# Presentation: 897157

## “Cardiovascular Assessment in the Pre-Approval and Post-Approval Settings for Drugs and Biologics Developed for the Treatment of Type 2 Diabetes Mellitus”Endocrinologic and Metabolic Drugs Advisory Committee July 1-2, 2008Hylton V. Joffe, M.D., M.M.Sc.Lead Medical Officer, Diabetes Drug GroupU.S. Food and Drug Administration

## Overview

- Introduction
- Type 2 diabetes mellitus
- FDA approach to diabetes drug development
- Cardiovascular assessment: considerations
- Points for discussion and questions to the panel

## 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; 357:844        *N Engl J Med*. 2007; 357:1775-7

## 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?

## 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)

## 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)

## 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

## Type 2 Diabetes Mellitus

- >150 million people worldwide
- >18 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; 339:229-34 *JAMA*. 2002; 287:2570-81       *Lancet*. 2005; 365:1333-46

## 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

## 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

## Older Trials with Cardiovascular Findings

- University Group Diabetes Program (UGDP)
- Tolbutamide increased cardiovascular mortality
- UK Prospective Diabetes Study (UKPDS)
- Non-significant reduction (p=0.052) 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; 352:837-53 and 854-65

## Trials with Cardiovascular Assessments

- ACCORD
- ADVANCE
- BARI 2D
- HEART 2D
- VADT
- PROactive
- RECORD
- ORIGIN
- NAVIGATOR
- ACE
- STOP-NIDDM
- DREAM

- Type 2 diabetes

- Pre-diabetes

- Primary CV or mortality endpoint

- Secondary CV endpoint

- Treatment regimens

- Specific drugs

## 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; 352:837-53              *N Engl J Med*. 2008; 358:2560-72

*N Engl J Med*. 1993; 329:977-86 *Diabetes Care*. 2004; 27: 1761-73

## 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

## Phase 2 Program

**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

- Placebo

- Dose C

- Dose B

- Run-in

- 12 weeks

- FDA Guidance to Industry on Diabetes Mellitus (Draft)

## 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)

## Phase 3 Program - Monotherapy

- Placebo (or active comparator)

- Dose B

- Dose A

- Run-in

- 24 weeks

- Enrollment of patients treated with diet and exercise only or after washout of a single anti-diabetic drug
- Generally low cardiovascular risk

- FDA Guidance to Industry on Diabetes Mellitus (Draft)

## Phase 3 Program – Add-on Trials

- Placebo + background anti-diabetic drug

- Dose B + background anti-diabetic drug

- Dose A + background anti-diabetic drug

- Run-in

- 24 weeks

- Stable near-maximal/maximal doses of background anti-diabetic drug

- Enrollment of patients with HbA1c 7-10% despite stable maximal/near-maximal doses of a background anti-diabetic drug

- FDA Guidance to Industry on Diabetes Mellitus (Draft)

## 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)

## 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

## 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 <7%
- Body weight
- Mechanistic (e.g., insulin sensitivity, postprandial glucose)

## 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

## 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

## Phase 3 Program - Safety

- _Some Caveats_:
- Multiplicity – if 100 associations are tested, 5 may be significant by chance (alpha=0.05)
- Studies rarely powered for safety
- Assessments of infrequent events (e.g., deaths, myocardial ischemia) are inconclusive
- Do not usually have adjudication committees

## 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

## 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

| Patients Exposed to Study Drug | Smallest Event Rate Ruled Out 
(95% confidence) |
| --- | --- |
| 1,500 | 20/10,000 or 0.20% |
| 2,500 | 12/10,000 or 0.12% |
| 5,000 | 6/10,000 or 0.06% |
| 10,000 | 3/10,000 or 0.03% |

## 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

## 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?

## 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?

## 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?

## 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?

- 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?

**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

- 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

**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?

- 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?

**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

- 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

**Large Cardiovascular Trial: Discussion Points**

## 2008 ADA Treatment Goals in Diabetes

| HbA1c | <7.0% |
| --- | --- |
| Blood pressure | <130/80 mmHg |
| LDL-cholesterol | <100 or <70 mg/dL |
| Serum triglycerides | <150 mg/dL |
| HDL cholesterol | >40 (men); >50 (women) mg/dL |
| Smoking cessation | Yes |
| Aspirin therapy | If history (or increased risk) of cardiovascular disease |

## 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?

- 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?

**Large Cardiovascular Trial: Discussion Points**

## Total Sample Sizes

| Annual Event Rate |  | Total Sample Size to Rule Out Increased Risk of |  |  |
| --- | --- | --- | --- | --- |
| Drug | Comparator |  |  |  |
|  |  | 1.2 | 1.3 | 1.4 |
| 2% | 2% | 16,600 | 8,000 | 5,000 |
| 2% | 1.75% | >100,000 | 38,000 | 15,000 |
| 4% | 4% | 8,700 | 4,300 | 2,600 |
| 4% | 3.6% | >100,000 | 20,000 | 7,800 |
| 6% | 6% | 5,900 | 2,900 | 1,800 |
| 6% | 5.2% | >100,000 | 23,000 | 7,300 |

- α=0.05; 90% power; 5-year trial; 2-year recruitment

## 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)

## 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

## 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

- Statistics