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Last week, there was an unplanned debate between high leval health officials of America’s and Britain’s drug regulatory agencies over the role and value of hemoglobin A1c reduction in diabetes drug approval.

Janet Woodcock, the Director for the FDA Center for Drug Evaluation and Research and Sir Alasdair Breckenridge, chairman of the UK’s Medicines and Healthcare products Regulatory Agency, better known as the MHRA, discussed their thoughts on Avandia at the Third Annual Risk Management and Drug Safety Summit in Washington, D.C. on October 18, 2010.

Janet Woodcock discussed efforts to improve risk management and drug safety since passage of the FDA Amendments Act. She was followed at the podium by Breckenridge, who presented the European perspective on risk management and a pharmacovigilance “tool kit” for assessing and mitigating drug risks.

Near the end of his presentation, Breckenridge turned to the recent regulatory decisions on Avandia, GlaxoSmithKline’s beleaguered thiazolidinedione. Even though FDA and the European Medicines Agency took different regulatory paths – with FDA restricting distribution under a Risk Evaluation and Mitigation Strategy, and EMA suspending rosiglitazone’s license – Breckenridge stressed the extensive collaboration between the two agencies that culminated in simultaneous announcements on September 23, 2010.

BACKGROUND TO THE DEBATE

On September 23, 2010, the U.S. Food and Drug Administration announced that it will significantly restrict the use of the diabetes drug Avandia (rosiglitazone) to patients with Type 2 diabetes who cannot control their diabetes on other medications. These new restrictions are in response to data that suggest an elevated risk of cardiovascular events, such as heart attack and stroke, in patients treated with Avandia. Meanwhile, Avandia has been taken off of the market in Europe. European regulators say that the risk of heart attack associated with Avandia is too great a safety concern to continue its use for most people.

AVANDIA & THE INCREASED RISK OF HEART ATTACK

The FDA confirmed that studies show that Avandia® increases a patients’ risk of suffering a heart attack by 43% and cardiac-related death by 64%. These Avandia® side effects may not have been adequately disclosed by the manufacturer and an Avandia® Recall has yet to materialize.

There have been multiple panels held to determine whether there should be an Avandia® Recall and despite the staggering amount of lawsuits filed against the product an Avandia® A recall has not been ordered. Since Avandia® has yet to receive a recall if you or your loved ones uses Avandia® and are worried that your health is at risk speak to your doctor immediately.

If you were prescribed the diabetes drug Avandia® and after taking Avandia® you suffered a heart attack or stroke then you may be eligible for compensation. Heart Attacks and Strokes have been identified as Avandia® Side Effects. In addition, if you have suffered other side effects associated with taking Avandia®, you should contact an attorney to discuss your rights. You may be entitled to compensation.

Other reported side effects from taking Avandia include:

• Death
• Heart Attacks
• Congestive Heart Failure
• PPH – Primary Pulmonary Hypertension
• Bone Fractures
• Blindness
• Liver Failure
• Hepatitis

THE DEBATE ON AVANDIA
“If you think about the difference between what Europe has done and what the U.S. has done, in fact I would suggest there was very little difference indeed, and it was an example of regulatory authorities working together in a global manner,” he said. (“The Pink Sheet” offers an analysis of why they diverged in their final judgment.)

Following these glowing remarks about alignment among regulators on both sides of the Atlantic, Breckenridge took the Avandia post-mortem a step further, and perhaps one too far for Woodcock.

“The question I’ve asked myself is if Avandia came through for licensing today, with the information we had, what should be done, what would we have done? How has regulation advanced? Well firstly, it wouldn’t have been approved for efficacy on a surrogate marker [HbA1c]. That would not be accepted,” he said. Some in industry concur that there is now a higher hurdle, at least commercially, for diabetes products.

Fortunately for the audience, Woodcock hung around after her presentation to hear Breckenridge’s speech, and during a question and answer session, while still sitting in the audience, Woodcock pounced on the British knight’s skepticism toward HbA1c. Here is an abbreviated transcript of the exchange, along with some first-hand, editorial observations noted in brackets:

Woodcock: “If you’re not going to use hemoglobin A1c or serum glucose … what are you going to use for efficacy in diabetes? No drug in type 2 diabetes has ever been shown to improve cardiovascular outcomes.”

Breckenridge: “I believe this illustrates the problem with antidiabetic drugs. I believe it’s going to be increasingly difficult to develop any drug for diabetes which has got a suggestion that Avandia did have, and I think drugs like Avandia are going to die at a much earlier stage and be killed at a much earlier stage than developed.”

Woodcock: “I would say the question with rosiglitazone is a safety issue, it’s not an efficacy issue … I think hemoglobin A1c is more than a surrogate … I date as an internist from the era when people walked around with untreated type 2 diabetes. They hit my emergency room they were in hyperosmolar coma. That’s a life-threatening disease. Or they had severe invasive soft tissue infection with gram negative organisms, or they were dehydrated and had blurry vision and CNS issues.”

Breckenridge: [apparently attempting to explain that not all type 2 diabetics are in such dire straits] “I can remember as well, and I’m not sort of swapping stories with you, but patients with type 2 diabetes are the rather large ladies who you see walking around in the United Kingdom and I’m afraid Washington as well.” [disapproving murmurs from the audience.

Woodcock: “But if you go untreated long enough with type 2 diabetes that’s what you get into. It’s a progressive disease. So the idea that you don’t need treatments for type 2 diabetes I think is an incorrect …. ”

Breckenridge: “I’m not suggesting that ….”

Woodcock: “You will get renal failure, you’ll get amputation … It’s a symptomatic disease. People have studied this and they’ve looked at central nervous system effects of hyperglycemia … There are people walking around with blood sugar 300, 400 and so on. That is not good for you, acutely. And sub-acutely, glycemic control has been shown to be correlated with progression of retinopathy, renal failure and so forth, and neuropathy to some extent. [By now standing, holding the microphone and looking as comfortable as a talk show host on a TV production set] So I would take issue with the fact that hemoglobin A1c is a bad surrogate. I think it’s a very good surrogate for efficacy. I don’t think it tells you anything about safety of a drug just like most surrogates for efficacy.”

Breckendridge: “I’m afraid I disagree with you there, Janet. I think by the definition of a surrogate, hemoglobin A1c fulfills all the criteria … and the point I was trying to make was that if you take, in the development of a drug in the latter phase of the drug, and you had a drug which was effective by affecting the surrogate, but it had some other not just potential but huge changes, big changes which were known at the time in a possible adverse event which diabetics are already prone to, the manufacturers, I would suggest, would have a very, very careful look at that before continuing with its development.”

Woodcock: “I don’t think we’re in disagreement, I’m simply saying I thought the earlier definitions [of a surrogate] were mainly done by statisticians, like Prentiss and others … that it should contain all outcomes. That’s completely naive from a biological perspective, because you may perfectly control the disease and kill people from something else. It’s unrelated to the pathway of the disease. So I think expectation that a surrogate for efficacy would take care of your safety evaluation is unrealistic, and I think we’re saying the same thing, which is for chronic diseases there’s going to have to be a much more thorough safety evaluation, it’s longer term, includes more patients, looks for more outcomes than we have traditionally had.”

Breckenridge: “And I think diabetes is an especially difficult case for the reason I described. If you’ve got a disease whose natural history is to develop vascular disease anyway, then a drug which is going to influence that in any kind of adverse way is not good news.”

Woodcock: “The sulfonylureas have long had a warning in the United States for cardiovascular disease because the only time that was studied long-term there was a signal.”

Breckenridge: “And so do the thiazide diuretics, too.”

Woodcock: [laughing] “So there’s a lot of things we don’t know.”

LEGAL RIGHTS OF PATIENTS INJURED BY AVANDIA

The law in most states provides several personal injury claims for persons who have been seriously injured by a prescription drug with excessive and dangerous side effects. These claims include strict liability for a defective product, breach of warranty, negligence, and misrepresentation. Damages sought against pharmaceutical companies for dangerous drug side effects and injuries include at least the following types of damages:

• Physical pain and suffering, mental anguish;
• Physical impairment;
• Medical expenses associated with efforts to remedy the injuries as a result of the original surgery;
• Loss of earnings and/or earning capacity; and
• In the case of a patient’s death, the family of the victim may file a wrongful death action and seek damages.

Avandia has been taken off of the market in Europe. European regulators say that the risk of heart attack associated with Avandia is too great a safety concern to continue its use for most people.

In simultaneous news briefings Thursday, the European Medicines Agency and the U.S. Food and Drug Administration announced their long-awaited decisions on the fate of GlaxoSmithKline’s controversial drug. The European regulator said it would stop authorizing marketing of Avandia, which will be off the market within the next few months.

The FDA said new patients will be able to get a prescription for Avandia, but only if they can’t control their blood sugar with other medications. Doctors will have to document that their patients are eligible to receive the drug and have been briefed on its risks. FDA expects the restricted plan “will limit use of Avandia significantly.”

“Although the European Medicines Agency went further by actually suspended marketing of the drug, both regulatory decisions result in essentially the same outcome, virtually complete elimination of the use of this drug by patients around the world,” said Dr. Steve Nissen of the Cleveland Clinic. Nissen, who published the first paper linking Avandia to heart risks, said only a small number of U.S. patients would receive the drug under the new restrictions.

GlaxoSmithKline’s chief medical officer, Dr. Ellen Strahlman, said in a statement that the company will voluntarily stop promoting Avandia in all countries where it operates.

“As a matter of prudence we are restricting access,” said the FDA’s Dr. Janet Woodcock. “We are not withdrawing the drug at this time because there is considerable uncertainty about this signal and whether or not it is valid.”

The European Commission still must approve the recommendations by the European Medicines Agency, a process that could take several weeks. Decisions by the health regulators usually are not challenged. “In light of all the information available and including results from some very recent studies, the committee concluded that as of today, the benefits of rosiglitazone can no longer be considered to outweigh its risks,” Dr. Hans-Georg Eichler, EMA’s senior medical officer, said Thursday.

FDA Commissioner Margaret Hamburg said the FDA’s decision reflects its unique powers to restrict access to medications. While pulling a drug off the market is an extremely rare event in the U.S., it is more common in Europe, where drugs are approved on a conditional basis. “We are taking somewhat different strategies, but both strategies are designed to assure the goals of safety and effectiveness,” Hamburg said in a briefing with reporters. The FDA’s decision on Avandia is likely to draw ire from safety advocates and U.S. lawmakers, though it essentially concurs with the opinion outside experts reached earlier this year. In July, a 33-member panel of medical experts voted 20-12 to keep Avandia available in the U.S. Of the 20 who voted to keep it on the market, 10 said it should only be available on a limited basis. The FDA is not required to follow the group’s advice, though it often does.

The FDA has confirmed that studies show that Avandia® increases a patients’ risk of suffering a heart attack by 43% and cardiac-related death by 64%. These Avandia® side effects may not have been adequately disclosed by the manufacturer and an Avandia® Recall has yet to materialize. In addition to the risk of heart attacks and stroke, there are other concerns about Avandia including an increased risk of:

• Congestive Heart Failure
• PPH – Primary Pulmonary Hypertension
• Bone Fractures
• Blindness
• Liver Failure
• Hepatitis

The law in most states provides several personal injury claims for persons who have been seriously injured by a prescription drug with excessive and dangerous side effects. These claims include strict liability for a defective product, breach of warranty, negligence, and misrepresentation. Damages sought against pharmaceutical companies for dangerous drug side effects and injuries include at least the following types of damages:

• Physical pain and suffering, mental anguish and physical impairment;
• Medical expenses associated with efforts to remedy the injuries as a result of the original surgery;
• Loss of earnings and/or earning capacity, and
• In the case of a patient’s death, the family of the victim may file a wrongful death action and seek damages.

Montes Herald Law Group, L.L.P.

Attorneys: Rachel Montes and Tom Herald

1121 Kinwest Parkway, Suite 100

Irving, Texas 75063

Telephone (214) 522-9401

Toll Free (877) 529-8899

Facebook @ Montes Law Group, P.C

LEGAL RIGHTS OF PATIENTS INJURED BY AVANDIA