© Crown copyright 2005 Safeguarding public health Review of Unlicensed Medicines MHRA meetings with interested parties March 2011

© Crown copyright 2005

Safeguarding public health

Review of Unlicensed Medicines

MHRA meetings with

interested parties

March 2011

Title: RUM progress report


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



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



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



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



Proposals largely unchanged………



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



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)



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



General Monograph for Unlicensed Medicines

Definitions

Scope

Production

Labelling requirements

Requirements for Formulated Preparations



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




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




2010

Allopurinol oral suspensionBapivacaine and fentanyl injectionChloral hydrate oral solutionMagnesium glycerophosphate oral solutionMidazolam oral solutionPhosphate oral solutionPropylene glycol solutionWarfarin oral suspension



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



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.



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.



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.



Proposals developed further since last consultation…..



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



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


Safeguarding public health

RUM: Structural Reform“option 8”



Requirements

• Must apply equally to importers and manufacturers

• Must have minimum possible regulatory impact

• Must provide regulatory oversight of key safety issues



Principles

MHRA wishes to know about only products/activities:

That raise safety concerns

That may not meet special clinical need requirements



Previous Proposals

Considered feedback

Current Government policies

- Together suggest previous proposals too complex (“option 7”)

- New proposals developed (“option 8”)



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



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



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



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



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



Decision Tree



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



English Language Labelling

MHRA is aware that these will impact particularly on importers

Comments invited



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



Discussion…..

Feedback welcome …..

Documents

© Crown copyright 2005 Safeguarding public health Review of Unlicensed Medicines MHRA meetings with interested parties March 2011