Post by cm5 on May 21, 2016 12:41:02 GMT -5
See below for Exubera review: INITIAL CLINICAL REVIEW FOR INCLUSION IN ADVISORY
COMMITTEE BRIEFING DOCUMENT
Application Type NDA
Submission Number 000
Submission Code N
Letter Date 27 Dec 04
Stamp Date 27 Dec 04
PDUFA Goal Date 27 Oct 05
Reviewer Name Karen Murry Mahoney, MD
Review Completion Date 4 Aug 05
Established Name Exubera®
(Proposed) Trade Name Exubera®
Therapeutic Class Inhaled insulin
7.1.11 Human Carcinogenicity
Malignant neoplastic adverse events in humans are discussed in Sections 7.1.2.1, 7.1.3.2 and
7.1.6. Overall, malignant neoplasms did not occur at a higher frequency in inhaled insulin
patients than in comparator patients for either Type 1 or Type 2 diabetics. In controlled Phase 2
and Phase 3 trials in Type 2 diabetics, discontinuations due to neoplasia did not occur more
frequently among inhaled insulin group patients than among control patients. One case of lung
carcinoma occurred in the inhaled insulin groups, and one in the oral agent groups. Pulmonary
neoplasms are to be discussed in Dr. Seymour's pulmonary safety review. For all Phase 2 and
Phase 3 trials, controlled and uncontrolled, neoplastic adverse event terms leading to
discontinuation were numerically more frequent and slightly (not statistically significantly) more
frequent on a person-time basis in the inhaled insulin groups than in the control groups.
The applicant did not conduct animal carcinogenicity studies with inhaled insulin.
Clinical Review
Karen Murry Mahoney, MD
NDA 21868 N 000
Exubera® (inhaled human insulin)
Page 159 of 294
7.1.12 Special Safety Studies
Dr. Seymour's pulmonary safety review will include discussion of specific pulmonary safety
studies; please see Section 7.1.3.3 for a discussion of insulin antibody studies.
Malignant neoplastic adverse events in humans are discussed in Sections 7.1.2.1, 7.1.3.2 and
7.1.6. Overall, malignant neoplasms did not occur at a higher frequency in inhaled insulin
patients than in comparator patients for either Type 1 or Type 2 diabetics. In controlled Phase 2
and Phase 3 trials in Type 2 diabetics, discontinuations due to neoplasia did not occur more
frequently among inhaled insulin group patients than among control patients. One case of lung
carcinoma occurred in the inhaled insulin groups, and one in the oral agent groups. Pulmonary
neoplasms are to be discussed in Dr. Seymour's pulmonary safety review. For all Phase 2 and
Phase 3 trials, controlled and uncontrolled, neoplastic adverse event terms leading to
discontinuation were numerically more frequent and slightly (not statistically significantly) more
frequent on a person-time basis in the inhaled insulin groups than in the control groups.
The applicant did not conduct animal carcinogenicity studies with inhaled insulin.
Clinical Review
Karen Murry Mahoney, MD
NDA 21868 N 000
Exubera® (inhaled human insulin)
Page 159 of 294
7.1.12 Special Safety Studies
Dr. Seymour's pulmonary safety review will include discussion of specific pulmonary safety
studies; please see Section 7.1.3.3 for a discussion of insulin antibody studies.
Afrezza
During the clinical development program for Afrezza in which Afrezza use was
compared primarily with other insulin use1
, two cases of pulmonary malignancies
were identified in Afrezza-exposed patients: One was identified after 120 days of
treatment in a 62-year-old male subject with a prior history of smoking. The other
involved a non-small cell bronchogenic carcinoma in an Afrezza-exposed patient in
an uncontrolled trial. The patient was “a 67-year-old male subject with a history of
heavy smoking and a family history of lung cancer” [2].
Two additional lung cancers were spontaneously reported at 2.5 and 3.5 years,
respectively, after clinical trial discontinuation in a 59-year-old male non-smoker and
in a 73-year-old female non-smoker who had been prescribed a high dose of Afrezza
During the clinical development program for Afrezza in which Afrezza use was
compared primarily with other insulin use1
, two cases of pulmonary malignancies
were identified in Afrezza-exposed patients: One was identified after 120 days of
treatment in a 62-year-old male subject with a prior history of smoking. The other
involved a non-small cell bronchogenic carcinoma in an Afrezza-exposed patient in
an uncontrolled trial. The patient was “a 67-year-old male subject with a history of
heavy smoking and a family history of lung cancer” [2].
Two additional lung cancers were spontaneously reported at 2.5 and 3.5 years,
respectively, after clinical trial discontinuation in a 59-year-old male non-smoker and
in a 73-year-old female non-smoker who had been prescribed a high dose of Afrezza
4.2 Adequacy of Safety Assessments
4.2.1 Overall Exposure at Appropriate Doses/Durations and Demographics of Target
Populations
Between the data cutoff dates of the 2010 Resubmission (15 May 2010) and the 2013
Resubmission (31 July 2013), 1055 new subjects participated in Afrezza TI clinical studies. As
of the database lock for the Resubmission, the total Afrezza TI development program has
exposed 2647 subjects to Afrezza TI using the MedTone inhaler and 370 using the Gen2 inhaler
(total 3017) in phase 2/3 clinical studies. Overall, 896 subjects were exposed to Afrezza TI for 0
to 3 months, 978 for >3 to 6 months, 419 for >6 to 12 months, and 724 for >12 months.
4.2.1 Overall Exposure at Appropriate Doses/Durations and Demographics of Target
Populations
Between the data cutoff dates of the 2010 Resubmission (15 May 2010) and the 2013
Resubmission (31 July 2013), 1055 new subjects participated in Afrezza TI clinical studies. As
of the database lock for the Resubmission, the total Afrezza TI development program has
exposed 2647 subjects to Afrezza TI using the MedTone inhaler and 370 using the Gen2 inhaler
(total 3017) in phase 2/3 clinical studies. Overall, 896 subjects were exposed to Afrezza TI for 0
to 3 months, 978 for >3 to 6 months, 419 for >6 to 12 months, and 724 for >12 months.
CDC SEER Stat Fact Sheets: Lung and Bronchus Cancer
Number of New Cases and Deaths per 100,000: The number of new cases of lung and bronchus cancer was 57.3 per 100,000 men and women per year. The number of deaths was 46.0 per 100,000 men and women per year. These rates are age-adjusted and based on 2009-2013 cases and deaths.
Lifetime Risk of Developing Cancer: Approximately 6.6 percent of men and women will be diagnosed with lung and bronchus cancer at some point during their lifetime, based on 2010-2012 data.
Prevalence of This Cancer: In 2013, there were an estimated 415,707 people living with lung and bronchus cancer in the United States.
Number of New Cases and Deaths per 100,000: The number of new cases of lung and bronchus cancer was 57.3 per 100,000 men and women per year. The number of deaths was 46.0 per 100,000 men and women per year. These rates are age-adjusted and based on 2009-2013 cases and deaths.
Lifetime Risk of Developing Cancer: Approximately 6.6 percent of men and women will be diagnosed with lung and bronchus cancer at some point during their lifetime, based on 2010-2012 data.
Prevalence of This Cancer: In 2013, there were an estimated 415,707 people living with lung and bronchus cancer in the United States.