Risk Management Plan

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Risk Management Plan

• 24. April 2008
• Helge Gydesen
• Epidemiology
• Novo Nordisk A/S

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Agenda
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Rofecoxib (VIOXX)

• Merck Co
• Introduced 1999 Withdrawn 2004
• Indications Osteoarthritis and Acute Pain
• Withdrawn due to Heart attack and stroke

Cerivastatin

• Bayer A. G.
• Introduced Late 1990s Withdrawn 2001
• Cholesterol lowering
• Withdrawn due to Rhabdomyolysis leading to renal
  failure

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Regulatory guidance

• Three guidelines from FDA
• The ICH E2E Guideline
• EU risk management Guideline
• All can be found on International Society for
  PharmacoEpidemiology (ISPE) homepage
  www.pharmacoepi.org under the left hand heading
  resources

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EU-RMP

• EU-RMP required at MAA submission
• New active, biosimilar or generic with risk
  minimisation for reference substance
• New dosage form, route, indication, manufacture
  process for biotech product
• On request of authorities
• If Marketing Authorization Holder (MAH)
  identifies a safety concern
• Other situations for centrally authorised
  product. e.g. bibliographical applications, fixed
  combination, certain hybrid products

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Risk management - Definition and purpose

• A Risk Management system is a set of
  pharmacovigilance activities and interventions
  designed to proactively identify, characterise
  and prevent or minimise risks relating to
  medicinal products, including risk communication
  and the assessment of the effectiveness of risk
  minimisation interventions.
• The purpose of the Risk Management Plan (RMP) is
  
• to identify the risks associated with a medicinal
  product
• develop methods to clarify further the safety
  profile of a product
• plan ways to minimise risk to individual patients
  in clinical use.

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Risk Management Plan Development
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Epidemiology in The Risk Management Framework

• Risk assessment / measurement
• estimation and evaluation of risk
• Risk confrontation
• determining acceptable level of risk
• Risk intervention
• risk control action
• Risk communication
• interactive exchange of risk information
• Risk management evaluation
• evaluating effectiveness of activities

• Epidemiology population based evidence
• Epidemiology population based evidence
• Public Health perspective
• Public Health perspective
• Epidemiology population based evidence

Safety Risk Management provides a formal
framework in which epidemiological activities and
public health perspective are integrated in the
development and life-cycle management of therapies
Managing the risks from Medical Products Use.
Creating the framework for Risk Management.
Report to the FDA CommissionerMay 1999 164
pages http//www.fda.gov/oc/tfrm/riskmanagement.
pdf
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Who is contributing

• International Product Safety (IPS) is the owner
  of the document
• Contributions from the pre-clinical and clinical
  development area
• BIG contribution from Epidemiology
• Discussions with Marketing on the Post Marketing
  Activities

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Risk management - The role of Epidemiology

• Author and maintain the epidemiological sections
  of a Risk Management Plan (RMP) as per guidelines
  from regulatory authorities and NN SOP on ongoing
  basis. Support the updating of RMP periodically.
  Provide epidemiological expertise in Risk
  management activities throughout the life cycle
  of NN products.
• Provide timely epidemiology support to project
  teams to design and implement epidemiological
  studies, to review study proposal from internal
  and external sources, to analyze adverse events
  reporting data, and to interpret and report on
  data analysis results to other line functions.
• Contribute in safety risk evaluation once a
  safety signal has been detected and in
  communication of safety information and thereby
  propose and implement risk minimization
  activities.
• Provide epidemiology support in preparation of
  Periodic/ Annual Safety Reports (PSUR/ASR) if
  required by the regualatory authorities.

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Risk management - Future

• Global Epidemiology will be involved in all Risk
  Management Activities in NN
• Input to design and protocol
• Timely epidemiology support to project teams to
  design and implement epidemiological studies to
  evaluate safety issues.
• Setup an organised collaborative team with IPS as
  an Integrated Risk Management Expert Group
  (IRMEG) within NN.
• Responsible for study design, analysis,
  interpretation and publication of studies related
  to safety issues of NN products.
• Conduct epidemiological studies to support risk
  management activities
• Review and Meta analysis of LTR to address safety
  issues
• Make sure resources are allocated when new post
  approval safety studies (PASS) are initiated and
  required
• Resources in budget to conduct or for outsourcing
  for epidemiological studies to gather knowledge
  about target indications.

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When to start the work with the RMP?
Phase IV
Exposure
Phase III
(Potential Denominator)
Phase II
Phase I
FIM
ProductLife Cycle
Approval
Drug Discovery/Preclinical
Clinical Development
Post Marketing
h
h
h
Pharmacovigilance
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RMP A change in approach

• Proactive in stead of reactive
• Not a defensive approach, in stead demonstrate
  safety
• Focus on different type of epidemiological
  studies in stead of normal pharmacovigilance
• Pharmaco epidemiology in stead of standard
  pharmacovigilance

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Risk management Plans examples of identified
risks EXUBERA

• Smoking-induced alterations in Pharmacokinetics
  (drug interaction studies/passive smoking)
• Changes in Pulmonary Function (Long term PASS,
  Special Asthma study, Paediatric studies)
• Increased Insulin Antibody Levels (Long term
  PASS, Paediatric studies)
• Rare Pulmonary Events (Epi Lung Cancer study)
• 11 studies running until 2019, covering more than
  75000 patients

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CONCLUSIONS

• Risk Management is a new area under development
• Clinical Epidemiology is a crucial area of
  information
• Will create discussions of the right level of
  post marketing activities Observational studies,
  utilization of databases (internal/external)
• BUT ABOVE ALL Epidemiological/statistical
  expertise will be needed in the future
  development of this area

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Any questions or comments?
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