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Cardiovascular Assessment in the PreApproval and PostApproval Settings for Drugs and Biologics Devel

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Title: Cardiovascular Assessment in the PreApproval and PostApproval Settings for Drugs and Biologics Devel


1
Cardiovascular Assessment in the Pre-Approval
and Post-Approval Settings for Drugs and
Biologics Developed for the Treatment of Type 2
Diabetes MellitusEndocrinologic and Metabolic
Drugs Advisory Committee July 1-2,
2008Hylton V. Joffe, M.D., M.M.Sc.Lead Medical
Officer, Diabetes Drug GroupU.S. Food and Drug
Administration
2
Overview
  • Introduction
  • Type 2 diabetes mellitus
  • FDA approach to diabetes drug development
  • Cardiovascular assessment considerations
  • Points for discussion and questions to the panel

3
Introduction
  • Anti-diabetic drugs are indicated to improve
    glycemic control and are approved on the basis of
    HbA1c
  • Safety concerns with some anti-diabetic drugs
    have led to suggestions for a more extensive
    cardiovascular assessment during the approval
    process

N Engl J Med. 2007 357844 N Engl J Med.
2007 3571775-7
4
Introduction
  • This advisory committee meeting will explore this
    proposal and associated complex issues
  • Should a long-term cardiovascular trial be
    required?
  • Show benefit vs. rule out harm?
  • All new therapies or only those with a safety
    signal?
  • Challenges related to trial design?
  • Timing relative to approval?
  • What to do with currently marketed therapies?

5
Presentations
  • Natural history of type 2 diabetes and
    macrovascular complications (Dr. David Nathan)
  • HbA1c as a surrogate for glycemic control and
    microvascular complications (Dr. Robert Ratner)
  • Evaluating benefit and risk in type 2 diabetes
    statistical considerations (Dr. Thomas Fleming)
  • Clinical macrovascular outcomes with
    anti-diabetic drugs What we already know
    (Professor Rury Holman)

6
Presentations (continued)
  • Clinical macrovascular outcomes with
    anti-diabetic drugs Ongoing studies (Dr. Hertzel
    Gerstein)
  • Need for cardiovascular assessment during
    approval process for antidiabetic drugs (Dr.
    Steven Nissen)
  • Challenges in designing a cardiovascular trial
    for type 2 diabetes (Dr. Robert Califf)

7
Agenda
  • Day 1
  • Introductory FDA presentation
  • Presentations from experts in the field
  • Panel questions to the presenters
  • Panel discussion (will be continued on Day 2)
  • Day 2
  • Open public hearing
  • FDA Comments (Dr. Mary Parks)
  • Continued panel discussion
  • Questions to the panel

8
Type 2 Diabetes Mellitus
  • gt150 million people worldwide
  • gt18 million people in the United States
  • 2-4 fold higher risk of cardiovascular death
  • Most deaths due to cardiovascular disease/stroke
  • Other important long-term complications
  • Peripheral vascular disease
  • Retinopathy, nephropathy, and neuropathy

N Engl J Med. 1998 339229-34 JAMA. 2002
2872570-81 Lancet. 2005 3651333-46
9
Pharmacological Therapies
  • Alpha-glucosidase inhibitors
  • Amylin analogues (pramlintide acetate)
  • Biguanides (metformin)
  • Bile acid sequestrants (colesevelam)
  • Dipeptidyl peptidase 4 inhibitors (sitagliptin
    phosphate)
  • Glinides
  • Glucagon-like peptide 1 analogues (exenatide)
  • Insulin
  • Sulfonylureas
  • Thiazolidinediones

10
Macrovascular Complications
  • Intensive glycemic control appears to reduce
    macrovascular complications in type 1 diabetes
  • No conclusive evidence of macrovascular risk
    reduction with any of the FDA-approved treatments
    for type 2 diabetes

11
Older Trials with Cardiovascular Findings
  • University Group Diabetes Program (UGDP)
  • Tolbutamide increased cardiovascular mortality
  • UK Prospective Diabetes Study (UKPDS)
  • Non-significant reduction (p0.052) in myocardial
    infarction/ sudden death with intensive therapy
  • Reduction in diabetes-related death and all-cause
    mortality in a substudy of 342 overweight
    patients given metformin
  • Increase in diabetes-related death with metformin
    add-on to sulfonylurea

Diabetes. 1970 19 (Supp 2) 747-830 Lancet.
1998 352837-53 and 854-65
12
Trials with Cardiovascular Assessments
  • ACCORD
  • ADVANCE
  • BARI 2D
  • HEART 2D
  • VADT
  • PROactive
  • RECORD
  • ORIGIN
  • NAVIGATOR
  • ACE
  • STOP-NIDDM
  • DREAM

Treatment regimens
Type 2 diabetes
Primary CV or mortality endpoint
Specific drugs
Pre-diabetes
Secondary CV endpoint
13
Current FDA Approval Process
  • Anti-diabetic drugs are indicated to improve
    glycemic control
  • HbA1c is the primary efficacy endpoint
  • Correlates with mean blood glucose over 3 months
  • Unlike some other biomarkers relied upon for drug
    approval, there is symptomatic benefit with daily
    control of hyperglycemia
  • Lowering of HbA1c reduces the risk of onset,
    progression of microvascular complications

Lancet. 1998 352837-53 N Engl J
Med. 2008 3582560-72
N Engl J Med. 1993 329977-86 Diabetes Care.
2004 27 1761-73
14
Package Inserts
  • Drug X is indicated as an adjunct to diet and
    exercise to improve glycemic control in adults
    with type 2 diabetes mellitus
  • There have been no clinical studies establishing
    conclusive evidence of macrovascular risk
    reduction with Drug X or any other oral
    antidiabetic drug
  • Package inserts do not mention improvement in
    long-term sequelae of diabetes

15
Phase 2 Program
  • Dose-finding, randomized, double-blind,
    controlled, trials in patients treated only with
    diet/exercise or on a stable dose of metformin

Dose A
Dose B
Dose C
Run-in
Placebo
12 weeks
FDA Guidance to Industry on Diabetes Mellitus
(Draft)
16
Phase 3 Program
  • 6-month, randomized, double-blind, controlled
    trials with 6-18 month extensions
  • Placebo-controlled or active-controlled
    (non-inferiority)
  • Monotherapy
  • Add-on to other commonly used anti-diabetic drugs
  • Placebo-controlled trials usually 6 months in
    duration to limit long-term exposure to
    hyperglycemia

FDA Guidance to Industry on Diabetes Mellitus
(Draft)
17
Phase 3 Program - Monotherapy
  • Enrollment of patients treated with diet and
    exercise only or after washout of a single
    anti-diabetic drug
  • Generally low cardiovascular risk

Dose A
Dose B
Run-in
Placebo (or active comparator)
24 weeks
FDA Guidance to Industry on Diabetes Mellitus
(Draft)
18
Phase 3 Program Add-on Trials
Enrollment of patients with HbA1c 7-10 despite
stable maximal/near-maximal doses of a background
anti-diabetic drug
Stable near-maximal/maximal doses of background
anti-diabetic drug
Dose A background anti-diabetic drug
Dose B background anti-diabetic drug
Run-in
Placebo background anti-diabetic drug
24 weeks
FDA Guidance to Industry on Diabetes Mellitus
(Draft)
19
Phase 3 Development Program
  • A typical program has the following core phase 3
    trials
  • Placebo-controlled monotherapy trial
  • Add-on to metformin
  • Add-on to sulfonylurea
  • Add-on to thiazolidinedione
  • Other phase 3 trials
  • Active-controlled, monotherapy trial
  • Add-on to dipeptidyl-peptidase 4 inhibitor
  • Add-on to insulin
  • Add-on to dual agents (e.g., metformin
    sulfonylurea)

20
Phase 3 Program Extension Trials
  • In active-controlled trials, the randomized
    treatments can be continued into the extension
    trial
  • In placebo-controlled trials, placebo-treated
    patients are given active therapy during the
    extension trial to limit prolonged hyperglycemia
    (e.g., another anti-diabetic drug or the
    investigational agent)
  • Uncontrolled extensions limit interpretability of
    efficacy and safety

21
Phase 3 Program - Efficacy
  • Primary efficacy endpoint HbA1c
  • Sensitivity analyses
  • Subgroup analyses
  • Secondary efficacy endpoints
  • Fasting plasma glucose
  • HbA1c responder analyses
  • e.g., proportion of patients achieving HbA1c lt7
  • Body weight
  • Mechanistic (e.g., insulin sensitivity,
    postprandial glucose)

22
Phase 3 Program - Safety
  • Deaths
  • Non-fatal serious adverse events
  • Discontinuations
  • Other adverse events
  • Events of special interest (some are
    drug-specific)
  • Laboratory data
  • Vital signs
  • Electrocardiograms

23
Phase 3 Program - Safety
  • Unpooled analyses
  • Individual trial data
  • Pooled analyses
  • Grouping of data from two or more similar trials
  • Useful for analyzing infrequent events (e.g.,
    deaths)
  • Meta-analyses
  • Not routinely performed but multiple clinical
    trials required for the marketing application
    may allow for this to be incorporated in the
    safety analysis

24
Phase 3 Program - Safety
  • Some Caveats
  • Multiplicity if 100 associations are tested, 5
    may be significant by chance (alpha0.05)
  • Studies rarely powered for safety
  • Assessments of infrequent events (e.g., deaths,
    myocardial ischemia) are inconclusive
  • Do not usually have adjudication committees

25
Phase 3 Program Sample Sizes
  • ICH E1A recommended pre-approval exposures for
    drugs developed for chronic, non-life-threatening
    conditions
  • 1,500 subjects total
  • 300-600 subjects for 6 months
  • 100 subjects for 1 year
  • Minimum pre-approval sample sizes for type 2
    diabetes
  • 2,500 phase 2/3 total
  • 1,300-1,500 exposed 1 year
  • 300-500 exposed 18 months
  • Specific safety concern(s) may require larger
    exposures

26
Rule of Three
  • If we expose 2,500 patients to the study drug and
    see no cases of event A then we have ruled out
    incidence rates for event A of 0.12 or higher
    with 95 certainty

27
Clinical Trial Challenges
  • Worsening glycemia over time if therapy is not
    altered
  • Protecting participants from prolonged
    hyperglycemia
  • HbA1c entry criteria
  • Duration of placebo-controlled phase
  • Glycemic rescue therapy
  • Progressive nature of type 2 diabetes
    necessitates a multidrug anti-diabetic regimen in
    long-term trials, limiting the ability to tease
    apart the effects of a single drug

28
Points for Consideration and Discussion
  • What changes are recommended to phase 2/3 trials
    to enhance detection of a cardiovascular safety
    signal prior to drug approval?
  • Independent, blinded cardiovascular adjudication?
  • Meta-analysis of safety data from phase 2/3
    trials?
  • Changes to sample sizes/duration of exposures?

29
Points for Consideration and Discussion
  • Should a long-term cardiovascular trial be
    required to show benefit or rule out an
    unacceptable increase in cardiovascular risk?
  • Conclusive evidence of cardiovascular benefit has
    not been established for any drug for type 2
    diabetes despite several large, long-term trials
  • If ruling out harm, what non-inferiority margin
    do you recommend?

30
Points for Consideration and Discussion
  • In the absence of a concerning cardiovascular
    safety signal during Phase 2/3, should there
    still be a requirement to conduct a long-term
    cardiovascular trial?
  • When should such a study be conducted?
  • What about already marketed therapies?

31
Large Cardiovascular Trial Discussion Points
  • Benefit vs. rule out harm (if harm, what
    magnitude)?
  • Patient population?
  • Comparator(s)?
  • Primary endpoint?
  • What should the HbA1c target be?
  • How to define and manage deteriorating glycemia?
  • How to manage other cardiovascular risk factors?
  • Whether to ensure comparability of glycemia and
    cardiovascular risk factors across treatment
    groups?
  • Trial size and duration?

32
Large Cardiovascular Trial Discussion Points
  • Patient population?
  • Pre-diabetes? New-onset diabetes? Longstanding
    diabetes?
  • Generalizability?
  • Statistical power?
  • DREAM (pre-diabetes without cardiovascular
    disease)
  • 1 with MACE over median 3 year follow-up
  • ADOPT (new-onset diabetes)
  • Up to 25 with inadequate glycemic control over
    4-6 years

33
Large Cardiovascular Trial Discussion Points
  • What should the comparator be?
  • Drug X vs. Placebo
  • Drug X vs. Placebo as add-on to standard therapy
  • Drug X vs. Drug Y as add-on to standard therapy
  • How should deteriorating glycemia (which may vary
    between treatment groups) be defined, managed?
  • How do we interpret the effects of one drug
    within a multidrug regimen?
  • If ruling out harm in an active-controlled trial,
    how much do we need to know about the
    cardiovascular effects of the comparator?

34
Large Cardiovascular Trial Discussion Points
  • What should the primary endpoint be? Composite?
  • Cardiovascular death (or all-cause mortality)
  • Nonfatal myocardial infarction
  • Nonfatal stroke
  • Include other events in the primary endpoint?
  • Coronary revascularization?
  • Lower-extremity amputations?
  • Predefine, justify, accurately capture and analyze

35
2008 ADA Treatment Goals in Diabetes
36
Large Cardiovascular Trial Discussion Points
  • Should investigators be encouraged to manage
    blood pressures, lipid profiles, aspirin use, and
    other cardiovascular factors to current
    guidelines (which will not necessarily ensure
    comparability across treatment groups)?
  • OR
  • Should algorithms be used post-randomization with
    the intent of equalizing these risk factors
    across treatment groups?

37
Total Sample Sizes
a0.05 90 power 5-year trial 2-year
recruitment
38
Questions to the Committee
  • It should be assumed that an anti-diabetic
    therapy with a concerning CV safety signal during
    Phase 2/3 development will be required to conduct
    a long-term cardiovascular trial. For those
    drugs or biologics without such a signal, should
    there be a requirement to conduct a long-term
    cardiovascular trial ? (vote yes/no
    requested)
  • If yes, please discuss when such a study should
    be conducted?
  • Pre-approval?
  • Post-approval? If a long-term cardiovascular
    trial is required post-approval, please discuss
    whether this study should be ongoing at the time
    of approval (i.e., trial already initiated at
    time of approval)

39
Questions to the Committee
  • No currently marketed therapy for type 2 diabetes
    has established conclusive evidence of
    macrovascular benefit
  • Most marketed therapies for type 2 diabetes have
    not been tested for lack of cardiovascular harm
  • Therefore, please discuss how any suggestion for
    a requirement for a long-term cardiovascular
    trial should be applied to existing anti-diabetic
    therapies

40
Acknowledgements
  • Ilan Irony, M.D
  • Karen Mahoney, M.D.
  • Robert Misbin, M.D.
  • Valerie Pratt, M.D.
  • Joanna Zawadzki, M.D.
  • Joy Mele, M.S.
  • Todd Sahlroot, Ph.D.
  • Mary Parks, M.D. Director, Division of Metabolism
    and Endocrinology Products
  • Curtis Rosebraugh, M.D., M.P.H. Director, Office
    of Drug Evaluation II
  • Robert Temple, M.D. Associate Director, Office of
    Medical Policy
  • John Jenkins, M.D. Director, Office of New Drugs
  • Gerald Dal Pan, M.D., M.H.S. Director, Office of
    Surveillance Epidemiology

FDA clinical diabetes team
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