Multisource (generic) products
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Transcript of Multisource (generic) products
WHO Prequalification Programme June 2007
Training Workshop on Dissolution, Pharmaceutical Product Interchangeability and
Biopharmaceutical Classification System.
Hotel Bratislava1 Malyshko Street
Kyiv, UkraineDate: 25 to 27 June 2007
Multisource (generic) products
WHO Prequalification Programme June 2007
Introduction to the course
Presenter: Dr Lembit Rägo
Director and Coordinator, Quality Assurance and Safety: Medicines QSM)
Medicines Policy and Standards (PSM)
World Health Organization
Geneva, Switzerland
E-mail: [email protected]
WHO Prequalification Programme June 2007
Topics covered
I. Multisource (generic) medicines: WHO Global perspective
II. Prequalification Programme and its links to WHO normative functions
III. Overview of new WHO guidelines and recommendations regarding multisource (generic) products
WHO Prequalification Programme June 2007
I. Multisource (generic) medicines: WHO Global perspective
Innovative and generic medicines
Generic medicines and public health
Regulatory requirements and structure of the dossier for generic medicines
WHO Prequalification Programme June 2007
Usual perceptions may not help to make judgments about medicines …
… and even pharmacists and medical doctors may not be in capacity of taking decisions without specific training
SmellAppearance Taste
WHO Prequalification Programme June 2007
Why medicines are special category of products?
Consumers, patients and health care workers have limited capacity to judge there
– SAFETY– QUALITY– EFFICACY
WHO Prequalification Programme June 2007
Are all medicines safe, effective and meet quality criteria?
No, they are not, and no they do not
Some are safe, but not effective or necessarily meet the quality criteria
Some may be effective, meet quality criteria but are not safe
Some meet quality criteria but are not necessarily safe or have any efficacy
WHO Prequalification Programme June 2007
Quality - Safety
Some safety parameters are determined by quality
Some safety parameters are determined by the intrinsic properties of active pharmaceutical ingredient
– However, in fact QUALITY in general perception (and often in policy documents) is incorporating also expectations for efficacy and safety without necessarily saying so
WHO Prequalification Programme June 2007
What type of medicines we have?
Originator products
Multisource (generic) products
– KEY – INTERCHANGEABILITY, more important THERAPEUTIC INTERCHANGEABILITY
– ALL LITERATURE IS BASED ON ORGINATORS
– No interchangeability – NEED FOR NEW SAFETY and EFFICACY DATA, NEW BOOKS HAVE TO BE WRITTEN
WHO Prequalification Programme June 2007
How regulatory approach differs for originators and generics?
For innovator products proof of QUALITY, SAFETY and EFFICACY is needed
For multisource products QUALITY, safety and efficacy data is referred to the originator data, providing only evidence about THERAPEUTIC NTERCHANGEABILITY
THERAPEUTIC INTERCHANGEABILITY is judged based on bioequivalence (BE) studies, dissolution data as surrogate for BE, or in certain cases other means such as clinical testing is allowed
WHO Prequalification Programme June 2007
Generic drugs
In case of SAFETY and EFFICACY the only way for a generic is to refer to originator product
– Thus the efficacy (indications, dosing) and safety information (side effects, warnings etc.) can not be different
WHO Prequalification Programme June 2007
Generic medicines are pharmaceutical products that contain well-established "actives"
They are:- intended to be interchangeable with the original product, - usually manufactured without a licence from the original manufacturer,- marketed after the expiry of patent or other exclusivity rights,- marketed either under a non-proprietary name (INN or other approved name) or under brand names ("branded generics").
WHO Prequalification Programme June 2007
Medicine = tablet + information
Good quality drug information including PILs is a shared responsibility of industry and regulators
Regulators with limited resources could do more for public health by trusting scientific assessments by well resourced DRAs and concentrating more on ensuring the accuracy of drug information in national settings
Not only accuracy of information, but also its proper communication is important
GOOD QUALITY INFORMATION is needed also for GENERIC MEDICINES
WHO Prequalification Programme June 2007
…and realities
In many countries do not have enough resources to check information or approve SPCs and PIL
In some countries prescription only medicines do not have PIL (OTC medicines have) …but can be obtained without any prescription
Most of the World population has only one prescription for all medicines – banknote. Can this give them also the information they need and understand?
WHO Prequalification Programme June 2007
Generics and public health
In poor countries drugs are largest household and second largest public expenditure for health
WHO Prequalification Programme June 2007
0 10 20 30 40 50 60 70
South AfricaArgentina
JordanTunisia
ThailandIndonesia
ChinaEgypt
Mali
LithuaniaSloveniaEstoniaPolandCroatia
HungaryCzech Rep.
Bulgaria
NorwayNetherlands
United StatesUK
DenmarkSpain
FranceItaly
GermanyGreece
Developed countries(7 - 20%)
Transitional countries(15 - 30%)
Developing countries(24 - 66 %)
Pharmaceutical spending, as % of total health spending
WHO Prequalification Programme June 2007
What are the potential benefits of generics?
Better access to needed medicines.
Well chosen generics make government or household spend less without loss of quality or safety
1998 study by US Congressional Budget Office: average generic medicine prescription price was less than one third of average price of single-source innovator brand drug
WHO Prequalification Programme June 2007
Generic Drugs Market Share in Dollars is Low and Declining
11.9% 12.2%10.4% 9.6% 8.6%
42.0% 42.5% 42.0% 41.3%
10.6%
38.6%40.9%
0%
10%
20%
30%
40%
50%
1993 1994 1995 1996 1997 1998
Perc
ent o
f tot
al p
harm
aceu
tical
mar
ket
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Average Price Per Prescription for Brand Name is Approximately Three Times Generic Drugs
35 3740
43
48
54
13 13 14 1417 17
0
10
20
30
40
50
60
1993 1994 1995 1996 1997 1998
DO
LLA
RS
BRANDSGENERICS
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Why are generics less expensive?
Not because they are inherently different in composition from patented drugs,
but mainly because of the structure of the generics market:
– more competitive,– free from IPRs, – often with minimal R&D cost– and the substantive marketing cost that goes into new
branded proprietary drugs
WHO Prequalification Programme June 2007
Generic medicines: public health value Essential medicines are those that satisfy the priority health care needs of
the population. They are selected with due regard to public health relevance, evidence on efficacy and safety, and comparative cost-effectiveness.
The WHO Model Essential Medicines List (EML) includes around 300 drugs that should provide safe and effective treatment for the majority of diseases.
Model lists are informational and educational tools originally intended for developing countries, but an increasing number of developed countries also use the key components of the essential drugs concept
WHO Essential Medicines List (EML) still contains mostly generic medicines
WHO Prequalification Programme June 2007
WHO Essential Medicines List -evidence and information for action
WHOModel EM List
ClinicalGuidelines
Evidence,Systematic
Reviews
ModelFormulary
Drug QualityInformation
CostInformation
Monitoringsafety & use
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Rapidly changing drugs markets: Czech Republic*, 1990 and 2000
16.2 7.1
48.639.8
15.5 44.6
19.7 8.5
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
1990 2000
Unbranded Other brands Origin/ licensed status n/a
*2000 Population: 10.3 million Source: IMS Health, customised study. Data from 52 countries/areas
WHO Prequalification Programme June 2007
What is required for regulatory approval of generics?
FDA requirements for generic drugs (www.fda.gov/cder/ogd):
Generic drugs must: 1. contain the same active ingredients as the innovator drugs
as the innovator drug2. be identical in strength, dosage form, and route of
administration3. have the same use indications 4. meet the same batch requirements for identity , strength,
purity and quality5. be manufactured under the same strict standards of GMP
required for innovator products.6. be bio-equivalent
WHO Prequalification Programme June 2007
Global Generic Content Issues
Stability
Bioequivalence Study Requirements
Comparator Product
Impurity Specifications
Batch Documentation
Colorants
Relative Lack of Harmonization for Pharmacopeial Methods
WHO Prequalification Programme June 2007
Regulations: Global/Regional vs National
National regulations still differ a lot – especially for generics
What is ICH and what it is not?
Regional harmonization initiatives
Do global norms exist for generics?
WHO Prequalification Programme June 2007
Structure of the dossier
Would it be harmonised a lot of resources would be saved
– Industries would have one dossier structure for different submissions
– Regulators could communicate better
WHO Prequalification Programme June 2007
II. Prequalification Programme and its links to WHO normative functions
What it is and what are its objectives?
How it functions?
What are the linked to prequalification activities?
How it links to WHO normative activitis?
Which standards it uses?
WHO Prequalification Programme June 2007
Quality related safety of medicines still an issue – DEG tragedy in
Panama in 2006
The medical nightmare of Lucia Cruz, a 74-year-old grandmother, began in mid-September 2006 when she realized that she had not urinated in two days. She was hospitalized but eventually she died.
By today death toll beyond 100
The death were likely caused by diethylene glycol (DEG) found in medicines. It is toxic to the kidneys and can cause deadly renal failure.
– Pictures. 1. Waiting for answer. 2. A popular medicine in Panama that turned to be a killer. 3. Medicines traced down and removed from supply chain
WHO Prequalification Programme June 2007
What is WHO doing to help the countries?
Normative functions
Capacity building
Prequalification
– "Three in one" – more tuned to real public health problems, immediate feedback, better quality, higher efficiency
WHO Prequalification Programme June 2007
Prequalification of essential medicines
The UN prequalification program is an action plan for expanding access for patients
with
HIV/AIDS
Tuberculosis
Malaria
Reproductive health
Avian flu medicines (oseltamivir) ?
by ensuring quality, efficacy and safety of medicines procured using international
funds (e.g. GFTAM, UNITAID)
WHO Prequalification Programme June 2007
How prequalification is organized? (I)
Role of WHO: Managing and organizing the project on behalf of the United Nations.
• provides technical and scientific support and guarantee that international norms and standards are applied all through the process including assessment, inspection (GMP, GCP, GLP) and quality control
Partners: • UNICEF, UN Population Fund (UNFPA), UNAIDS
and with the support of the World Bank (IPC group); WHO disease oriented programs
WHO Prequalification Programme June 2007
How prequalification is organized? (II)
Stakeholders: • Anti-malarial and anti-TB products: Roll Back Malaria and Stop
TB (Global Drug Facility); HIV/AIDS Department; other disease oriented programs
• Interested Governments (donors and beneficiaries)• Funding partners: Governments (Belgium, France, China etc.),
Gates Foundation, UNITAID
WHO Prequalification Programme June 2007
How prequalification is organized? (III)
Beneficiaries: • UN Procurement, Global Fund and UNITAID procurement,
NGOs (e.g. MSF)• National Regulatory Agencies• Developing country industries
Actors: Qualified assessors and inspectors from National DRAs (also from National Quality Control Laboratories) of ICH and associated countries, and inspectorates belonging to PIC/S
Open also to developing country assessors and inspectors
WHO Prequalification Programme June 2007
Assessment procedure- Product dossiers (I)
Innovator products• Abridged procedure if approved by stringent authorities like
EMEA and US FDA• Assessment reports from Drug Regulatory Authorities (DRSs),
WHO Certificate of Pharmaceutical Product (CPP), batch certificate, update on changes
• Trusting scientific expertise of well-established DRAs• What if not covered by these options?
WHO Prequalification Programme June 2007
Assessment procedure- Product dossiers (II)
Multisource (generic) products • Full dossier with all data and information requested• Quality : information on starting materials and finished product
including API details, specifications, stability data, formulation, manufacturing method, packaging, labelling etc
• Efficacy and safety: Bio-equivalence study or clinical study report
• US FDA tentative approvals for ARVs – recognition scientific assessment based on information exchange (Confidentiality agreement between US FDA and WHO); the same approach will soon apply for EU Art58 and Canadian JCPA procedure)
Commercial sample Requested, but not always analyzed before prequalification.
WHO Prequalification Programme June 2007
Prequalification: the technical documents are WHO normative
documents
The Expert Committee documents pass wide international consultation and are finally adopted by the Committee composed of outstanding international technical experts
New TRS No 943 with 41st Report from 2007
– Updated PQ general procedure– PQ of QC labs procedure
WHO Prequalification Programme June 2007
Which medicines and why PQ Programme deals with?
Application to include a product on Expression of Interest (EOI) Lists published comes from WHO disease oriented programs
Products should be of high public health value
Products must be in line with WHO treatment guidelines
Products must be in line with Essential Medicines List
Rare exceptions from these principles, if justified
WHO Prequalification Programme June 2007
New Product Group from 2006: Selected Reproductive Health Products
WHO Prequalification Programme June 2007
Current status
Started with HIV/AIDS products in 2001 – malaria and TB products joined later
Prequalified products (May 2007) "Active" dossiers in pipeline (2006)
• 159 HIV related medicines 60+ • 12 anti-tuberculosis medicines 25+• 5 anti-malarial medicines 30+• 176 115+
WHO Prequalification Programme June 2007
Regulatory Challenge: ANTIMALARIALS Antimalarials prequalified so far
Artesunate 50mg Tablets Sanofi-Synthelabo Blister 25 blister of 12
Artemether/ 20mg Tablets Novartis Pharma Blister 30 blisters of 6, 12, 18 or 24
lumefantrine 120mg
Artemotil 50mg/ml Sol inj ARTECEF BV 10 or 100 ampoules each of 1ml
Artemotil 150mg/ml Sol inj ARTECEF BV 10 or 100 ampoules each of 1ml
Artesunate 50mg Tablets Guilin Pharmaceutical Co Ltd PVC/AI Blister 12
– Some other manufacturers may have also achieved GMP level but GMP alone is not enough for prequalification
WHO Prequalification Programme June 2007
Outcome of 2006
44 products listed (32 in 2005) - 38% more than in 2005
But …– No new antimalarials– No new TB drugs (but 4 new ones added in early
2007)– No new QC labs
WHO Prequalification Programme June 2007
Year 2006: statistics (1)
INSPECTIONSINSPECTIONS
A total of 49 (2005 – 52) inspections were carried out:– 17 (20) inspections of the manufacturing sites of finished
product manufacturers– 10 (10) inspections of the manufacturing sites of active
pharmaceutical ingredients (APIs)– 15 (14) inspections of contract research organizations (CROs)– 7 (8) inspections of national pharmaceutical quality control
laboratories (NPQCLs) in Africa.
WHO Prequalification Programme June 2007
Inspections: where?
India – 28
China – 6
Belgium - 1
Canada – 1
Malaysia - 1
France - 1
South Africa – 3
Switzerland - 1
United States – 1
Cameroon, Ghana, Kenya, Madagascar, Niger, Uganda – all 1
WHO Prequalification Programme June 2007
Year 2006: statistics (2)
AssessmentsAssessments
A total 334 (222 – 2005) assessment reports linked to 334 HIV/AIDS-related products were written
A total of 78 (52) assessment reports — linked to 70 (50) TB products were written
A total of 29 (73) assessment reports were written, linked to than 31 (40) malaria products
– All together 75% increase in the number of assessment reports!
More facts will be soon in Annual Report 2006 on the web
WHO Prequalification Programme June 2007
Publications 2005/2006
New, more user friendly prequalification web site launched in November 2006, updated and improved also later: http://mednet3.who.int/prequal/
Articles: – Dekker TG, van Zyl AJ, Gross O, Tasevska I, Stahl M,
Rabouhans ML, Rägo L. Ongoing monitoring of antiretroviral products as part of WHO’s Prequalification Programme. Journal of Generic Medicines, 2006, 3(2):96–105.
WHO Prequalification Programme June 2007
Capacity building of National Regulatory Authorities and Manufacturers
Both remain important components and need strengthening
Both need improvement and new approaches
NB! In 2006 programme started to deliver in addition to general training focused to selected manufacturers technical assistance
WHO Prequalification Programme June 2007
Training and related activities in 2007
In June 2007 two days workshop in cooperation with WHO/EMRO about prequalification in Cairo
In June three days workshop on BE/BCS and dissolution testing (new course) in cooperation with EURO and FIP in Ukraine
In November 2007 TBS on Medicines Quality and Prequalification
In November 2007 upon request from Chinese Gov on week training in China
Targeted more specific trainings (EURO, WPRO)
Repeating Pharmaceutical Development course in EURO region in October, training of assessors in AFRO (planning stage) …
WHO Prequalification Programme June 2007
Prequalification of Quality Control Laboratories (1)
So far only for AFRO region, potential expansion
3 QC Labs prequalified– South Africa, CENQAM - 6/2005– South Africa, RIIP - 7/2005– Algeria, LNCPP - 10/2005
3 QC Lab near to PQ??– South Africa, Kenya, Tanzania
11 QC Labs audited, corrective measures proposed– Cameroon, Mali, Madagascar, Niger, Senegal– Ghana, Etiopia, Kenya NQCL, Kenya MEDS, Uganda, Tanzania
4 QC Labs expressed interest, but not send LIF yet– Benin, Burkina Faso, Cote d'Ivoire, Guinea
WHO Prequalification Programme June 2007
Prequalification of Quality Control Laboratories (2)
Technical assistance– Experts provided to 2 QC Labs : Ethiopia and Tanzania– Several in AFRO have received free of charge International Pharmacopoeia and
other docs, plus chemical reference substances for ARVs
10 of the QC Labs were involved in Proficiency testing (Phase 3, 07/2004 - 06/2006)
– Algeria, South Africa CENQAM, South Africa RIIP– Mali, Niger, Senegal– Ghana, Kenya MEDS, Tanzania, Uganda
3 other African QC Labs took part in Proficiency testing (Phase 3, 07/2004 - 06/2006)
– Morocco, Tunisia, Zimbabwe