Article 58:

A route to scientific opinion

Eric PelfreneEMEA

Open forum on Key Issues on TB Drug Development New Delhi

5-6 May 2008

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Agenda1. EU Registration procedures2. EMEA3. “Article 58” Opinion principles4. “Article 58” Procedure & Evaluation5. “Article 58” EU experiences 6. Other peculiarities of “Article 58”

procedure

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1. EU Registration Systems in 2008

-1 National Regulatory Authority (e.g. Spain) performs assessment of MAA and issues…-1 National authorisation(= RMS)

-up to 26 other National Regulatory Authorities can “mutually recognise” the Spanish assessment (=CMS)

- Managed at EMEA by single scientific committee

- Generates binding scientific opinion- Max. 210 days to Opinion- Peer review system Final Decision

- 1 marketing authorisation valid EU- 1 Trade name- 1 common Product information

- Transparent system (e.g. EPAR) - Access to potentially 500 million users

LondonBrussels

- Parallel submissions in RMS and CMS

- RMS performs assessment- Peer review system by CMS

(90 days):-Assessment report-SPC, PL and labelling

-RMS and CMS grant Marketing authorisations after agreement (in 30 days)- Only, If no authorisation has been granted

CENTRALISEDMRP DECENTRALISED

NATIONAL

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2. EMEAThe EMEA is conceived as an interface of co-operation and co-ordination of Member States’activities with respect to medicinal products

Opening EMEA London – Jan 1995- Manages centralised procedure- Network for scientific advice/scientific opinions and evaluation which generates scientific opinionsfor EU Marketing Authorisations and “Article 58”…

- Coordination pharmacovigilance, inspection - Transparency/information and databases together with MSs and other interested parties all over the EU

Partnership with the European Commission in Brussels which issues Pan European marketing authorisation

LondonBrussels

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3. “Article 58” Opinions

EU Regulation

EU Regulation

(EC) No. 726/2004

(EC) No. 726/2004

EU Regulation

EU Regulation

(EC) No. 2309/93

(EC) No. 2309/93

repealed by

repealed by

Pre-submission PrimaryEvaluation

ClockStop

SecondaryEvaluation

Opinion

Decision

PostAuthorisation

D.1D.120

D.121

D.210D.277

Rap/Co-RapDay 80 Assessment

Reports

LoQ Answers

AssessmentReport on answers

D. 180 Hearing?

-Ph.Vigilance-Variations-Extensions-Renewal

Scientific Advice

Rap/Co-Rap

Centralised ProcedureCentralised Procedure

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3. “Article 58” Opinions

Article 58 of Regulation (EC) No. 726/2004

“1. The Agency may give a scientific opinion, in the context of cooperation with the World Health Organization, for the evaluation of certain medicinal products for human use intended exclusively for markets outside the Community. For this purpose, an application shall be submitted to the Agency in accordance with the provisions of Article 6. The Committee for Medicinal Products for Human Use may, after consulting the World Health Organisation, draw up a scientific opinion in accordance with the provisions of Articles 6 to 9. The provisions of Article 10 shall not apply.

2. The said Committee shall establish specific procedural rules for the implementation of paragraph 1, as well as for the provision of scientific advice.”

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3. “Article 58” OpinionsWhy ?Why ? Scope ?Scope ?

• Responds to the unavailability of medicinal products whose Marketing Authorizations are no longer in place in EU for commercial reasons but are still of use for countries outside the EUoutside the EU

• Access to essential medicines for countries lacking the regulatory capacity for assessing new medicinal products for their markets

• Responds to the need to protect protect publicpublic health and to give scientific scientific assistance to nonassistance to non--membermember countries in the context of cooperation with WHO while at the same time allowing rapid accessrapid access to those countries for important new important new medicinal products

• Vaccines used or of possible use in the WHO Expanded Programme On Immunization (EPI)

• Vaccines for protection against a WHO public health priority disease

• Vaccines that are part of a WHO managed stock pile for emergency response

• Medicinal products for WHO target diseases such as HIV/AIDS, malaria, tuberculosis, lymphatic filariasis(elephantiasis), trachoma, leishmaniasis, schistosomiasis, African trypanosomiasis(sleeping sickness), onchocerciasis (river blindness), dengue fever, Chagas disease, leprosy

medicinal products

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3. “Article 58” Opinions CHMP Guideline

http://www.emea.europa.eu/pdfs/human/regaffair/557904en.pdfhttp://www.emea.europa.eu/pdfs/human/regaffair/557904en.pdf

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4. “Article 58” Procedures

Adoption of CHMP SCIENTIFIC OPINION

Adoption of CHMP OPINION

D210

Centralized Procedure Article 58

ELIGIBILITY

PRE SUBMISSION

SUBMISSION VALIDATION

PRIMARY EVALUATION

SECONDARY EVALUATION

CLOCK STOP

D0

D1

D120

D121

COMMISSION DECISION

EC Decision Making ProcessEC Decision Making ProcessTranslation check of production informationTranslation check of production information

TexteWHO

EXPERTISE

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4. “Article 58” Evaluation“Art. 58” EVALUATION PROCEDURE MIRRORS the PROCEDURE for medicinal products intended to be marketed in the EU (BUT NO EC DECISION!) i.e.:

as for EU medicines taking into account possible adjustments as appropriate (e.g. stability, RMP etc..) - In absence of EU/ICH guidelines, or otherwise justified, WHO guidelines apply

Possibility to accept exceptionally old NTA format if justified

Not mandatory

Further to WHO recommendations

With consultation of relevant WPs/SAG

Possible nomination WHO Experts to be involved in Assessment review

and Observers from WHO and observers from NCAs may attend relevant WPs, CHMP plenary discussions

SCIENTIFIC ADVICE

Similar DATA REQUIREMENTS & EVALUATION STANDARDS

Submission CTD

Invented Name

Eligibility by CHMP

REVIEW PROCESS TIMELINES

RAPPORTEUR APPOINTMENT PROCESS

EXPERTS’ NOMINATION

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5. “Article 58” Scientific Opinions – EU experiences

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5. “Article 58” Scientific Opinions – EU experiences

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5. “Article 58” Scientific Opinions – EU experiences

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5. “Article 58” Scientific Opinions – EU experiences

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5. “Article 58” Scientific Opinions – EU experiences – Art.58 Certificate

http://www.emea.europa.eu/Inspections/index.html

http://www.emea.europa.eu/Inspections/index.html

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5. “Article 58” Scientific Opinions – EU experiences – Art.58 Certificate

http://www.emea.europa.eu/Inspections/Certificates.html

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5. “Article 58” Scientific Opinions –EU experiences – Art.58 Certificate

EMEA Certificates of Medicinal Products (CPPs) adopted under Art. 58 of Reg. 726/2004:

For a product for which an application has been submitted under Art. 58 of Reg. (EC) No. 726/2004, once validated by EMEA

• either under evaluation[no product information incl. but composition, GMP status of allsites can be incl.] or• once the opinion has been adopted by the CHMP

According to WHO rules/guidelines Only upon request from of Applicant/Scientific

Opinion Holder(s) with the exception of Anti-counterfeiting activities, where request from developing countries MSs can be made

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5. “Article 58” Scientific Opinions – EU experiences – Art.58 Certificate

This Certificate will stipulate that:

• the specific medicinal product is intended exclusively for markets outside the European Union[i.e. No EU MA]

• MP has undergone an evaluation procedure = Centralised procedure [w/o EC decision, no EU MA]

• GMP status of all manufacturing sites [for finish product, batch release, quality control sites, labelling, etc…]

•includes latest Product information[SPC mandatory, rest labelling and EPAR upon request]

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5. “Article 58” Scientific Opinions – EU experiences – Art.58 Certificate

certificate@emea.europa.eu.

Requesting EMEA Certificates of Medicinal Products:

All requests for certificates submitted by e-mail should be sent to certificate@emea.europa.eu. Requests that are sent to the e-mail addresses of EMEA staff members may be delayed. Questions and comments about the EMEA Certificates of Medical products are also welcome at certificate@emea.europa.eu.

Other questions, not related to the EMEA Certificates of Medicinal Product, should be sent to info@emea.europa.eu.

General Information:Notification on new Application FormNotification on Arrangements for Requesting Certificates - December 2007 What's new for Certification - 8 November 2005 Notification on Increase of the Administrative Charges for EMEA of Certificates of Medicinal Products Notification on Stopping Legalisation of Certificates of Medicinal Products from 1 Nov 2005 Information package Rev 8Questions and Answers

Send all queries regarding this content to:

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6. Other peculiarities of “Article 58” procedure

• Inspection during the evaluation:– Co-ordination pre-opinion inspections (GMP, GCP ,…) ?

•Manufacturers located in the EEA :– Supervisory Authority = Competent Authority of Member State that granted the manufacturing

authorization•Manufacturers located outside the EEA :

– Competent Authority of the Rapporteur's Member State

• Post-marketing follow-up:– Implementation of Risk Management Plans ?– Implementation of changes post opinion at national level ?– Adverse Events reporting / collection ?

• EU awareness of specific problems due to differences between the EU and developing countries:– Organisation of health care systems and ADRs reporting systems?– How to inform the patients?– How to communicate with health care professionals?

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OTHER ?Lymphatic filariasis,

Trachoma,,Dengue fever, leprosy..etc.

ANTI-MALARIA(3 WHO/CHMP Art.58

Eligibility granted – 5 under discussion)

HIV/AIDS(3 SOs adopted)

Combination vaccines

(3 WHO/CHMP Art.58 Eligibility granted – 1 Art.58 start/2SAs)

ANTI-LEISHMANIOSIS

(1 WHO/CHMP Art.58 Eligibility granted)

7. “Article 58” pipeline

ANTI-ONCHOCERCIASIS

(1 WHO/CHMP Art.58 Eligibility granted)

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Thank youfor your attention.

Contact Details:

General EMEA mailing box:Article58@emea.europa.eu