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Diabetes Care 30:3141-3144, 2007
DOI: 10.2337/dc07-1908
© 2007 by the American Diabetes Association
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Reviews/Commentaries/ADA Statements
Commentary

Lessons From the Avandia Controversy

A new paradigm for the development of drugs to treat type 2 diabetes

Robert I. Misbin, MD

From the Division of Endocrinology and Metabolism, Food and Drug Administration, Silver Spring, Maryland

Address correspondence and reprint requests to Robert I. Misbin, MD, 711 Schindler Dr., Silver Spring, MD 20903. E-mail: robert.misbin{at}fda.hhs.gov

Abbreviations: ADOPT, A Diabetes Outcome Progression Trial • DCCT, Diabetes Control and Complications Trial • FDA, Food and Drug Administration • TZD, thiazolidinedione

Sulfonylureas used to be the only oral agents available in the U.S. to treat patients with type 2 diabetes. The biguanide phenformin had been used widely in the 1950s and 1960s but was removed from the market in 1977 because of lactic acidosis (1). Other biguanides, including metformin, were felt to be safer and had been used extensively elsewhere in the world. But a biguanide did not become available in the U.S. until 1995 (2).

The year 1995 marked a sea change in availablilty of drugs to treat type 2 diabetes. The approval of metformin, a biguanide, was followed by the approval of acarbose, a galactosidase inhibitor that, like metformin, had been widely used in Europe. A new drug application for acarbose had been rejected by the Food and Drug Administration (FDA) 3 years earlier, but in 1995 the regulatory environment had become friendlier, owing in large part to the finding of the Diabetes Control and Complications Trial (DCCT) that aggressive treatment of hyperglycemia prevented or delayed complications of diabetes (3). Approval of the thiazolidinedione (TZD) troglitazone and the non-sulfonylurea insulin secretagog repaglinide followed soon after, along with additional members of the newly approved classes.

In 2005, the uninterrupted succession of new drug approvals came to an end. Muraglitazar was a dual peroxisome proliferator–activated receptor agonist. It was different chemically from the TZDs and fibrates but was believed to combine the desirable pharmacological effects of both. Muraglitazar was highly effective in lowering A1C and had favorable effects on serum lipids. But contrary to what one might expect, muraglitazar appeared to increase the risk of adverse events related to cardiac ischemia (4). This might have been considered an isolated event were it not for the recent brouhaha that rosiglitazone (Avandia) also increased the risk of cardiac ischemia.

The Avandia affair began with a meta-analysis showing that rosiglitazone increased the risk of myocardial infarction. Its release by the New England Journal of Medicine online on 21 May 2007 with an accompanying editorial (5,6) generated a journalistic blitzkrieg against rosiglitazone and the FDA (7). A congressional committee hearing took place even before the article appeared in print. But an FDA advisory committee concluded by a vote of 22 to 1 on 30 July 2007 that the evidence against rosiglitazone was insufficient to recommend that it be withdrawn from the market.

The Avandia affair undermined the confidence that patients have in the drugs they take and in the physicians who prescribe those drugs. It cast further doubt on the FDA's ability to protect patients from harm. One hopes that the deliberations of the advisory committee will put the issues into perspective. But the FDA should not ignore the perceived shortcomings in the regulatory process that allowed the Avandia affair to get out of hand.

Even before the Avandia affair, Dr. David Nathan had expressed skepticism about the recent approval of sitagliptin, apparently unimpressed by the extensive body of data that was available on the FDA Web site (8). What the FDA should take away from Dr. Nathan's criticism and from the Avandia affair is that the time has come to reassess what should be expected of a new drug to treat diabetes. That a new drug is more effective than placebo in lowering glucose levels is no longer enough. New drugs should be tested in comparison with other antidiabetes agents that are already in use (9). A plan should be in place at the time of approval that will determine what benefit and harm can be expected from chronic use (10). In the following sections, I highlight problems with the approval process that are illustrated by Avandia and suggest a new paradigm for the development of drugs to treat type 2 diabetes.

Lessons from the Avandia controversy

Reducing A1C may not be enough.
The DCCT and UKPDS (UK Prospective Diabetes Study) showed that intensive treatment to lower A1C reduced the risk of nephropathy, retinopathy, and neuropathy in patients with type 1 (3) and type 2 diabetes (11,12). Clinical benefit has also been reported for acarbose (13,14). Based on the DCCT, the FDA accepted A1C as a surrogate marker for approval of new drugs to treat diabetes. The standards of approval were discussed at an FDA advisory committee meeting in March 1998. Although a guidance to the industry for the development of drugs to treat diabetes was never issued by the FDA, the main points of the draft guidance discussed by the advisory committee were largely incorporated into the standards used by the European Agency for the Evaluation of Medicinal Products (EMEA), which have been posted on the EMEA Web site since 2002.

In contrast to older agents, use of TZDs has not been shown to decrease the risk of the complications of diabetes. Clinical benefit was presumed to follow as a consequence of reduction in A1C. In the absence of direct evidence of benefit, the report alleging increased risk of myocardial ischemia with rosiglitazone was particularly unsettling.

Outcome trials need to be considered.
The anomaly that muraglitazar and rosiglitazone decreased glucose levels but appeared to increase the risk of cardiac ischemia has led Psaty and Furburg (6) to call for large, long-term randomized clinical trials to be completed as soon as possible after approval of a new antidiabetes agent to identify the health benefits and risk of the new treatment. These authors have previously cautioned against the uncritical acceptance of surrogate end points (15) and have recently pointed out that the American Diabetes Association acknowledges that lowering A1C to prevent macrovascular disease is based on epidemiological studies rather than controlled clinical trials (16).

Although I recognize the desirability of long-term outcome trials, I have little doubt that hyperglycemia per se is harmful. Requiring that an outcomes trial be completed before approval would delay the approval of new drugs. In my judgment, approval of drugs to treat type 2 diabetes should continue to be based on change in A1C, but a dedicated safety trial should be completed before approval. Additional safety data should accrue from extension of pivotal trials for 2 years beyond the date of approval.

It may be appropriate for the FDA to require a commitment to begin an outcomes trial as a condition of approval. But this requirement should be driven by safety concerns related to the drug in question. It is unreasonable to expect that a single drug manufacturer should be expected to bear the burden of answering fundamental questions such as the nature of the relationship between diabetes and heart disease. The ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial, funded by the National Institutes of Health, is attempting to address such issues.

Performance of a successful outcomes trial presupposes the knowledge of what outcomes need to be measured, what the population of interest is, how frequently those outcomes occur in the population to be tested, and what the appropriate comparators are. There are two basic approaches to this type of trial. The manufacturers of pioglitazone and rosiglitazone each employed different approaches to measuring long-term outcomes. Neither has been successful (17,18).

One approach is a placebo-controlled trial in which the new agent is added to background therapy. The problem with this design is that any benefit observed with the new drug can be attributed to better control of hyperglycemia per se rather than to a specific action of the new drug. Thus, the PROactive (PROspective pioglitAzone Clinical Trial in macroVascular Events) study largely confirmed the finding from the UK PDS that lowering blood pressure and glucose levels reduced the risk of complications of diabetes (19). An alternative approach is to compare two treatment regimens believed to have equivalent effectiveness for control of hyperglycemia. A problem here is that there is no gold standard for comparison. In the RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes) trial, rosiglitazone plus metformin was compared with a sulfonylurea plus metformin. But there is no body of evidence that sulfonylureas plus metformin reduce cardiovascular end points. Furthermore, good patient care can be expected to reduce statistical power because the adverse event of interest is less likely to occur than previously thought.

As the medical officer at the FDA who initially reviewed the Avandia application, I recommended that a postmarketing safety trial be a condition of approval. This recommendation was based on an imbalance of cardiac ischemic events, weight gain, and lipid alterations in controlled trials of 6–12 months’ duration (20). That a safety trial was not performed was noted by Congressman Waxman to be a failure of FDA management (21). On the other hand, the postmarketing trial that was performed, A Diabetes Outcome Progression Trial (ADOPT), has provided useful safety data even though its primary objective was to assess durability of efficacy. Troglitazone had been removed from the market because of an unacceptably high risk of liver failure (22). But ADOPT showed that chronic use of rosiglitazone was safe to the liver. Of particular interest is the finding from ADOPT that rosiglitazone increases the risk of fracture in postmenopausal women (23). The same was found for pioglitazone in PROactive, a long-term study designed to examine cardiac effects (24). The increased risk of fracture was unexpected and illustrates that a postmarketing safety study should cast a broad net.

Combination therapy trials should be reevaluated.
Troglitazone was initially approved to be used in combination with insulin. Indications for monotherapy and use with sulfonylureas followed. Troglitazone was never labeled to be added to metformin monotherapy. By contrast, the initial approval for rosiglitazone was for add-on to metformin monotherapy. Thus, the path chosen for the development of rosiglitazone seems largely to have been driven by a desire to fulfill a void in the market (TZD plus metformin) rather than by differences in pharmacology between troglitazone and rosiglitazone.

That sponsors seek to develop new drugs to fill a marketing niche can be partially attributed to the FDA. According to the standards currently employed, clinical trials are needed for each of the situations in which the drugs will be used: monotherapy and combinations with metformin, sulfonylureas, insulin, etc. This approach needs to be reconsidered. There are no examples of approved drugs that were effective as monotherapy or in combination with metformin but were not effective in combination with other agents. Thus, requiring efficacy trials for each situation appears to be unnecessary. By contrast, safety issues have emerged in some situations but not others. For example, congestive heart failure emerged as a problem in the trial of rosiglitazone with insulin but not in trials of rosiglitazone monotherapy. It should also be noted that it is problematic to evaluate the efficacy of a new drug in insulin-treated patients because of the need to adjust the dose of insulin based on changes in glycemia. For these reasons, combination trials with insulin should be structured to evaluate safety.

New paradigm for the development of drugs to treat type 2 diabetes

Trial design.
Approval of new drugs to treat type 2 diabetes should recognize the recommendations of the American Diabetes Association that patients with type 2 diabetes should generally be treated with metformin at the time of diagnosis (25). Implementation of this recommendation will make it difficult to conduct placebo-controlled monotherapy trials. Drug-naïve patients will become increasingly scarce and ethical considerations prevent them from remaining untreated. For these reasons, the period of placebo-only treatment should be 8–12 weeks (Table 1, trial A). The pivotal monotherapy trial should be a 6- to 12-month comparison of the new drug, drug X, to metformin (trial B). A second pivotal trial (trial C) should compare drug X to placebo in patients who are receiving metformin but whose hyperglycemia is not adequately controlled.


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  		Table 1— Paradigm for development of new drugs to treat type 2 diabetes

 
A safety trial that does not exclude patients who may be at risk of adverse events should be completed before approval. As illustrated by the trials with rosiglitazone, cardiac adverse events are more likely to be found in insulin-treated patients. Trial D in the proposed paradigm compares one or more doses of drug X (including the maximal dose to be marketed) with placebo in patients who are receiving insulin with or without oral agents. The insulin dose should be adjusted to account for the activity of drug X such that there be little difference between the arms with respect to change in glucose levels. Under these circumstances, safety issues that emerge can be attributed to drug X and not to differences in glycemic control. The primary end point should be reports of serious adverse events. A secondary end point, change in insulin dose, should assess efficacy. Subset analyses should be based on background oral antidiabetes treatment. In some circumstances, enrichment with patients using TZDs or other oral agents may be appropriate.

A safety trial has not previously been required before approval of oral antidiabetes agents currently marketed in the U.S. However, concerns about vascular events in postpartum women taking bromocriptine led the FDA to require that a safety trial be completed before approval of Cycloset. Details of this trial have been published (26).

Trials A–D should provide the data on efficacy and safety to form the basis for a new drug application. Extensions of these trials should continue during the time it takes the FDA to review the application (10 months for a standard review and 6 months for a priority review). As already required, a safety update on ongoing trials should be submitted to the FDA before regulatory action. Extensions of these trials for an additional 2 years should be required for approval.

The extension trials will provide long-term comparisons of drug X to metformin (trials A and B), metformin plus drug X versus metformin plus standard therapy (trial C), and insulin plus drug X versus insulin plus standard therapy (trial D). New trials may be required to begin after approval to examine safety issues that emerged during the FDA review.

Approval.
Drug X should be approved if its efficacy is superior to that of placebo (trials A and C), noninferior to metformin (trial B), noninferior to standard therapy with respect to serious adverse events (trial D), and does not have other serious safety problems. It might still be appropriate to approve drug X even if it is less effective than metformin, particularly if it represents a novel mechanism of action and raises no safety concerns.

The FDA does not have the authority to require that a new drug be superior to existing drugs. On the other hand, the FDA is not required to have proof that a new drug is unsafe to deny approval and should set a high standard for drugs that offer no advantage over existing therapy. Even for a novel agent, a few cases of a rare but life-threatening event, such as agranulocytosis, may be sufficient to prevent approval.

Labeling.
New drugs should be labeled for treatment of hyperglycemia in patients with type 2 diabetes, but no claim for reducing the risk of complications should be allowed unless directly supported by data. There should be no distinction between first- and second-line therapy or between monotherapy and combination therapy. Data from pivotal trials should be shown in the label to provide insight into what clinical effects can be expected under what conditions. Gaps, uncertainties, or inconsistencies should be acknowledged, such as lack of information in certain populations. In some circumstances, sponsors should be required to perform postmarketing trials to address remaining issues. Failure to complete these trials should be posted on the FDA Web site. From the clinical review and action letter posted by the FDA on its Web site, professional organizations can develop recommendations about how a new drug should be used in relation to other approved agents.

Looking ahead

Table 1 is a summary of a suggested paradigm for clinical trials to develop new drugs for type 2 diabetes. With better knowledge and experience, this paradigm may need to change. But the goal should remain the same. New drugs should continue to be developed to reduce the global burden of diabetes and its complications. Regulators should set high standards but should also be pragmatic. Fear of uncertainty should not be allowed to stifle innovation.

Footnotes

The opinions expressed in this article represent those of the author and do not necessarily reflect the official position of the Food and Drug Administration.

A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received for publication October 1, 2007. Accepted for publication October 1, 2007.

References

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