneous Preparations
Title: RUM progress report
© Crown copyright 2005
General Monograph for Unlicensed Medicines
Definitions
Scope
Production
Labelling requirements
Requirements for Formulated Preparations
Title: RUM progress report
© Crown copyright 2005
Published Monographs for Unlicensed Medicines
2008
Caffeine citrate injection Caffeine citrate oral solution Dantrolene oral suspension Levomenthol cream Mercaptopurine oral suspension Paediatric phenobarbital oral solution Potassium chloride oral solution Sodium chloride oral solution Sodium fluoride oral solution
Title: RUM progress report
© Crown copyright 2005
Published Monographs for Unlicensed Medicines
2009
Adrenaline and cocaine intranasal solutionCaptopril oral solutionCocaine pasteCompound glucose, sodium chloride and sodium
citrate oral solutionHydrocortisone sodium phosphate oral solutionPotassium dihydrogen phosphate oral solutionVancomycin oral solution
Title: RUM progress report
© Crown copyright 2005
Published Monographs for Unlicensed Medicines
2010
Allopurinol oral suspensionBapivacaine and fentanyl injectionChloral hydrate oral solutionMagnesium glycerophosphate oral solutionMidazolam oral solutionPhosphate oral solutionPropylene glycol solutionWarfarin oral suspension
Title: RUM progress report
© Crown copyright 2005
Work programme for monographs for Unlicensed Medicines
2011
Bupivacaine and diamorphine injection Clozapine oral suspension Dinoprostone oral solution Coal tar paste Coal tar and salicylic acid ointment Salicylic acid cream Salicylic acid ointment Silver nitrate solution Sodium chloride nebuliser solution Sodium carbonate oral solution Cefuroxime eye drops Disodium edetate eye drops
Title: RUM progress report
© Crown copyright 2005
Pharmacovigilance – ProposalsIntroduction
Pharmacovigilance (PhV) is a key activity in ensuring the safety of all medicinal products throughout their lifecycle.
A significant element of effective PhV is the reporting and analysis of suspected adverse drug reactions (ADRs).
ProposalsDuty on UK manufacturers and importers to
communicate to the MHRA all suspected (ADRs) – not just serious ADRs.
Promote reporting of suspected ADRs by healthcare professionals and patients via the Yellow Card system.
Title: RUM progress report
© Crown copyright 2005
Pharmacovigilance – The FutureConsultation
General support for strengthened PhV. Positive response to promoting Yellow Card
reporting via patient and healthcare professional information.
Concern regarding complexity and cost.
Solutions
Practical system – electronic reporting. Simplicity – report all suspected ADRs. Realistic timelines. Use patient and healthcare professional
information to encourage Yellow Card reporting.
Title: RUM progress report
© Crown copyright 2005
Advertising
■ It would be permissible to circulate simple price lists to potential healthcare professional
customers in response to an enquiry provided no product claims are made.
■ It would be acceptable to promote the service offered.
Title: RUM progress report
© Crown copyright 2005
Proposals developed further since last consultation…..
Title: RUM progress report
© Crown copyright 2005
Patient Information
Object of reform
- Patient information requirements should be strengthened
Options going forward
- General support in the consultation for information with unlicensed medicines
- No requirement for information in every case
- BUT professional guidance will cover this
Title: RUM progress report
© Crown copyright 2005
Labelling
Object of reform
- Labelling requirements should be strengthened
Options going forward
- Generally support in the consultation for standard labelling
- Labelling should be in English
- Labelling requirements should follow those set out in the British Pharmacopoeia and MHRA Guidance Note 25
© Crown copyright 2005
Safeguarding public health
RUM: Structural Reform“option 8”
Title: RUM progress report
© Crown copyright 2005
Requirements
• Must apply equally to importers and manufacturers
• Must have minimum possible regulatory impact
• Must provide regulatory oversight of key safety issues
Title: RUM progress report
© Crown copyright 2005
Principles
MHRA wishes to know about only products/activities:
That raise safety concerns
That may not meet special clinical need requirements
Title: RUM progress report
© Crown copyright 2005
Previous Proposals
Considered feedback
Current Government policies
- Together suggest previous proposals too complex (“option 7”)
- New proposals developed (“option 8”)
Title: RUM progress report
© Crown copyright 2005
Option 8
Manufacture/import of unlicensed medicines may be performed with minimal regulation (i.e. no notifications needed) for licence holders unless:
- Change of category on master licence is required for manufacturers (MS)· Variation for new categories
- Item is on a “Restricted List”· Variation required to permit import/manufacture
Real-time feedback of changes via Risk Based Inspection (RBI) programme
Title: RUM progress report
© Crown copyright 2005
Master Licences – activities
Currently the MS has a range of categories of activities specified
- Requires rationalising- May need some new categories/sub-categories
Categories may be added by means of variation
MHRA will conduct survey to assist rationalisation
- Probably no fee for resulting updates
Title: RUM progress report
© Crown copyright 2005
Restricted List - products
A licence holder must apply for their licence to be varied for items on this list to be added to their licence
Application similar to current import notification (28 days etc.). Granted variation will have appropriate validity period Provision for urgent applications (incl. Out-of-hours)
Assessment against risk and compliance with licence
Fee per variation. New variation required on expiry
Additional fee for referral to Expert Committee
Title: RUM progress report
© Crown copyright 2005
Example Restricted List
Products with the same drug substance and pharmaceutical form as products with EU or UK national licences, except where prepared from these licensed products, or from another “notified” unlicensed product. Public listings of licensed products can be made available
Products from outside the EEA
Imported products not licensed in the country of origin
Specific products with safety concerns
Title: RUM progress report
© Crown copyright 2005
Notifications under RBI Programme – MS holders
Changes within existing licence categories to be notified via Inspectorate
- Where new API used for manufacture of a product from raw materials (i.e. not from another product)· - aims to capture “unknowns”
- Could exclude unlicensed products with BP Monographs· (but these could still appear on Restricted List)
- Could also publish guidance giving acceptable APIs to limit number of notifications required
Title: RUM progress report
© Crown copyright 2005
Decision Tree
Title: RUM progress report
© Crown copyright 2005
Preliminary Impact Assessment
“Back of envelope” estimate of volumes
Review of import notifications and of sample product lists from large specials manufacturers
The total numbers falling within the restricted list was less for manufacturers than importers by a factor of approximately 1:5 - many products are prepared from existing licensed products and
are thus not in the Restricted List
Currently, the total number of notifications per annum from importers is ~75,000
~10% of this is expected under Option 8 from importers. If manufacturers notify ~20% of this, a total of ~10,000 submissions per annum might be expected under Option 8
Title: RUM progress report
© Crown copyright 2005
English Language Labelling
MHRA is aware that these will impact particularly on importers
Comments invited
Title: RUM progress report
© Crown copyright 2005
Transitional Arrangements
Under consideration:
Variation applications during introductory year
- Used to gather data and set baseline for licence holders
- No fees in this period- Major issues only for regulatory action
Title: RUM progress report
© Crown copyright 2005
Discussion…..
Feedback welcome …..