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

Although the Food and Drug Administration’s decision to keep rosiglitazone on the market with a risk management program in place that preserves some access to the controversial diabetes drug, the plan is expected to squelch most prescribing and therefore, could have an effect that approaches that in Europe, where it will no longer be marketed.

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 (TZD). 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 this week. 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.

Additionally, the FDA instructed the drug’s manufacturer, GlaxoSmithKline, to commission an independent readjudication of the RECORD (Rosiglitazone Evaluated for Cardiovascular Outcomes in Oral Agent Combination Therapy for Type 2 Diabetes) trial, which was submitted to the FDA in August 2009 and was undertaken to further explore cardiovascular safety signals seen in earlier trials.

At the same time, the European Medicines Agency announced it was pulling it off the shelves in the European Union, based on the same evidence reviewed by the FDA.

The FDA’s decision reflects the majority opinion of an FDA advisory panel, which in July met to review the cardiovascular safety data of the drug. The majority of the panel members voted to keep the drug on the market but with more warnings and restrictions on its use, but a significant proportion advocated that it should be taken off the market.

Rosiglitazone has been dogged for years by conflicting data on its cardiovascular safety profile and the decision to restrict access came on the heels of an ever-increasing debate about rosiglitazone’s cardiovascular safety. The RECORD trial, sponsored by GlaxoSmithKline, found no increased risk in myocardial infarction, overall death, or cardiovascular death. But several trials came to conflicting conclusions about whether the drug increased the risk of MI; 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).

The lead author of the meta-analysis, Dr. Steven E. Nissen, a vocal advocate for the withdrawal of rosiglitazone from the market, said in an interview that both the FDA and EMA decisions will result in almost the same outcomes and that rosiglitazone will soon be rarely used.

Even though the FDA did not opt for market withdrawal, the drug in the United States “is essentially off the market,” as long as the REMS is well executed, which he expects it will be. “What you have to actually do in order to prescribe the drug now is you have to say you’ve tried every other diabetes drug, including pioglitazone, and the patient couldn’t tolerate them. There’s nobody that meets that description,” said Dr. Nissen, chairman of the department of cardiovascular medicine, Cleveland Clinic Foundation.

At the July panel meeting, Dr. Nissen told the panel and the FDA that, with another thiazolidinedione available as an alternative (pioglitazone), continued marketing of rosiglitazone could not be medically or ethically justified. But, in the interview, he was positive about the agency’s decision. His message to clinicians is to “stop using the drug, get people on something else, and move on.”

Endocrinologist Clifford Rosen agreed. “This effectively puts an end to rosiglitazone in the United States ... it will be very, very rare to have a patient on rosiglitazone,” said Dr. Rosen, professor of medicine at Tufts University, Boston, and senior scientist at Maine Medical Center, Scarborough. He was among the 10 panel members at the July meeting who voted in favor of allowing continued marketing but with more warnings in the label and restrictions in its use.

The FDA decision “basically puts an end to rosiglitazone prescriptions in the United States,” he said in an interview. “It’s almost impossible for an individual practitioner to write a prescription after spending 20 minutes talking about risk, having the patient sign an informed consent and then filling out forms to send to the FDA. It’s just not going to happen.”

Dr. Rosen added that he expects that most patients who are on the drug now will probably be switched to other drugs. “Maybe a few people who have been on it for a long time, feel great, and have good glucose control might stay on it, but those individuals still need to have full informed consent and have the risks explained to them.”

Keeping a patient on rosiglitazone under the REMS “will be an onerous task” and the use of the drug will be “minimal,” said Dr. Paul Jellinger, professor of clinical medicine, University of Miami, and past president of the American College of Endocrinology and the American Association of Clinical Endocrinologists. Patients can easily be switched form rosiglitazone to pioglitazone, or a non-TZD drug, such as an incretin-based treatment, he said in an interview.

Dr. Jellinger said that he thought the FDA decision was appropriate and that the FDA acted on behalf of patient safety, based on substantial amount of data. Although there was “considerable uncertainty, there remains a potential risk and there is a signal that suggests there may be a relationship.”

One of the cardiologists on the panel in July, Dr. Sanjay Kaul of the Cedars-Sinai Heart Institute in Los Angeles, said in an interview that the FDA’s decision is “the right call to keep the drug accessible but with significant restrictions that have teeth.” The decision, though, “reflects the uncertainty in the evidence – it is insufficient to either implicate the drug or exonerate it.”

During the press briefing, Dr. Woodcock said, “We still believe there is considerable uncertainty about the magnitude of the cardiovascular risk.” 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,” she said.

The FDA also decided to terminate the Thiazolidinedione Intervention with Vitamin D Evaluation (TIDE) study, also sponsored by GlaxoSmithKline, which 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. The panel had voted 19-11 to continue the TIDE trial, if rosiglitazone remained on the U.S. market.

Dr. Rosen, who was among those strongly opposed to continuing the study, lauded the decision to halt the TIDE study because it would be unethical to continue the study and subject people to a randomized trial that involved a drug ”where we know the risk and benefit is not established beyond pioglitazone.”

Dr. Kaul was among the panelists who supported continuing TIDE. ”If you stop the study, how else are you going to resolve this uncertainty,” he said. But he agrees with the FDA decision. “The FDA had to do what they did,” but pointed out that considerable controversy over the drug remains.

Dr. Jellinger also would have liked the TIDE study to continue, and found it “unusual” that the gold standard of clinical trials, the prospective randomized, controlled study, was trumped by studies like meta-analyses.

During the press briefing, Dr. Woodcock said that 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.”

It will take several months to fully implement the REMS program, 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, 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 be available only 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.”

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

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.”

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 also 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.

Dr. Nissen has received research support from Takeda Pharmaceutical Co., AstraZeneca, Daiichi Sankyo Co., and several other pharmaceutical companies and has consulted for a many such companies without financial compensation. All payments from any for-profit entity are paid directly to charity. Dr. Rosen reports receiving a lecture fee from GlaxoSmithKline and grant support from Eli Lilly & Co., Merck & Co., and Novartis. Dr. Kaul has received research support from Hoffmann-La Roche and has been a consultant for that company as well as from Novo-Nordisk. Dr. Jellinger is on the speakers bureaus of Amylin Pharmaceuticals, Eli Lilly, Merck, Novo-Nordisk, Sanofi-Aventis, and Takeda.

Although the Food and Drug Administration’s decision to keep rosiglitazone on the market with a risk management program in place that preserves some access to the controversial diabetes drug, the plan is expected to squelch most prescribing and therefore, could have an effect that approaches that in Europe, where it will no longer be marketed.

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 (TZD). 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 this week. 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.

Additionally, the FDA instructed the drug’s manufacturer, GlaxoSmithKline, to commission an independent readjudication of the RECORD (Rosiglitazone Evaluated for Cardiovascular Outcomes in Oral Agent Combination Therapy for Type 2 Diabetes) trial, which was submitted to the FDA in August 2009 and was undertaken to further explore cardiovascular safety signals seen in earlier trials.

At the same time, the European Medicines Agency announced it was pulling it off the shelves in the European Union, based on the same evidence reviewed by the FDA.

The FDA’s decision reflects the majority opinion of an FDA advisory panel, which in July met to review the cardiovascular safety data of the drug. The majority of the panel members voted to keep the drug on the market but with more warnings and restrictions on its use, but a significant proportion advocated that it should be taken off the market.

Rosiglitazone has been dogged for years by conflicting data on its cardiovascular safety profile and the decision to restrict access came on the heels of an ever-increasing debate about rosiglitazone’s cardiovascular safety. The RECORD trial, sponsored by GlaxoSmithKline, found no increased risk in myocardial infarction, overall death, or cardiovascular death. But several trials came to conflicting conclusions about whether the drug increased the risk of MI; 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).

The lead author of the meta-analysis, Dr. Steven E. Nissen, a vocal advocate for the withdrawal of rosiglitazone from the market, said in an interview that both the FDA and EMA decisions will result in almost the same outcomes and that rosiglitazone will soon be rarely used.

Even though the FDA did not opt for market withdrawal, the drug in the United States “is essentially off the market,” as long as the REMS is well executed, which he expects it will be. “What you have to actually do in order to prescribe the drug now is you have to say you’ve tried every other diabetes drug, including pioglitazone, and the patient couldn’t tolerate them. There’s nobody that meets that description,” said Dr. Nissen, chairman of the department of cardiovascular medicine, Cleveland Clinic Foundation.

At the July panel meeting, Dr. Nissen told the panel and the FDA that, with another thiazolidinedione available as an alternative (pioglitazone), continued marketing of rosiglitazone could not be medically or ethically justified. But, in the interview, he was positive about the agency’s decision. His message to clinicians is to “stop using the drug, get people on something else, and move on.”

Endocrinologist Clifford Rosen agreed. “This effectively puts an end to rosiglitazone in the United States ... it will be very, very rare to have a patient on rosiglitazone,” said Dr. Rosen, professor of medicine at Tufts University, Boston, and senior scientist at Maine Medical Center, Scarborough. He was among the 10 panel members at the July meeting who voted in favor of allowing continued marketing but with more warnings in the label and restrictions in its use.

The FDA decision “basically puts an end to rosiglitazone prescriptions in the United States,” he said in an interview. “It’s almost impossible for an individual practitioner to write a prescription after spending 20 minutes talking about risk, having the patient sign an informed consent and then filling out forms to send to the FDA. It’s just not going to happen.”

Dr. Rosen added that he expects that most patients who are on the drug now will probably be switched to other drugs. “Maybe a few people who have been on it for a long time, feel great, and have good glucose control might stay on it, but those individuals still need to have full informed consent and have the risks explained to them.”

Keeping a patient on rosiglitazone under the REMS “will be an onerous task” and the use of the drug will be “minimal,” said Dr. Paul Jellinger, professor of clinical medicine, University of Miami, and past president of the American College of Endocrinology and the American Association of Clinical Endocrinologists. Patients can easily be switched form rosiglitazone to pioglitazone, or a non-TZD drug, such as an incretin-based treatment, he said in an interview.

Dr. Jellinger said that he thought the FDA decision was appropriate and that the FDA acted on behalf of patient safety, based on substantial amount of data. Although there was “considerable uncertainty, there remains a potential risk and there is a signal that suggests there may be a relationship.”

One of the cardiologists on the panel in July, Dr. Sanjay Kaul of the Cedars-Sinai Heart Institute in Los Angeles, said in an interview that the FDA’s decision is “the right call to keep the drug accessible but with significant restrictions that have teeth.” The decision, though, “reflects the uncertainty in the evidence – it is insufficient to either implicate the drug or exonerate it.”

During the press briefing, Dr. Woodcock said, “We still believe there is considerable uncertainty about the magnitude of the cardiovascular risk.” 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,” she said.

The FDA also decided to terminate the Thiazolidinedione Intervention with Vitamin D Evaluation (TIDE) study, also sponsored by GlaxoSmithKline, which 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. The panel had voted 19-11 to continue the TIDE trial, if rosiglitazone remained on the U.S. market.

Dr. Rosen, who was among those strongly opposed to continuing the study, lauded the decision to halt the TIDE study because it would be unethical to continue the study and subject people to a randomized trial that involved a drug ”where we know the risk and benefit is not established beyond pioglitazone.”

Dr. Kaul was among the panelists who supported continuing TIDE. ”If you stop the study, how else are you going to resolve this uncertainty,” he said. But he agrees with the FDA decision. “The FDA had to do what they did,” but pointed out that considerable controversy over the drug remains.

Dr. Jellinger also would have liked the TIDE study to continue, and found it “unusual” that the gold standard of clinical trials, the prospective randomized, controlled study, was trumped by studies like meta-analyses.

During the press briefing, Dr. Woodcock said that 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.”

It will take several months to fully implement the REMS program, 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, 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 be available only 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.”

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

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.”

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 also 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.

Dr. Nissen has received research support from Takeda Pharmaceutical Co., AstraZeneca, Daiichi Sankyo Co., and several other pharmaceutical companies and has consulted for a many such companies without financial compensation. All payments from any for-profit entity are paid directly to charity. Dr. Rosen reports receiving a lecture fee from GlaxoSmithKline and grant support from Eli Lilly & Co., Merck & Co., and Novartis. Dr. Kaul has received research support from Hoffmann-La Roche and has been a consultant for that company as well as from Novo-Nordisk. Dr. Jellinger is on the speakers bureaus of Amylin Pharmaceuticals, Eli Lilly, Merck, Novo-Nordisk, Sanofi-Aventis, and Takeda.

Although the Food and Drug Administration’s decision to keep rosiglitazone on the market with a risk management program in place that preserves some access to the controversial diabetes drug, the plan is expected to squelch most prescribing and therefore, could have an effect that approaches that in Europe, where it will no longer be marketed.

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 (TZD). 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 this week. 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.

Additionally, the FDA instructed the drug’s manufacturer, GlaxoSmithKline, to commission an independent readjudication of the RECORD (Rosiglitazone Evaluated for Cardiovascular Outcomes in Oral Agent Combination Therapy for Type 2 Diabetes) trial, which was submitted to the FDA in August 2009 and was undertaken to further explore cardiovascular safety signals seen in earlier trials.

At the same time, the European Medicines Agency announced it was pulling it off the shelves in the European Union, based on the same evidence reviewed by the FDA.

The FDA’s decision reflects the majority opinion of an FDA advisory panel, which in July met to review the cardiovascular safety data of the drug. The majority of the panel members voted to keep the drug on the market but with more warnings and restrictions on its use, but a significant proportion advocated that it should be taken off the market.

Rosiglitazone has been dogged for years by conflicting data on its cardiovascular safety profile and the decision to restrict access came on the heels of an ever-increasing debate about rosiglitazone’s cardiovascular safety. The RECORD trial, sponsored by GlaxoSmithKline, found no increased risk in myocardial infarction, overall death, or cardiovascular death. But several trials came to conflicting conclusions about whether the drug increased the risk of MI; 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).

The lead author of the meta-analysis, Dr. Steven E. Nissen, a vocal advocate for the withdrawal of rosiglitazone from the market, said in an interview that both the FDA and EMA decisions will result in almost the same outcomes and that rosiglitazone will soon be rarely used.

Even though the FDA did not opt for market withdrawal, the drug in the United States “is essentially off the market,” as long as the REMS is well executed, which he expects it will be. “What you have to actually do in order to prescribe the drug now is you have to say you’ve tried every other diabetes drug, including pioglitazone, and the patient couldn’t tolerate them. There’s nobody that meets that description,” said Dr. Nissen, chairman of the department of cardiovascular medicine, Cleveland Clinic Foundation.

At the July panel meeting, Dr. Nissen told the panel and the FDA that, with another thiazolidinedione available as an alternative (pioglitazone), continued marketing of rosiglitazone could not be medically or ethically justified. But, in the interview, he was positive about the agency’s decision. His message to clinicians is to “stop using the drug, get people on something else, and move on.”

Endocrinologist Clifford Rosen agreed. “This effectively puts an end to rosiglitazone in the United States ... it will be very, very rare to have a patient on rosiglitazone,” said Dr. Rosen, professor of medicine at Tufts University, Boston, and senior scientist at Maine Medical Center, Scarborough. He was among the 10 panel members at the July meeting who voted in favor of allowing continued marketing but with more warnings in the label and restrictions in its use.

The FDA decision “basically puts an end to rosiglitazone prescriptions in the United States,” he said in an interview. “It’s almost impossible for an individual practitioner to write a prescription after spending 20 minutes talking about risk, having the patient sign an informed consent and then filling out forms to send to the FDA. It’s just not going to happen.”

Dr. Rosen added that he expects that most patients who are on the drug now will probably be switched to other drugs. “Maybe a few people who have been on it for a long time, feel great, and have good glucose control might stay on it, but those individuals still need to have full informed consent and have the risks explained to them.”

Keeping a patient on rosiglitazone under the REMS “will be an onerous task” and the use of the drug will be “minimal,” said Dr. Paul Jellinger, professor of clinical medicine, University of Miami, and past president of the American College of Endocrinology and the American Association of Clinical Endocrinologists. Patients can easily be switched form rosiglitazone to pioglitazone, or a non-TZD drug, such as an incretin-based treatment, he said in an interview.

Dr. Jellinger said that he thought the FDA decision was appropriate and that the FDA acted on behalf of patient safety, based on substantial amount of data. Although there was “considerable uncertainty, there remains a potential risk and there is a signal that suggests there may be a relationship.”

One of the cardiologists on the panel in July, Dr. Sanjay Kaul of the Cedars-Sinai Heart Institute in Los Angeles, said in an interview that the FDA’s decision is “the right call to keep the drug accessible but with significant restrictions that have teeth.” The decision, though, “reflects the uncertainty in the evidence – it is insufficient to either implicate the drug or exonerate it.”

During the press briefing, Dr. Woodcock said, “We still believe there is considerable uncertainty about the magnitude of the cardiovascular risk.” 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,” she said.

The FDA also decided to terminate the Thiazolidinedione Intervention with Vitamin D Evaluation (TIDE) study, also sponsored by GlaxoSmithKline, which 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. The panel had voted 19-11 to continue the TIDE trial, if rosiglitazone remained on the U.S. market.

Dr. Rosen, who was among those strongly opposed to continuing the study, lauded the decision to halt the TIDE study because it would be unethical to continue the study and subject people to a randomized trial that involved a drug ”where we know the risk and benefit is not established beyond pioglitazone.”

Dr. Kaul was among the panelists who supported continuing TIDE. ”If you stop the study, how else are you going to resolve this uncertainty,” he said. But he agrees with the FDA decision. “The FDA had to do what they did,” but pointed out that considerable controversy over the drug remains.

Dr. Jellinger also would have liked the TIDE study to continue, and found it “unusual” that the gold standard of clinical trials, the prospective randomized, controlled study, was trumped by studies like meta-analyses.

During the press briefing, Dr. Woodcock said that 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.”

It will take several months to fully implement the REMS program, 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, 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 be available only 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.”

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

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.”

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 also 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.

Dr. Nissen has received research support from Takeda Pharmaceutical Co., AstraZeneca, Daiichi Sankyo Co., and several other pharmaceutical companies and has consulted for a many such companies without financial compensation. All payments from any for-profit entity are paid directly to charity. Dr. Rosen reports receiving a lecture fee from GlaxoSmithKline and grant support from Eli Lilly & Co., Merck & Co., and Novartis. Dr. Kaul has received research support from Hoffmann-La Roche and has been a consultant for that company as well as from Novo-Nordisk. Dr. Jellinger is on the speakers bureaus of Amylin Pharmaceuticals, Eli Lilly, Merck, Novo-Nordisk, Sanofi-Aventis, and Takeda.