Managing variations Current situation & Perspective...SEDALGIN NEO 10 X Type IA 1 X Type IB 4 X Type...

BGPharmA Current Regulatory ChallengesRegarding Pharmaceuticals

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Roumyana SharenkovaRegulatory Affairs Director

Actavis EAD

Maria Traikova, MDDeputy Director Medical and Regulatory affairsSOPHARMA PLC

Managing variationsCurrent situation &

Perspective

Rossen KazakovExecutive DirectorBGPharmA


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BGPharmAn Bulgarian Generic Pharmaceutical Association is

the national representative body for the wholeGeneric industry in Bulgaria.

n BGPharmA aims at:n Consolidating the Generic industry in its efforts to

develop and provide affordable medicines for allpatient groups, and

n Developing and assisting for the adoption andimplementation of a Coherent Generic MedicinesPolicy by the government and health careinstitutions.


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Challenges – past andfuture

n New rules for price setting and getting reimbursementstatus:n Two commissions (Pricing and PDL), two prices, no

negotiation with MoH or NHIFn Lowest max. retail price from 9 countries, 20% price

linkage for PDL (50% in draft)n Strong opposition from ABPhM and EGA re 50% price

linkage draft clause– letters to Prime Ministern Lack of capacity in MoH to implement new PDL on time

(April 2007) – delay to Jan 2009? – YESn Delay to April 2009? – YES/NO


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n Generics Bulletin, 10 January 2008 Issue 196n “Bulgarian firms win pricing concession”

n Generic drugs in Bulgaria will be eligible forreimbursement provided they are priced at no more than80% of the reference brand's cost, according to apositive list ordinance just published in the country'sofficial gazette. A previous draft ordinance had proposedprice linkage at 50%.

n While the ABPhM remained opposed in principle tolinking the price of generics to the price of referenceproducts, the 80% limit at least provided a framework inwhich generics could compete.

Price linkage recent case:


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n SCRIP, February 1st No 3332n “…It has been agreed that generic medicines whose

prices are no higher than 80% of their brand referenceprices will be entitled to reimbursement. The ministryinitially decided that the maximum price should be 50%of the reference price, but this was opposed by theindustry led by the association of Bulgarianpharmaceutical manufacturers (ABPhM).

n It received support from the European Genericmedicines Association which wrote a letter to Bulgaria'sprime minister and said the 50% restriction wasanticompetitive and gave market advantages toproducers of original drugs.

Price linkage recent case:


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n Companies still have to wait up to 90 days to havethe prices of their Rx products approved by thehealth ministry's Pricing Commission and another90 days before a reimbursement decision is madeby the PDL Commission.

n Term too long and delays products entering themarket, as price applications could only besubmitted after receiving marketing authorizations.

n Immediate inclusion of Gx medicines in the PDL,after obtaining MA is needed – time and costsaved by government and patients!


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Pharma Forum – barriers toGeneric medicines

n Eric Gorka (Sandoz) – EGA president:n “Over €20 billion in savings is being secured for

patients and healthcare systems by genericmedicines competition, but this can only beeffective, increased and sustainable on conditionthat generic medicines are ensured rapid marketentry. A quick look at the market entrance of thetop 35 off-patent molecules shows that in somecases the first generic medicine only entered themarket up to 20 months after the patent expired.”


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Highly cost-containmentpolicy environment

n Lack of budget resources continues – 4.3%from GDP.

n Global Economic Crisis appeals more thanever to the rational and optimal use ofmedicines and resources!

n Still no incentives from the state to promotegeneric consumption, which can bring moresavings to the budget and the healthcaresystem.


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n Policy and healthcare financing in CEE


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n No free pricing for non-reimbursed drugs,except OTCs (G10 Rec. 6)

n Reference pricing system – good or bad?n Co-payment increases by lowering levels of

reimbursement.n Pressure on prices of both generics and

brand medicines.n No price/volume negotiations.


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Final Recommendations of theHigh Level Pharmaceutical Forum


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Communication from theCommission - A Call for Action

Brussels, 1.7.2003


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The situation today

n EGA WELCOMES THE ADOPTION OF THEREVISED VARIATIONS REGULATION:

n Considering it a “positive step” toward simplifyingand optimising the system of changes to MarketingAuthorisations, the EGA welcomes the EuropeanCommission’s adoption of the EU Regulation onthe examination of amendments to the terms ofmarketing authorisations for medicinal products forhuman use and veterinary medicinal products.


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The situation todayn Bulgarian pharmaceutical act fully harmonized with

the EU legislationn Bulgaria is EU member since 1 Jan 2007n Since mid 2006 the industry is in constant process

of:n Changing the API suppliersn Upgrading the production facilitiesn Improving the quality managementn Optimizing the product portfolion Improving the dossiers (CMC) via variations


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Variations –clearly the very difficult part

n For old products with deficiency of API supplyn For transition to validated API suppliersn For related variations (more than one at a time)n For different compositions on different marketsn For administrative purposes (packs, PIL, blisters)n For further harmonization (readability, Braile,

blisters in BG etc.)n For whatever reasons


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Actavis BulgariaVariations 2006-2008

165

531

700

0

100

200

300

400

500

600

700

2006 2007 E 2008


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Actavis BulgariaVariations split 2007-2008

308 305 380

81 80 90144 142 157

050

100150200250300350400

Type IA Type IB Type II

2007Jan-Oct 2008E 2008


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Variations splitDomestic-Imported products

151 154

40 40

52 90

0 100 200 300 400

Type IA

Type IB

Type II

BalkanpharmaActavis Group hf.


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In our case

n No of registered products in Bulgaria – 155n No of countries with market presence – over 25,

incl:n EU countriesn Russian Ukrainen Ex-Soviet Union countriesn RoW (Tunnisie, Vietnam, Algerien etc.)

n Therefore – diverse picture with many icebergs


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No of variations (BG only)

0

100

200

300

400

500

600

700

800

number

2006 2007 2008 Totalyear

Total No 2006-2008 Variations by category - 2007

41; 17%

116; 49%

50; 21%

12; 5%18; 8%

I A I Б II NC NV


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Most common reasons forvariations

n Minor variations IAIA1 – Change in the name and/or address of the MAHIA 15 - Submission of a new or updated CEP for an

active substanceIA 25b – Change to comply with an update of the

relevant monograph of PhEurIA 36b – Change in the shape of container/closureIA 38a – Minor change to an approved test procedure


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n Minor variations IBIA 18 – Replacement of an excipient with a

comparable excipientIB 26 & 27- Changes in the specifications/test

procedures of the immediate packaging of thefinished product

IB 33 – Minor change in the manufacture of thefinished product

IB 37 & 38 – Change in the specification/testprocedure of the finished product


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n Major variations - Type IISafety reasons – update of SPC & PILChanges in module 3 referring to:- API supplier- manufacturing in-process control- release & shelf-life specifications- composition, etc.


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Main reasons for variations

n Process optimisation variationsbatch size, manufacturing process, specifications

(implementing the design space concept)n Administrative variationsname, address, CEP updates

(annual reporting system)n Flexibility Increasing variationsAPI sources, bulk manufacturing sites


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The worst - related variations

n Variation uponvariation

n Champion productsn Related variationsn Etc.


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Variation upon variationchampions in variations 2007

SEDALGIN NEO

10 X Type IA

1 X Type IB

4 X Type II


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LISINOPRIL3 x Type IB

2 x Type II

8 x Type IA


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Trimezol 480 mg

(Sulfamethoxazole & Trimetoprim)

7 x IA

3 x Type IB

3 x Type II


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Do we manage this?

n Workload?n Resources?n Internal co-ordination?n Uniformity across markets?n Expenses?


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VariationsAdministrative & financial burden

n Cir. 3,5 variation applications filed everyworking day

Expenditures per yearn 2007 – BGN 324,500n Jan-Oct 2008 – BGN 466,000


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Conclusions

n National MAs represent the vast majority ofauthorizations in the EEA (more than 80%)

n Community rules not harmonized

n Administrative burden for both agencies &industrial operators

n Logistic complications


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n Both agencies and companies will benefit fromfacilitating the preparation and review of thevariations

n Tell & do approach for minor variationsrequiring immediate reporting

n Introduction of annual reporting system forminor variations that should not require anyprior approval and be notified within twelvemonths following implementation (do & tellapproach)

Conclusions


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Conclusions

n Transitional period to be allowed forimplementation of Type II variations

n Introduction of grouping of variations in case ofseveral variations for one MA or more than oneMA affected by the exact same group ofvariations

n Worksharing procedure will be beneficial forglobally operating companies


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Our part

n Optimization of the internal communicationn Specialized task force for managing

variations (different from new submissions)n Better planningn Uniform approachn Time ruling


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Hence our support

n For revision of the variation regulationn For “DO and Tell” concept (type IA)n For default variations (type IB)n For grouping of variations into single submissionn For optimizing the workload of the agencies:

n Common rules with national variationsn Work sharing in CMDn Application for extension in the scope of variations


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Variations systemGermany

n Variations of national German MAs follow a nationalsystem, different from the EU one

n The majority of the national German Type IAvariations does not need official approval

n Transition period for implementation of Type IIvariation announced in the application form

n Grouping of variations belonging to one and the sameMA in one application form – for example changing oftest procedure, batch size increase, shelf-lifeextension and inclusion of new ADR in the SPC/PILwould be one application form only


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Variations systemThe Netherlands

n Type IA are implemented after confirmation ofreceipt and validation by the authorities

n Type IB - transition period for implementation isindicated by the applicant in terms of productionafter approval

n Type II – if not related to specific batches – 6month transition period for implementation; ifrelated to specific batches - than indicated bythe authorities;


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Variations systemPortugal

n Type IA – tacitly approved in 20 days, noofficial approval issued

n Type IB – implementation period pointedout in the application form

n Type II – the same as IB’s


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Variations systemRomania

n Type IA – official approval is issued

n Type IB – implementation period pointedout in the application form

n Changes in printed materials must beimplemented within 6 months followingapproval

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