FDA reviews diabetes drug approval process

The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee held its long-awaited meetings this week to decide whether to advise the FDA to raise the standards for approving diabetes drugs. With questions being raised about the benefits versus risks for other long-term drugs, such as treatments for cholesterol, mental illness and anemia, all facing similar scrutiny, the FDA’s final decision could change the entire framework for the approval of other drugs. The questions that weren’t asked or addressed in these Advisory Committee meetings, though, are as important to note as those that were.

Specifically, they looked at the question of if pharmaceutical companies should have to provide greater safety data showing the drugs don’t raise risks for cardiovascular disease, the leading cause of death. Another question considered was if such cardiovascular assessments should be completed before the drugs are approved or during the post-approval period; whether to impose specific design standards to address these questions, including the use of hardcore clinical outcomes rather than surrogate endpoints; and if longer-term post-approval trials need to be required for all new diabetic drugs, or just those where problems are suspected. A final question deliberated was if drug trials should show a benefit for cardiovascular disease outcomes for approval.

This controversy, as readers know, was raised after several major trials — ACCORD, ADVANCE and VADT — found that improved glycemic control and even aggressively lowering blood glucose levels did not lower cardiovascular events, and was actually capable of increasing mortality among diabetics. [See Google search tool on sidebar for background articles.] “If we take drugs forward that lower blood sugar but increase the risk of death and heart attack, we haven't done diabetics any favors,” said Dr. Steve Nissen, medical director of Cleveland Clinic’s Cardiovascular Coordinating Center.

As the background information for this week’s meetings from the FDA Center for Drug Evaluation and Research noted, all drugs that are approved by the FDA for the treatment of diabetes are approved based on their ability to improve glycemic control, using the surrogate measure of hemogloblin A1c. No diabetes drug currently on the market has shown evidence of reducing risk for macrovascular complications among type 2 diabetes, said the FDA. Yet, “the risk of dying from cardiovascular disease is 2-4 times higher among people with type 2 diabetes than among people without diabetes,” it said, despite the fact clinical practice guidelines for diabetes include targeting cardiovascular risk factors, such as cholesterol, smoking and blood pressure (keeping BP <130/80).

Nor has any diabetes drug shown beneficial cardiac effects in Type 2 diabetics, even though 75% of all deaths among diabetics are attributed to heart disease, said Dr. Nissen. He has argued that using surrogate endpoints and approving diabetes drugs merely because they lower blood glucose levels is too simplistic. “We must reduce the complications of diabetes, including cardiovascular effects.” There are currently ten classes of drugs that lower blood sugar and it is time for higher standards of evidence for drugs in the care of diabetics, he said. “We are not going to cause people to go blind and require dialysis,” by better drug approval standards, he said. We know how to lower blood sugars, but “we need ways to lower blood sugar that reduce the complications of diabetes. We’re not going to hurt anybody if we raise the bar here.” [Image, from the FDA’s meeting background documents, shows the drugs currently used for blood sugar management.]

Concerns over the absence of information on hard endpoints, such as cardiovascular disease events and deaths, or long-term safety data have repeatedly been raised over recent years. “Absence of information on the macrovascular effects of diabetes therapies is the unfortunate consequence of a regulatory policy that emphasizes the importance of glucose lowering, not health outcomes, as the therapeutic goal,” Dr. Nissen said.

On Tuesday, Dr. Nissen showed that a series of drugs were approved with almost no long-term data on their use in patients with heart disease, even though it is heart patients who get the drugs for a long time. And, it’s not unusual for unexpected side effects crop up that no one had thought probable.

Once a drug is approved, though, promises by sponsors to do further post-market trials [called phase 4 trials] to evaluate long-term safety and benefit often aren’t kept. “Only 14% of phase 4 commitments actually get done. That is one of the things that went wrong with [Avandia] — they never conducted the trial that they had committed to at the time of approval,” he said. As FDA News reported, the FDA recently sent GlaxoSmithKline a warning letter for also not reporting the findings of several postmarketing studies testing Avandia.

Dr. Nissen adamantly argued for long-term trials, one for pre-approval and another begun before the drug was approved but continued long-term to evaluate long-term efficacy. The idea of a pre-approval screening trial to better assess net risks and benefit gained support at the meeting, with Dr. Robert Califf, vice chancellor for clinical research at Duke University, supportive of the proposal. As Matthew Herper with Forbes reported, “most doctors present agreed that drugs should be tested for several years in 2,000 diabetics without heart disease before being approved. After hitting the market, many medicines would need to pass through even bigger studies that follow tens of thousands of people for many years.”

These longer studies could be a model for other types of drugs because researchers are increasingly questioning the benefits of longer-term drugs, said Dr. Clifford Rosen, an endocrinologist at the Jackson Laboratory in Maine and one of the panel members. He didn’t believe the change would slow the approval of new drugs much, perhaps six months, but it would raise costs for companies. Dr. Eric Felner of Emory University School of Medicine’s Department of Pediatrics, however, disagreed, believing a cardiovascular study requirement could result in unacceptable delays for the approval of new diabetes drugs.

The Heart.org and Forbes covered the controversial debates in more detail, as no consensus was reached on many of the issues. While the advisory committee’s recommendations have not yet been issued in writing, these discussions provide a good idea of what questions weren’t part of their considered recommendations.

After a lengthy discussion on statistical issues for how many adverse events would be required in a pre-approval trial to rule out a large hazard, no consensus was reached. The panel decided, in a 14-2 vote, on language that said drugs that exceed certain statistical safety measures be required to run an additional safety trial, but for drugs without such a signal, they should conduct a long-term trial or provide other evidence to rule out an unacceptable cardiovascular risk. The precise definition for an unacceptable risk, though, is still up in the air.

The panel also stopped short of issuing a recommendation that cardiovascular risk assessments be completed prior to a drug being approved. The panel recommended that the FDA require long-term studies to examine cardiovascular risks and that those trials be started before the drug is approved and completed after approval, during the post-market period. “The most important thing they were saying is: ‘Yea, you need cardiovascular outcome data,’” said Robert Temple, director of the FDA’s office of medical policy.

There had been considerable debate as to whether the cardiovascular outcome data needed to be available pre- or post-approval, and how this could be accomplished in the most timely and least burdensome way. Also left unresolved, according to most reports, is how long to require post-market trials to run and on the patient populations.

Dr. Saul Genuth of Case Western Reserve University, a nonvoting member of the advisory committee had said trials lasting 5 years seemed a reasonable and practical duration, even though they might not identify everything. He also said he would only “want a new drug to be better than any current drug at lowering glucose,” as he believed that lowering glucose itself lowers heart disease risk even though no trial has yet to provide evidence.

But, according to Heart.org, “virtually everyone on the panel agreed that the primary endpoint should be a composite of hard endpoints, preferably cardiovascular death, heart attack and stroke.”

Note that they did not include all-cause mortality among the hard clinical endpoints, leaving unanswered questions as to if drugs might raise risks for other causes of death like cancer, or if they have a positive impact on lifespans.

Most notably, the panel did not overturn the use of surrogate endpoints or say that new diabetes drugs needed to show a benefit to patients’ cardiovascular health to be approved.

The committee was in agreement that: “We don't need to show cardiovascular benefit given that these drugs already have a benefit in lowering blood glucose levels, which is known to be associated with a reduction in microvascular complications,” said Dr. Kenneth Burman from Washington Hospital Center in Washington, D.C., acting committee chair. Companies need only “to show lack of hazard.”

As Dr. John Jenkins with the FDA Office of New Drugs said in a press conference after the meetings, the agency will have to look at all of the committee’s discussions and make a decision. The committee is saying we should have more cardiovascular safety data during the approval process and that unacceptably high risks need to be ruled out before approval, he said. The FDA will be considering several options for evaluation cardiovascular risks, said Dr. Jenkins, including perhaps asking drug companies to continue randomized trials for up to 18 months, rather than the 12 weeks currently common, to assess efficacy for drug approval. Other options would be to require companies to include a prospective cardiovascular risk assessment trial as part of their NDA application process.

No word on when the FDA’s final decision will be issued. It appears that standards in the approval process for diabetes drugs may be upgraded to include assessments of whether the drugs raise risks of heart attacks, strokes and cardiovascular disease-related deaths. But, they’ll continue to be approved without evidence of benefits other than lowering blood sugars.