Tales of Avandia:

Evidence, Regulation, and Clinical Practice

Harry M Marks Institute of the History of Medicine Johns Hopkins University

Center for Clinical Trials, JHSPH September 1, 2010

Avandia Issues

• How well is the FDA balancing drug safety and efficacy?

• What kinds of studies count as evidence of risk and benefit?

• Did Glaxo SmithKline suppress evidence of avandia’s harm?

Pre-Avandia Issues

• What is the disease for which a drug is used?

• How is therapeutic benefit measured?

• How does the FDA adjudicate evidence of drug hazards?

• What is the FDA’s role in regulating clinical practice?

ROAD MAP

I. Disease Concepts: Diabetes

II. Surrogate Endpoints at the FDA

III.Drug labels and drug regulation

IV.Avandia

The Spectrum of Diabetes, c 1967

Camerini-Davalos Excerpta Medica (1967)

“What may be regarded as prediabetic today will

later be shown to be a clear manifestation that

the disease is present.”

-JW Conn, The Banting Memorial Lecture 1958

Diabetes 7 (1958), 355

The Spectrum of Diabetes, c 1967

Camerini-Davalos Excerpta Medica (1967)

Orinase Ad:

Annual

Increases

in Rx

Oral Hypoglycemic Agents

• Biguanides (metformin)

• Sulfonylureas– Orinase (tolbutamide)– Second generation sulfonylureas

• Thiazolidinediones (including Avandia)

FDA’s Rules for Surrogate Endpoints

• Sponsor must demonstrate that the surrogate endpoint is plausibly linked to clinical outcomes

– Biologically plausible– Predictor of disease progression and regression

• FDA may require studies to demonstrate clinical benefit/validity of surrogate endpoint

Federal Register 57 (1992): 58942-58958

1962 Drug Amendments

"No person shall introduce into interstate

commerce any drug, unless they have

demonstrated whether or not the drug is

safe and effective for use under the

conditions prescribed, recommended or

suggested in the proposed labeling thereof."

FDA: Action options

• Remove drug from market (may be FDA- or company-initiated)

• Restrict use (e.g. l-dopa)

• Modify drug labeling to include warnings

“He said, she said”

Limitations of Nissen meta-analysis

• Studies not intended to monitor CV effects of avandia

• No patient-level data

• Heterogeneity of study designs (all RCTs)

• No central adjudication of CV events in most studies

Limitations of RECORD study

• Open-label design (ascertainment bias?)

• Non-inferiority design

• Different practices among sites in referral to hospital for clinical endpoints

“These sponsored [web] links make

representations and/or suggestions about

the efficacy of avandia … but fail to

communicate any risk information. This

omission of risk information is particularly

concerning as… Avandia [has a] boxed

warning.”

-Michael Sauers [FDA] to GSK, March 26, 2009

GSK’s Proposed Labeling 7/09

Avandia Vote, July 14, 2010

• 3 No changes

• 7 Add new warnings to label

• 10 Revise label and restrict use

• 12 Withdraw from market

“He said, she said”

Questions and

Answers