# Presentation: 570659

## Toward a Rational Regulatory Policy for Development of Drugs to Treat Diabetes Mellitus

- Steven E. Nissen MD
- Chairman, Department of Cardiovascular Medicine
- Cleveland Clinic

**Disclosure**
***Consulting:*** Many pharmaceutical companies
***Clinical Trials:***** **AstraZeneca, Eli Lilly, Takeda, Sankyo, Sanofi-Aventis, Roche, and Pfizer. Companies are directed to pay any honoraria, speaking orconsulting fees directly to charity so that neither income nor tax deduction is received.

## Why are We Here?

- The ACCORD trial demonstrated that a drug regimen designed to lower blood glucose is ***capable ***of increasing mortality in diabetic patients.
-  Multiple rosiglitazone meta-analyses of CV outcomes showed improved glycemic control, but an increase in myocardial ischemic events.
- Many agents to treat diabetes have failed duringdevelopment, some to cardiotoxicity.
- No robust cardiovascular outcomes data existfor any current diabetes therapies.

## The Problem: Insufficient Clinical Trial Data

- In the absence of randomized CV outcomes trials, we are left with unsatisfactory methods to assess benefit and risk.
- These include meta-analyses or *post hoc *data “dredging” of randomized trials not designed to determine the benefits or risks of *specific *therapies.
- This was particularly evident at the recent ADAmeeting with attempts to determine the sourceof the excess mortality in ACCORD.
- No amount of “torturing” of the data will enable riskassessment when specific drugs usage notrandomized.

## ACCORD

| Drug Class or Name | Intensive Therapy | Standard Therapy |
| --- | --- | --- |
| Repaglinide | 50.2% | 17.7% |
| Rosiglitazone | 91.7% | 58.3% |
| Insulin | 77.3% | 55.4% |
|  glucosidase inhibitor | 23.2% | 5.3% |

- Bottom line: A regimen in which more patients received repaglinide, rosiglitazone, insulin and/or an glucosidase inhibitor showed increased mortality risk.

## More than 50 years after the initial introduction of oral anti-diabetic drugs....

- Although cardiovascular disease is the cause of death in 75% of diabetics, there exist no well-designed, adequately-powered comparative effectiveness trials evaluating macrovascular outcomes for diabetes drugs

## Slide 6

## Level of Evidence: Comparative Effectiveness Trials of Diabetes Drugs

| Outcome | Level of Evidence |
| --- | --- |
| All cause mortality | Low to very low |
| CV disease mortality | Low to very low |
| Nonfatal MI or stroke | Low to very low |
| Peripheral vascular disease | Low to very low |
| Microvascular outcomes | Low to very low |

## The Knowledge Gap

- The absence of information on macrovascular effects of diabetes therapies is the unfortunate consequence of current regulatory policy that emphasizes the importance of glucose lowering, not health outcomes, as a therapeutic goal.

## This Approach Has Created a New Disorder

- Glucocentricity

## Consequences of a “Glucocentric” Regulatory Approach to Diabetes Drugs

- Pre-approval studies focus on demonstratingmaximal glucose lowering effects.
- Patients are selected with relatively high HbA1clevels to enhance apparent “efficacy.”
- Studies seek “bragging” rights- “my drug lowersblood sugar more than your drug.”
- Patients at high CV risk are deliberately avoided.Why take a chance of an adverse safety signal?

## Consequences of a “Glucocentric” Regulatory Approach to Diabetes Drugs

- When safety signals arise, physicians stampede to the newest diabetes therapies (for which we know the least about safety).
- Example: After the rosiglitazone concernsemerged, the fastest growing diabetes class isa new class, a DPP-IV inhibitor (sitagliptin).
- However, this agent has limited glucose lowering efficacy (about half the effect of establishedtherapies) and virtually no long-term safety data.

## The Principal Dilemma

- How do we balance the need to bring new diabetes agents to patients in a timely fashion.
- vs.
- The need for more robust outcome datathat inform physicians of howto use these drugs safely and effectively

## Proposal: A Rational Approach to Approval of New Diabetes Drugs

- A Compromise with Two Components

- A pre-approval set of clinical trials designedto *rule out *a high level of CV risk.
- A large randomized outcomes trial that must be underway at the time of approval.

## Pre-Approval Development Program

- Pre-approval trials of sufficient size andduration to rule out a HR of 2.0 for MACE(upper 95% confidence interval).
- Required: Pre-specified pooling of CVoutcomes in all trials with adjudication by anindependent clinical endpoints committee.
- Useful: At least one study in patients at highCV risk, perhaps 1000 patients for 1-2 years.

## Pre-Approval Cardiovascular Studies

| Number of events | Upper 95% CI
excluded | Point estimate
of hazard ratio | Patient-years (2% annual event rate)
death, MI, stroke | Patient-years (3% annual event rate)
MACE |
| --- | --- | --- | --- | --- |
| 50 | 2.5 | 1.44 | 2500 | 1667 |
| 87 | 2.0 | 1.31 | 4350 | 2900 |
| 122 | 1.8 | 1.26 | 6100 | 4067 |
| 256 | 1.5 | 1.17 | 12800 | 8533 |

- MACE = major adverse CV events including death, MI, stroke, and hospitalization for revascularization

## 87 Events to Exclude Upper 95% CI of 2.0

| Active | Control |
| --- | --- |
| 43 | 44 |
| 48 | 39 |
| 35 | 52 |
| 53 | 34 |

- 1.23

- 0.67

- 1.56

- 0.4

- 0.5

- 2.0

- 1.5

- 1.0

- Control better

- Active better

- 2.5

- 0.67

- 0.98

## Implications of This Regulatory Approach

- Positives:
- Encourages sponsors to include patientswith higher levels of cardiovascular risk.
- Provides more reliable pre-approval databy adjudication of CV events for pooled trials
- Negatives:
- Modestly slows development programs,thereby delaying introduction of newdiabetes medications by 6-12 months

## Step II in Approval: An AdequatelyPowered Cardiovascular Outcomes Trial

- Assuming no evidence for excess CV risk (upper95% CI of HR <2.0), a new diabetes drug would beapprovable based on glucose-lowering efficacy...
- If an adequately-powered ongoing CV outcomes trialis underway (already enrolling patients).
- This outcomes study should also address any otherongoing safety issues (renal, fractures, skin)
- This policy is a compromise designed to balancespeedy approval with the need to promptly obtainevidence of benefit (or risk).

## Ongoing CV Study at Time of Approval

| MACE rate control group | 12% reduction | 15% reduction | 18% reduction |
| --- | --- | --- | --- |
|  | Approximate sample size per treatment group |  |  |
| 11% | NA | 6000 | 4000 |
| 13% | 7500 | 5000 | 3500 |
| 15% | 7000 | 4500 | 3000 |
| 17% | 6000 | 4000 | <3000 |

- MACE Endpoint: Death, MI, stroke or ACS hospitalizationalpha=0.05 (two tailed) and 80% power

## Promises Not Kept: Phase IV Commitments

|  | 1990-1994† | 1995-1999† | Total pending(9/30/2005)* |
| --- | --- | --- | --- |
| Number of new drugswith a Phase IVcommitment | 88 | 107 | 1231 |
| Number of Phase IVcommitments completed | 11 | 0 | 172 |
| Percentage Completed | 13% | 0% | 14% |

- † Public Citizen data

- * FDA report to Congress

## Quality of Cardiovascular Outcomes Trial: A Critical Issue

| Characteristic | ACCORD | ADVANCE |
| --- | --- | --- |
| History of macrovascular disease | 35% | 32% |
| Statins | 88% | 47% |
| Aspirin | 76% | 56% |
| ACE Inhibitor | 71% | Not reported |

## Those who cannot remember the past are condemned to repeat it.

*George Santayana, a Spanish-born American author in 1905*

## Dual PPARs: A Promising Approach

- Both hyperlipidemia and insulin resistance appear to promote atherosclerosis in diabetics.
- Accordingly, pharmaceutical companies have sought to develop dual  and  PPAR agonists combining:
- Fibrate-like effects, raising HDL and lowering triglycerides
- TZD-like effects, improving insulin sensitivity thereby lowering blood sugar.

## Muraglitazar Advisory Panel(Sept 8, 2005)

- The first dual PPAR to reachthis stage of the approval process

## Muraglitazar Development Program

| CV 168006
104 weeks
monotherapy |  | CV 168018
24 weeks
monotherapy |  | CV 168021
24 weeks
+glyburide |  | CV 168021
78 weeks
+metformin |  | CV 168025
26 weeks
+metformin |  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| mura0.5 mg | 236 | mura
2.5 mg | 111 | mura
2.5 mg | 191 | mura
2.5 mg | 233 | mura
5 mg | 587 |
| mura1.5 mg | 236 | mura
5 mg | 114 | mura
5 mg | 193 | mura
5 mg | 205 | Pio
30 mg | 572 |
| mura5 mg | 236 | Pbo | 115 | Pbo | 199 | Pbo | 214 |  |  |
| mura10 mg | 236 |  |  |  |  |  |  |  |  |
| mura20 mg | 236 |  |  |  |  |  |  |  |  |
| Pio15 mg | 236 |  |  |  |  |  |  |  |  |

| Totals |  |
| --- | --- |
| Muraglitazar <5 mg | 2374 |
| pio or placebo | 1351 |

## HbA1c: Change from Baseline (%)

- Placebo

- Mura 2.5mg

- Mura 5mg

- -0.32

- Open 5mg

- Mean baseline

- 8.0

- 8.0

- 7.9

- 10.7

- -1.05

- -1.23

- -2.62

**Notes:**
There were also differences in blood pressure favoring pioglitazone treatment.  Systolic blood pressure increased 2.3 mm/Hg in the glimepiride group (shown in blue) and was unchanged in the pioglitazone group (shown in orange), p=0.03.  Diastolic pressure rose .9 mm in the glimepiride group and fell .9 mm in the pioglitazone group, P=0.003.

## Lipid Parameters: Change from Baseline (%)

- Triglycerides

- HDL-cholesterol

- LDL-cholesterol

- -2

- -18

- -27

- 10

- 2

- 16

**Notes:**
There were also differences in blood pressure favoring pioglitazone treatment.  Systolic blood pressure increased 2.3 mm/Hg in the glimepiride group (shown in blue) and was unchanged in the pioglitazone group (shown in orange), p=0.03.  Diastolic pressure rose .9 mm in the glimepiride group and fell .9 mm in the pioglitazone group, P=0.003.

## The Panel Meeting September 5, 2005

- Although there appears to be an higher incidenceof major adverse cardiovascular events, the sponsor argues there there is:
- “Lack of biologic plausibility for CV risk with muraglitazar based on”:
-  Beneficial effects on markers of CV risk
-  Broad diversity among reported CV events
-  No increase in CV events with increasing dose
- Absence of off-target CV toxicity in non-clinicalor clinical studies

## The panel votes 8:1 to approve muraglitazar as monotherapy and 7:2 to approve use with metformin.

- They vote 7:2 *against* approval in combination with sulfonylureas, requesting more data.

## Six Weeks after the Advisory Panel

## Individual Components of Composite

## Commonly Used CV Composite Endpoints

## Muraglitazar: Epilogue

- The FDA issues an “approvable” letter requesting additional CV safety data.
- After ongoing extension trials confirm the CV hazard, all development of the drug halted.
- However, a risky agent came close to approval.
- A clear standard requiring an upper CI <2.0for the HR for CV events would have precluded the necessity for an advisory panel.

## The slippery slope of surrogate endpoints in diabetes drug development

- Ezetimibe was approved to treathyperlipidemia on the basis of a reductionin LDL-C averaging 16-18%
- What should we do with a diabetes drugthat lowers blood sugar (HbA1c by 1.1%),but increases LDL-C by 16-18%?

- If a 16-18% reduction in LDL-C is sufficient to demonstrate benefit, what inference should we draw when a drug increases LDL-C by a comparable amount?

## Rosiglitazone

## Rosiglitazone Approval Package (1999)

| Percent Change from baseline in LDL-C* |  |  |  |
| --- | --- | --- | --- |
| Baseline LDL | Study 011 | Study 024 | Study 020 |
| Overall | 24% | 20% | 13% |
| LDL<130 | 32% | 24% | 23% |
| LDL 130-160 | 14% | 11% | 11% |
| LDL>160 | 7% | 5% | 1% |

- *Statistical Review
- Joy D. Mele M.S.
- Mathematical Startistician

- “Weight/lipids – Patients treated with RSG manifest undesirablechanges in weight and lipids...”†

- † Medical Review
- Robert I Misbin MD.

## Rosiglitazone Advisory Panel: CV Events

| Ischemic Heart Disease Events |  |  |  |
| --- | --- | --- | --- |
| RSG
n=2902 | Placebo
n=601 | Metforminn=225 | SU
n=626 |
| 36 (1.2%) | 3 (0.5%) | 3 (1.3%) | 4 (0.6%) |

| Rosiglitazone | Comparators | Relative Risk |
| --- | --- | --- |
| 36/2902 (1.24%) | 10/1452 (0.69%) | 1.8 (0.9-3.6) |

- FDA Reviewer: “A post-marketing study to evaluate long-term safety of RSG should be required for approval.”

## What Happened to Mandated SafetyStudy of Rosiglitazone? The Adopt Trial

- Not a safety study, a “marketing” study, designedto show greater durability of glucose loweringwith rosiglitazone.
- Cardiovascular events collected in a haphazardfashion (not adjudicated!)
- Because of the LDL-raising effect of rosiglitazone,more patients received statins (p<0.01).
- HR 1.33 for myocardial infacrtion (0.80-2.21).The pre-approval signal never goes away!

## Rosiglitazone Post-marketing Studies

- Many small, short term “marketing” studies to show glycemia reduction in various populations.
- No well-designed randomized  trials to measurehealth outcomes (RECORD underpowered).
- By 2007, 42 trials were completed with 14,237patients.
- FDA analysis in July 2007: Odds ratio formyocardial ischemia 1.4 (95% CI 1.1-1.8)
- The pre-approval signal never goes away!

## Rosiglitazone in Retrospect

- If an upper CI <2.0 for the HR for CV events had been required for approval in 1999, rosigltazone would not have been approved without more safety data.
- If a large, well-powered outcomes trial had been mandated in 199, we would not have to wait until 2014 (15 years after approval) to determine if this drug is safe or not.

## PPARs: a Special Case

- At least 50 IND’s filed following last approvalof a TZD, nearly all terminated due to toxicity.
- Toxicities observed in animals are also evident clinically - cardiac, skeletal muscle, renal, bone marrow. (El Hage)
- Most development programs terminated withoutany publication of the toxicities encountered.
- PPARs all activate different genes and must beconsidered individually- this is NOT a “drugclass”

## Gene Expression with PPAR Agents

- Bioinformatics. 2004 Nov 22;20(17):3108-27. Epub 2004 Jun 24.

- Gene Expression with PPAR Agents

## Diabetes, Glycemia and CV Disease

- The goal of merely lowering blood glucose levelsin diabetes is too simplistic. We must reduce the complications of diabetes, including CV disease.
- With respect to CV disease it appears important*how *you lower blood sugar as well as *how much*.
- Diabetes drugs, even within the same “class” may yield dramatically different CV outcomes.
- Clinical outcomes trials comparing alternative diabetes therapies are essential to determine the optimal approach to prevent CV morbidity-mortality.

## Two Components: A new paradigm for Diabetes Drug development

- Sufficient pre-approval data to exclude a excess hazard of CV events (an upper CI for the hazard ratio not to exceed 2.0.
- A robust post-approval outcome programto provide data in a timely fashion (anongoing outcomes trial at the time of approval)

## Slide 45