Ketek, FDA Hearing,

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Ketek (telithromycin)Decisions and
proceduresin the European Union

• Örjan Mortimer, MD, Senior Expert,
• Delegate EMEA/CHMP-PhVWP
• Medical Products Agency, Sweden

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Outline of the presentation

• Regulatory System in the European Union (EU)
• Ketek
• indications, changes to product information
• assessments of hepatic safety
• renewal of Marketing Authorization
• assessments after the renewal
• Summary

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A (De)Centralized Network
EMEA
HMPC
CHMP
WP
PhVWP
COMP
CVMP
WP
WP
SE
WP
WP
WP
DE
NL
UK
FR
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European Medicines Agency (EMEA)

• The EMEA coordinates the evaluation and
  supervision of medicinal products throughout the
  European Union.
• The Agency brings together the scientific
  resources of the 25 EU Member States in a network
  of the national competent authorities.

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The EMEA

• A network of some 3,500 European experts
  underpins the scientific work of the EMEA and its
  committees.
• Began its activities in 1995, when the European
  system for authorizing medicinal products was
  introduced
• Is primarily involved in the Centralised
  Procedure (CP).

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CHMP and Working Parties (WP)
Biotechnology WP
Safety WP
Pharmacovigilance WP
Quality WP
CHMP
Efficacy WP
Herbal Medicinal Product WP
Scientific advisory groups (SAGs)
Bloododucts Workin Party
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CHMP responsibilities

• Opinions on granting, variation, suspension, of
  an authorization according to the CP
• Opinion on any scientific matter concerning the
  evaluation of medicinal products for human use in
  the EU.

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CHMP responsibilities

• Should formulate an opinion whenever there is
  disagreement between member states within other
  procedures as the mutual recognition procedure
  and decentralised procedure.
• General guidance, provide Guidelines

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Regulatory Procedures in EU. The Centralised
Procedure

• Where the centralised procedure is used,
  companies submit one single marketing
  authorization application to the EMEA.
• A single evaluation is carried out through the
  Committee for Medicinal Products for Human Use
  (CHMP).

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Regulatory Procedures in EU. The Centralised
Procedure (CP)

• If the Committee concludes that quality, safety
  and efficacy of the medicinal product is
  sufficiently proven, it adopts a positive
  opinion.
• The opinion is sent to the Commission to be
  transformed into a single market authorization
  valid for the whole of the European Union.

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Scope of Centralised Procedure

• Mandatory for medicinal products
• Developed by biotech processes
• New therapies for AIDS, cancer, neurodegenerative
  disorders, diabetes, and in May 08, for
  auto-immune diseases other auto-immune
  dysfunctions, viral diseases
• Orphans
• Optional
• Other new active substances
• Generics (eligibility applications)
• Biosimilar products

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The Centralised procedure 1
Peer Review 1 MS
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The Centralised Procedure 2
Peer Review 1 MS
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Rapporteurs Obligations

• Presubmission Phase
• Organising assessment team
• Agency and/or External
• Contact with applicant
• Assessment of MAA
• Responsible for assessment according to timetable
• scientific quality
• coordination with co-rapporteur, rest of CHMP,
  WP, external expertise
• contact with applicant
• Post authorisation
• Life-cycle perspective
• Variations, specific obligations/FUMs
• Periodic Safety Update Reports (PSURs), Risk
  Management Plans (RMP), reassessments, renewals,
  etc

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Ketek granted EU-MA June 2001Indications

• Treatment (in patients of 18 years or older)
• mild to moderate community-acquired pneumonia,
• acute exacerbation of chronic bronchitis,
• acute sinusitis,
• and as an alternative to beta-lactams for
  tonsillitis / pharyngitis (in patients 12 years
  or older).
• The dose recommendation is two 400 mg tablets
  once daily for 5 to 10 days.

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Ketek usage in the EU

• In total estimated 13 million courses (world wide
  estimate 27 million courses)
• France gt 50
• Also extensive use in Italy, Germany, Spain and
  Greece

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Most important Variations ( Update of Product
Information)

• March 2002 interaction with rifampicin
• November 2002 update of information regarding
  visual disturbances
• April 2003 aggravation of Myasthenia gravis

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Variations of product information

• October 2003
• ADR section updated with info concerning hepatic
  ADRs, anaphylactic reactions and visual disorders
• Driving section updated with information
  concerning visual disorders which may impair the
  ability to drive

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Variations of product information

• November 2004 monitoring of PT-INR while
  patients are receiving telithromycin and
  anticoagulants simulataneously
• July 2005 transient loss of consciousness added
  to ADR section and accordingly also a driving
  warning was introduced

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Variations of product information

• February 2006 warnings regarding severe
  hepatitis and liver failure which may occur with
  short latency and in most cases were reversible.
  Patient should be informed of signs and symptoms
• September 2006 contraindication in patients
  with previous liver reactions during exposure to
  telithromycin hepatic fatalities

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Assessment of hepatic safety January 2006

• The PhVWP and the CHMP considered that
• characteristics of serious hepatic reactions were
  not well described in the product information
• that the short latency to onset of these
  reactions was of concern in patients treated in
  primary care
• an update of product information be requested

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Hepatic safety January 2006 contd.

• further assessment of available data needed
• a Risk Management Plan on hepatic safety be
  requested
• Accordingly, the product information was updated
  and a List of Question was sent to the MAH

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Assessment hepatic safety, May 2006.(Follow-up
measure 26).

• Most of the available data on hepatic safety was
  considered consistent with the current labelling.
• No risk factors could be identified except a
  tendency for patients with CAP to be at higher
  risk of liver reactions

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Assessment hepatic safety, May 2006.

• The RMP was considered satisfactory and the
  presented protocol for an epi-study of severe
  hepatic events in the USA should be updated.
• The risk-benefit of Ketek was still considered
  favourable

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Assessment hepatic safety, May 2006.

• The assessment of available data on hepatic
  safety of Ketek in the EU member states was
  continued.

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Renewal of the Marketing Authorization

• The application for renewal of the MA was
  assessed in parallell with the re-assessment of
  the hepatic safety
• In June 2006, the CHMP considered the
  benefit-risk of Ketek continues to be favourable
  based on a review of the available information
  (quality, efficacy and safety).

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Renewal of the Marketing Authorization

• Considering the increased awareness of safety
  issues, especially the hepatic safety, the CHMP
  was of the opinion that one additional five-year
  renewal on the basis of pharmacovigilance ground
  was required.
• The MAH should continue to submit annual Periodic
  Safety Update Reports

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Assessment of cases of serious hepatic ADRs
reported in the EU (September 2006).

• 49 cases reported in the EU, most of them in
  France and Germany.
• For 3 fatal cases (all from France) limited
  information was provided and/or there were other
  factors causing the hepatic reaction

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Assessment of cases of serious hepatic ADRs
reported in the EU (September 2006)

• The reporting rate or serious hepatic reactions
  was estimated to be 4-10 cases per million
  courses
• These data were in line with the current product
  information and did not alter the conclusions
  drawn by the CHMP in June 2006.

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Assessment of cases of serious hepatic ADRs
reported in the EU (September 2006)

• Taking global data into consideration,
  information regarding the occurrence of fatal
  hepatic reactions should be added to the product
  information.
• Further evaluation of the prescription and
  reporting of ADRs in the EU warranted.
• A full Risk Management Plan was requested
  (according to the new legislation)

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Additional regulatory measures in the EU

• The product information has been updated with
  regard to hepatic safety
• contraindication in patients who have experienced
  a hepatic reaction during treatment with Ketek
• add information that fatal hepatic reactions have
  been reported

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Summary

• Ketek was authorized in the EU gt 5 years ago
• The Product Information has been updated with
  safety information regarding
• risk of interactions
• visual disturbances
• risk of aggravation of myasthenia gravis, some
  fatal
• risk of loss of consciousness
• risk of serious hepatic reactions, some fatal

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Summary

• Re-assessment of the hepatic safety was made in
  parallell with the renewal of the MA
• The Marketing Authorization was renewed by the
  EU-commission in July 2006, based on the CHMP
  opinion.
• A second five-year renewal will take place.

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Summary

• Annual Periodic Safety Update Reports should be
  submitted, and several safety issues are closely
  monitored.
• A full Risk Management Plan has been requested
  (Submitted 13 December 2006)
• The use of Ketek in the EU is extensive and will
  be followed closely.