Agency experiences nine months on - The MHRA ... - TOPRA

Variation Regulation 1234/2008
MHRA <strong>experiences</strong>
9 <strong>months</strong> on
05 October 2010
TOPRA annual symposium
Dr Krystyna Fielden
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Overview:
‣ Metrics for variations submitted : Type IA, IB, II
• An analysis pre- and post- 2010
Key issues 9 <strong>months</strong> on
‣Type IA rejections
• The top 12 change codes
• common deficiencies
> administrative
> scientific, technical
> review of ‘real life’ rejection letter – interactive session
‣Grouping within Type IA, IB and II:
• trends
• grouping explained: past and present
• rules for grouping explained: practical application of Art 7 (a) and (b)
> ‘real life’ examples of acceptable and unacceptable groupings
> fee considerations consequential vs related changes
> groups and bulks
Slide 2
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Variations Metrics (1) :
• nearly a ¼ million changes to Marketing Authorisations submitted EU wide each year
• about 80% for ‘purely National’ (single MS, non-MR) authorisations
• over 25,000 in the UK alone
Breakdown of variations
35000
30000
25000
Number
20000
15000
10000
TYPE IA
TYPE IB
TYPE II
TOTAL
5000
0
98/99
99/00
00/01
2001/02
2002/03
2003/04
2004/05
2005/06
2006/07
2007/08
2008/09
Slide 3
Year
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Metrics (2): Number of variations received by MHRA in
the last 20 <strong>months</strong> – trends in the new system
Number of variations received (monthly)
4000
3500
1234/2008
3000
Number
2500
2000
1500
IA
IB
II
TOTAL
1000
500
0
Jan-
09
Feb-
09
Mar-
09
Apr-
09
May-
09
Jun-
09
Jul-
09
Aug-
09
Sep-
09
Oct-
09
Nov-
09
Dec-
09
Month of receipt
Jan-
10
Feb-
10
Mar-
10
Apr-
10
May-
10
Jun-
10
Jul-
10
Aug-
10
Slide 4
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Metrics (3): Comparative breakdown of variations
Variations breakdown - Old system
TYPE IA
TYPE IB
Typo
TYPE II
Breakdown of variations (New system)
Number of changes per individual PL:
‣ Generally 3 or fewer
Number of variations per PL:
‣ Maximum – 21
‣ Average – approx. 2.3
IA in
IA an
TYPE IA
TYPE IB
TYPE II
Slide 5
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Metrics (4): impact of grouping
% of variations as "Groupings"
35.0
30.0
25.0
%
20.0
15.0
Type IA
Type IB
Type II
10.0
5.0
0.0
Jan-10 Feb-10 Mar-10 Apr-10 May-10 Jun-10 Jul-10 Aug-10
Month of receipt
Slide 6
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Metrics (5): Type IA Notifications - Refused
Unacceptable Type IA
45.0
40.0
1234/2008
35.0
30.0
%%
25.0
20.0
15.0
10.0
5.0
0.0
Jan-
09
Feb-
09
Mar-
09
Apr-
09
May-
09
Jun-
09
Jul-
09
Aug-
09
Sep-
09
Oct-
09
Nov-
09
Month of receipt
Dec-
09
Jan-
10
Feb-
10
Mar-
10
Apr-
10
May-
10
Jun-
10
Jul-
10
Slide 7
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Observation (1) : some change codes more problematic
than others e.g.Type IAs requiring QP declarations
Reject rate overall 60%
attributed to deficient QP declarations
QP dec
Imp date
CEP
other
450
400
350
Submitted Jan – Aug 2010
300
Rejected
390
250
200
150
Granted 628
total
1,018
100
50
38%
54%
40% 34%
total
0
Granted
B.II.B.2.B.1 B.II.B.2.B.2 B.III.1.A.1
B.III.1.A.3
Batch
cert
Batch
cert/QC
CEP
update
CEP
new
Rejected
40%
Slide 8
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Observation (2) : some companies have more problems than others
Type IA determined Jan-Sept 2010: % reject rate per company
50
45
40
35
30
25
20
15
10
5
0
0‐10%
10‐20%
20‐30%
Number of Companies In Band
Number of Companies In Band
30‐40%
40‐50%
50‐60%
60‐70%
70‐80%
80‐90%
90‐100%
1800
1600
1400
1200
1000
800
600
400
200
0
Total cases in Band
0‐10%
Total cases in Band
10‐
20%
20‐
30%
30‐
40%
40‐
50%
50‐
60%
60‐
70%
70‐
80%
80‐
90%
90‐
100%
A B C D E F G H I J
A B C D E F G H I J
Slide 9
Reject rate (%)
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Hot issues 9 <strong>months</strong> on
‣TYPE IA REJECTIONS
‣GROUPING
Slide 10
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Type IA <strong>experiences</strong> (1): most common categories
change code description IA/IA in
%
A.7 Deletions A 17.3
A.1 MAH name/address IN 7.9
B.III.1.A.2 Update to API CEP A 7.7
A = administrative (34.9%)
B.II.B = FP manuf sites (12.2%)
B.III = API (11.7%)
B.II.B.1.A Secondary packaging IN 4.8
C.I.9.C DDPS IN 4.8
B.III.1.A.3 API new CEP new manufacturer IN 4
B.II.B.2.B.1 Batch release IN 4
A.5.B Name change manufacturer other A 3.6
B.II.D.1.C Additional test parameter to FPS A 3.5
B.II.B.2.A QC site for FP A 3.4
A.5.A Name change manufacturer BR IN 3.3
A.4 Name change - API Manufacturer A 2.8
Slide 11
Total 67.1%
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Type IA <strong>experiences</strong> (2): common deficiencies
‣ Administrative
• Application form not completed correctly or non-compliant
with ‘Special MAIL 5’ requirements
• Wrong (or inappropriate) change code selected
• Classification guideline pages missing/ not ticked
• Missing supporting documents
• including updated product information
• artwork includes unrelated changes
• Implementation date
• no date specified;
Do & Tell
• implementation date in the future
• Avoidance of grouping: Type IA must be stand-alone
• can’t be dependent on parallel IB/II variations
Slide 12
• Mixed procedure types (Purely National/European)
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Type IA <strong>experiences</strong> (3): common deficiencies
‣ Scientific/specific change codes
‣ Site deletions : no relevant site remaining on the licence (cond #2)
‣ Increase batch size API/FP up to x10: current scale approved by TIA
‣ Change in batch size FP of gel, oint: default Type IB (CMD Q&A)
‣ FPS deletion of non-significant/obsolete tests:
• Not justified eg LoD, Av. Weight, active content (!!)
‣ API specification deletion of non-significant/obsolete tests:
• Not justified
‣ QP declarations – API:
• Missing, incomplete (sites omitted), invalid (lack of audit)
‣ CEP/TSE certification
• Out of date/superceded (MHRA checks the EDQM website!)
‣ Change in manuf. process of active substance (DMF)
• Type IB if the change refers to the restricted part
Slide 13
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Type IA <strong>experiences</strong> (4): interactive session
Rejection letters
‣ Real life examples shared with delegates
‣Type IAs rejected June/Aug 2010
‣ Do you agree/disagree with MHRA’s decisions?
‣ ? What quality assurances procedures are in place to
‣avoid the common errors previously described
‣ensure getting it right first time
Slide 14
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Hot issues 9 <strong>months</strong> on
‣TYPE IA REJECTIONS
‣GROUPING
Slide 15
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Multiple variations: past and present
Previously:-
Consequential changes
Umbrella changes
Bulks (multiple single changes)
Now:-
Grouping
Worksharing
Grouping & Worksharing
Slide 16
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Multiple variations in the past system (1)
Consequential changes
‣ is unavoidable and is a direct result of the main change
• Not simply a change occurring at the same time
‣ included as a single application with the main change
‣ Can be
• IA + consequential IA
• IB + consequential IA or IB
• II + II
• May apply to products (different form, strengths) of same MA
‣ Examples are rare e.g. :-
• IB FPM + IA consequential QC + Batch Release
• Type II New indication s4.1 + consequential changes
e.g. s4.2, 4.4, 4.8 … Unavoidable + one set of data
Slide 17
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Multiple variations in the past system (2)
“Umbrella” grouped changes (Type II)
‣Single application for a main change, and
• One or more related changes
‣Clear relationship between the changes
‣Common data set
‣Examples are :-
• New FPM + change to manufacturing process
• Update to SPC:
• s4.3 Contraindications
• s4.4 Special Warnings and precautions
Linked changes + one set of data
Slide 18
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Multiple variations in the past system (3)
Traditional Bulk: identical single change
• Single specific variation
• Identically applied to products:
• different strengths, forms of same MA
• Or to > 1 MAH (same holder)
• UK: Same company “PL” number
• reduced fee for bulk members
• One variation form; one set of data
• European: example UK/H/234/01-03/IB/023
Identical change to more than one product/MA + one set of data
Slide 19
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Rules for Grouping:- 1234/2008 Article 7
• Separate submissions “shall” be
submitted for each change to a MA
• Grouping in a single application “may”
be allowed in certain cases
DEFAULT
OPTIONAL
Different rules for grouping (and WS) for IAs v IB, II, Extensions
Type IA Art 7(a) anything goes!
• single or multiple changes
• combine IA in or IA
• changes can be unrelated
• apply to one or more MAs
(same MAH)
• MRP group number assigned
by RMS only if > 1MA
Type IB, II, EA Art 7(b) Caution!
• more than one change is grouped
• can combine types IA in , IA, IB, II,
• changes must be related
• Annex III, published CMD list
• Or else approved by the CA
• applied to only one MA
• MRP group number assigned by RMS
WS if > 1 MA
Slide 20
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Annex III Cases for grouping: Article 7(2)(b)
14 cases listed for grouping Extension / II / IB e.g.
‣ Single or mixed categories are possible e.g.
• Type II + consequential Type II
• Type II + consequential Type IB + IA
‣ Administrative changes to SPC/label/PIL
‣ Changes to ASMF, VAMF or PMF
‣ “Project changes” to improve the manufacturing process
• Product or active
‣ Changes to the Pharmacovigilance system
‣ Changes consequential to PSUR, SO, FUM, USR
Other cases as agreed with
CA/RMS/CMD(h)/EMEA
Slide 21
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Grouping - general principles and conditions
1. Grouping of variations should always be justified
- Changes should be consequential
- and/or related
- i.e. meaningful to be reviewed simultaneously
Common supporting data across all products
2. Quality, Nonclinical and Clinical cannot be mixed unless justified
3. Quality variations to active substance cannot be mixed with
finished product variations, unless consequential/justified
4. Grouping should not delay the submission and implementation
of updates to the safety information
Prior agreement (unless Annex III or CMD published
Slide 22
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MAH
MR Procedure Group number
UK/H/0254/IA/048/G
UK/H/0254/001
UK/H/0254/002
Combined MRP group number
UK/H/xxxx/IA/210/G
IA In QC & BR site
IA In tab markings
IA updated CEP
MR Procedure Group number
UK/H/0255/IA/025/G
UK/H/0255/001
UK/H/0255/003
IA In QC & BR site
IA In tab markings
Type IA IA grouping illustrated – Article 7(a) 7(a)
IA updated CEP
Slide 23
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MAH
MR Procedure Group number
UK/H/0254/II/049/G
Amoxycillin 125mg/5ml
Amoxycillin 250mg caps
Amoxycillin 1g IV
Combined MRP WS number
UK/H/xxxx/WS/011
Prior agreement from CA
II Amoxycillin EDMF
IB test procedure FP
IA tighter spec FP
Prior agreement from CA
MR Procedure Group number
UK/H/0255/II/026/G
Co-amoxiclav 125/31 Sus
Co-amoxiclav 357mg tab
C0amoxiclav 1.2g IV
Type IB IB grouping & WS WS illustrated – Article 7(b) 7(b)
II Amoxycillin EDMF
IB test procedure FP
IA tighter spec FP
Slide 24
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MHRA <strong>experiences</strong> : (1) Company queries
• Regulations require prior agreement for Grouping (non Annex III)
•VariationQueries @mhra.gsi.gov.uk for specific queries
Total queries: 418
New Variation 2% Implementation Queries received in period 01 Jan – 09 Sept 2010
1%
1%
1%
11%
MHRA Variation
Implementation Team :
weekly review of queries
3%
Group 82%
Procedures 3%
Classification 11%
Legal Status 1%
Misc 1%
Worksharing 1%
N/A 2%
81%
Grouping to be agreed prior to submission
Slide 25
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MHRA <strong>experiences</strong> : (2) Quality Type IB/II Grouping
‣ Main change: addition of FP manufacturer B.II.b.1.e (Group Type IB)
• addition of primary packaging site B.II.b.1.b (Type IA In )
• addition of secondary packaging site B.II.b.1.a (Type IA In )
• change to method of manufacture B.II.b.1.e (Type IB)
• increase in batch size
B.II.b.4.a (Type IA)
‣Main change: formulation change e.g. film-coat composition (Group Type IB)
• Excipient changes, batch formulation
• Manufacturing process changes
Significant excipient
• Updated SPC, label/PIL
changes may be Type II
‣Main change: change to primary packaging (Group Type IB)
• Qualitative/quantitative composition of container and closure
• Dimensional changes to container/closure or alternative configuration
• Suppliers of components
• Changes in pack sizes
Slide 26
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MHRA <strong>experiences</strong> : (3) Quality Type IB/II Grouping
‣Main change: Multiple changes to the FPS (Group Type II)
• Tablet description (editorial)
• Tighter limits (existing parameter)
• Wider limits (existing parameter)
• New FPS (test and limit)
• Deletion of non-significant parameter
Test methods and
limits can be grouped
‣Main change: multiple changes to active substance specification
• Test methods and limits (as above)
‣Main change: new active substance manufacturer (Type II)
• New related substances (tests and limits)
• New residual solvents (tests and limits)
Slide 27
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MHRA <strong>experiences</strong> : (4) Unacceptable Quality Grouping
‣Main change: Update to the MA before a planned repeat use MRP
• updates to the SPC
• multiple updates to Module 3.2S
• multiple updates to Module 3.2P
‣ three separate variations should be submitted for each of the above;
‣ multiple changes within each variation may be grouped.
‣Main change: Changes related to new dosage manufacturer:
• bulk manufacture, packaging, batch control testing and release
• batch size (downscaling to 10-fold) of the Drug Product
• manufacturing process
• Change in test methods/specification of the finished product
• Addition of a new test parameter
• Deletion of a test parameter
• Tightening of specification limits
• Broadening of specification limits
• Change in immediate packaging composition
‣ three separate grouped variations should be submitted
v1
v2
v3
Slide 28
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MHRA <strong>experiences</strong> : (5) Unacceptable Quality Grouping
‣Main change: change the supplier of the drug substance resin
complex with related changes:
• 2% increase in potency of the resin complex
• Consequential update to s2 of the SPC
- new expression of strength
• Formulation adjustment of active and excipients
• Manufacturing batch formula
• Manufacturing process an validation
• FPS methods/specification : additional impurities
• Updated stability data
Extension
application
The proposed changes include changing the currently-registered active to a
different active, which will require Section 2 of the SmPC to change. This
falls outside the scope of a variation (including Grouping/s) but can
appropriately be submitted as an Extension application
Slide 29
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MHRA <strong>experiences</strong> : (6) Clinical Groupings - acceptable
‣ Main change: update the SPC of a generic product in line with brand leader
• C.1.2 (1B) for changes in-line with that of the reference product
C.1.3 (1B) for changes added at the request of the MHRA
C.1.z) (1B) for addition of an excipient warning
• acceptable as a Group, Type 1B submission
‣Main change: update to the safety information in the SPC as recommended by
the PSUR and as requested by MHRA following assessment of the PSUR.
• The changes affect sections 4.3, 4.4, 4.5, 4.6, 4.8 and 4.9
• Acceptable a s Group C.1.3, submission
- Type IB/II submission dependant on which documentation is supplied
• Annex III No.11 “all varns in a group consequential to assessment of a PSUR”
therefore single fee applicable
Slide 30
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MHRA <strong>experiences</strong> : (7) Clinical Groupings - acceptable
‣ Main change: Following Article 30 procedure, to update the SPC/PIL in line
with the harmonised texts.
• The changes affect sections 4.1 to 4.9 and section 6.6
• Acceptable as group C.1.1.b, single Type 1B fee, submission on the condition all
documentation can be supplied
‣Main change: Minor changes to the SPC to reflect current guidelines
• Section 1: add “Powder and solvent for solution for injection or infusion” to
product name in line with SPC guideline
• Section 2: declare excipients in compliance with the Excipients Guideline
and QRD template
• Section 6.1: change ‘diluent’ to ‘solvent in line with the Pharmaceutical Form
• Section 6.3, 6.4 : editorial update to ‘shelf life’ and ‘storage’ statements in
line with CHMP/QWP/609/96/Rev 2
• Section 6.6: amended in line with QRD template; additional improved user
information to the user - ‘non-guideline’ change
• Acceptable as Group C.1.z, Type 1B submission
Slide 31
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MHRA <strong>experiences</strong> : (8) Unacceptable Clinical Groupings
‣ Main change: To update the SPC “in line with best current information”
• Section 4.3-4.4 and 5.2: new drug interactions (arising from new studies)
• Section 5.2 Pharmakokinetics: new wording to reflect food-effect (new study)
• Section 4.4: new warning floppy iris syndrome (review of literature/case studies)
• Section 4.5 Interactions: update requested by CA following PSUR assessment
• Section 4.8: Update of undesirable effects (requested by CA following PSUR
assessment)
• Section 4.9 Overdose: updated following case reviews
v5
v2
v3
v4
v1
‣ Section 4.5, 4.8: Updates in line with the requests following the
assessment of a PSUR can be submitted as C.I.3 variations.
‣ Individual variations for each other section of the SmPC
- Submit as C.1.4 if the changes result from new data
Slide 32
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MHRA <strong>experiences</strong> : (9) Unacceptable Clinical Groupings
Main change: “To update the clinical particulars section of
the SPC as a minor IB Group variation”
• Sections 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.8 and 4.9 updated in line
with the reference product
• Section 4.5 to include some additional interactions with alcohol,
general anaesthetics and phenytoinin line with the current BNF
and standard text books
• Section 4.9 overdose section in line with current information
provided in Toxbase.
v1
v2
TWO variations should be submitted:
‣ C.I.2.a (Group Type 1B) for SPC update in line with the reference product
‣ C.I.4 (Group Type II) for additional data to update SPC inline with the BNF
and standard text books and to update overdose section in line with Toxbase.
Slide 33
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MHRA <strong>experiences</strong> : (10) Grouping Fees, illustrated
Group fee
Type II
Group
MAH 1
½ Type II
Group Bulk
MA (global) 1
IV bag 250mg
IV bag 500mg
Single fees
£1,860 Type II std £824
£930 ½ Type II
std
£412
Total £2,709 Type IB £314
½ Type IB £157
Total £1,707
II II
New non-PVC
container and port
tubes
IB
Manufacturing
process; reduced
overage AS
IA
Tighter IPC limits
Slide 34
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MHRA <strong>experiences</strong> : (10) Grouping Fees, illustrated
MAH 1
IB
New securitainer
(3 <strong>months</strong> data)
MA (global) 1
Capsules 25mg
Capsules 50mg
Capsules 100mg
IB
Increased shelf life
(real time data)
Group fee
Single
fees
Type IB Group £700 Type IB
x 3
£942
IB
New pack size
½ Type IB
Group Bulk x 2
£700 ½ Type B
x 6
£942
Total £1,400 Total £1,884
Slide 35
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What should you pay: Group fee or single fee??
MAH 1
Type IB
Extend the retest period
of the active substance
MA (global)
Amoxycillin 125mg/5ml
Amoxycillin 250mg/5ml
Amoxycillin 250mg Caps
Amoxicillin 500mg Caps
Amoxicillin 1g IV solution
Traditional
bulk (single
change)
!!! Not a group !!!
Single fee
Type IB £700
4 x ½ Type IB £350
Total £2,100
Slide 36
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Summary: hints and tips
‣ Study the regulations: 1234/2008 allows greater flexibility
• European guidelines and BPGs
• MHRA guidance and National fees regulation
‣ Take care with Type IAs
• remember the dirty dozen (change codes)!
• Avoid the common errors
‣ Remember Grouping (worksharing) is optional
• Groups not defined in the regulations require pre-approval
• Changes must be related (consequential and umbrella changes)
• Sensible application of Type IB vs Type II
‣ Choice of submission/procedure depends on company strategy
• Reduced admin. burden (single vs multiple applications)
• Procedure timetables
• Criticality of implementation dates
• Need for simultaneous approvals … etc
‣ Fee implications (single vs group)
‣ In case of doubt, ask us :-
‣ a first port of call : MHRA website Variations Q&A
‣ general enquiries: variationqueries@mhra.gsi.gov.uk
‣ for MR grouping and worksharing numbers MR-DCprocedures @mhra.gsi.gov.uk
Slide 37
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THANK YOU FOR YOUR ATTENTION
Krystyna Fielden
Unit Manager, LD PLAT 2
Medicines and Healthcare products Regulatory <strong>Agency</strong>
+44 (0) 207 084 2188
krystyna.fielden@mhra.gsi.gov.uk
Slide 38
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Slide 39
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MAH submits variation
query (template) to RIS
variationqueries@mhra...
By day 14
MHRA management of of
requests for groupings
RIS team reviews the
query
Day 0
RIS informs MAH of
outcome:
• agreement
• rejection
• propose alternative
Is the Query
• published?
• repeated?
No
Yes
RIS decides on
the proposed
grouping
VIG assessor
decides on the
proposed
grouping
No
Query routed to VIG assessor
“new variation assessment
board”
Is consultation
needed?
Yes
VIG assessor takes
query to:
• VIG meeting (Mon)
• internal consultation
Slide 40
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New fees for grouped variations (more than one change)
LICENCE VARIATIONS APPLICATIONS Fee £ Fully eCTD
Group variation fees
Type IB National/CMS 700 666
Type IB RMS/Reference 1,380 1,311
Type II National/CMS 1,860 1,767
Type II RMS/Reference 2,250 2,137
Type II Complex National/CMS 10,150 10,099
Type II Complex RMS/Reference 17,160 16,320
Extended Type II
Complex
Extended Type II
Complex
National/CMS 29,600 28,120
RMS/Reference 41,200 39,140
Slide 41
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Annex III variations : National fees applied to a single product
Annex III changes
No. 2
• Type II Paed indication – inhaler
• Type II New spacer device
No. 3
• Type IB Method of manufacture - oral solution
• Type IB increased batch size >10 fold
No. 5 Update to a ASMF
• Type IB manufacturing process
• Type IA batch size