Benefit and Managing the Risk

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Benefit and Managing the Risk

• Dr. Neville Jackson

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Benefit

• As efficacious as short-acting SC regular insulin
  in patients with type 1 diabetes or insulin
  requiring type 2 diabetes
• Effective in type 2 DM used alone, in combination
  with basal insulin, and in combination with oral
  agent
• Provides long-term glycemic control in both type
  1 and type 2 diabetes
• Most patients preferred INH over previous SC
  insulin and OA treatments

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Risks

• Hypoglycemia event rates as for other insulins
• Increased insulin antibodies compared to injected
  insulins
• No association with clinical outcomes
• Pulmonary effects
• Cough mostly post-inhalational
• PFT declines small, early, non-progressive,
  reversible
• Risk management plan to explore mechanism and
  follow the longer-term effect

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Risk Minimization and Proposed Studies
Activities to Minimize Risk Activities to Minimize Risk Activities to Minimize Risk Activities to Minimize Risk Activities to Minimize Risk Activities to Minimize Risk Ongoing/Proposed Studies and Activities to Assess Risk Ongoing/Proposed Studies and Activities to Assess Risk Ongoing/Proposed Studies and Activities to Assess Risk Ongoing/Proposed Studies and Activities to Assess Risk Ongoing/Proposed Studies and Activities to Assess Risk Ongoing/Proposed Studies and Activities to Assess Risk Ongoing/Proposed Studies and Activities to Assess Risk
Label Label HCP Edu/Cust. Care HCP Edu/Cust. Care Blister Package Differentia-tion Blister Package Differentia-tion Large Simple Trial (5 yr) LT PFT Safety (5 yr) Epi Lung Cancer (12 yr) Asthma/ COPD Ped. Mecha-nistic Enhanced Pharmaco-vigilance Program
Important Identified Risks Important Identified Risks Important Identified Risks Important Identified Risks Important Identified Risks Important Identified Risks Important Identified Risks
Change in Pulmonary Function Change in Pulmonary Function Ö Ö Ö Ö Ö Ö Ö Ö Ö Ö
Impact of Smoking Impact of Smoking Ö Ö Ö Ö Ö Ö Ö
Important Potential Risks Important Potential Risks Important Potential Risks Important Potential Risks Important Potential Risks Important Potential Risks
1 and 3 mg Dose Inequivalence 1 and 3 mg Dose Inequivalence Ö Ö Ö Ö Ö Ö
Increased Insulin Antibody Levels Increased Insulin Antibody Levels Ö Ö Ö Ö Ö Ö Ö Ö
Asthma and COPD Asthma and COPD Ö Ö Ö Ö Ö Ö
Rare Pulmonary Events Rare Pulmonary Events Ö Ö Ö Ö Ö Ö Ö
Limited Information Limited Information
Congestive Heart Failure Congestive Heart Failure Ö Ö Ö Ö Ö
Very Elderly Subjects (?75 yrs) Very Elderly Subjects (?75 yrs) Ö Ö Ö Ö Ö Ö Ö
Pregnancy Pregnancy Ö Ö Ö Ö Ö
Children and Adolescents Children and Adolescents Ö Ö Ö Ö Ö Ö
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Education and Customer Care

• Labeling
• Call center
• Healthcare professional training
• Patient training support
• Instruction video
• Instruction manual
• Quick reference guide
• Device replacement
• Enhanced pharmacovigilance to increase the follow
  up on the reporting of rare respiratory adverse
  events

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Use of 1 mg and 3 mg Blisters in the Clinical
Program

• 1 mg and 3 mg blisters were used safely and
  effectively in the clinical program
• All patients were dispensed 1 mg and 3 mg
  blisters at treatment initiation
• Patients were instructed to self-titrate by 1 mg
  increments, dependent upon home glucose
  monitoring
• Instructions were given to use as few blisters as
  possible at each dosing session

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Use of Doses in Phase 3 Efficacy Studies
Percent of Patients
Dose (mg insulin, nominal)
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Proposed Dosing Information for the Label
Patient Weight Initial Dose per Meal Approximate IU Dose Number of 1 mg Blisters per Dose Number of 3 mg Blisters per Dose
30 to 39.9 kg 1 mg per meal 3 IU 1 -
40 to 59.9 kg 2 mg per meal 6 IU 2 -
60 to 79.9 kg 3 mg per meal 8 IU - 1
80 to 99.9 kg 4 mg per meal 11 IU 1 1
100 to 119.9 kg 5 mg per meal 14 IU 2 1
120 to 139.9 kg 6 mg per meal 16 IU - 2
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Assuring Safe Use of 1 3 mg Blisters

• Education of patients to self-titrate by 1 mg
  increments
• Clear tactile and visual differentiation of the
  blisters
• Education of physicians to closely monitor
  patients on initiation of INH therapy
• Manage the risk of substitution of 1 x 3 mg with
  3 x 1 mg blisters by clear labeling, including
  secondary packaging, and education
• Where unavoidable substitution is necessary,
  specific instructions to use 2 x 1 mg in place of
  1 x 3 mg

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Risk Management - Protocols
Ongoing Proposed Start End
Large Simple Trial (5-year) (1069) ? 2006 2014
Long-Term PFT Safety Studies (5-year) (1022/1029) ? 2012
Epidemiology Lung Cancer Study (12-year) (1071) ? 2006 2019
Asthma (1028) ? 2008
COPD (1030) ? 2011
Mechanistic Studies
BAL (1052/1053) ? 2006
Clinical Mechanistic Study ? 2006 2008
PreClinical Mechanistic Study ? 2006 2007
Expanded Analysis of existing PFTs in database ? 2005 2006
Pediatric Studies ? 2006 2009
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Multinational, Long-term Large Simple Trial to
Evaluate Pulmonary Safety

• Objectives
• Persistent decline in FEV1 of 20 or more
• Serious respiratory adverse events
• Enroll 5,000 patients - North America, Europe, LA
• Broad entry criteria as per approved label
• Recruitment from primary care practices with
  diverse patient population
• Targeted recruitment of 5-10 very elderly (?75
  years)
• Randomization to Exubera or usual care for 5
  years
• Spirometry measurements (FEV1) at baseline and
  then prospectively, consistent with approved
  label
• Follow up per usual medical care with concomitant
  medications permitted
• All randomized patients followed for collection
  of SAEs even if they discontinue treatment