FDA: Rosiglitazone Can Remain on the Market – With Big Restrictions

The Food and Drug Administration announced on Sept. 23 that it would preserve access to the controversial diabetes drug rosiglitazone, but only with what it called “significant restrictions.”

Under a risk evaluation and mitigation strategy (REMS), rosiglitazone will be available only to new patients with type 2 diabetes who are unable to adequately manage their blood glucose on pioglitazone or are unable to take pioglitazone, the only other approved thiazolidinedione.

However, patients who are already taking rosiglitazone may continue if, through the REMS program, they acknowledge their understanding of the drug’s potential cardiac risks, Dr. Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, said during a press briefing.

About 600,000 U.S. patients are taking the drug; Dr. Woodcock said the REMS program will “significantly reduce” that number, while ensuring that those who continue will fully understand its potential risk.

The European Medicines Agency, however, took a stronger stance on rosiglitazone, pulling it off the shelves in the European Union. Over the summer, EMA’s Committee for Medicinal Products for Human Use reviewed existing data and determined that rosiglitazone’s risks outweighed its benefits.

The FDA and EMA were aware of one another’s strategies but chose to handle the issue differently, Dr. Woodcock noted. “We heard very clearly from providers and patients that rosiglitazone is very effective for some patients who cannot tolerate other diabetes medications. We believe that this restricted use will enable health care providers and patients to be fully informed of the data and the concerns about the drug, and to make an informed decision if they want to remain on it.”

In a press statement, Dr. Ellen Strahlman, GlaxoSmithKline’s chief medical officer, said, “Our primary concern continues to be patients with type 2 diabetes, and we are making every effort to ensure that physicians in Europe and the U.S. have all the information they need to help them understand how these regulatory decisions affect them and their patients.”

The statement noted that “the company continues to believe that [rosiglitazone] is an important treatment for patients with type 2 diabetes and is now working with the FDA and EMA to implement the required actions … GSK will voluntarily cease promotion of [rosiglitazone] in all the countries in which it operates and will continue to respond to requests for information and support from healthcare professionals and patients.”

Rosiglitazone has been dogged for years by conflicting data on its cardiovascular safety profile. The recent RECORD trial, sponsored by the drug’s manufacturer, GlaxoSmithKline, was intended to settle the matter once and for all. But its findings of no increased risk in heart attack, overall death, and cardiovascular death failed to sway the FDA’s decision to restrict rosiglitazone access.

“The signal [of increased risk] has not been completely refuted by any evidence, so we think it is prudent to restrict access, and make sure that those using and prescribing the medication are aware of the facts and make the choice in an informed manner,” Dr. Woodcock said.

It will be “several months” before the REMS program can be fully implemented, Dr. Joshua Sharfstein said during the briefing. Until then, “Patients who are taking rosiglitazone should continue to do so, and consult their physician to discuss the possibility of selecting another medication without this concern of cardiac ischemia,” said Dr. Sharfstein, the FDA’s principal deputy commissioner. “Once the REMS is in place, physicians will need to enroll patients before they can continue to receive the drug.”

When the REMS is active, Dr. Sharfstein reiterated, rosiglitazone will only be available to patients who cannot control their blood sugar on any other medication, and who are unable to take pioglitazone for medical reasons. “Doctors will have to document this, and also that they have discussed the risks of rosiglitazone in order for the patient to receive the drug.”

The decision to restrict access came on the heels of an ever-increasing debate about rosiglitazone’s cardiovascular safety. Several trials have come to conflicting conclusions about whether the drug increased the risk of heart attack; a highly touted 2007 meta-analysis of 42 studies concluded that it increased that risk by up to 43%, and the risk of cardiovascular death by up to 64% (N. Engl. J. Med. 2007;356:2457-71).

In a statement released immediately after the FDA decision, Dr. Steven Nissen, the author of the meta-analysis, said that both the FDA and EMA decisions will result in essentially the same outcome and predicted that rosiglitazone “will quickly become a rarely used therapy.”

“By severely restricting access to rosiglitazone, the FDA is ensuring that only a few individuals in America will continue to take this drug. Only those patients who have failed to respond to all other therapies will be eligible to receive it,” said Dr. Nissen, chairman of cardiovascular medicine at the Cleveland Clinic.

Researchers had hoped the RECORD study would set the rosiglitazone risk story straight. But in July, the FDA panel tasked with reviewing the drug’s safety questioned RECORD and its adjudication of cardiovascular events, Dr. Woodcock said. “RECORD was an open-label trial, and it was determined that we can’t rely on those results, even though they did not show a significantly increased risk of cardiac harm. Therefore, the questions raised by the meta-analysis have not really been answered. We still believe there is considerable uncertainty about the magnitude of the cardiovascular risk.”

The FDA will ask GlaxoSmithKline to conduct an independent review of RECORD’s adjudication at a patient record level in an effort, Dr. Sharfstein said, “to catch events that occurred but which might have not been properly referred to the adjudication committee.”

At the press briefing, Dr. Woodcock also announced the termination of the Thiazolidinedione Intervention with Vitamin D Evaluation (TIDE) study, also sponsored by GlaxoSmithKline. TIDE was designed to determine any difference in cardiovascular safety between rosiglitazone and pioglitazone. In July, the FDA put TIDE on a partial hold, allowing patient enrollment, but not treatment. Today, Dr. Woodcock said the readjudication of RECORD should provide the answers needed to make the best decision about rosiglitazone’s future.

About 30 other drugs already carry REMS programs, including three formulations of pioglitazone. Pioglitazone tablets; pioglitazone/metformin tablets; and extended-release pioglitazone/metformin tablets all require the dispensing of a medical guide along with the medication – the most common REMS plan.

But other REMS programs – including the one that will be established for rosiglitazone – are much more restrictive, such as the one for the antiepileptic vigabatrin. That REMS requires not only a medication guide, but a communication plan to ensure reporting of adverse events, elements to assure safe use, and a system to ensure that physicians, pharmacies, and patients who do not comply with the rules lose access to the drug.

The Food and Drug Administration announced on Sept. 23 that it would preserve access to the controversial diabetes drug rosiglitazone, but only with what it called “significant restrictions.”

Under a risk evaluation and mitigation strategy (REMS), rosiglitazone will be available only to new patients with type 2 diabetes who are unable to adequately manage their blood glucose on pioglitazone or are unable to take pioglitazone, the only other approved thiazolidinedione.

However, patients who are already taking rosiglitazone may continue if, through the REMS program, they acknowledge their understanding of the drug’s potential cardiac risks, Dr. Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, said during a press briefing.

About 600,000 U.S. patients are taking the drug; Dr. Woodcock said the REMS program will “significantly reduce” that number, while ensuring that those who continue will fully understand its potential risk.

The European Medicines Agency, however, took a stronger stance on rosiglitazone, pulling it off the shelves in the European Union. Over the summer, EMA’s Committee for Medicinal Products for Human Use reviewed existing data and determined that rosiglitazone’s risks outweighed its benefits.

The FDA and EMA were aware of one another’s strategies but chose to handle the issue differently, Dr. Woodcock noted. “We heard very clearly from providers and patients that rosiglitazone is very effective for some patients who cannot tolerate other diabetes medications. We believe that this restricted use will enable health care providers and patients to be fully informed of the data and the concerns about the drug, and to make an informed decision if they want to remain on it.”

In a press statement, Dr. Ellen Strahlman, GlaxoSmithKline’s chief medical officer, said, “Our primary concern continues to be patients with type 2 diabetes, and we are making every effort to ensure that physicians in Europe and the U.S. have all the information they need to help them understand how these regulatory decisions affect them and their patients.”

The statement noted that “the company continues to believe that [rosiglitazone] is an important treatment for patients with type 2 diabetes and is now working with the FDA and EMA to implement the required actions … GSK will voluntarily cease promotion of [rosiglitazone] in all the countries in which it operates and will continue to respond to requests for information and support from healthcare professionals and patients.”

Rosiglitazone has been dogged for years by conflicting data on its cardiovascular safety profile. The recent RECORD trial, sponsored by the drug’s manufacturer, GlaxoSmithKline, was intended to settle the matter once and for all. But its findings of no increased risk in heart attack, overall death, and cardiovascular death failed to sway the FDA’s decision to restrict rosiglitazone access.

“The signal [of increased risk] has not been completely refuted by any evidence, so we think it is prudent to restrict access, and make sure that those using and prescribing the medication are aware of the facts and make the choice in an informed manner,” Dr. Woodcock said.

It will be “several months” before the REMS program can be fully implemented, Dr. Joshua Sharfstein said during the briefing. Until then, “Patients who are taking rosiglitazone should continue to do so, and consult their physician to discuss the possibility of selecting another medication without this concern of cardiac ischemia,” said Dr. Sharfstein, the FDA’s principal deputy commissioner. “Once the REMS is in place, physicians will need to enroll patients before they can continue to receive the drug.”

When the REMS is active, Dr. Sharfstein reiterated, rosiglitazone will only be available to patients who cannot control their blood sugar on any other medication, and who are unable to take pioglitazone for medical reasons. “Doctors will have to document this, and also that they have discussed the risks of rosiglitazone in order for the patient to receive the drug.”

The decision to restrict access came on the heels of an ever-increasing debate about rosiglitazone’s cardiovascular safety. Several trials have come to conflicting conclusions about whether the drug increased the risk of heart attack; a highly touted 2007 meta-analysis of 42 studies concluded that it increased that risk by up to 43%, and the risk of cardiovascular death by up to 64% (N. Engl. J. Med. 2007;356:2457-71).

In a statement released immediately after the FDA decision, Dr. Steven Nissen, the author of the meta-analysis, said that both the FDA and EMA decisions will result in essentially the same outcome and predicted that rosiglitazone “will quickly become a rarely used therapy.”

“By severely restricting access to rosiglitazone, the FDA is ensuring that only a few individuals in America will continue to take this drug. Only those patients who have failed to respond to all other therapies will be eligible to receive it,” said Dr. Nissen, chairman of cardiovascular medicine at the Cleveland Clinic.

Researchers had hoped the RECORD study would set the rosiglitazone risk story straight. But in July, the FDA panel tasked with reviewing the drug’s safety questioned RECORD and its adjudication of cardiovascular events, Dr. Woodcock said. “RECORD was an open-label trial, and it was determined that we can’t rely on those results, even though they did not show a significantly increased risk of cardiac harm. Therefore, the questions raised by the meta-analysis have not really been answered. We still believe there is considerable uncertainty about the magnitude of the cardiovascular risk.”

The FDA will ask GlaxoSmithKline to conduct an independent review of RECORD’s adjudication at a patient record level in an effort, Dr. Sharfstein said, “to catch events that occurred but which might have not been properly referred to the adjudication committee.”

At the press briefing, Dr. Woodcock also announced the termination of the Thiazolidinedione Intervention with Vitamin D Evaluation (TIDE) study, also sponsored by GlaxoSmithKline. TIDE was designed to determine any difference in cardiovascular safety between rosiglitazone and pioglitazone. In July, the FDA put TIDE on a partial hold, allowing patient enrollment, but not treatment. Today, Dr. Woodcock said the readjudication of RECORD should provide the answers needed to make the best decision about rosiglitazone’s future.

About 30 other drugs already carry REMS programs, including three formulations of pioglitazone. Pioglitazone tablets; pioglitazone/metformin tablets; and extended-release pioglitazone/metformin tablets all require the dispensing of a medical guide along with the medication – the most common REMS plan.

But other REMS programs – including the one that will be established for rosiglitazone – are much more restrictive, such as the one for the antiepileptic vigabatrin. That REMS requires not only a medication guide, but a communication plan to ensure reporting of adverse events, elements to assure safe use, and a system to ensure that physicians, pharmacies, and patients who do not comply with the rules lose access to the drug.

The Food and Drug Administration announced on Sept. 23 that it would preserve access to the controversial diabetes drug rosiglitazone, but only with what it called “significant restrictions.”

Under a risk evaluation and mitigation strategy (REMS), rosiglitazone will be available only to new patients with type 2 diabetes who are unable to adequately manage their blood glucose on pioglitazone or are unable to take pioglitazone, the only other approved thiazolidinedione.

However, patients who are already taking rosiglitazone may continue if, through the REMS program, they acknowledge their understanding of the drug’s potential cardiac risks, Dr. Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, said during a press briefing.

About 600,000 U.S. patients are taking the drug; Dr. Woodcock said the REMS program will “significantly reduce” that number, while ensuring that those who continue will fully understand its potential risk.

The European Medicines Agency, however, took a stronger stance on rosiglitazone, pulling it off the shelves in the European Union. Over the summer, EMA’s Committee for Medicinal Products for Human Use reviewed existing data and determined that rosiglitazone’s risks outweighed its benefits.

The FDA and EMA were aware of one another’s strategies but chose to handle the issue differently, Dr. Woodcock noted. “We heard very clearly from providers and patients that rosiglitazone is very effective for some patients who cannot tolerate other diabetes medications. We believe that this restricted use will enable health care providers and patients to be fully informed of the data and the concerns about the drug, and to make an informed decision if they want to remain on it.”

In a press statement, Dr. Ellen Strahlman, GlaxoSmithKline’s chief medical officer, said, “Our primary concern continues to be patients with type 2 diabetes, and we are making every effort to ensure that physicians in Europe and the U.S. have all the information they need to help them understand how these regulatory decisions affect them and their patients.”

The statement noted that “the company continues to believe that [rosiglitazone] is an important treatment for patients with type 2 diabetes and is now working with the FDA and EMA to implement the required actions … GSK will voluntarily cease promotion of [rosiglitazone] in all the countries in which it operates and will continue to respond to requests for information and support from healthcare professionals and patients.”

Rosiglitazone has been dogged for years by conflicting data on its cardiovascular safety profile. The recent RECORD trial, sponsored by the drug’s manufacturer, GlaxoSmithKline, was intended to settle the matter once and for all. But its findings of no increased risk in heart attack, overall death, and cardiovascular death failed to sway the FDA’s decision to restrict rosiglitazone access.

“The signal [of increased risk] has not been completely refuted by any evidence, so we think it is prudent to restrict access, and make sure that those using and prescribing the medication are aware of the facts and make the choice in an informed manner,” Dr. Woodcock said.

It will be “several months” before the REMS program can be fully implemented, Dr. Joshua Sharfstein said during the briefing. Until then, “Patients who are taking rosiglitazone should continue to do so, and consult their physician to discuss the possibility of selecting another medication without this concern of cardiac ischemia,” said Dr. Sharfstein, the FDA’s principal deputy commissioner. “Once the REMS is in place, physicians will need to enroll patients before they can continue to receive the drug.”

When the REMS is active, Dr. Sharfstein reiterated, rosiglitazone will only be available to patients who cannot control their blood sugar on any other medication, and who are unable to take pioglitazone for medical reasons. “Doctors will have to document this, and also that they have discussed the risks of rosiglitazone in order for the patient to receive the drug.”

The decision to restrict access came on the heels of an ever-increasing debate about rosiglitazone’s cardiovascular safety. Several trials have come to conflicting conclusions about whether the drug increased the risk of heart attack; a highly touted 2007 meta-analysis of 42 studies concluded that it increased that risk by up to 43%, and the risk of cardiovascular death by up to 64% (N. Engl. J. Med. 2007;356:2457-71).

In a statement released immediately after the FDA decision, Dr. Steven Nissen, the author of the meta-analysis, said that both the FDA and EMA decisions will result in essentially the same outcome and predicted that rosiglitazone “will quickly become a rarely used therapy.”

“By severely restricting access to rosiglitazone, the FDA is ensuring that only a few individuals in America will continue to take this drug. Only those patients who have failed to respond to all other therapies will be eligible to receive it,” said Dr. Nissen, chairman of cardiovascular medicine at the Cleveland Clinic.

Researchers had hoped the RECORD study would set the rosiglitazone risk story straight. But in July, the FDA panel tasked with reviewing the drug’s safety questioned RECORD and its adjudication of cardiovascular events, Dr. Woodcock said. “RECORD was an open-label trial, and it was determined that we can’t rely on those results, even though they did not show a significantly increased risk of cardiac harm. Therefore, the questions raised by the meta-analysis have not really been answered. We still believe there is considerable uncertainty about the magnitude of the cardiovascular risk.”

The FDA will ask GlaxoSmithKline to conduct an independent review of RECORD’s adjudication at a patient record level in an effort, Dr. Sharfstein said, “to catch events that occurred but which might have not been properly referred to the adjudication committee.”

At the press briefing, Dr. Woodcock also announced the termination of the Thiazolidinedione Intervention with Vitamin D Evaluation (TIDE) study, also sponsored by GlaxoSmithKline. TIDE was designed to determine any difference in cardiovascular safety between rosiglitazone and pioglitazone. In July, the FDA put TIDE on a partial hold, allowing patient enrollment, but not treatment. Today, Dr. Woodcock said the readjudication of RECORD should provide the answers needed to make the best decision about rosiglitazone’s future.

About 30 other drugs already carry REMS programs, including three formulations of pioglitazone. Pioglitazone tablets; pioglitazone/metformin tablets; and extended-release pioglitazone/metformin tablets all require the dispensing of a medical guide along with the medication – the most common REMS plan.

But other REMS programs – including the one that will be established for rosiglitazone – are much more restrictive, such as the one for the antiepileptic vigabatrin. That REMS requires not only a medication guide, but a communication plan to ensure reporting of adverse events, elements to assure safe use, and a system to ensure that physicians, pharmacies, and patients who do not comply with the rules lose access to the drug.