proof of interchangeability of pharmaceutical products and ......pharmaceuticals are generic (73% in...
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Proof of interchangeability of Proof of interchangeability of pharmaceutical products and assurance pharmaceutical products and assurance
of their quality in Ukraineof their quality in Ukraine
ее--mail: mail: baulabaula@@pharmapharma--center.center.kievkiev..uauasite: site: www.www.pharmapharma--center.center.kievkiev..uauaphone:phone: +38 (044) 498 4303+38 (044) 498 4303
OlgaOlga BaulaBaulaState Pharmacological CenterState Pharmacological Center MoHMoH UkraineUkraine
ICDRABerne, 16 September, 2008
Population = 46.3 millionPopulation = 46.3 million
The geographical center of Europe is situated on The geographical center of Europe is situated on the territory of Ukrainethe territory of Ukraine
•• Area Area –– 603,700 km2603,700 km2(5,7 % area of Europe)(5,7 % area of Europe)
•• 2nd in Europe by area size2nd in Europe by area size
UkraineUkraineCapital Capital –– KievKiev
Situated in the SouthSituated in the South--East East of Eastof East--European Valley European Valley (Central(Central--Eastern Europe)Eastern Europe)
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Pharmaceutical Sector of UkrainePharmaceutical Sector of UkraineIn
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Registration certificatesRegistration certificates1297212972
Finished pharmaceutical Finished pharmaceutical products (FPP)products (FPP)
1086910869 FFP packaging from in bulkFFP packaging from in bulk872872
Active pharmaceutical Active pharmaceutical ingredients (API)ingredients (API)
12411241Domestic Domestic –– 3322 (3322 (25,625,6%)%)
Imported Imported –– 75477547 (58,1%)(58,1%) Domestic Domestic –– 101101 (0,8%)(0,8%)
Imported Imported –– 761761 (5,9%)(5,9%)
DoemsticDoemstic –– 192192 (1,5%)(1,5%)
Imported Imported –– 10491049 (8,1%)(8,1%)
Share in money Share in money –– $2 billion$2 billion
Increase of market shareIncrease of market share–– at least 20% per yearat least 20% per year
ManufactureManufacture– 147 domestic enterprises147 domestic enterprises
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BackgroundBackground
19931993 –– registration process for pharmaceuticals was launched in registration process for pharmaceuticals was launched in UkraineUkraine
19961996 –– adoption of the Law of Ukraine adoption of the Law of Ukraine ““On MedicinesOn Medicines””
20012001 –– alignment of rules governing pharmaceuticals in Ukraine with alignment of rules governing pharmaceuticals in Ukraine with EU principlesEU principles
20052005 –– adoption of a set of regulations related to generic adoption of a set of regulations related to generic interchangeabilityinterchangeability
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Regulatory requirements for equivalence assessment of generic products in Ukraine
Decree of the Cabinet of Ministers of Ukraine of May 26, 2005 № 376 (as amended)
Order of the Ministry of Health of Ukraine of 26.08.2005 №426 (as amended)
Order of the Ministry of Health of Ukraine of 17.04.2007 №190
Guidelines 42 – 7.1.2005 “Guidelines on clinical trials. Bioavailability and bioequivalence studies”
State Pharmacopoeia of Ukraine – 1st edition –Supplement 2 2008. 5.14.2 “Bioavailability and bioequivalence studies of generic products”
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Harmonization
Regulatory requirements adopted in Ukraine concerning bioavailability and bioequivalence studies of generic products have beendeveloped in compliance developed in compliance withwith EMEA guidelines EMEA guidelines andandWHO recommendationsWHO recommendations
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Pharmaceuticals are
Generic (73% in Ukraine)
Innovator (13% in Ukraine)
equivalentequivalent(therapeutically (therapeutically
interchangeable)interchangeable)
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Quality
Efficacy
Safety
Has reliable evidence Has reliable evidence of efficacy, safety and of efficacy, safety and quality, is originally quality, is originally registered based on full registered based on full registration dossier and registration dossier and is/was under the patent is/was under the patent protectionprotection
Meets the same Meets the same quality, efficacy and quality, efficacy and safety standards as an safety standards as an innovation product,innovation product,
designed for its designed for its therapeutic therapeutic
interchangeabilityinterchangeabilityand marketed after and marketed after expiry of the patent or expiry of the patent or exclusivity right to an exclusivity right to an innovation productinnovation product
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Bioequivalence
Pharmaceutical alternatives
InterchangeabilityInterchangeability
Pharmaceutical equivalence
Identity of qualitative and quantitative parameters of active ingredientIdentity of dosage formIdentity or similarity ofexcipient’s contentEquivalence of pharmaceutical developmentEquivalence of quality specifications and requirements to manufacture (GMP)
Same molar amount of the same active pharmaceutical moietyActive pharmaceutical ingredient has different chemical form (other salts or ethers) Different pharmaceutical form (tablets, capsules) Equivalence of pharmaceutical developmentEquivalence of quality specifications and requirements to manufacture (GMP)
Two products are bioequivalent if they are:Pharmaceutically equivalent or pharmaceutically alternativesHave similar bioavailabilityProvide the same efficacy and safety after administration in thesame molar dose
InterchangeabilityMain feature of generic is a therapeutic interchangeabilityMain feature of generic is a therapeutic interchangeability
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Structure of pharmaceuticals registered in UkraineStructure of pharmaceuticals registered in Ukraine
7%
13%
73%
2%
3%
2%
GenericInnovatorOther pharmaceuticalsBiologicalHomeopathicTraditional herbal / products of well-established use
3% 2%5%5%
9%
19%
57%
Solid oralParenteralTopicalLiquid oralNasal, ophthalmic, aerosolBiologicalHomeopathic
About 5500 generic products which interchangeability to be justiAbout 5500 generic products which interchangeability to be justified including:fied including:
35%35% -- registered based on BE/BA documented evidenceregistered based on BE/BA documented evidence
AboutAbout 1,5%1,5% -- pharmaceutical products registered for pharmaceutical products registered for ««historical reasonshistorical reasons»»
63%63% -- generic productsgeneric products ??????
Equivalence assessment procedure
ComparatorComparator GenericGeneric
At least 3 bathes from which one with interim results of dissolution
testing is selected
At least 1/10 manufacturing batch or manufacturing batch
(<100 000 items)
Pharmaceutical equivalence or alternatives
In vitro comparative studies using dissolution testing
In vivo comparative studies
In vitro/in vivo correlation (IVIVC)
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In vitro comparative studies
Biowaiver –is a procedure for registration of solid dosage forms based onBiopharmaceutics Classification System (BCS) and results of in vitrocomparative studies using dissolution testing
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FPP dissolution
(FPP)
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API solubility API solubility
(API)(API)
API permeability API permeability
(API)(API)
Products registered throughbiowaiver procedure
• Diazepam
• ASA
• Letrozole
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Applications for registration rejectedApplications for registration rejected
Lack of pharmaceutical equivalenceLack of pharmaceutical equivalence
Inadequate quality of APIInadequate quality of API
Improper selection of a comparator productImproper selection of a comparator product
NonNon--evident BE/BAevident BE/BA
In 2007 each fifth application for registration was rejectedIn 2007 each fifth application for registration was rejected
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Example of comparative pharmacokinetic studies ofFluconazole
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112.802398.3170AUCinf
109.787096.6373AUClast
98.674089.5639Cmax
Upper 90%Lower 90%Parameter
Reference product
Test product
Mean values of plasma concentration (R and T) Substance – Fluconazole
Example of comparative pharmacokinetic studies ofRiluzole
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109.089386.5047AUCinf
108.811986.6426AUClast
103.515170.5435Cmax
Upper 90%Lower 90%Parameter
Mean values of plasma concentration (R and T) Substance – Riluzole
Reference product
Test product
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Stages of quality assurance of generic productStages of quality assurance of generic product
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Stages of quality assurance of generic productStages of quality assurance of generic product
Established and justified during pharmaceutical development
Justified by the bioequivalence
assessment using in vivo and/or in vitro
methods
Provision at manufacturing
processEvaluation and improvement
throughout the product lifecycle
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Ensuring GMP of pharmaceutical production of finished and investigational products prior to registration
Conducting all clinical trials only in compliance with GCP
Enforcement of post-marketing drug monitoring
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WHO External assessment of regulatory functions in Ukraine
To address medium term update of BE/BA status of previously registered
Improved coordination of regulatory functions
Capacity building
NextNext ststepseps
OlgaOlga BaulaBaula
State Pharmacological CenterState Pharmacological Center MoHMoH UkraineUkraine
е-mail: [email protected]: www.pharma-center.kiev.uaphone: +38 (044) 498 4303