FDA guidelines to quantify CHD risk in diabetes products: a good idea?

The recommendation is part of new industry guidance that applies to all diabetes drugs under development.

In December 2008, the FDA recommended that manufacturers developing new drugs and biologics for type 2 diabetes provide evidence that the therapy will not increase the risk for cardiovascular events such as myocardial infarction.

Although many have applauded the FDA on the decision, the guidelines have ignited some controversy among others. Ripu Hundal, MD, associate director of the Diabetes & Metabolic Diseases Center at Christiana Care, Newark, Del., said that, “the question becomes whether this a step in the right direction or whether it will instead hamper or delay the arrival of novel drugs into the market.”

As part of the process of evaluating the cardiovascular safety of diabetes drugs, the FDA has recommended approaches to the pooling of data from different studies as well as the use of adjudication committees made up of outside cardiologists. The committees will try to ensure consistency and impartiality in determining which events from the studies are included in analyses comparing the drug to comparators, either placebo or active. The agency is expected to evaluate how the recommendations intended to inform comprehensive labeling on product safety will be applied to already approved antidiabetic drugs and to release further guidance in the future.

Ripu Hundal, MD, said the guidelines may increase patient safety but could also slow down new drug development. Photo by: Sam Trasatti

Endocrine Today spoke with many of the leading researchers in the field about the new regulatory stance. Some endocrinologists, like Harmeet Narula, MD, assistant professor of clinical medicine at Stony Brook University Medical Center, said they have conflicting opinions about the FDA recommendation.

“On the one hand, I am, as most endocrinologists are, excited that this protects my patients from being exposed to potentially harmful drugs. I am also somewhat concerned that this may slow down new drug development,” Narula said.

“Many pharmaceutical companies may not spend the billions of dollars in research and development to develop new and exciting diabetes therapies, as the cost of these long-term CV safety trials may make this unprofitable.”

Darren K. McGuire, MD, MHSc, FAHA, FACC, associate professor at the University of Texas Southwestern Medical Center at Dallas, said this shift in regulatory policy is not just a good move but also a necessary one. McGuire said he is reminded of how cardiovascular drugs were put under similar requirements by the FDA a few decades ago and drug development not only remained but continues to be active.

“While many argue that we can’t afford to take this approach, I would propose that we can’t afford not to,” McGuire said.

FDA guidelines

Zachary T. Bloomgarden, MD, clinical professor in the department of medicine at Mount Sinai School of Medicine, outlined the key points in the FDA recommendation.

The document begins by acknowledging that “reliance on HbA1c remains an acceptable primary efficacy endpoint for approval of drugs seeking an indication to treat hyperglycemia secondary to diabetes,” said Bloomgarden, a member of the Endocrine Today Editorial Board.

“In the wake of questions regarding CV safety of diabetes treatment, some authors suggested that simply demonstrating that an agent improves glycemia was not adequate, asking rather that there be proof of health benefits for every new agent,” he said.

The document does, however, require that sponsors demonstrate that new antidiabetic therapy will not result in an unacceptable increase in CV risk. For each new treatment, an independent CV endpoints committee is required to prospectively adjudicate, in a blinded fashion, CV events during all phase-2 and -3 trials.

Precise statistical criteria are given in the document, requiring that the meta-analysis shows that the upper bound of the two-sided 95% CI for the estimated risk ratio (test:control) be <1.8 to allow approval.

Bloomgarden said it is instructive to consider the number of patients and the characteristics that would be required for these proposed trials. People participating in clinical trials are, in general, somewhat healthier than the overall population with the given condition, with annual CV event rates of asymptomatic diabetic patients probably well below 1%, he said.

Changes to trials

Researchers in the VA Diabetes Trial screened more than 20,000 patients to obtain just under 1,800 high-risk patients with the mean age of 60 years and diabetes duration of 11.5 years. These patients had an overall rate of MI, stroke, inoperable CVD, CV death, and coronary, peripheral artery and cerebrovascular intervention of 5.6% per year.

“Calculation of the sample size [of VADT-type patients] required to distinguish a 25% greater event rate over a two-year period reveals that, for a 0.05% type 1 error with a statistical power of 80%, roughly 2,200 persons would be required in each group — approximately 2.5 times as many persons as the VA trial, although observed for a shorter period of time,” Bloomgarden said.

Bloomgarden said that to fulfill the newly proposed requirement studies of such patients, the trial population would need to be considerably larger. To distinguish a 2.5% vs. 2% annual event rate, a two-year study would require nearly 7,000 patients in each group.

“One can speculate that such studies, although of great intrinsic interest, would be far more expensive to carry out than has been the case up until now for registration trials of drug approval, with the potential undesirable consequence of reducing interest on the part of the pharmaceutical industry in developing new therapies for the treatment of diabetes,” Bloomgarden concluded.

Many pointed out that the FDA requirements are unique to diabetes and so constitute an undue burden upon drug development for diabetes, but not other diseases.

Endocrine Today’s Chief Medical Editor, Alan J. Garber, MD, PhD, specifically pointed to the pre-approval requirement for the demonstration of confidence intervals for the hazard ratio of CHD events to be less than 1.8, otherwise a pre-approval CHD trial is mandated.

“If the ratio is between 1.3 and 1.8 then a post-approval trial will be required. However, in order to get enough patients to generate such a ratio, there has to be a fundamental redesign of the phase-3 trials to include many more sick patients with high risks for CHD as well as diabetes,” Garber said.

“This reorders the way diabetes drugs will be developed and may greatly increase costs,” Garber noted.

Necessary regulation

McGuire noted the concept of outcomes assessment for clinically relevant endpoints is a relatively new concept to the field of diabetes research — with historical precedence for both micro- and macrovascular assessments heavily reliant on surrogate markers of effects. But those in cardiology, according to

McGuire, have endorsed the morbid/mortal data approach since the early 70s, driven primarily by FDA regulatory requirements of the Cardiovascular and Renal Drugs Panel.

“Despite that regulatory approach by the FDA, cardiovascular drug development did not ‘shut down’ as many in the endocrinology realm are proposing may result in the wake of the new guidance,” McGuire said. “In fact, CV drug development remained and continues to be vigorously active, and after 30 years of regulatory-required morbidity and mortality outcomes assessments, we have evidence-based therapies for virtually every domain of cardiology,” McGuire said.

“The landscape has changed and continues to change dramatically in the field of diabetes on two key fronts necessitating this shift in the regulation of such drugs focusing on increasing diligence to assess CV effects of diabetes mellitus drugs,” McGuire said.

First, until 1995, endocrinologists had very few therapies available to treat diabetes in the United States. That in itself yielded some imperative to expedite development of new therapies, McGuire said.

However, there are now more than 30 formulations representing nine classes of medication approved for use in the United States, with 12 novel classes of agents to treat hyperglycemia in advanced development, McGuire said.

“We now have some luxury to more critically appraise diabetes therapies to ensure that at the very least, new and existing drugs are not exacerbating CVD risk,” McGuire said. Secondly, he noted, the burgeoning global prevalence of type 2 diabetes and its commensurate global public health burden of CV risk amplifies the clinical necessity of establishing increased levels of certainty that the drugs used have neutral, at worst, and ideally favorable CV effects in this high-risk population of patients.

“The disease is simply too common and too morbid to continue to do otherwise,” McGuire said.

Benefit of the guidelines

Hundal said it is imperative to look into safety of any drug being introduced in the market, and he said the FDA recommendations are appropriate.

“We need to have safety design and protocols built into all phase-2 and -3 studies to see if there is any evidence of adverse effects. There should be protocols with continued observation and follow-up of these patients for at least five years or so, even after the drug has been approved for use in the market,” Hundal said.

“To be fair, we need to incorporate the importance of keeping lipids and blood pressure at target into these protocols, while trying to look into antihyperglycemic and CV safety of a particular new drug.”

Karen Earle, MD, medical director of the Center for Diabetes Services, California Pacific Medical Center, said a major benefit for endocrinologists and patients is that pharmaceutical companies will be forced to evaluate not just surrogate endpoints for diabetes, such as HbA1c lowering, but also the long-term effects of diabetes medications.

“These longer-term studies are critical for our treatment of diabetics,” she said, “especially since I am seeing diabetes in younger patients. If I were to consider treatment with a diabetes agent for up to 30 to 40 years, I need to feel confident that this medication is not harming my patient.”

However, Earle said she is concerned that the stricter rules may delay new diabetes treatments from entering the market.

“With the latest numbers showing almost 24 million Americans with diabetes and 66% of those with diabetes not meeting blood glucose goals, we are in desperate need for newer and better medications for our patients,” Earle said.

“It will not benefit all of the patients with existing disease to delay approval for new medications due to the longer study periods needed to evaluate for CV endpoints.”

Potential delays in drug development

Richard Dolinar, MD, senior fellow in Healthcare Policy, Heartland Institute, Chicago, said one of the major issues is the substantial increased expense of bringing these new diabetes drugs into the marketplace.

Richard Dolinar

“The unintended consequence will be that it will delay, dissuade, or stop the development of new diabetes drugs because of the decreased economic incentive to do so,” said Dolinar, a member of the Endocrine Today Editorial Board.

“Impossible to determine will be how many new drugs might have been developed had it not been for this decision — new drugs that might have decreased suffering, saved lives, or perhaps even saved money,” he said.

According to Dace Trence, MD, director of the Diabetes Care Center at the University of Washington Medical Center, an additional problem is the inability of the insurer or consumer to afford these newly released medications.

Dace Trence

“Endocrinologists see the entire spectrum of diabetes and have to be able to individually tailor treatment regimens to patient-specific needs. The larger the tool box, the more options and the greater ability to achieve targeted treatment goals in patients.

“A ‘one-shoe-fits-all’ approach just does not work in diabetes treatment. The possibility that research and development will slow to a trickle is very real,” Trence said.

Micro- vs. macrovascular complications

There is ample evidence that poor control of diabetes increases the risk of microvascular and macrovascular complications, Hundal said.

“Cardiovascular disease accounts for 50% to 80% of diabetic fatalities each year, with 70,000 deaths in United States per year attributable to diabetes,” Hundal said. “With better control of hyperglycemia, one can halt the progression or new development of microvascular complications (37% decreased risk for each 1% drop in HbA1c). On the contrary, such type of evidence is still lacking as far as macrovascular disease is concerned.”

The guidelines have left many endocrinologists wondering if this will signal a shift in focus from microvascular to macrovascular disease. “I do not feel there needs to be a shift in the way we approach our patients,” said Narula.

Harmeet Narula

“Diabetes therapy is all about risk reduction — reducing the risk of both micro- and macrovascular disease, using proven strategies like good blood pressure and lipid control, smoking cessation and increased physical activity.

“We need to balance the risks and benefits of tight glucose control in each patient, but our approach to all patients remains the same: individualized therapy based on a patient’s risks for micro- and macrovascular disease.”

Garber said in the January 10 issue of Endocrine Today that five major trials have failed to conclude that there is a link between glucose and CHD risk in patients with type 2 diabetes.

“In every one of these trials, event rates have clearly been much lower than historical or expected or both,” Garber said. “Widespread implementation of effective CHD risk reduction strategies has eliminated the bulk of the CHD excess in populations of patients with type 2 diabetes. We have therefore succeeded in our primary goal, namely to reduce CHD in patients with type 2 diabetes.”

Garber suggested that perhaps endocrinologists should move on to secondary goals, such as microvascular risk reduction. “This has always been an issue in diabetes management but only recently has been understood to be the proper focus of diabetes management,” Garber said.

Cardiovascular risk

Other than the antidiabetic therapies, what could be causing the cardiovascular risk?

“I do not think this excess CV risk is related to diabetes therapies,” Narula said. “I strongly feel the increased risk of CV disease in diabetics is due to the underlying disease — a combination of hyperglycemia-mediated increased vascular risk, amplified by concomitant high blood pressure, smoking, physical inactivity and abdominal obesity — risk factors commonly seen in conjunction with hyperglycemia amongst diabetics and especially type 2 diabetics.”

Earle said the difficulty in obtaining data about diabetes has made it difficult to pinpoint what could be causing the CV risk.

“Early trials of diabetes, such as DCCT, were only able to show a link between tight blood glucose control with decreased microvascular endpoints,” Earle said. “Only decades after the trial was completed were CV endpoints obtained.

“I believe most of the increased CV risks seen in our diabetes patients are due to insulin resistance and altered metabolism, and many diabetes treatments do not target these areas,” Earle said.

Hypoglycemia is an important limiting factor in achieving perfect glycemic control, Hundal said. “There are always more documented hypoglycemic episodes in the intensive arm of the major trials vs. the standard arm.”

Recent evidence has shown that hypoglycemia may promote the proarrhythmic picture and that older patients who are at a higher risk for CVD may be at an even higher risk with each hypoglycemic episode, according to Hundal.

“So we need to have a better way of recording these events during the trials, as it will help us to better understand the role of hypoglycemia on CV events,” Hundal said.

FDA’s Decision on Evaluating CV Risk in Drugs for Type 2 Diabetes

Positives Negatives Increased patient safety; decreased risk of patients being exposed to potentially harmful drugs. Will likely impede drug development. Tightens the regulations, considering the responses the FDA received after the loose regulations of the last several years. Pharmaceutical companies will limit the number of therapies they might consider developing for diabetes therapy due to the long time and significant costs large trials take. Refocusing vascular disease as an important goal of therapy in patients with diabetes. Often confuses the public when they hear a statistical aberration, as being of meaningful clinical risk. Source: Harmeet Narula, MD

Looking to the future

The FDA has indicated that it is confident that currently marketed antidiabetic therapies are safe and effective when used according to approved labeling. The agency said it is continuing to evaluate how the recommendations will be applied to already approved antidiabetic drugs and expects to release further guidance in the future.

“Overall, this decision from the FDA won’t have any bearing on our present way of treating diabetes,” said Hundal. “Implementing these tough standards will assure patient safety and the physician’s willingness to use medications aggressively earlier on in the disease process. We should be aggressive in managing blood sugars but at the same time not be oblivious of risk for hypoglycemia, target blood pressure and lipids, as well as implementing strategies to encourage patients to exercise and lose weight.”

Narula believes there is urgency for action on a population level as the epidemic of obesity increases worldwide. “With the huge budget deficits facing nations in the developed and the developing world, it is high time that the policy makers focus on this pandemic before it’s too late,” Narula said. – by Angelo Milone

Does the FDA’s recommendation regarding CV risk potential in type 2 diabetes drugs seem reasonable?

For more information:

• Psaty BM. N Engl J Med. 2007;356:2522-2524.
• ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-2572.
• Duckworth W. N Engl J Med. 2008;DOI:10.1056/NEJMoa0808431.