DRAFT SLIDES FOR NDA 21198 ADVISORY COMMITTEE PRESENTATIONS

1
DRAFT SLIDES FOR NDA 21-198 ADVISORY COMMITTEE
PRESENTATIONS
2
Joint Advisory Committee MeetingFDA Presentations

• Clinical Efficacy and Safety
• Mary H. Parks, MD (DMEDP)
• Actual-Use Trials
• Daiva Shetty, MD (DOTCDP)
• Label Comprehension Studies
• Karen Lechter, JD, PhD (DDMAC)

3
Joint Advisory Committee Meeting on
Nonprescription Availability of Pravastatin 10 mg

• Friday, July 14, 2000
• Mary H. Parks, MD
• Division of Metabolic and Endocrine Drug Products
• Center for Drug Evaluation and Research

4
NDA 21-198

• Sponsors rationale for nonprescription
  Pravastatin
• Definition of the OTC-target population
• Clinical studies reviewed in DMEDP
• Safety of Pravastatin
• Conclusions benefit-risk relationship of
  nonprescription pravastatin

5
Sponsors Rationale
MRFIT. JAMA. 19862562823-2828.
6
Sponsors Rationale

• Clinical trials demonstrate reduction in
  cardiovascular events with lipid-lowering drugs
• primary and secondary prevention
• across a broad range of cholesterol levels

7
Sponsors Rationale

• Inadequate treatment of population to NCEP Goals
• lt 2 CHD risk factors present
• treatment goal LDL-Clt160 mg/dL
• ? 2 CHD risk factors present
• treatment goal LDL-Clt130 mg/dL
• established CHD
• treatment goal LDL-Clt100 mg/dL

8
Sponsors Rationale

• Consumer interest
• low-fat, diet foods
• dietary supplements
  
• Unrestricted access to pravastatin provides an
  adjunct for lowering cholesterol

9
OTC-Target PopulationSponsors Definition

• Who should use
• told by MD to lower cholesterol but not on drug
  treatment
• total-C 200-240 mg/dL, LDL-C gt 130 mg/dL
• Who should NOT use
• presence of CHD or DM
• on prescription lipid-lowering drug
• children and pregnant women

10
Clinical Studies Reviewed

• 10 and 40 mg placebo-controlled studies
• PREDICT
• (Pravachol Experience in a Documented
  Consumer-Use Trial)
• 24-wk, randomized, open-label
• Rx vs OTC pravastatin groups
• OPTIONS
• (OTC Pravachol in an Observed Naturalistic
  Setting)
• 12-wk, open-label, uncontrolled
• OTC pravastatin in HMO setting

11
Issues Addressed

• LDL-C reduction
• Necessity of MD involvement
• Adherence to drug treatment
• Clinical cardiovascular benefit
• Safety
• Clinical trials
• Postmarketing

12
LDL-C Reduction
13
LDL-C Reduction

• 18-22 LDL-C reduction
• placebo-controlled studies
• diet enforced
• in non OTC-target population

14
PREDICTQualified and Treated
Randomization to OTC or Rx group
Study Physician Consult treatment guidelines
applied
Qualified for Treatment
Qualified and Treated Subgroup 15 of OTC and 19
of Rx group
15
PREDICTTreatment Guidelines
16
LDL-C ReductionPREDICT

• Qualified and treated subgroups
• 18 required dose titration to 20 or 40 mg to
  achieve NCEP goals
• 17-18 LDL reduction for both OTC and Rx patients

17
PREDICTQualified and Treated
Randomization
RX n1948
OTC n1924
499 treated
355 treated
Qualified and Treated 352 (99.2 of treated)
Qualified and Treated 253 (50.7 of treated)
18
NECESSITY OF PHYSICIAN INVOLVEMENT
19
PREDICTStudy Drug Discontinuation
20
PREDICTMD Recommended Discontinuations
21
Necessity of MD Involvement

• OTC self-selection
• overtreatment
• undertreatment
• inappropriate treatment

22
Adherence to Therapy
23
OPTIONSSubject Disposition
n2207
n782
n404
n321
n156
24
Clinical Cardiovascular Benefit
25
Clinical Cardiovascular Benefit?

• not demonstrated
• in OTC target population
• for OTC product and dose
• in OTC setting

26
SafetyClinical Trials
27
Safety - Clinical Trials

• 10 mg dose
• No rhabdomyolysis, myoglobinuria, or hepatic
  toxicity
• Incidence of myalgias lt 2
• Incidence of hepatic enzyme elevation similar
  between pravastatin and placebo (lt 2)
• Discontinuation of medication due to reported AEs
  higher in the OTC group vs Rx group (PREDICT)

28
Safety - Clinical Trials

• 40 mg dose
• 3 placebo-controlled trials of 5yrs
• consecutive 3x ULN liver enzyme rates lt 1 for
  pravastatin no significant difference to placebo
• no cases of hepatic failure
• 1 case of reported rhabdomyolysis

29
Limitations of Safety Assessments

• Clinical Trials
• exclusion of patients on interacting drugs
• exclusion of patients with co-morbid conditions
• scheduled MD visits and safety monitoring

30
Safety - Spontaneous Reports

• Liver Failure
• Rhabdomyolysis

31
Liver Failure

• Case definition
• clinical diagnosis of liver failure stated by
  reporter
• liver transplant
• Reporting time period
• from marketing until 2/25/00

32
Liver Failure

• 13 Cases
• 8 domestic, 5 foreign
• dose
• 10 mg (3 cases), 20 mg (6), 40 mg (1), unknown
  (3)
• 10 unconfounded cases

33
Liver Failure

• No increase from background rate of idiopathic
  liver failure

34
Rhabdomyolysis

• Case definition
• clinical diagnosis of rhabdomyolysis
• CPK gt 10,000 IU/L
• Reporting time period
• marketing until April-May 2000
• Background rate unknown for this AE

35
Rhabdomyolysis35 Cases
36
Dispensed Prescriptions for Pravastatin in U.S.
1999 (Total Rx 12,871,000)
64
Rxs
27
9
Source IMS HEALTH National Prescription Audit
37
Rhabdomyolysis

• True incidence rate unknown but risk exists
• Potential increased risk
• concomitant use with certain medications
• fibrates, cyclosporine, erythromycin
• co-morbid medical conditions
• Cases may increase with increase use of 10 mg
  dose in OTC setting

38
Safety of OTC Pravastatin

• Dependent upon
• Comprehension of label
• Following label instructions
• No self-titration
• No use by high-risk individuals in the
  unrestricted, unsupervised OTC setting
• drug-drug interactions
• co-morbid medical conditions

39
Summary of Issues Addressed

• LDL-C reduction
• Adherence to drug treatment
• Necessity of MD involvement
• Clinical cardiovascular benefit
• Safety

40
Conclusion

• What is the balance of benefit versus risk of
  nonprescription pravastatin?