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


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]

mailto:[email protected]


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


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


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


Why medicines are special category of products?

Consumers, patients and health care workers have limited capacity to judge there

– SAFETY– QUALITY– EFFICACY


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


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


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


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


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


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").


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


…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?


Realities…


Generics and public health

In poor countries drugs are largest household and second largest public expenditure for health


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


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


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


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


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


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 Essential Medicines List -evidence and information for action

WHOModel EM List

ClinicalGuidelines

Evidence,Systematic

Reviews

ModelFormulary

Drug QualityInformation

CostInformation

Monitoringsafety & use


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


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

http://www.fda.gov/cder/ogd


Global Generic Content Issues

Stability

Bioequivalence Study Requirements

Comparator Product

Impurity Specifications

Batch Documentation

Colorants

Relative Lack of Harmonization for Pharmacopeial Methods


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?


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


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?


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


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


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)


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


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


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


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?


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.


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


[email protected]


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


New Product Group from 2006: Selected Reproductive Health Products


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+


News example


Transparency:

WHO Public Inspection

Reports (WHOPIRs)


WHO Public Assessment Reports (WHOPARs)


Increased transparency about the "pipeline"


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


Since 2005 annual reports; 2006 annual report on the web


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


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.


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


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


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.


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


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) …


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


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


Summary and conclusion

Quality can not be assessed, tested or inspected on the product, BUT

It has to be built into it!

We have (manufacturers and regulators) the obligation to ensure it with all the means we have, in the best way we

can.

Multisource (generic) products

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