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Teriparatide or LY333334Teriparatide or LY333334Eli Lilly & CompanyEli Lilly & CompanyNDA 21-318NDA 21-318
Teriparatide or LY333334Teriparatide or LY333334Eli Lilly & CompanyEli Lilly & CompanyNDA 21-318NDA 21-318
Metabolic-Endocrine Drugs Metabolic-Endocrine Drugs Advisory CommitteeAdvisory Committee Bethesda, Maryland Bethesda, Maryland 27 July 200127 July 2001
Bruce V. Stadel, MD, MPH Bruce V. Stadel, MD, MPH Medical Safety ReviewerMedical Safety Reviewer Division of Metabolic-Endocrine Drug ProductsDivision of Metabolic-Endocrine Drug Products
Metabolic-Endocrine Drugs Metabolic-Endocrine Drugs Advisory CommitteeAdvisory Committee Bethesda, Maryland Bethesda, Maryland 27 July 200127 July 2001
Bruce V. Stadel, MD, MPH Bruce V. Stadel, MD, MPH Medical Safety ReviewerMedical Safety Reviewer Division of Metabolic-Endocrine Drug ProductsDivision of Metabolic-Endocrine Drug Products
Center for Drug Evaluation and ResearchCenter for Drug Evaluation and Research
2Metabolic-Endocrine Drugs Advisory Committee Metabolic-Endocrine Drugs Advisory Committee 27 July 2001
P-VALUE CAVEATP-VALUE CAVEATP-VALUE CAVEATP-VALUE CAVEATIn analyses of efficacy, hypotheses are ordinarily specified in advance of a study, and the use of p-values is focused on testing the pre-specified hypotheses. In analyses of safety, there usually are no pre-specified hypotheses, but there is still a need to assess the data to identify potential areas of concern. P-values as a descriptive tool are useful for this, with the understanding that a p-value associated with a new safety finding does not have the same meaning as a p-value associated with either the testing of a pre-specified efficacy hypothesis or a previously observed safety finding. New safety findings from one study should generally be tested in other studies, before a decision is made regarding validity.
3Metabolic-Endocrine Drugs Advisory Committee Metabolic-Endocrine Drugs Advisory Committee 27 July 2001
Issues from Preclinical & Phase 1 Clinical Studies
Issues from Preclinical & Phase 1 Clinical Studies
Phase I clinical studies• Hypotension & tachycardia • Decreased RR & QT intervals• Increased serum & urine calcium
Preclinical studies• Renal histopathology & malfunction• Osteosarcoma
Phase I clinical studies• Hypotension & tachycardia • Decreased RR & QT intervals• Increased serum & urine calcium
Preclinical studies• Renal histopathology & malfunction• Osteosarcoma
4Metabolic-Endocrine Drugs Advisory Committee Metabolic-Endocrine Drugs Advisory Committee 27 July 2001
Main Phase 3 Clinical Trials Main Phase 3 Clinical Trials
Main Phase 3 Clinical Trials Main Phase 3 Clinical Trials
• GHAC: 1637 postmenopausal women >1 vertebral fracture Placebo, 20 mcg, 40 mcg*
• GHAJ: 437 men Low bone mineral density
Placebo, 20 mcg, 40 mcg*
* 20 mcg or 40 mcg = LY333334 20 mcg or 40 mcg
per day, by subcutaneous injection
• GHAC: 1637 postmenopausal women >1 vertebral fracture Placebo, 20 mcg, 40 mcg*
• GHAJ: 437 men Low bone mineral density
Placebo, 20 mcg, 40 mcg*
* 20 mcg or 40 mcg = LY333334 20 mcg or 40 mcg
per day, by subcutaneous injection
5Metabolic-Endocrine Drugs Advisory Committee Metabolic-Endocrine Drugs Advisory Committee 27 July 2001
Patient Disposition Patient Disposition Numbers of Patients Randomized in Numbers of Patients Randomized in
Clinical Trials Clinical Trials
Patient Disposition Patient Disposition Numbers of Patients Randomized in Numbers of Patients Randomized in
Clinical Trials Clinical Trials
LY333334Study Placebo 20 mcg 40 mcg
GHAC 544 541 552
GHAJ 147 151 139
Active ControlGHAF 125 122
GHAH 73 73
6Metabolic-Endocrine Drugs Advisory Committee Metabolic-Endocrine Drugs Advisory Committee 27 July 2001
Duration of Treatment Duration of Treatment Numbers of Patients Numbers of Patients
Treated in Clinical Trials Treated in Clinical Trials
Duration of Treatment Duration of Treatment Numbers of Patients Numbers of Patients
Treated in Clinical Trials Treated in Clinical Trials
• GHAC: 1394 (85%) of the women were treated with LY333334 or placebo for 13-23 months
• GHAJ: 381 (87%) of the men were treated LY333334 or placebo for 6-14 months
• GHAC: 1394 (85%) of the women were treated with LY333334 or placebo for 13-23 months
• GHAJ: 381 (87%) of the men were treated LY333334 or placebo for 6-14 months
7Metabolic-Endocrine Drugs Advisory Committee Metabolic-Endocrine Drugs Advisory Committee 27 July 2001
Duration of Treatment Duration of Treatment Numbers of Patients Numbers of Patients
Treated in Clinical TrialsTreated in Clinical Trials
Duration of Treatment Duration of Treatment Numbers of Patients Numbers of Patients
Treated in Clinical TrialsTreated in Clinical Trials • 1452 Patients were treated with
LY33334 for >3 months
• This provides 95% confidence for detecting an event which occurs once in 484 or fewer treated patients
• 1452 Patients were treated with LY33334 for >3 months
• This provides 95% confidence for detecting an event which occurs once in 484 or fewer treated patients
8Metabolic-Endocrine Drugs Advisory Committee Metabolic-Endocrine Drugs Advisory Committee 27 July 2001
Serious Adverse EventsSerious Adverse EventsSerious Adverse EventsSerious Adverse Events
• Fatal or life-threatening• Hospitalization or prolongation of
hospitalization• Severe or permanent disability• Cancer • Congenital abnormality• Drug overdose• Other
• Fatal or life-threatening• Hospitalization or prolongation of
hospitalization• Severe or permanent disability• Cancer • Congenital abnormality• Drug overdose• Other
9Metabolic-Endocrine Drugs Advisory Committee Metabolic-Endocrine Drugs Advisory Committee 27 July 2001
Serious Adverse Events Serious Adverse Events During Clinical Trials During Clinical Trials
Number (%) of PatientsNumber (%) of Patients
Serious Adverse Events Serious Adverse Events During Clinical Trials During Clinical Trials
Number (%) of PatientsNumber (%) of Patients LY333334Study Placebo 20 mcg 40 mcg P-value
GHAC 113 (21%) 93 (17%) 109 (20%) 0.31
GHAJ 16 (11%)
Active Control
15 (10%) 14 (10%) 0.96
GHAF 11 ( 9%) 13 (11%) 0.62
GHAH 9 (12%) 9 (12%) 1.00
10Metabolic-Endocrine Drugs Advisory Committee Metabolic-Endocrine Drugs Advisory Committee 27 July 2001
Adverse Events of Any Severity Adverse Events of Any Severity During Clinical TrialsDuring Clinical Trials
Adverse Events of Any Severity Adverse Events of Any Severity During Clinical TrialsDuring Clinical Trials
LY333334Adverse Event 20 mcg 40 mcg
Back Pain
Nausea & Headache
Leg Cramps
Gout & Arthralgia
Urolithiasis
Dizziness, Syncope,& Vertigo * *
*Possible rare increase in severe dizziness
11Metabolic-Endocrine Drugs Advisory Committee Metabolic-Endocrine Drugs Advisory Committee 27 July 2001
Heart Rate and Blood PressureHeart Rate and Blood PressureHeart Rate and Blood PressureHeart Rate and Blood Pressure
• No differences between treatment groups in routine measurements
• LY333334 40 mcg versus placebo 1 hour after dosing mean increase = 5 beats/minute range = 68-104 for LY333334 47-100 for placebo
• Phase 4 commitment for 20 mcg data on heart rate, blood pressure, and ECG
• No differences between treatment groups in routine measurements
• LY333334 40 mcg versus placebo 1 hour after dosing mean increase = 5 beats/minute range = 68-104 for LY333334 47-100 for placebo
• Phase 4 commitment for 20 mcg data on heart rate, blood pressure, and ECG
12Metabolic-Endocrine Drugs Advisory Committee Metabolic-Endocrine Drugs Advisory Committee 27 July 2001
4-hour Postdose Serum Calcium 4-hour Postdose Serum Calcium During GHAC During GHAC LY333334 20 mcg versus placeboLY333334 20 mcg versus placebo
4-hour Postdose Serum Calcium 4-hour Postdose Serum Calcium During GHAC During GHAC LY333334 20 mcg versus placeboLY333334 20 mcg versus placebo Median increased 0.08-0.12 mmol/L (p<0.01)
Frequency of hypercalcemia (>2.64 mmol/L) Number (%) of patients
LY333334 Placebo 20 mcg P-value
1 episode 7 (1%) 44 (8%)>2 episodes 1 (<1%) 16 (3%) <0.01
Hypercalcemia range = 2.65-2.89 mmol/L
13Metabolic-Endocrine Drugs Advisory Committee Metabolic-Endocrine Drugs Advisory Committee 27 July 2001
4-hour Postdose Serum Calcium 4-hour Postdose Serum Calcium During GHAC During GHAC LY333334 20 mcg versus placebo LY333334 20 mcg versus placebo
Number (%) of PatientsNumber (%) of Patients
4-hour Postdose Serum Calcium 4-hour Postdose Serum Calcium During GHAC During GHAC LY333334 20 mcg versus placebo LY333334 20 mcg versus placebo
Number (%) of PatientsNumber (%) of Patients
Actiontaken
PlaceboLY33333420 mcg P-value
Calciumadjustment 3 (1%) 39 (7%) <0.01
Study drugadjustment 3 (1%) 15 (3%) <0.01
Studydiscontinued 1 (<1%) 1 (<1%) 1.00
14Metabolic-Endocrine Drugs Advisory Committee Metabolic-Endocrine Drugs Advisory Committee 27 July 2001
24 Hour Urine Calcium 24 Hour Urine Calcium During GHAC During GHAC LY333334 20 mcg versus placeboLY333334 20 mcg versus placebo
24 Hour Urine Calcium 24 Hour Urine Calcium During GHAC During GHAC LY333334 20 mcg versus placeboLY333334 20 mcg versus placebo
Median increased 0.10-0.76 mmol (p<0.01)
Frequency of hypercalciuria (>7.5 mmol/24 hrs) Number (%) of patients
LY333334 Placebo 20 mcg P-value
1 episode 101 (19%) 96 (18%)>2 episodes 14 ( 3%) 26 ( 5%) 0.46
Hypercalciuria range = 7.6-20.2 mmol/24 hrs
15Metabolic-Endocrine Drugs Advisory Committee Metabolic-Endocrine Drugs Advisory Committee 27 July 2001
Serum Total Alkaline PhosphataseSerum Total Alkaline Phosphatase During GHAC During GHAC
LY333334 20 mcg versus placeboLY333334 20 mcg versus placebo
Serum Total Alkaline PhosphataseSerum Total Alkaline Phosphatase During GHAC During GHAC
LY333334 20 mcg versus placeboLY333334 20 mcg versus placebo
Median increased 3.00-10.00 U/L (p<0.01)
Frequency above upper limit of normal (131-174 U/L depending on age, race)
LY333334 Placebo 20 mcg P-value
5 (1%) 8 (2%) 0.40
Median increased 3.00-10.00 U/L (p<0.01)
Frequency above upper limit of normal (131-174 U/L depending on age, race)
LY333334 Placebo 20 mcg P-value
5 (1%) 8 (2%) 0.40
16Metabolic-Endocrine Drugs Advisory Committee Metabolic-Endocrine Drugs Advisory Committee 27 July 2001
Post-Treatment Follow-up Post-Treatment Follow-up Study GHBJStudy GHBJ
Numbers of Patients Enrolled From Numbers of Patients Enrolled From Clinical Trials Clinical Trials
Post-Treatment Follow-up Post-Treatment Follow-up Study GHBJStudy GHBJ
Numbers of Patients Enrolled From Numbers of Patients Enrolled From Clinical Trials Clinical Trials
LY333334Study Placebo 20 mcg 40 mcg
GHAC 414 436 412
GHAJ 127 121 107
Active ControlGHAF 97 94
GHAH 53 52
17Metabolic-Endocrine Drugs Advisory Committee Metabolic-Endocrine Drugs Advisory Committee 27 July 2001
Serious Adverse EventsSerious Adverse Events in Post-treatment Follow-up in Post-treatment Follow-up
Number (%) of PatientsNumber (%) of Patients
Serious Adverse EventsSerious Adverse Events in Post-treatment Follow-up in Post-treatment Follow-up
Number (%) of PatientsNumber (%) of Patients LY333334Study Placebo 20 mcg 40 mcg P-value
GHAC 49 (12%) 73 (17%) 54 (13%) 0.10
GHAJ 11 (9%)
Active Control
19 (16%) 16 (15%) 0.20
GHAF 7 (7%) 1 (1%) 0.03
GHAH 4 (8%) 1 (2%) 0.18
18Metabolic-Endocrine Drugs Advisory Committee Metabolic-Endocrine Drugs Advisory Committee 27 July 2001
19Metabolic-Endocrine Drugs Advisory Committee Metabolic-Endocrine Drugs Advisory Committee 27 July 2001
Adverse Events of Any Severity Adverse Events of Any Severity in Post-treatment Follow-up in Post-treatment Follow-up
GHAC Patients Enrolled in GHBJGHAC Patients Enrolled in GHBJNumber (%) of PatientsNumber (%) of Patients
Cardiovascular Disorder* Cardiovascular Disorder*
Adverse Events of Any Severity Adverse Events of Any Severity in Post-treatment Follow-up in Post-treatment Follow-up
GHAC Patients Enrolled in GHBJGHAC Patients Enrolled in GHBJNumber (%) of PatientsNumber (%) of Patients
Cardiovascular Disorder* Cardiovascular Disorder* Placebo 20 mcg 40 mcg P-value
During trial 4 (1%) 9 (2%) 11 (3%)
In follow-up 7 (2%) 15 (3%) 20 (5%) Total 8 (2%) 17 (4%) 22 (5%) 0.03
*55% heart murmurs and valve disorders
20Metabolic-Endocrine Drugs Advisory Committee Metabolic-Endocrine Drugs Advisory Committee 27 July 2001
Laboratory Safety Variables Laboratory Safety Variables in Post-treatment Follow-upin Post-treatment Follow-up
GHAC Patients Enrolled in GHBJGHAC Patients Enrolled in GHBJLY333334 20 mcg versus PlaceboLY333334 20 mcg versus Placebo
Laboratory Safety Variables Laboratory Safety Variables in Post-treatment Follow-upin Post-treatment Follow-up
GHAC Patients Enrolled in GHBJGHAC Patients Enrolled in GHBJLY333334 20 mcg versus PlaceboLY333334 20 mcg versus Placebo
Serum Creatinine Median increased 1.0 mcmol/L
Frequency above upper limit of normal (101 mcmol/L) LY333334 Placebo 20 mcg P-value 7 (2%) 17 (4% ) 0.06Range: (104-115) (104-137)
21Metabolic-Endocrine Drugs Advisory Committee Metabolic-Endocrine Drugs Advisory Committee 27 July 2001
OsteosarcomaOsteosarcomain U.S. Populationin U.S. Population OsteosarcomaOsteosarcomain U.S. Populationin U.S. Population
Average annual incidence in Women and men >50 years of age is 4 cases per million per year, increasing at the older ages
Total in U.S. = about 300 per year
Occurrence similar by gender and race
Average annual incidence in Women and men >50 years of age is 4 cases per million per year, increasing at the older ages
Total in U.S. = about 300 per year
Occurrence similar by gender and race
22Metabolic-Endocrine Drugs Advisory Committee Metabolic-Endocrine Drugs Advisory Committee 27 July 2001
Osteosarcoma Osteosarcoma in Paget’s Diseasein Paget’s DiseaseOsteosarcoma Osteosarcoma in Paget’s Diseasein Paget’s Disease
Cumulative incidence in clinical series of patients with Paget’s Disease 1-5% Occurrence in Paget’s Disease patients is generally at >50 years of age
Cumulative incidence in clinical series of patients with Paget’s Disease 1-5% Occurrence in Paget’s Disease patients is generally at >50 years of age
23Metabolic-Endocrine Drugs Advisory Committee Metabolic-Endocrine Drugs Advisory Committee 27 July 2001
Paget’s Disease Paget’s Disease in U.S. Populationin U.S. Population
Paget’s Disease Paget’s Disease in U.S. Populationin U.S. Population
NHANES* I (1971-75)
• 3936 anteroposterior x-rays of pelvic region
• Prevalence of Paget’s Disease about 1% in women and men >50 years of age, increasing with age
• Prevalence generally similar by gender and age
*National Health and Nutrition Examination Survey
NHANES* I (1971-75)
• 3936 anteroposterior x-rays of pelvic region
• Prevalence of Paget’s Disease about 1% in women and men >50 years of age, increasing with age
• Prevalence generally similar by gender and age
*National Health and Nutrition Examination Survey
24Metabolic-Endocrine Drugs Advisory Committee Metabolic-Endocrine Drugs Advisory Committee 27 July 2001
Paget’s Disease Paget’s Disease in Clinical Trial Population in Clinical Trial Population
Paget’s Disease Paget’s Disease in Clinical Trial Population in Clinical Trial Population
• A 64 year old man was found to have Paget’s Disease of the pelvis 2 months after completing 13 months of treatment with LY333334 40 mcg in clinical trial GHAJ • The diagnosis was by pelvic x-ray and bone scan. A bone
scan shortly before enrollment in GHAJ did not show the disease although a very mild form cannot be ruled out
• The investigator called this possibly drug related; Lilly called it probably coincidental
• A 64 year old man was found to have Paget’s Disease of the pelvis 2 months after completing 13 months of treatment with LY333334 40 mcg in clinical trial GHAJ • The diagnosis was by pelvic x-ray and bone scan. A bone
scan shortly before enrollment in GHAJ did not show the disease although a very mild form cannot be ruled out
• The investigator called this possibly drug related; Lilly called it probably coincidental
25Metabolic-Endocrine Drugs Advisory Committee Metabolic-Endocrine Drugs Advisory Committee 27 July 2001
Osteosarcoma Surveillance Osteosarcoma Surveillance Osteosarcoma Surveillance Osteosarcoma Surveillance
• Post-treatment follow-up study GHBJ
• Drug use data and spontaneous adverse event reports
• Case-control study based on cases from referral centers and controls from residential areas of the cases
• Population-based case-control study using the SEER* system or other registry
*Surveillance, Epidemiology, and End Results
• Post-treatment follow-up study GHBJ
• Drug use data and spontaneous adverse event reports
• Case-control study based on cases from referral centers and controls from residential areas of the cases
• Population-based case-control study using the SEER* system or other registry
*Surveillance, Epidemiology, and End Results
26Metabolic-Endocrine Drugs Advisory Committee Metabolic-Endocrine Drugs Advisory Committee 27 July 2001
Osteosarcoma SurveillanceOsteosarcoma SurveillanceOsteosarcoma SurveillanceOsteosarcoma Surveillance Attributable risk • If incidence = 4/million/year, and relative risk = 3, then attributable risk =12-4 = 8/million
• If 250,000 people use drug, there would be 2 attributable cases per year
Attributable risk • If incidence = 4/million/year, and relative risk = 3, then attributable risk =12-4 = 8/million
• If 250,000 people use drug, there would be 2 attributable cases per year
27Metabolic-Endocrine Drugs Advisory Committee Metabolic-Endocrine Drugs Advisory Committee 27 July 2001
AcknowledgementsAcknowledgementsAcknowledgementsAcknowledgements
CDER Review Team
• Medical: Bruce S. Schneider, MD Bruce V. Stadel, MD, MPH• Pharm/Tox: Gemma Kuijpers, PhD • Statistics: Joy Mele, MS • Biopharmaceutics: Jim Wei, PhD Sang Chung, PhD• Chemistry: Yvonne Yang, PhD • Project Management: Randy Hedin, RPh
CDER Review Team
• Medical: Bruce S. Schneider, MD Bruce V. Stadel, MD, MPH• Pharm/Tox: Gemma Kuijpers, PhD • Statistics: Joy Mele, MS • Biopharmaceutics: Jim Wei, PhD Sang Chung, PhD• Chemistry: Yvonne Yang, PhD • Project Management: Randy Hedin, RPh